HYDROPHOBICALLY TAGGED SMALL MOLECULES AS INDUCERS OF PROTEIN DEGRADATION (Fri, 25 Apr 2014)
Provided are bifunctional small molecules of Formula (I): or pharmaceutically acceptable salts thereof, wherein M represents a small organic molecule which binds, covalently or non-covalently, a kinase, such as Her3 protein kinase; L1 represents a linker; and RH represents a hydrophobic group. An example of a compound of Formula (I) is a compound of Formula (II): Also provided are pharmaceutical compositions comprising a compound of Formula (I) or (II) and methods of using such compounds for treating proliferative diseases.
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Ribosome Structure and Protein Synthesis Inhibitors (Fri, 07 Mar 2014)
<p id="p-0001" num="0000">The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism.</p>
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COMPOUNDS USEFUL FOR PROMOTING PROTEIN DEGRADATION AND METHODS USING SAME (Fri, 15 Nov 2013)
The present invention includes compounds that act as degraders of a target protein, wherein degradation is independent of the class of the target protein or its localization. In one embodiment, the invention comprises a compound comprising a protein degradation moiety covalently bound to a linker, wherein the ClogP of the compound is equal to or higher than 1.5. The target protein contemplated within the invention comprises a posttranslational modified protein or intracellular protein. Compounds of the present invention may be used to treat disease states wherein protein degradation is a viable therapeutic approach, such as cancer or any sort of oxidative stress disease state.
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COMPOUNDS AND METHODS FOR INDUCING APOPTOSIS IN CANCER CELLS USING A BH3 ALPHA-HELICAL MIMETIC (Fri, 08 Nov 2013)
<p id="p-0001" num="0000">A novel BH3 α-helical mimetic, BH3-M6, which binds to Bcl-X<sub>L </sub>and prevents its binding to fluorescently-labeled Bak-BH3 peptide in vitro with an IC<sub>50 </sub>value of 734 nM is presented herein. BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-X<sub>L</sub>, Bcl-2 and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in a cell-free system and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6-induced apoptosis is caspase- and Bax-dependent. Furthermore, human cancer cells with high Bcl-2 or Bcl-X<sub>L </sub>levels are more sensitive to BH3-M6-induced cell death, suggesting that this compound can overcome drug resistance due to Bcl-2 or Bcl-X<sub>L </sub>overexpression. The pan-Bcl-2 inhibitor BH3-M6 may be encapsulated in a micelle to provide a more bioavailable therapeutic agent. Specifically, the BH3-M6 compound may be encapsulated within a micelle comprising a multiblock copolymer according to the methods described herein.</p>
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CYTOTOXIC-DRUG DELIVERING MOLECULES TARGETING HIV (CDM-HS), CYTOTOXIC ACTIVITY AGAINST THE HUMAN IMMUNODEFICIENCY VIRUS AND METHODS OF USE (Fri, 01 Nov 2013)
The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as CDM-Hs, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by introducing cytotoxic moieties to gp120-expressing cells, thereby causing cell death and preventing cell infection and spread of HIV. It is shown that CDM-Hs bind to gp120 and gp-120 expressing cells competitively with CD4, and these compounds cause cell death of HIV-infected cells, thereby decreasing viral infectivity. Compounds and methods are described herein.
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METHODS OF TREATING INFLAMMATORY AND AUTOIMMUNE DISEASES AND DISORDERS (Fri, 18 Oct 2013)
Compositions and methods for treating or ameliorating the symptoms of inflammatory or autoimmune disease or disorder are described herein. The compositions contain a nanolipogel for sustained delivery of an effective amount of one or more active agents of choice, preferably a drug for treating or ameliorating the symptoms of inflammatory or autoimmune disease or disorder. The nanolipogel includes a lipid bilayer surrounding a hydrogel core, which may optionally include a host molecule, for example, an absorbent such as a cyclodextrin or ion-exchange resin. In preferred embodiments at least one of active agents is an immunosuppressant.
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VEHICLES FOR CONTROLLED DELIVERY OF DIFFERENT PHARMACEUTICAL AGENTS (Fri, 18 Oct 2013)
A "nanolipogel" is a delivery vehicle including one or more lipid layer surrounding a hydrogel core, which may include an absorbent such as a cyclodextrin or ion-exchange resin. Nanolipogels can be constructed so as to incorporate a variety of different chemical entities that can subsequently be released in a controlled fashion. These different incorporated chemical entities can differ dramatically with respect to size and composition. Nanolipogels have been constructed to contain co-encapsulated proteins as well as small hydrophobic drugs within the interior of the lipid bilayer. Agents incorporated within nanolipogels can be released into the milieu in a controlled fashion, for example, nanolipogels provide a means of achieving simultaneous sustained release of agents that differ widely in chemical composition and molecular weight. Additionally, nanolipogels can favorably modulate biodistribution.
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Carbon Nanotube Compositions and Methods of Use Thereof (Fri, 23 Aug 2013)
<p id="p-0001" num="0000">Carbon nanotube (CNT)-based compositions for activating cellular immune responses are provided. The CNTs function as high surface area scaffolds for the attachment of T cell ligands and/or antigens. The CNT compositions function as artificial antigen-presenting cells (aAPCs) or as modular vaccines. The disclosed CNT aAPCs are efficient at activating T cells and may be used to activate T cells ex vivo or in vivo for adoptive or active immunotherapy.</p>
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DUAL INHIBITORS OF FARNESYLTRANSFERASE AND GERANYLGERANYLTRANSFERASE I (Fri, 26 Jul 2013)
<p id="p-0001" num="0000">Many GTPases such as Ras, Ral and Rho require post-translational farnestylation or geranylgeranylation for mediating malignant transformation. Dual farnesyltransferase (FT) (FTI) and geranylgeranyltransferase-I (GGT-1) inhibitors (GGTI) were developed as anticancer agents from based on an ethylenediamine scaffold. On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating extensive structure-activity relationship studies. The most potent inhibitor is compound exhibited an in vitro hFTase IC<sub>50 </sub>value of 25 nM and a whole cell H-Ras processing IC<sub>50 </sub>value of 90 nM. Several of the inhibitors proved highly selective for hFTase over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of an inhibitor cocrystallized with farnesyl pyrophosphate in the active site of rat FTase illustrates that the para-benzonitrile moiety is stabilized by a π-π stacking interaction with the Y361β residue, suggesting an importance of this component of the inhibitors.</p>
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COMPOUNDS AND METHODS FOR THE INHIBITION OF VCB E3 UBIQUITIN LIGASE (Fri, 19 Jul 2013)
The present invention relates to novel compounds which find utility as modulators, especially inhibitors of VCB E3 Ubiquitin Ligase and as bioactive agents for use as therapeutics for the stimulation of erythropoiesis in a patient or subject including inducement of EPO production in the patient or subject, for the treatment of chronic anemia and ischemia (limits brain injury during episodes of localized anemia, ischemia and/or stroke and damage to cardiovascular tissue during cardiovascular ischemia), as well as enhancing wound healing processes. Pharmaceutical compositions comprising effective amounts of compounds according to the present invention alone or in combination with an additional erythropoieses stimulating agent such as EPO under the tradename procrit or epogen or darbapoietin alfa under the tradename aranesp. Methods of stimulating erythropoiesis in a subject or patient, including increasing the number of red blood cells and/or hematocrit of the patient, treating anemia, including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy, ischemia, stroke and damage to cardiovascular tissue during cardiovascular ischemia as well as enhancing wound healing processes and preventing/reducing scarring secondary to healing represent additional aspects of the present invention. Local enhancement of angiogenesis through induction of VEGF including wound healing and reduction of stent occlusion remain additional aspects of the present invention.
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COMPOUNDS & METHODS FOR THE ENHANCED DEGRADATION OF TARGETED PROTEINS & OTHER POLYPEPTIDES BY AN E3 UBIQUITIN LIGASE (Fri, 19 Jul 2013)
The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.
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ENZYMATIC SYNTHESIS OF POLY(AMINE-CO-ESTERS) AND METHODS OF USE THEREOF FOR GENE DELIVERY (Fri, 07 Jun 2013)
Poly(amine-co-ester) polymers, methods of forming active agent-load nanoparticies therefrom, and methods of using the nanoparticies for drug delivery are disclosed. The nanoparticies can be coated with an agent that reduces surface charge, an agent that increases cell-specific targeting, or a combination thereof. Typically, the loaded nanoparticies are less toxic, more efficient at drug delivery, or a combination thereof compared to a control other transfection reagents. In some embodiments, the nanoparticies are suitable for in vivo delivery, and can be administered systemically to a subject to treat a disease or condition.
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REPROGRAMMING UROKINASE INTO AN ANTIBODY-RECRUITING ANTICANCER AGENT (Fri, 17 May 2013)
The present invention relates to chimeric (preferably, bifunctional) compounds, compositions comprising those compounds and methods of treating cancer in a patient or subject, especially including metastatic cancer where cancer cells exhibit ovrexpression (heightened expression) of cell surface urokinase-type plasminogen activator receptor (urokinase receptor) compared to normal (non-cancerous) cells. The compounds preferably covalently bind to the urokinase receptor and recruit native antibodies of the patient or subject where the antibodies can selectively degrade and/or deactivate targeted cancer cells through antibody-dependent cellular phagocytosis and/or antibody-dependent cellular cytotoxicity (ADCC) against a large number and variety of cancers, thus providing cancer cell death and/or an inhibition of growth, elaboration and/or metastasis of the cancer, including remission and cure of the patient's cancer.
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CATECHOL DIETHERS AS POTENT ANTI-HIV AGENTS (Fri, 19 Apr 2013)
The present invention is directed to novel catechol diether compounds, pharmaceutical compositions therefrom and methods for inhibiting reverse transcriptase and treating HIV infections, especially included drug resistant strains of HIV 1 and 2 and/or secondary disease states and/or conditions which occur as a consequence of HIV infection.
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MULTIBLOCK COPOLYMER FILMS, METHODS OF MAKING SAME, AND USES THEREOF (Fri, 09 Nov 2012)
A method for forming an isoporous graded film comprising multiblock copolymers and isoporous graded films. The films have a surface layer and a bulk layer. The surface layer can have at least 1 x 1014 pores/m2 and a pore size distribution (dmax/dmin)) of less than 3. The bulk layer has an asymmetric structure. The films can be used in filtration applications.
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DRUG THERAPY TO INHIBIT CHEMOTHERAPY-INDUCED ADVERSE EFFECTS AND RELATED PHARMACEUTICAL COMPOSITIONS, DIAGNOSTICS, SCREENING TECHNIQUES AND KITS (Fri, 02 Nov 2012)
The invention provides a method of treatment comprising reducing therapy-induced adverse effects (TIAE), including chemotherapy-induced adverse effects (CIAE), such as chemotherapy-induced peripheral neuropathy (CIPN) and/or chemotherapy-induced cardiovascular adverse effects (CICAE) in a subject being treated with a CIAE-inducing anti-cancer active ingredient by co-administering to the subject a pharmaceutically effective amount of a NCS-1-protective composition. Related pharmaceutical compositions, diagnostics and screening techniques are also provided.
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CALIBRATION OF NANOSTRUCTURE SENSORS (Fri, 21 Sep 2012)
The present invention relates to uniform nanostructure biosensors and methods of calibrating the response of nanostructure biosensors. The invention overcomes device to device variability that has made quantitative detection difficult. The described biosensors have uniform characteristics that allow for more reliable comparison across devices. The methods of the invention comprise normalizing the initial current rate, as measured by the nanostructure biosensor following the addition of an analyte, to device characteristics of the biosensor. The device characteristics of the biosensor which can be used to normalize the response include baseline current and transconductance, Calibration of responses allows for the generation of calibration curves for use in all devices to quantitatively detect an analyte, without the need for individual device calibration.
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(--)- HUPERZINE A PROCESSES AND RELATED COMPOSITIONS AND METHODS OF TREATMENT (Fri, 14 Sep 2012)
The invention provides (1) processes for making substantially-pure (-) huperzine A and substantially-pure (-) huperzine A derivatives; (2) compositions useful in making substantially-pure (-) huperzine A and substantially-pure (-) huperzine A derivatives; and (3) methods of treating or preventing neurological disorders using substantially-pure (-) huperzine A and substantially-pure (-) huperzine A derivatives.
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VIRTUAL HYDROGEN STORAGE PROCESSES AND RELATED CATALYSTS AND SYSTEMS (Fri, 24 Aug 2012)
The present invention relates to virtual hydrogen storage processes which electrocatalytically reduce a liquid organic hydrogen carrier (LOHC) in a direct organic fuel cell/flow battery. Novel homogeneous catalysts comprising a tridendate, redox-active pincer ligand complex and related direct organic fuel cell/flow battery systems are also provided.
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COMPOUNDS AND METHODS FOR INDUCING APOPTOSIS IN CANCER CELLS USING A BH3 ALPHA-HELICAL MIMETIC (Fri, 20 Jul 2012)
A novel BH3 α-helical mimetic, BH3-M6, which binds to Bcl-XL and prevents its binding to fluorescently-labeled Bak-BH3 peptide in vitro with an IC50 value of 734 nM is presented herein. BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-XL, Bcl-2 and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in a cell-free system and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6-induced apoptosis is caspase- and Bax- dependent. Furthermore, human cancer cells with high Bcl-2 or Bcl-XL levels are more sensitive to BH3-M6-induced cell death, suggesting that this compound can overcome drug resistance due to Bcl-2 or BCI-XL overexpression. The pan-Bcl-2 inhibitor BH3-M6 may be encapsulated in a micelle to provide a more bioavailable therapeutic agent. Specifically, the BH3-M6 compound may be encapsulated within a micelle comprising a multiblock copolymer according to the methods described herein.
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SMALL-MOLECULE HYDROPHOBIC TAGGING OF FUSION PROTEINS AND INDUCED DEGRADATION OF SAME (Fri, 15 Jun 2012)
The present invention relates to the ability to regulate any protein of interest in living systems with small molecules. In particular, the present invention relates to the discovery that appending a hydrophobic moiety to the surface of a protein can mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. An aspect of the present invention relates to bifunctional small molecules that bind a number of proteins, including, for example, a self-labeling tag such as bacterial dehalogenase (HaloTag protein) and present a hydrophobic group on its surface. Hydrophobic tagging of the HaloTag protein with a hydrophobic moiety (e.g. an adamantyl moiety) was effected and the tagging induced the degradation of cytosolic, isoprenylated, and transmembrane fusion proteins in cell culture. The present invention also demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting RasG12V-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models.
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SMALL-MOLECULE HYDROPHOBIC TAGGING OF FUSION PROTEINS AND INDUCED DEGRADATION OF SAME (Fri, 15 Jun 2012)
The present invention relates to the ability to regulate any protein of interest in living systems with small molecules. In particular, the present invention relates to the discovery that appending a hydrophobic moiety to the surface of a protein can mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. An aspect of the present invention relates to bifunctional small molecules that bind a number of proteins, including, for example, a self-labeling tag such as bacterial dehalogenase (HaloTag protein) and present a hydrophobic group on its surface. Hydrophobic tagging of the HaloTag protein with a hydrophobic moiety (e.g. an adamantyl moiety) was effected and the tagging induced the degradation of cytosolic, isoprenylated, and transmembrane fusion proteins in cell culture. The present invention also demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting RasG12V-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models.</p>
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BIFUNCTIONAL MOLECULES WITH ANTIBODY-RECRUITING AND ENTRY INHIBITORY ACTIVITY AGAINST THE HUMAN IMMUNODEFICIENCY VIRUS (Fri, 25 May 2012)
The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as ARM- HI's, function through orthogonal pathways, by inhibiting the gpl20-CD4 interaction, and by recruiting anti-DNP antibodies to gpl20-expressing cells, thereby preventing cell infection and spread of HIV. It has been shown that ARM-HI's bind to gpl20 and gp-120 expressing cells competitively with CD4, thereby decreasing viral infectivity as shown by an MT-2 cell assay, the binding leading to formation of a ternary complex by recruiting anti-DNP antibodies to bind thereto, the antibodies present in the ternary complex promoting the complement-dependent destruction of the gpl20-expressing cells. Compounds and methods are described herein.
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USE OF CRYOGENIC ION CHEMISTRY TO ADD A STRUCTURAL CHARACTERIZATION CAPABILITY TO MASS SPECTROMETRY THROUGH LINEAR ACTION SPECTROSCOPY (Fri, 20 Apr 2012)
The present invention relates to mass spectrometry and infrared spectrometry and in particular, to a method of providing highly resolved infrared spectra of mass-selected, complex (e.g., biopolymer, polypeptide, organic chemical, an organometallic compound, a carbohydrate, a polynucleotide or oligonucleotide compound) ions to be obtained in a general fashion.
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ENVIRONMENTALLY SENSITIVE COMPOSITIONS (Fri, 13 Apr 2012)
An environmentally sensitive membrane binding polypeptide, pH (low) -sensitive membrane peptide (pHLIP) has improved insertion kinetics balanced with solubility to selectively target acidic tissues.
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ENVIRONMENTALLY SENSITIVE COMPOSITIONS (Fri, 13 Apr 2012)
An environmentally sensitive membrane binding polypeptide, pH (low) -sensitive membrane peptide (pHLIP) has improved insertion kinetics balanced with solubility to selectively target acidic tissues.</p>
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COMPOUNDS AND METHODS FOR ACEMIF INHIBITION AND THE TREATMENT OF PARASITES (Fri, 16 Mar 2012)
The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new pharmacophores, Hookworms are blood-feeding, intestinal nematode parasites infect up to 600 million people worldwide. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (rAceMIF) provided partial protection from disease, thus establishing a "proof-of-concept" for targeting AceMIF to prevent or treat infection. A high-throughput screen (HTS) against rAceMIF identified six AceMIF-specific inhibitors. A non-steroidal anti-inflammatory drug (NSAID), sodium meclofenamate, could be tested in an animal model to assess the therapeutic efficacy in treating hookworm disease. Furosemide, an FDA-approved diuretic, exhibited submicromolar inhibition of rAceMIF tautomerase activity. Structure-activity relationships of a pharmacophore based on furosemide included one analogue that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity. Compounds and methods for inhibiting AceMIF and treating parasitic, including hookworm infections represent additional aspects of the invention.
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Potent chimeric NRTI-NNRTI bifunctional inhibitors of HIV-1 reverse transcriptase (Fri, 23 Dec 2011)
<p id="p-0001" num="0000">The present invention relates to compounds, in particular, dual antagonists comprising a nucleoside reverse transcriptase inhibitor (NRTI) or a nucleoside competitive reverse transcriptase inhibitor and a non-nucleoside reverse transcriptase inhibitor (NNRTI), linked together using a chemical linker, which may be used to inhibit HIV (HIV-1) reverse transcriptase and in the treatment of HIV infections, more severe cases of HIV infections, including ARC and AIDS, including reducing the likelihood of these infections and disease states.</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="224.45mm" wi="75.10mm" file="US08513205-20130820-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <chemistry id="CHEM-US-00002" num="00002"> <img id="EMI-C00002" he="225.30mm" wi="75.52mm" file="US08513205-20130820-C00002.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <chemistry id="CHEM-US-00003" num="00003"> <img id="EMI-C00003" he="60.88mm" wi="58.00mm" file="US08513205-20130820-C00003.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> </p>
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COMPOUNDS AND METHODS OF MODULATING MITOCHONDRIAL BIOENERGETIC EFFICIENCY THROUGH AN INTERACTION WITH ATP SYNTHASE (COMPLEX V) AND ITS SUBUNITS (Fri, 02 Dec 2011)
The present invention provides, in part, methods of identifying compounds that can bind to an ATP synthase complex, increase bioenergetic efficiency, decrease oxygen consumption or the rate thereof, increase oxygen utilization efficiency, increase cell survival or any combination thereof, and methods of using compounds and/or identified compounds to increase bioenergetic efficiency, increase oxygen utilization efficiency, decrease oxygen consumption, increase cell survival, or any combination thereof.
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MIF MODULATORS (Fri, 11 Nov 2011)
The invention provides novel heterocyclic compounds, pharmaceutical compositions and methods of treatment that modulate levels of MIF expression and treat disorders associated with high or low levels of MIF expression.
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CHIMERIC SMALL MOLECULES FOR THE RECRUITMENT OF ANTIBODIES TO CANCER CELLS (Fri, 19 Aug 2011)
<p id="p-0001" num="0000">The present invention relates to chimeric chemical compounds which are used to recruit antibodies to cancer cells, in particular, prostate cancer cells or metastasized prostate cancer cells. The compounds according to the present invention comprise an antibody binding terminus (ABT) moiety covalently bonded to a cell binding terminus (CBT) through a linker and optionally, a connector molecule.</p>
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A PROCESS FOR PRODUCING A CARRIER ORGANISM CONTAINING A HETEROLOGOUS METAGENOMIC DNA (Fri, 05 Aug 2011)
A process for recovering a carrier organism containing a heterologous metagenomic ONA, the gene product of which may be produced in a cell from a carrier organism other than the organism which is the source of the heterologous metagenomic DNA.
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ACCELERATED MRI WITH NONLINEEAR SPATIAL ENCODING GRADIENTS (Fri, 22 Jul 2011)
In a method of magnetic resonance imaging, a set of nonlinear, mutually orthogonal magnetic gradient encoding fields are sequentially and separately generated in an imaging region [100]. Using multiple receiver coils having nonuniform sensitivity profiles, echo data representing signal intensities in the imaging region is sequentially acquired as the magnetic gradient encoding fields are sequentially generated [102]. A reconstructed image of the imaging region is computed from the acquired echo data [104], and the reconstructed image is then be stored and/or displayed on a display monitor [106].
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Riboswitches, methods for their use, and compositions for use with riboswitches (Fri, 24 Jun 2011)
<p id="p-0001" num="0000">It has been discovered that certain natural mRNAs serve as metabolite-sensitive genetic switches wherein the RNA directly binds a small organic molecule. This binding process changes the conformation of the mRNA, which causes a change in gene expression by a variety of different mechanisms. Modified versions of these natural “riboswitches” (created by using various nucleic acid engineering strategies) can be employed as designer genetic switches that are controlled by specific effector compounds. Such effector compounds that activate a riboswitch are referred to herein as trigger molecules. The natural switches are targets for antibiotics and other small molecule therapies. In addition, the architecture of riboswitches allows actual pieces of the natural switches to be used to construct new non-immunogenic genetic control elements, for example the aptamer (molecular recognition) domain can be swapped with other non-natural aptamers (or otherwise modified) such that the new recognition domain causes genetic modulation with user-defined effector compounds. The changed switches become part of a therapy regimen—turning on, or off, or regulating protein synthesis. Newly constructed genetic regulation networks can be applied in such areas as living biosensors, metabolic engineering of organisms, and in advanced forms of gene therapy treatments.</p>
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AMPHIPHILIC COMPOSITIONS AND METHODS FOR PREPARING AND USING SAME (Fri, 13 May 2011)
The invention relates to amphiphilic C-glycoside derivatives, to methods of using them and to processes for synthesizing them. Specifically, the invention relates to novel cyclic and linear enone-glycolipids and cyclic ketone-glycolipids.
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AMPHIPHILIC COMP0UNDS AND METHODS FOR PREPARING AND USING SAME (Fri, 13 May 2011)
The invention relates to amphiphilic C-glycoside derivatives, to methods of using them and to processes for synthesizing them. Specifically, the invention relates to novel cyclic and linear enone-glycolipids and cyclic ketone-glycolipids.</p>
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BIFUNCTIONAL MOLECULES WITH ANTIBODY-RECRUITING AND ENTRY INHIBITORY ACTIVITY AGAINST THE HUMAN IMMUNODEFICIENCY VIRUS (Fri, 22 Apr 2011)
The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as ARM-H' function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by recruiting anti-DNP antibodies to gp120-expressing cells, thereby preventing cell infection and spread of HIV. It has been shown that ARM-H's bind to gp120 and gp-120 expressing cells competitively with CD4, thereby decreasing viral infectivity as shown by an MT-2 cell assay, the binding leading to formation of a ternary complex by recruiting anti-DNP antibodies to bind thereto, the antibodies present in the ternary complex promoting the complement-dependent destruction of the gp120-expressing cells. Compounds and methods are described herein.
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ANTI-HEPATITIS C ACTIVITY OF MESO-TETRAKIS-PORPHYRIN ANALOGUES (Fri, 18 Mar 2011)
<p id="p-0001" num="0000">The present invention relates to porphyrin analogues, their use in pharmaceutical compositions alone, or combination with other agents and in the treatment and/or prophylaxis of flaviviridae viral infections, especially hepatitis C viral infection, and secondary disease states and/or conditions associated with same.</p>
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Excitatory glycine receptors and methods (Fri, 25 Feb 2011)
<p id="p-0001" num="0000">The invention provides isolated N-methyl-D-aspartate type 3B (NR3B) polypeptides, functional fragments and peptides, encoding nucleic acid molecules and polynucleotides, and specific antibodies. Also provided are excitatory glycine receptors, containing either NR3B or NR3A polypeptides. Further provided are methods for detecting excitatory glycine receptor ligands, agonists and antagonists. The invention also provides related diagnostic and therapeutic methods.</p>
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Protein binding miniature proteins (Fri, 04 Feb 2011)
<p id="p-0001" num="0000">The present invention provides a protein scaffold, such as an avian pancreatic polypeptide, that can be modified by substitution of two or more amino acid residues that are exposed on the alpha helix domain of the polypeptide when the polypeptide is in a tertiary form.</p>
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GLMS RIBOSWITCHES, STRUCTURE-BASED COMPOUND DESIGN WITH GLMS RIBOSWITCHES, AND METHODS AND COMPOSITIONS FOR USE OF AND WITH GLMS RIBOSWITCHES (Fri, 24 Dec 2010)
<p id="p-0001-en" num="0000">The glmS riboswitch is a target for antibiotics and other small molecule therapies. Compounds can be used to stimulate, active, inhibit and/or inactivate the glmS riboswitch. The atomic structures of the glmS riboswitch can be used to design new compounds to stimulate, active, inhibit and/or inactivate riboswitches.</p>
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GEMM RIBOSWITCHES, STRUCTURE-BASED COMPOUND DESIGN WITH GEMM RIBOSWITCHES, AND METHODS AND COMPOSITIONS FOR USE OF AND WITH GEMM RIBOSWITCHES (Fri, 19 Nov 2010)
Disclosed is the crystal structure of a GEMM riboswitch from V. cholerae bound to c- di-GMP. The crystal structures show that the RNA binds the ligand within a three helix junction that involves base pairing and extensive base stacking. The symmetric c-di-GMP is recognized asymmetrically with respect to the both the bases and the backbone. Also disclosed are methods of identifying and using compounds and compositions that modulate GEMM riboswitches.
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MODIFIED MINIATURE PROTEINS (Fri, 29 Oct 2010)
<p id="p-0001-en" num="0000">The present invention generally relates to modified miniature proteins, including modified avian pancreatic polypeptides (aPP) and modified pancreatic peptide YYs (PYY). One aspect of the invention is generally directed to various aPPs that have been modified such that they do not substantially form multimers in solution, for example through the addition of a proline switch. Another aspect of the invention is generally directed to modified PYYs, such as YY3. Yet another aspect of the invention is generally directed to composites of modified miniature proteins formed from portions of different miniature proteins such as aPP and/or PYY, optionally with a proline switch. Still other aspects of the invention are generally directed to methods of making such proteins, methods of using such proteins, kits involving such proteins, and the like.</p>
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Pseudobase benzo[c]phenanthridines with improved efficacy, stability and safety (Fri, 08 Oct 2010)
<p id="p-0001" num="0000">Pseudobase benzo[c]phenanthridines and the pharmaceutically acceptable salts thereof of Formula I</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="33.10mm" wi="69.26mm" file="US08362028-20130129-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <br/> are provided herein. The variables R, R<sub>1</sub>, R<sub>2</sub>, R<sub>3</sub>, and R<sub>4 </sub>are defined herein. Certain pseudobase benzo[c]phenanthridines provided herein act as prodrugs, targeting the parent benzo[c]phenanthridinium alkaloid to hydrophilic or hydrophobic regions in the body. Pharmaceutical compositions comprising a pseudobase benzo[c]phenanthridine and a carrier, excipient, or diluent are provided herein. Methods of treating or preventing microbial, fungal and or viral infections and methods of treating diseases and disorders responsive to protein kinase C modulation, topoisomerase I, and/or topoisomerase II modulation are also provided. </p>
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Compounds and Methods for the Treatment of Viruses and Cancer (Fri, 03 Sep 2010)
<p id="p-0001-en" num="0000">The present invention relates to compounds according to the formula I: Where R<sup>a </sup>is H or an optionally OH-substituted C<sub>1</sub>-C<sub>3 </sub>alkyl; R<sub>1 </sub>is OR<sup>1</sup>, an optionally substituted C<sub>4-12 </sub>carbocyclic group which may be saturated or unsaturated (including aromatic) or an optionally substituted heterocyclic group; R<sup>1 </sup>is an optionally substituted C<sub>1</sub>-C<sub>14 </sub>hydrocarbyl group or an optionally substituted heterocyclic group; R<sub>2</sub>, R<sub>3 </sub>and R<sub>4 </sub>are each independently H, an optionally substituted C<sub>1</sub>-C<sub>4 </sub>alkyl group (preferably CH<sub>3</sub>, CH<sub>2</sub>CH<sub>3 </sub>or CF<sub>3</sub>), halogen (preferably F, Cl, Br), OR, CN, NO<sub>2</sub>, a C<sub>1</sub>-C<sub>6 </sub>thioether, a C<sub>1</sub>-C<sub>6 </sub>thioester group, an optionally substituted CO<sub>2</sub>R group, an optionally substituted COR group or an optionally substituted OCOR group (preferably R<sub>4 </sub>is H); R is H or an optionally substituted C<sub>1</sub>-C<sub>6 </sub>alkyl group; RHET is an optionally substituted heterocyclic group; and pharmaceutically acceptable salts, solvates or polymorphs thereof.</p> <p id="p-0002-en" num="0000"> <chemistry id="chem-us-00001-en" num="00001"> <img id="emi-c00001" he="27.52mm" wi="52.92mm" file="US20100222352A1-20100902-C00001.TIF" img-content="chem" img-format="tif"/> </chemistry> </p>
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Ribosome structure and protein synthesis inhibitors (Fri, 13 Aug 2010)
<p id="p-0001" num="0000">The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism.</p>
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RIBOSWITCHES, METHODS FOR THEIR USE, AND COMPOSITIONS FOR USE WITH RIBOSWITCHES (Fri, 30 Jul 2010)
<p id="p-0001-en" num="0000">It has been discovered that certain natural mRNAs serve as metabolite-sensitive genetic switches wherein the RNA directly binds a small organic molecule. This binding process changes the conformation of the mRNA, which causes a change in gene expression by a variety of different mechanisms. Modified versions of these natural “riboswitches” (created by using various nucleic acid engineering strategies) can be employed as designer genetic switches that are controlled by specific effector compounds. Such effector compounds that activate a riboswitch are referred to herein as trigger molecules. The natural switches are targets for antibiotics and other small molecule therapies. In addition, the architecture of riboswitches allows actual pieces of the natural switches to be used to construct new non-immunogenic genetic control elements, for example the aptamer (molecular recognition) domain can be swapped with other non-natural aptamers (or otherwise modified) such that the new recognition domain causes genetic modulation with user-defined effector compounds. The changed switches become part of a therapy regimen—turning on, or off, or regulating protein synthesis. Newly constructed genetic regulation networks can be applied in such areas as living biosensors, metabolic engineering of organisms, and in advanced forms of gene therapy treatments.</p>
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NANOELECTRONIC-ENZYME LINKED IMMUNOSORBENT ASSAY SYSTEM AND METHOD (Fri, 23 Jul 2010)
<p id="p-0001-en" num="0000">The present invention relates to a device and method for determining the presence of a specific compound in solution. The device includes a nanosensor having an electrically conducting pathway between at least a first and second contact. The device also includes a first receptor, suitable for binding a specific compound in the solution, attached to the nanosensor, and a second receptor also suitable for binding the specific compound while the specific compound is bound to the first receptor. The second receptor is attached to an enzyme added to the solution. When the solution having the second receptor is added to the device, and a second compound that is a substrate for the enzyme is subsequently added to the solution, a measured difference in an electrical property in the device before and after the application of the second compound is indicative of the presence of the specific compound in the solution.</p>
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Azoles and related derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) in antiviral therapy (HIV) (Fri, 02 Jul 2010)
<p id="p-0001" num="0000">The present invention relates to novel heterocyclic compounds, including oxadiazole compounds, pharmaceutical compositions and their use in the inhibition of reverse transcriptase and the treatment of HIV (1 and 2) infections, AIDS and ARC and other viral infections.</p>
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PREQ1 RIBOSWITCHES AND METHODS AND COMPOSITIONS FOR USE OF AND WITH PREQ1 RIBOSWITCHES (Fri, 18 Jun 2010)
<p id="p-0001-en" num="0000">The preQ1 riboswitch is a target for antibiotics and other small molecule therapies. The preQ1riboswitch and portions thereof can be used to regulate the expression or function of RNA molecules and other elements and molecules. The preQ1 riboswitch and portions thereof can be used in a variety of other methods to, for example, identify or detect compounds. Compounds can be used to stimulate, active, inhibit and/or inactivate the preQ1 riboswitch. The preQ1 riboswitch and portions thereof, both alone and in combination with other nucleic acids, can be used in a variety of constructs and RNA molecules and can be encoded by nucleic acids.</p>
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PARALLEL MAGNETIC RESONANCE IMAGING USING NONLINEAR GRADIENT ENCODING (Fri, 18 Jun 2010)
In MRI by excitation of nuclear spins and measurement of RF signals induced by these spins in the presence of spatially-varying encoding magnetic fields, signal localization is performed through recombination of measurements obtained in parallel by each coil in an encircling array of RF receiver coils. Through the use of magnetic gradient fields that vary both as first-order and second-order Z2 spherical harmonics with position, radially-symmetric magnetic encoding fields are created that are complementary to the spatial variation of the encircling receiver coils. The resultant hybrid encoding functions comprised of spatially-varying coil profiles and gradient fields permits unambiguous localization of signal contributed by spins. Using hybrid encoding functions in which the gradient shapes are thusly tailored to the encircling array of coil profiles, images are acquired in less time than is achievable from a conventional acquisition employing only first-order gradient fields with an encircling coil array.
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LYSINE RIBOSWITCHES, STRUCTURE-BASED COMPOUND DESIGN WITH LYSINE RIBOSWITCHES, AND METHODS AND COMPOSITIONS FOR USE OF AND WITH LYSINE RIBOSWITCHES (Fri, 04 Jun 2010)
<p id="p-0001-en" num="0000">The lysine riboswitch is a target for antibiotics and other small molecule therapies. Compounds can be used to stimulate, active, inhibit and/or inactivate the lysine riboswitch.</p>
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Anti-viral nucleoside analogs and methods for treating viral infections, especially HIV infections (Fri, 26 Feb 2010)
<p id="p-0001" num="0000">The present invention relates to novel compounds according to the general formulas I, II, III, IV or V:</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="128.02mm" wi="51.05mm" file="US08193165-20120605-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <br/> wherein B is nucleoside base according to the structure: </p> <p id="p-0003" num="0000"><chemistry id="CHEM-US-00002" num="00002"> <img id="EMI-C00002" he="87.63mm" wi="52.92mm" file="US08193165-20120605-C00002.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <br/> and the remaining variables as defined in the specification, and pharmaceutical compositions comprising the compounds. The compounds are useful interalia as anti-viral agents in viral therapy. </p>
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MIF MODULATORS (Fri, 26 Feb 2010)
The invention provides novel heterocyclic compounds, pharmaceutical compositions and methods of treatment that modulate levels of MIF expression and treat disorders associated with high or low levels of MIF expression.
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MIF MODULATORS (Fri, 26 Feb 2010)
The invention provides novel heterocyclic compounds, pharmaceutical compositions and methods of treatment that modulate levels of MIF expression and treat disorders associated with high or low levels of MIF expression. </p>
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RIBOSWITCHES, METHODS FOR THEIR USE, AND COMPOSITIONS FOR USE WITH RIBOSWITCHES (Fri, 19 Feb 2010)
<p id="p-0001-en" num="0000">It has been discovered that certain natural mRNAs serve as metabolite-sensitive genetic switches wherein the RNA directly binds a small organic molecule. This binding process changes the conformation of the mRNA, which causes a change in gene expression by a variety of different mechanisms. Modified versions of these natural “riboswitches” (created by using various nucleic acid engineering strategies) can be employed as designer genetic switches that are controlled by specific effector compounds. Such effector compounds that activate a riboswitch are referred to herein as trigger molecules. The natural switches are targets for antibiotics and other small molecule therapies. In addition, the architecture of riboswitches allows actual pieces of the natural switches to be used to construct new non-immunogenic genetic control elements, for example the aptamer (molecular recognition) domain can be swapped with other non-natural aptamers (or otherwise modified) such that the new recognition domain causes genetic modulation with user-defined effector compounds. The changed switches become part of a therapy regimen-turning on, or off, or regulating protein synthesis. Newly constructed genetic regulation networks can be applied in such areas as living biosensors, metabolic engineering of organisms, and in advanced forms of gene therapy treatments.</p>
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NANOPARTICLES FOR USE AS SYNTHETIC PLATELETS AND THERAPEUTIC AGENT DELIVERY VEHICLES (Fri, 22 Jan 2010)
The invention relates to synthetic platelet compositions and methods useful in diminishing bleeding and blood loss. The synthetic platelets of the invention can comprise a biocompatible, biodegradable polymer, including, for example, a poly(lactic-co-glycolic acid)-poly-L-lysine (PLGA-PLL) block copolymer, having conjugated PEG arms terminating with RGD motif containing peptides. The invention further comprises compositions and methods useful in the delivery of therapeutic agents.
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SMALL MOLECULE INHIBITORS OF AUTOTAXIN METHODS OF USE (Fri, 18 Dec 2009)
Autotaxin (ATX) is a prometastatic enzyme initially isolated from the conditioned media of human melanoma cells that stimulates a myriad of biological activities including angiogenesis and the promotion of cell growth, survival, and differentiation through the production of lysophosphatidic acid (LPA). ATX increases the aggressiveness and invasiveness of transformed cells, and ATX levels directly correlate with tumor stage and grade in several human malignancies. To study the role of ATX in the pathogenesis of malignant melanoma, we developed antibodies and small molecule inhibitors against recombinant human protein. Immunohistochemistry of paraffin embedded human tissue demonstrates that ATX levels are markedly increased in human primary and metastatic melanoma relative to benign nevi. Chemical screens identified several small molecule inhibitors with binding constants ranging from nanomolar to low micromolar. Cell migration and invasion assays with melanoma cell lines demonstrate that ATX markedly stimulates melanoma cell migration and invasion, an effect suppressed by ATX inhibitors. The migratory phenotype can be rescued by the addition of ATX' s enzymatic product, LPA, confirming that the observed inhibition is linked to suppression of LPA production by ATX. Chemical analogues of the inhibitors demonstrate structure activity relationships important for ATX inhibition and indicate pathways for their optimization. These studies suggest that ATX is an approachable molecular target for the rational design of chemotherapeutic agents directed against human malignancies driven by the ATX/LPA axis, especially including malignant melanoma, among numerous others including breast and ovarian cancers.
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CHIMERIC SMALL MOLECULES FOR THE RECRUITMENT OF ANTIBODIES TO CANCER CELLS (Fri, 20 Nov 2009)
The present invention relates to chimeric chemical compounds which are used to recruit antibodies to cancer cells, in particular, prostate cancer cells or metastasized prostate cancer cells. The compounds according to the present invention comprise an antibody binding terminus (ABT) moiety covalently bonded to a cell binding terminus(CBT) through a linker and optionally, a connector molecule.
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CHIMERIC SMALL MOLECULES FOR THE RECRUITMENT OF ANTIBODIES TO CANCER CELLS (Fri, 20 Nov 2009)
The present invention relates to chimeric chemical compounds which are used to recruit antibodies to cancer cells, in particular, prostate cancer cells or metastasized prostate cancer cells. The compounds according to the present invention comprise an antibody binding terminus (ABT) moiety covalently bonded to a cell binding terminus(CBT) through a linker and optionally, a connector molecule. </p>
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POTENT CHIMERIC NRTI-NNRTI BIFUNCTIONAL INHIBITORS OF HIV-1 REVERSE TRANSCRIPTASE (Fri, 16 Oct 2009)
The present invention relates to compounds, in particular, dual antagonists comprising a nucleoside reverse transcriptase inhibitor (NRTI) or a nucleoside competititive reverse transcriptase inhibitor and a non-nucleoside reverse transcriptase inhibitor (NNRTI), linked together using a chemical linker, which may be used to inhibit HIV (HIV-1) reverse transcriptase and in the treatment of HIV infections, more severe cases of HIV infections, including ARC and AIDS, including reducing the likelihood of these infections and disease states.
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Process for the synthesis of arylamines from the reaction of an aromatic compound with ammonia or a metal amide (Fri, 18 Sep 2009)
<p id="p-0001" num="0000">A catalytic process for the synthesis of aromatic primary amines, reagent compositions for effecting the process, and transition metal complexes useful in the process, are provided.</p>
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Proteomimetic compounds as inhibitors of the interaction of nuclear receptor with coactivator peptides (Fri, 04 Sep 2009)
<p id="p-0001" num="0000">The present invention relates to compounds, pharmaceutical compositions and methods which inhibit the binding of coactivator proteins in nuclear receptors, including estrogen receptors (alpha and/or beta), androgen receptors, thyroid receptors and peroxisome proliferators-activated receptors, among others. Compounds according to the present invention may be useful in the treatment of a variety of disease states or conditions which are mediated through nuclear receptors.</p>
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IXODES SCAPULARIS SALIVARY PROTEINS AND METHODS OF USE FOR MODULATION OF THE ALTERNATIVE COMPLEMENT PATHWAY (Fri, 31 Jul 2009)
Ixodes Scapularis salivary proteins, including Ixodes Scapularis anti- complement protein (Isac) and Isac-like protein family (ILP family) proteins, biologically functional equivalents and fragments thereof, and nucleic acid molecules encoding the same are disclosed. ILP family proteins, gene products and polypeptide fragments bind to proteins with thrombospondin repeats. Thus, therapeutic methods involving modulating proteins with thrombospondin repeats using ILP family proteins and biologically active polypeptide fragments thereof are also disclosed. ILP family proteins, gene products and polypeptide fragments have biological activity in modulating the complement pathway through specific binding to properdin. Thus, therapeutic methods involving modulating the complement pathway using ILP family proteins and biologically active polypeptide fragments thereof are also disclosed. The specific binding of ILP family proteins to properdin also provides for methods of treating conditions associated with inappropriate complement pathway activation. Screening methods for selecting substances having an ability to bind to proteins with thrombospondin repeats, including properdin, are also disclosed. Screening methods for selecting substances having an ability to modulate complement pathway activity are also disclosed.
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Methods and apparatus for compensating field inhomogeneities in magnetic resonance studies (Fri, 19 Jun 2009)
<p id="p-0001" num="0000">One aspect of the present disclosure relates to a method or determining location(s) at which at least one magnetic article is to be positioned during a magnetic resonance imaging procedure of at least one subject. A magnetic field Bo is applied to a region that includes the at least one subject and does not include the at least one magnetic article. First magnetic resonance information about the region in response to the applied magnetic field BO is received. The first magnetic resonance information relates at least in part to one or more magnetic field inhomogeneities in the region. Based at least in part on the first magnetic resonance information, at least one first location proximate the at least one subject at which at least one paramagnetic article and/or diamagnetic article is to be positioned is determined, so as to at least partially compensate for the one or more magnetic field inhomogeneities.</p>
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BILE SALT COLLOIDS AND METHODS OF MAKING AND USING THEREOF (Fri, 27 Mar 2009)
Particulate compositions containing an active agent in combination with a bile salt or a polymer of a bile salt are described herein. The active agent may be the bile salt or polymer thereof. In one embodiment, the active agent is encapsulated in, coated onto, or incorporated into a matrix forming a polymeric microparticle or nanoparticle. The bile salt can be coated onto the surface of the particle or incorporated into a coating which is coated onto the surface of the particle. In another example, polymeric microparticles having active agent encapsulated therein can be dispersed in a bile salt emulsion. Alternatively, the bile salt can be incorporated into the polymeric microparticle or nanoparticle, for example, dispersed throughout the polymeric microparticle or nanoparticle or encapsulated in the core, where active agent(s) is in the core, the polymeric matrix, the coating, or a combination thereof. Active agent can be encapsulated in the core and/or can be dispersed throughout the microparticle. In another embodiment, the active agent is encapsulated in a microparticle, coating, layer, core, emulsion or dispersion formed of a polymer of a bile salt, such as polydeoxycholic acid. Suitable active agents include therapeutic, diagnostic, and/or prophylactic agents. The compositions are formulated for oral administration or administration to a mucosal (nasal, pulmonary, rectal, vaginal, buccal, sublingual).
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SYSTEM AND METHODS FOR MANIPULATING COHERENCE OF SPINS AND PSEUDOSPINS USING THE INTERNAL STRUCTURE OF STRONG CONTROL PULSES (Fri, 13 Mar 2009)

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MODIFIED MINIATURE PROTEINS (Fri, 13 Feb 2009)
The present invention generally relates to modified miniature proteins, including modified avian pancreatic polypeptides (aPP) and modified pancreatic peptide YYs (PYY). One aspect of the invention is generally directed to various aPPs that have been modified such that they do not substantially form multimers in solution, for example through the addition of a proline switch. Another aspect of the invention is generally directed to modified PYYs, such as YY3. Yet another aspect of the invention is generally directed to composites of modified miniature proteins formed from portions of different miniature proteins such as aPP and/or PYY, optionally with a proline switch. Still other aspects of the invention are generally directed to methods of making such proteins, methods of using such proteins, kits involving such proteins, and the like.
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NOVEL AZOLES AND RELATED DERIVATIVES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS) IN ANTIVIRAL THERAPY (HIV) (Fri, 09 Jan 2009)
The present invention relates to novel heterocyclic compounds, including oxadiazole compounds, pharmaceutical compositions and their use in the inhibition of reverse transcriptase and the treatment of HIV (1 and 2) infections, AIDS and ARC and other viral infections.
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HYDROXAMATE INHIBITORS OF INSULIN-DEGRADING ENZYME AND USES THEREOF (Thu, 25 Dec 2008)
The present invention provides a novel therapeutic approach for the prevention and treatment of infections and for the treatment of diabetes wherein the degradation of insulin is reduced through inhibition of insulin-degrading enzyme (IDE) by hydroxamate inhibitors.
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SYSTEMS AND METHODS FOR CMOS-COMPATIBLE SILICON NANO-WIRE SENSORS WITH BIOCHEMICAL AND CELLULAR INTERFACES (Fri, 19 Dec 2008)
The systems and methods described herein include a sensor for suitable for sensing chemical and biological substances. The sensor comprises a semiconductor layer formed in or on a substrate and a channel having nano-scale dimensions formed in the semiconductor layer, where the structure creates an electrically conducting pathway between a first contact and a second contact on the semiconductor layer. In certain preferred embodiments, the nano-scale channel has a trapezoidal cross-section with an effective width and exposed lateral faces, where the effective width is selected to have same order of magnitude as a Debye length (LD) of the semiconductor material of which the semiconductor layer is formed.
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PREQ1 RIBOSWITCHES AND METHODS AND COMPOSITIONS FOR USE OF AND WITH PREQ1 RIBOSWITCHES (Fri, 26 Sep 2008)
The preQ1 riboswitch is a target for antibiotics and other small molecule therapies. The preQ1riboswitch and portions thereof can be used to regualte the expression or function of RNA molecules and other elements and molecules. The preQ1 riboswitch and portions thereof can be used in a variety of other methods to, for example, identify or detect compounds. Compounds can be used to stimulate, active, inhibit and/or inactivate the preQ1riboswitch. The preQ1riboswitch and portions thereof, both alone and in combination with other nulcleic acids, can be used in a variety of constructs and RNA molecules and can be encoded by nucleic acids.
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Piperazinone compounds as anti-tumor and anti-cancer agents and methods of treatment (Fri, 12 Sep 2008)
<p id="p-0001-en" num="0000">The present invention relates to piperazinone compounds, pharmaceutical compositions containing those compounds and methods of treating tumors and cancer, among other disease states and conditions in mammalian patients, especially including humans.</p>
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Compounds and methods for the treatment of cancer (Fri, 18 Jul 2008)
<p id="p-0001" num="0000">(−)-(2S,4S)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)cytosine (also referred to as (−)-OddC) or its derivative and its use to treat cancer in animals, including humans.</p>
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Antiviral helioxanthin analogs (Fri, 11 Jul 2008)
<p id="p-0001-en" num="0000">The present invention relates to novel antiviral helioxanthin analogs. These compounds may particularly be used alone or in combination with other drugs for the treatment of the following: hepadnaviruses, flaviviruses, herpesviruses and human immunodeficiency virus. In addition, compounds according to the present invention can be used to prevent or reduce the likelihood of the occurrence of tumors secondary to virus infection as well as other infections or disease states that are secondary to the virus infection.</p>
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GLMS RIBOSWITCHES, STRUCTURE-BASED COMPOUND DESIGN WITH GLMS RIBOSWITCHES, AND METHODS AND COMPOSITIONS FOR USE OF AND WITH GLMS RIBOSWITCHES (Fri, 27 Jun 2008)
The glmS riboswitch is a target for antibiotics and other small molecule therapies. Compounds can be used to stimulate, active, inhibit and/or inactivate the glmS riboswitch. The atomic structures of the glmS riboswitch can be used to design new compounds to stimulate, active, inhibit and/or inactivate riboswitches.
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GLMS RIBOSWITCHES, STRUCTURE-BASED COMPOUND DESIGN WITH GLMS RIBOSWITCHES, AND METHODS AND COMPOSITIONS FOR USE OF AND WITH GLMS RIBOSWITCHES (Fri, 27 Jun 2008)
The glmS riboswitch is a target for antibiotics and other small molecule therapies. Compounds can be used to stimulate, active, inhibit and/or inactivate the glmS riboswitch. The atomic structures of the glmS riboswitch can be used to design new compounds to stimulate, active, inhibit and/or inactivate riboswitches.</p>
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DNA &; protein binding miniature proteins (Fri, 09 May 2008)
<p id="p-0001-en" num="0000">The present invention provides a protein scaffold, such as an avian pancreatic polypeptide, that can be modified by substitution of two or more amino acid residues that are exposed on the alpha helix domain of the polypeptide when the polypeptide is in a tertiary form. </p>
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Pseudobase benzo[c]phenanthridines with improved efficacy, stability, and safety (Fri, 28 Mar 2008)
<p id="p-0001-en" num="0000">Pseudobase benzo[c]phenanthridines and the pharmaceutically acceptable salts thereof of Formula I</p> <p id="p-0002-en" num="0000"> <br/> are provided herein. The variables R, R<sub>1</sub>, R<sub>2</sub>, R<sub>3</sub>, and R<sub>4 </sub>are defined herein. Certain pseudobase benzo[c]phenanthridines provided herein act as prodrugs, targeting the parent benzo[c]phenanthridinium alkaloid to hydrophilic or hydrophobic regions in the body. Pharmaceutical compositions comprising a pseudobase benzo[c]phenanthridine and a carrier, excipient, or diluent are provided herein. Methods of treating or preventing microbial, fungal and or viral infections and methods of treating diseases and disorders responsive to protein kinase C modulation, topoisomerase I, and/or topoisomerase II modulation are also provided. </p>
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METHODS AND COMPOSITIONS FOR THE USE OF LYSINE RIBOSWITCHES (Fri, 21 Mar 2008)
The lysine riboswitch is a target for antibiotics and other small molecule therapies. Compounds can be used to stimulate, active, inhibit and/or inactivate the lysine riboswitch.
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PROTEOMIMETIC COMPOUNDS AS INHIBITORS OF THE INTERACTION OF A NUCLEAR RECEPTOR WITH COACTIVATOR PEPTIDES (Fri, 14 Mar 2008)
The present invention relates to compounds, pharmaceutical compositions and methods which inhibit the binding of coactivator proteins in nuclear receptors, including estrogen receptors (alpha and/or beta), androgen receptors, thyroid receptors and peroxisome proliferators-activated receptors, among others. Compounds according to the present invention may be useful in the treatment of a variety of disease states or conditions which are mediated through nuclear receptors.
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Compounds and methods for treating tumors, cancer and hyperproliferative diseases (Wed, 05 Dec 2007)
<p id="p-0001-en" num="0000">The present invention relates to novel compounds, pharmaceutical compositions and methods for treating tumors, cancer and hyperproliferative diseases including psoriasis, genital warts and hyperproliferative cell growth diseases, including hyperproliferative keratinocyte diseases such as hyperkeratosis, ichthyosis, keratoderma or lichen planus. These compounds are described according to the chemical structure:</p> <p id="p-0002-en" num="0000"> <chemistry id="chem-us-00001-en" num="00001"> <img id="emi-c00001-en" he="16.09mm" wi="56.90mm" file="US07304092-20071204-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <ul id="ul0001-en" list-style="none"> <li>where R<sup>1 </sup>is H, OH, F, Cl, Br, I, a C<sub>1</sub>-C<sub>6 </sub>optionally substituted alkyl or alkenyl group, an optionally substituted aryl group or a</li> </ul> </p> <p id="p-0003-en" num="0000"> <chemistry id="chem-us-00002-en" num="00002"> <img id="emi-c00002-en" he="8.21mm" wi="8.30mm" file="US07304092-20071204-C00002.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <ul id="ul0002-en" list-style="none"> <li> group;</li> <li>R<sub>a </sub>is a H, OH, C<sub>1</sub>-C<sub>10</sub>, optionally substituted alkyl or alkenyl group, an optionally substituted O—(C<sub>1</sub>-C<sub>7 </sub>alkyl group) or O-aryl group, an amine group which is optionally substituted with at least one C<sub>1</sub>-C<sub>10 </sub>alkyl group which may be optionally substituted, or a single optionally substituted aryl group, biphenyl group, (C<sub>1</sub>-C<sub>6</sub>) alkylenearyl group, (C<sub>1</sub>-C<sub>6</sub>) alkylenebiphenyl group, heteroaryl group, heterocyclic group, (C<sub>1</sub>-C<sub>6</sub>) alkylene heteroaryl group or (C<sub>1</sub>-C<sub>6</sub>) alkylene heterocyclic group;</li> <li>R<sup>2 </sup>is a</li> </ul> </p> <p id="p-0004-en" num="0000"> <chemistry id="chem-us-00003-en" num="00003"> <img id="emi-c00003-en" he="8.21mm" wi="8.30mm" file="US07304092-20071204-C00003.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <ul id="ul0003-en" list-style="none"> <li> group;</li> <li>R<sub>b </sub>is a H, OH, C<sub>1</sub>-C<sub>10</sub>, optionally substituted alkyl or alkenyl group, an optionally substituted O—(C<sub>1</sub>-C<sub>7 </sub>alkyl group) or O-aryl group, an amine group which is optionally substituted with at least one C<sub>1</sub>-C<sub>10 </sub>alkyl group which may be optionally substituted, or a single optionally substituted aryl group, biphenyl group, (C<sub>1</sub>-C<sub>6</sub>) alkylenearyl group, (C<sub>1</sub>-C<sub>6</sub>) alkylenebiphenyl group, heteroaryl group, heterocyclic group, (C<sub>1</sub>-C<sub>6</sub>) alkylene heteroaryl group or (C<sub>1</sub>-C<sub>6</sub>) alkylene heterocyclic group;</li> <li>R<sup>3 </sup>and R<sup>6 </sup>are each independently selected from H, OH, F, Cl, Br, I, a C<sub>1</sub>-C<sub>6 </sub>optionally substituted alkyl or alkenyl group, an optionally substituted aryl group, a carbamate, alkylene carbamate, urethane or alkylene urethane;</li> <li>R<sup>4 </sup>is a</li> </ul> </p> <p id="p-0005-en" num="0000"> <chemistry id="chem-us-00004-en" num="00004"> <img id="emi-c00004-en" he="8.21mm" wi="8.30mm" file="US07304092-20071204-C00004.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <ul id="ul0004-en" list-style="none"> <li> group, wherein R<sub>b </sub>is as described above; and</li> <li>R<sup>5 </sup>is a</li> </ul> </p> <p id="p-0006-en" num="0000"> <chemistry id="chem-us-00005-en" num="00005"> <img id="emi-c00005-en" he="8.21mm" wi="8.30mm" file="US07304092-20071204-C00005.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <ul id="ul0005-en" list-style="none"> <li> group, wherein R<sub>b </sub>is as described above,</li> <li>with the proviso that at least one of R<sup>1 </sup>and R<sup>2 </sup>or R<sup>4 </sup>and R<sup>5 </sup>contains an R<sub>a </sub>or R<sub>b </sub>group which is an amine group which is optionally substituted with at least one C<sub>1</sub>-C<sub>10 </sub>alkyl group which may be optionally substituted, or a single optionally substituted aryl group, biphenyl group, (C<sub>1</sub>-C<sub>6</sub>) alkylenearyl group, (C<sub>1</sub>-C<sub>6</sub>) alkylenebiphenyl group, heteroaryl group, heterocyclic group, (C<sub>1</sub>-C<sub>6</sub>) alkylene heteroaryl group or (C<sub>1</sub>-C<sub>6</sub>) alkylene heterocyclic group;</li> <li>or a stereoisomer, pharmaceutically acceptable salt, solvate, and polymorph thereof.</li> </ul> </p>
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Enantioselective Phosphoramidite Compounds and Catalysts (Fri, 09 Nov 2007)
<p id="p-0001-en" num="0000">This invention relates to phosphoramidite compounds and catalyst complexes which can be used to provide enantioselective reactions including hydroamination reactions, etherification reactions and conjugate addition reactions and allylic substitution reactions, among others. In a first aspect, the present invention is directed to phosphoramidite and related compounds according to general structure (I), where Z is absent or is a group containing O, N or S, preferably O; R<sup>1 </sup>and R<sup>2 </sup>are independently an optionally substituted C<sub>1-12 </sub>alkyl group, an optionally substituted (CH<sub>2</sub>)<sub>n</sub>-aromatic group or (CH<sub>2</sub>)<sub>n</sub>-heteroaromatic group, or are linked together to form an optionally substituted aliphatic or (CH<sub>2</sub>)<sub>n</sub>-aromatic dianion of a diol, diamine, dithiol, aminoalcohol, aminohiolate or a alcoholthiol group; R<sup>3′</sup> and R<sup>3 </sup>are each independently H, an optionally substituted C<sub>1</sub>-C<sub>12 </sub>alkyl group or an optionally substituted (CH<sub>2</sub>)<sub>n</sub>-aromatic group with the proviso that R<sup>3′</sup> and R<sup>3 </sup>are not both H, or together R<sup>3′</sup> and R<sup>3 </sup>form an optionally substituted C<sub>5</sub>-C<sub>15 </sub>saturated or unsaturated carbocyclic ring; R<sup>4 </sup>is H, an optionally substituted C<sub>1</sub>-C<sub>12 </sub>alkyl group or an optionally substituted (CH<sub>2</sub>)<sub>n</sub>-aromatic group; R<sup>5 </sup>is absent, H, an optionally substituted C<sub>1</sub>-C<sub>12 </sub>alkyl group or an optionally substituted (CH<sub>2</sub>)<sub>n</sub>-aromatic or (CH<sub>2</sub>)<sub>n</sub>-heteroaromatic group; R<sup>a </sup>and R<sup>a′</sup> are each independently H or a C<sub>1</sub>-C<sub>3 </sub>alkyl group, or R<sup>a </sup>and R<sup>a′</sup> together with the carbon to which they are attached form a optionally substituted C<sub>5</sub>-C<sub>15 </sub>saturated or unsaturated carbocyclic or heterocyclic ring, or an aromatic or heteroaromatic ring; R<sup>6 </sup>and R<sup>7 </sup>are each independently H, an optionally substituted C<sub>1</sub>-C<sub>12 </sub>alkyl group or an optionally substituted (CH<sub>2</sub>)<sub>n</sub>-aromatic group, with the proviso that R<sup>5</sup>, R<sup>6 </sup>and R<sup>7 </sup>cannot simultaneously be H, and when R<sup>a </sup>and R<sup>a′</sup>, together with the carbon to which they are attached, form a carbocyclic ring, heterocyclic ring or an aromatic or heteroaromatic ring, R<sup>5 </sup>is absent or is preferably H; R<sup>6 </sup>and R<sup>7 </sup>are preferably H or CH<sub>3</sub>; and each n is independently 0, 1, 2, 3, 4, 5 or 6 and wherein at least one of the carbon atoms attached to the nitrogen of the phosphoramidite group is a chiral center. <chemistry id="chem-us-00001-en" num="1"><img id="emi-c00001" he="40.89mm" wi="69.85mm" file="US20070259774A1-20071108-C00001.TIF" img-content="chem" img-format="tif"/></chemistry></p>
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METHOD OF PREDICTION OF THE THREE-DIMENSIONAL CONFORMATION OF FLEXIBLE PROTEINS (Fri, 09 Nov 2007)
Computer-implemented methods to predict the structure of an alternative conformation for a macromolecule comprising a hinge. Computer- implemented methods of predicting the location of a hinge in a polypeptide. Computer readable medium and a system useful for practicing the methods in a computing environmentare also provided.
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PROCESS FOR THE SYNTHESIS OF ARYLAMINES FROM THE REACTION OF AN AROMATIC COMPOUND WITH AMMONIA OR A METAL AMIDE (Fri, 28 Sep 2007)
A catalytic process for the synthesis of aromatic primary amines, reagent compositions for effecting the process, and transition metal complexes useful in the process, are provided.
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PROCESS FOR THE SYNTHESIS OF ARYLAMINES FROM THE REACTION OF AN AROMATICCOMPOUNDS WITH AMMONIA OR A METAL AMIDE (Fri, 28 Sep 2007)
A catalytic process for the synthesis of aromatic primary amines, reagent compositions for effecting the process, and transition metal complexes useful in the process, are provided.</p>
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Modified triple-helix forming oligonucleotides for targeted mutagenesis (Fri, 21 Sep 2007)
<p id="p-0001" num="0000">High affinity, chemically modified triplex-forming oligonucleotides (TFOs) and methods for use thereof are disclosed. TFOs are defined as triplex-forming oligonucleotides which bind as third strands to duplex DNA in a sequence specific manner. Triplex-forming oligonucleotides may be comprised of any possible combination of nucleotides and modified nucleotides. Modified nucleotides may contain chemical modifications of the heterocyclic base, sugar moiety or phosphate moiety. A high affinity oligonucleotide (K<sub>d</sub>≦2×10<sup>−8</sup>) which forms a triple strand with a specific DNA segment of a target gene DNA is generated. It is preferable that the K<sub>d </sub>for the high affinity oligonucleotide is below 2×10<sup>−10</sup>. The nucleotide binds or hybridizes to a target sequence within a target gene or target region of a chromosome, forming a triplex region. The binding of the oligonucleotide to the target region stimulates mutations within or adjacent to the target region using cellular DNA synthesis, recombination, and repair mechanisms. The mutation generated activates, inactivates, or alters the activity and function of the target gene.</p>
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CYTISINE AND ACETYLCHOLINE ANALOGS AND METHODS OF TREATING MOOD DISORDERS (Sat, 08 Sep 2007)
The present invention relates to compounds which are derivatives of cytisine or acetylcholine which exhibit activity as agonists, partial agonists or antagonists of nicotinic acetylcholine receptors and may be used in modulating these receptors and in treating mood disorders in patients in need of therapy.
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Crystalline xpt guanine riboswitch from Bacillus subtilis and structure-based compound identification employing said riboswitch (Thu, 06 Sep 2007)
Riboswitches and modified versions of riboswitches can be employed as designer genetic switches that are controlled by specific effector compounds. Such effector compounds that activate a riboswitch are referred to herein as trigger molecules. The natural switches are targets for antibiotics and other small molecule therapies. In addition, the architecture of riboswitches allows actual pieces of the natural switches to be used to construct new non-immunogenic genetic control elements, for example the aptamer (molecular recognition) domain can be swapped with other non-natural aptamers (or otherwise modified) such that the new recognition domain causes genetic modulation with user-defined effector compounds. The changed switches become part of a therapy regimen-turning on, or off, or regulating protein synthesis. Newly constructed genetic regulation networks can be applied in such areas as living biosensors, metabolic engineering of organisms, and in advanced forms of gene therapy treatments. Compounds can be used to stimulate, active, inhibit and/or inactivate riboswitches. Atomic structures of riboswitches can be used to design new compounds to stimulate, active, inhibit and/or inactivate riboswitches.
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MRI INVOLVING SUBJECT-SPECIFIC DIAMAGNETIC AND PARAMAGNETIC PASSIVE SHIMMING (Fri, 27 Jul 2007)
One aspect of the present disclosure relates to a method of determining location (s) at which at least one magnetic article is to be positioned during a magnetic resonance imaging procedure of at least one subject in order to perform subject-specific diamagnetic and paramagnetic passive shimming. A magnetic field Bo is applied to a region that includes the at least one subject and does not include the at least one magnetic article. First magnetic resonance information about the region in response to the applied magnetic field BO is received. The first magnetic resonance information relates at least in part to one or more magnetic field inhomogeneities in the region. Based at least in part on the first magnetic resonance information, at least one first location proximate the at least one subject at which at least one paramagnetic article and/or diamagnetic article is to be positioned is determined, so as to at least partially compensate for the one or more magnetic field inhomogeneities.
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Compounds and methods to increase anti-P-glycoprotein activity of baicalein by alkylation on the A ring (Fri, 13 Jul 2007)
<p id="p-0001" num="0000">The present invention is directed to analogs of baicalein according to formula (I): where R<sup>5 </sup>is H, (C<sub>1</sub>-C<sub>12</sub>)alkyl, (C<sub>2</sub>-C<sub>13</sub>)acyl, or an optionally substituted phenyl or benzyl group, an acyl group, a C<sub>1</sub>-C<sub>20 </sub>alkyl or ether group, a phosphate, diphosphate, triphosphate or phosphodiester group; R<sup>6 </sup>and R<sup>7 </sup>are each independently H, (C<sub>1</sub>-C<sub>12</sub>)alkyl, (C<sub>2</sub>-C<sub>13</sub>)acyl, or an optionally substituted phenyl or benzyl or together form a —OCR<sup>1</sup>R<sup>2</sup>O— group wherein each of R<sup>1 </sup>and R<sup>2 </sup>is independently H, a C<sub>1</sub>-C<sub>3 </sub>alkyl group or an optionally substituted phenyl or benzyl group; and R<sup>8 </sup>is H, OH, an O-acyl group, a C<sub>1</sub>,-C<sub>4 </sub>alkyl or alkoxy group, F, Cl, Br or I, or a pharmaceutically acceptable salt thereof, which exhibit anti-P-glycoprotein activity and methods of enhancing the bioavailability of active compounds, especially orally administered compounds, by inhibition of P-glycoprotein 170 (P-gp 170) and/or CYP450 enzyme, especially CYP450 3A4 enzyme. Pharmaceutical compositions based upon these novel derivatives according to the present invention are also described herein.</p>
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CATALYSTS FOR ARYL SULFIDE SYNTHESIS AND METHOD OF PRODUCING ARYL SULFIDES (Fri, 08 Jun 2007)
The present invention relates to the formation of aryl sulfides and aryl thiols from aryl halides and thiols, thiolates or thiolate equivalents. The present invention provides a catalyst for the coupling of aryl halides with alkyl or aryl thiols or a hydrogen sulfide equivalent to form aryl alkyl, aryl silyl or diaryl sulfides. The reaction encompasses bromoarenes and other similar compounds containing leaving groups as well as nitrile, ester, keto, free hydroxyl, free amino, free carboxylic acid and other common functionalities. The invention can be used to prepare pharmaceutical compounds, especially including their intermediates, agricultural agents and aryl sulfide polymers.
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Terephthalamide peptidomimetic compounds and methods (Fri, 01 Jun 2007)
<p id="p-0001-en" num="0000">The present invention relates to compounds and pharmaceutical compositions based upon terephthalamide which are proteomimetic and to methods for inhibiting the interaction of an alpha-helical protein with another protein or binding site. Methods for treating diseases or conditions which are modulated through interactions between alpha helical proteins and their binding sites are other aspects of the invention. Methods of inhibiting the binding of proteins to their binding sites are other aspects of the present invention. </p>
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COMPOUNDS AND METHODS FOR THE TREATMENT OF VIRUSES AND CANCER (Fri, 06 Apr 2007)
The present invention relates to compounds according to the formula I: Where Ra is H or an optionally OH-substituted C1-C3 alkyl; R1 is OR1, an optionally substituted C4-12 carbocyclic group which may be saturated or unsaturated (including aromatic) or an optionally substituted heterocyclic group; R1 is an optionally substituted C1-C14 hydrocarbyl group or an optionally substituted heterocyclic group;; R2 , R3 and R4 are each independently H, an optionally substituted C1-C4 alkyl group (preferably CH3, CH2CH3 or CF3), halogen (preferably F, Cl, Br), OR, CN, NO2, a C1-C6 thioether, a C1-C6 thioester group, an optionally substituted CO2R group, an optionally substituted COR group or an optionally substituted OCOR group (preferably R4 is H); R is H or an optionally substituted C1-C6 alkyl group; RHET is an optionally substituted heterocyclic group; and pharmaceutically acceptable salts, solvates or polymorphs thereof.
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COMPOUNDS AND METHODS FOR THE TREATMENT OF MALARIA AND CANCER (Fri, 29 Sep 2006)
Formula (I): Where R1 is an optionally substituted C3-C12 hydrocarbyl group (preferably a cyclic alkyl group), an optionally substituted heterocyclic group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group; R is a C(O)yR' group (preferably forming an optionally substituted C2-C5 acyl group), or a S(O)xR' group, where y is 0 or 1 and x is 0, 1 or 2 and R' is H or an optionally substituted C1-C12 alkyl group, or R' is an optionally substituted C5-C12 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group; R5, R6, R7, R8, R9 and R10 are each independently selected from H, an optionally substituted C1-C12 hydrocarbyl group, including a C5-C12 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aromatic group or an optionally substituted heteroaromatic group, or R5 and R6, R7 and R8 or R9 and R10 together form a keto (C=O) group; RN is H, an optionally substituted C1-C12 hydrocarbyl group, an optionally substituted heterocyclic group, an optionally substituted aromatic group, or an optionally substituted heteroaromatic group; A is Formula (II): a Formula (III): group, or a Formula (IV) or Formula (V) group, where Z is N, O or S; Ra is H, a C1-C12 optionally substituted hydrocarbyl group or an optionally substituted aromatic group; n is from 0 to 3; and pharmaceutically acceptable salts thereof. Compounds according to the invention are useful in one or more aspects to inhibit farnesyl transferase, or to treat malaria, neoplasia, a hyperproliferative disease state or arthritis, including rheumaroid arthritis or osteoarthritis.
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Enantioselective amination and etherification (Fri, 08 Sep 2006)
<p id="p-0001-en" num="0000">The present invention is directed to a catalyst composition, comprising: (1) a catalyst precursor having the general structure MSX<sub>n </sub>wherein M is a transition metal selected from the group consisting of iridium, molybdenum, and tungsten; S is a coordinating ligand; X is a counterion; and n is an integer from 0 to 5; and (2) a phosphoramidite ligand having the structure wherein O—C<sub>n</sub>—O is an aliphatic or aromatic diolate and wherein R<sub>1</sub>, R<sub>2</sub>, R<sub>3 </sub>and R<sub>4 </sub>are selected from the group consisting of substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted aliphatic groups, and combinations thereof, with the proviso that at least one of R<sub>1</sub>, R<sub>2</sub>, R<sub>3</sub>, or R<sub>4 </sub>must be a substituted or unsubstituted aryl or heteroaryl group. The present invention is also directed to activated catalysts made from the above catalyst composition, as well as methods of allylic amination and etherification using the above catalysts.</p>
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BETA-PEPTIDES (Fri, 28 Jul 2006)
β-peptide regions of polypeptides can serve as structural mimics of α-helices in wild type proteins. Because α-helices of one protein often bind to a target protein in a biological pathway, a polypeptide that contains a helical β-peptide region can be used to disrupt this type of protein-protein binding. As a result, polypeptides that contain a helical ß-peptide region can be used to treat conditions involving this type of protein­ protein binding, such as viral infections and cell proliferation.
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BETA-PEPTIDES (Fri, 28 Jul 2006)
.beta.-peptide regions of polypeptides can serve as structural mimics of .alpha.-helices in wild type proteins. Because .alpha.-helices of one protein often bind to a target protein in a biological pathway, a polypeptide that contains a helical .beta.-peptide region can be used to disrupt this type of protein-protein binding. As a result, polypeptides that contain a helical ~- peptide region can be used to treat conditions involving this type of protein~ protein binding, such as viral infections and cell proliferation. </p>
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ANTI-VIRAL NUCLEOSIDE ANALOGS AND METHODS FOR TREATING VIRAL INFECTIONS,ESPECIALLY HIV INFECTIONS (Thu, 29 Jun 2006)
</p> <p>compounds according to the genera] Formulae (I, Π,</p> <p>(I) (III) (IV) (V) ITJ, rV or V); wherein B is nucleoside base according <BR> <BR> to the structure Formula (VI); R is H, F, CI, Br, I, <br> Q-C. alkyl (preferably CH<sub>3</sub>),-C≡N, -C≡C-R„ Formula <br> jj (VTJ); X is H, Ci-G, alkyl (preferably, CH<sub>3)</sub>, F, CI,</p> <p>X Br or 1 ; Z is 0 or CH<sub>2</sub>, with the proviso that Z is CH<sub>2</sub> iV c6 xx. and not O when the compound is according to general <br> formula Π, R<sup>3</sup> is -C≡C-H and R<sup>J</sup> is H or a phosphate, <br> diphosphate, triphosphate or phosphotriester group; R<sup>1</sup> <br> (VI) <br> is H, an acyl group, a ^-C^ alkyl or an ether group; <br> R2 is H, an acyl group, a CI-C20 alkyl or ether group, a <BR> <BR> phosphate, diphosphate, triphosphate, phosphodiester <br> group or a Formula;(VIII) or Formula (IX) group; Nu <br> is a radical of a biologically active antiviral compound <br> (VII) such that an amino group or hydroxy] group from <br> said biologically active antiviral compound forms a</p> <p>0 phosphate, phosphoramidate, carbonate or urethane <br> (VIII) group with the adjacent moiety; R8 is H, or a C1-C20 O <sup>1</sup> — Γ _ (I ) <br> :~ °Τ Γ ~ alky] or ether group, preferably a C 1-C12 alkyl group; <br> k is 0-12, preferably, 0-2; R3 is selected from a C1 -C4 <br> alkyl (preferably, CH3), -(CH2)n-C≡C-R<sub>a</sub>, Formula <br> (XI) (X) or Formula (XI); R3a and R3b are independently <br> (X) <br> IT) selected from H, F, CI , Br or I ; R4 and R5 are o independently selected from H, F, Cl, Br, I, OH, o C1 -C4 alkyl (preferably, CH3),-(CH2)n-C=C-Ra! <br> (XM) (XIII) <br> -|CH|)„-C=C-R,. Formula(XII) or FormuIa(XTTI) with the proviso that <br> R4 and R5 are not both H; Ra is H, F, Cl, Br, I, or</p> <p>-CI -C4 alkyl, preferably H or CH3; Y is H, F, CI , Br, 1 or -C l-C4 alky! preferably H or CH3; and n is 0, t, 2,3, 4 or 5, preferably 2 and their anomers harmaceuticall acce table salts, solvates, or ol mor hs thereof.
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STRUCTURE-BASED COMPOUND DESIGN INVOLVING RIBOSWITCHES (Sat, 27 May 2006)
Riboswitches and modified versions of riboswitches can be employed as designer genetic switches that are controlled by specific effector compounds. Such effector compounds that activate a riboswitch are referred to herein as trigger molecules. The natural switches are targets for antibiotics and other small molecule therapies. In addition, the architecture of riboswitches allows actual pieces of the natural switches to be used to construct new non-immunogenic genetic control elements, for example the aptamer (molecular recognition) domain can be swapped with other non-natural aptamers (or otherwise modified) such that the new recognition domain causes genetic modulation with user-defined effector compounds. The changed switches become part of a therapy regimen-turning on, or off, or regulating protein synthesis. Newly constructed genetic regulation networks can be applied in such areas as living biosensors, metabolic engineering of organisms, and in advanced forms of gene therapy treatments. Compounds can be used to stimulate, active, inhibit and/or inactivate riboswitches. Atomic structures of riboswitches can be used to design new compounds to stimulate, active, inhibit and/or inactivate riboswitches.
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STRUCTURE-BASED COMPOUND DESIGN INVOLVING RIBOSWITCHES (Sat, 27 May 2006)
Riboswitches and modified versions of riboswitches can be employed as designer genetic switches that are controlled by specific effector compounds. Such effector compounds that activate a riboswitch are referred to herein as trigger molecules. The natural switches are targets for antibiotics and other small molecule therapies. In addition, the architecture of riboswitches allows actual pieces of the natural switches to be used to construct new non- immunogenic genetic control elements, for example the aptamer (molecular recognition) domain can be swapped with other non-natural aptamers (or otherwise modified) such that the new recognition domain causes genetic modulation with user-defined effector compounds. The changed switches become part of a therapy regimen-turning on, or off, or regulating protein synthesis. Newly constructed genetic regulation networks can be applied in such areas as living biosensors, metabolic engineering of organisms, and in advanced forms of gene therapy treatments. Compounds can be used to stimulate, active, inhibit and/or inactivate riboswitches. Atomic structures of riboswitches can be used to design new compounds to stimulate, active, inhibit and/or inactivate riboswitches. </p>
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Glycosylated indolocarbazole synthesis (Wed, 03 May 2006)
<p id="p-0001-en" num="0000">Indolocarbazoles are furanosylated (e.g., <b>7</b>) with acetals (e.g., <b>8</b>) or their open chain congeners (e.g., <b>9</b>) under conditions known to promote acetal exchange or formation, such as protic or Lewis acids. Furanosylated indolocarbazoles (e.g., <b>10</b>) are also prepared via ring contraction of pyranosylated indolocarbazoles (e.g., <b>11</b>) under conditions know to effect oxidation and benzylic acid type rearrangements, and pyranosylated indolocarbazoles (e.g., <b>11</b>) are prepared via ring expansion of the furanosylated congeners (e.g., <b>10</b>) <chemistry id="chem-us-00001-en" num="00001"><img id="emi-c00001-en" he="240.62mm" wi="75.52mm" file="US07038043-20060502-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/></chemistry><chemistry id="chem-us-00002-en" num="00002"><img id="emi-c00002-en" he="109.14mm" wi="66.38mm" file="US07038043-20060502-C00002.TIF" alt="embedded image" img-content="chem" img-format="tif"/></chemistry></p>
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Protein binding miniature proteins (Fri, 30 Dec 2005)
<p id="p-0001-en" num="0000">The present invention provides a protein scaffold, such as an avian pancreatic polypeptide, that can be modified by substitution of two or more amino acid residues that are exposed on the alpha helix domain of the polypeptide when the polypeptide is in a tertiary form.</p>
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β-peptides (Fri, 16 Dec 2005)
<p id="p-0001" num="0000">β-peptide regions of polypeptides can serve as structural mimics of α-helices in wild type proteins. Because α-helices of one protein often bind to a target protein in a biological pathway, a polypeptide that contains a helical β-peptide region can be used to disrupt this type of protein-protein binding. As a result, polypeptides that contain a helical β-peptide region can be used to treat conditions involving this type of protein-protein binding, such as viral infections and cell proliferation.</p>
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Ribosome structure and protein synthesis inhibitors (Fri, 09 Dec 2005)
<p id="p-0001-en" num="0000">The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism.</p>
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CUL4 E3 LIGASE MEDIATORS AS REGULATORS OF P53 (Fri, 02 Dec 2005)
The invention relates to assays for identifying modulators of p53­ubiquitination by CUL4 E3 ligase complexes. This assays allows detection of agents and compounds that affect p53 ubiquitination and thus, cell cycle regulation and cell survival in cells. In some assays, an increase in ubiquitination, in comparison to a test sample lacking a test compound, indicates a stimulation of p53 ubiquitination activity, whereas a reduction in p53 ubiquitination indicates an inhibitor of activity. The assays provided may be suited, for example, for high-throughput screening of agents. The invention further relates to methods of modulating p53 activity in a cell, such as a cell of a mammal, by administering agents which decrease expression or activity of a member of a CUL4 E3 ligase complex, or which block the binding of p53 to a CUL4 E3 ligase complex.
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Antiviral agents and methods of treating viral infections (Fri, 25 Nov 2005)
<p id="p-0001-en" num="0000">The present invention relates to methods of treating viral or fungal infections using 3-aminopyridine-2-carboxyaldehyde thiosemicarbazone (3-AP) and 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone (3-AMP) and its prodrug forms and to pharmaceutical compositions comprising these compounds. </p>
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Compounds and methods for the treatment of cancer (Fri, 25 Nov 2005)
<p id="p-0001-en" num="0000">(−)-(2S,4S)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)cytosine (also referred to as (−)-OddC) or its derivative and its use to treat cancer in animals, including humans.</p>
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ENANTIOSELECTIVE PHOSPHORAMIDITE COMPOUNDS AND CATALYSTS (Fri, 25 Nov 2005)
This invention relates to phosphoramidite compounds and catalyst complexes which can be used to provide enantioselective reactions including hydroamination reactions, etherification reactions and conjugate addition reactions and allylic substitution reactions, among others. In a first aspect, the present invention is directed to phosphoramidite and related compounds according to general structure (I), where Z is absent or is a group containing O, N or S, preferably O; R1 and R2 are independently an optionally substituted C1-12 alkyl group, an optionally substituted (CH2)n-aromatic group or (CH2)n-heteroaromatic group, or are linked together to form an optionally substituted aliphatic or (CH2)n-aromatic dianion of a diol, diamine, dithiol, aminoalcohol, aminohiolate or a alcoholthiol group; R3’ and R3 are each independently H, an optionally substituted C1-C12 alkyl group or an optionally substituted (CH2)n-aromatic group with the proviso that R3’ and R3 are not both H, or together R3’ and R3 form an optionally substituted C5-C15 saturated or unsaturated carbocyclic ring; R4 is H, an optionally substituted C1-C12 alkyl group or an optionally substituted (CH2)n-aromatic group; R5 is absent, H, an optionally substituted C1-C12 alkyl group or an optionally substituted (CH2)n-aromatic or (CH2)n-heteroaromatic group; Ra and Ra’ are each independently H or a C1-C3 alkyl group, or Ra and Ra’ together with the carbon to which they are attached form a optionally substituted C5-C15 saturated or unsaturated carbocyclic or heterocyclic ring, or an aromatic or heteroaromatic ring; R6 and R7 are each independently H, an optionally substituted C1-C12 alkyl group or an optionally substituted (CH2)n-aromatic group, with the proviso that R5, R6 and R7 cannot simultaneously be H, and when Ra and Ra’, together with the carbon to which they are attached, form a carbocyclic ring, heterocyclic ring or an aromatic or heteroaromatic ring, R5 is absent or is preferably H; R6 and R7 are preferably H or CH3; and each n is independently 0, 1, 2, 3, 4, 5 or 6 and wherein at least one of the carbon atoms attached to the nitrogen of the phosphoramidite group is a chiral center.
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ENANTIOSELECTIVE PHOSPHORAMIDITE COMPOUNDS AND CATALYSTS (Fri, 25 Nov 2005)
This invention relates to phosphoramidite compounds and catalyst complexes which can be used to provide enantioselective reactions including hydroamination reactions, etherification reactions and conjugate addition reactions and allylic substitution reactions, among others. In a first aspect, the present invention is directed to phosphoramidite and related compounds according to general structure (I), where Z is absent or is a group containing O, N or S, preferably O; R1 and R2 are independently an optionally substituted C1-12 alkyl group, an optionally substituted (CH2)n-aromatic group or (CH2)n- heteroaromatic group, or are linked together to form an optionally substituted aliphatic or (CH2)n-aromatic dianion of a diol, diamine, dithiol, aminoalcohol, aminohiolate or a alcoholthiol group; R3~ and R3 are each independently H, an optionally substituted C1-C12 alkyl group or an optionally substituted (CH2)n-aromatic group with the proviso that R3~ and R3 are not both H, or together R3~ and R3 form an optionally substituted C5-C15 saturated or unsaturated carbocyclic ring; R4 is H, an optionally substituted C1-C12 alkyl group or an optionally substituted (CH2)n-aromatic group; R5 is absent, H, an optionally substituted C1-C12 alkyl group or an optionally substituted (CH2)n-aromatic or (CH2)n-heteroaromatic group; Ra and Ra~ are each independently H or a C1-C3 alkyl group, or Ra and Ra~ together with the carbon to which they are attached form a optionally substituted C5-C15 saturated or unsaturated carbocyclic or heterocyclic ring, or an aromatic or heteroaromatic ring; R6 and R7 are each independently H, an optionally substituted C1-C12 alkyl group or an optionally substituted (CH2)n-aromatic group, with the proviso that R5, R6 and R7 cannot simultaneously be H, and when Ra and Ra~, together with the carbon to which they are attached, form a carbocyclic ring, heterocyclic ring or an aromatic or heteroaromatic ring, R5 is absent or is preferably H; R6 and R7 are preferably H or CH3; and each n is independently 0, 1, 2, 3, 4, 5 or 6 and wherein at least one of the carbon atoms attached to the nitrogen of the phosphoramidite group is a chiral center. </p>
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NOVEL ANTIVIRAL HELIOXANTHIN ANALOGS (Fri, 18 Nov 2005)
The present invention relates to novel antiviral helioxanthin analogs. These compounds may particularly be used alone or in combination with other drugs for the treatment of the following: hepadnaviruses, flaviviruses, herpesviruses and human immunodeficiency virus. In addition, compounds according to the present invention can be used to prevent or reduce the likelihood of the occurrence of tumors secondary to virus infection as well as other infections or disease states that are secondary to the virus infection.
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Novel nucleosides and related processes, pharmaceutical compositions and methods (Fri, 28 Oct 2005)
<p id="p-0001-en" num="0000">The invention provides novel nucleosides and related processes, pharmaceutical compositions, and methods. The novel nucleosides are useful in a wide variety of antiviral, antineoplastic, and antibacterial applications. Preferred embodiments of the instant invention include novel 2 halogen-substituted, 3 halogen-substituted, and 2′,3′dihalogen-substituted analogues of 3-deazaadenosine, and novel 3 halogen-substituted analogues of 3-deazaguanosine. Compounds of the instant invention, including 4-Amino-6-fluoro-1-(β-D-ribofuranosyl)imidazo[4,5-c]pyridine and 6-Amino-7-bromo-1,5-dihydro-1-β-<smallcaps>D</smallcaps>-ribofuranosylimidazo[4,5-c]pyridin-4-one, have exhibited potent antiviral and anticancer activity in vitro. The compounds are also useful in the concomitant treatment of bacterial infections associated with viral infections such as AIDS. </p>
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Ribosome structure and protein synthesis inhibitors (Fri, 21 Oct 2005)
<p id="p-0001-en" num="0000">The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism. </p>
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Proteomimetic compounds and methods (Fri, 30 Sep 2005)
<p id="p-0001-en" num="0000">The present invention relates to compounds and pharmaceutical compositions which are proteonaimetic and to methods for inhibiting the interaction of an alpha-helical protein with another protein or binding site. Methods for treating diseases or conditions which are modulated through interactions between alpha helical proteins and their binding sites are other aspects of the invention. In particular, the invention relates to treatment of viral infections using terphenyl derivatives.</p>
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TEREPHTHALAMIDE PEPTIDOMIMETIC COMPOUNDS AND METHODS (Fri, 02 Sep 2005)
The present invention relates to compounds and pharmaceutical compositions based upon terephthalamide which are proteomimetic and to methods for inhibiting the interaction of an alpha-helical protein with another protein or binding site. Methods for treating diseases or conditions which are modulated through interactions between alpha helical proteins and their binding sites are other aspects of the invention. Methods of inhibiting the binding of proteins to their binding sites are other aspects of the present invention.
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TEREPHTHALAMIDE PEPTIDOMIMETIC COMPOUNDS AND METHODS (Fri, 02 Sep 2005)
The present invention relates to compounds and pharmaceutical compositions based upon terephthalamide which are proteomimetic and to methods for inhibiting the interaction of an alpha-helical protein with another protein or binding site. Methods for treating diseases or conditions which are modulated through interactions between alpha helical proteins and their binding sites are other aspects of the invention. Methods of inhibiting the binding of proteins to their binding sites are other aspects of the present invention. </p>
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RUTHENIUM-CATALYZED HYDROAMINATION OF OLEFINS (Fri, 26 Aug 2005)
Applicants have unexpectedly discovered that catalysts made from a ruthenium catalyst precursor or preformed ruthenium catalysts as otherwise described in the present specification are capable of effecting the addition of a N-H bond across an olefin C=C (olefinic) bond of a substrate with a high degree of regioselectivity and enantioselectivity in high yield. These addition reactions proceed in an anti-Markovnikov or Markovnikov fashion depending upon the catalyst precursor used to generate the ruthenium catalyst which actually participates in the addition reaction. The present invention relates to methods of adding N-H bonds across an olefinic bond in a substrate, using a ruthenium catalyst precursor or catalyst I comprising a compound according to the general structure I: Formula (I) where Ru is a ruthenium atom; L1 represents one or more coordinated ancillary ligands, which may be all the same ligand or which may be a combination of different ligands, each of which may be neutral or formally charged, and each of which may be monodentate and coordinated to ruthenium through a single atom or which may be linked or chelated and bound through more than one atom; L2 represents one or more formally charged ligands which are the same or different and which are optionally susceptible to removal with a strong acid; and x is 0-6, preferably 1, y is 0-6, preferably 2 and n is 1-4, preferably 1.
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COMPOUNDS AND METHODS TO INCREASE ANTI-P-GLYCOPROTEIN ACTIVITY OF BAICALEIN BY ALKYLATION ON THE A RING (Fri, 19 Aug 2005)
The present invention is directed to analogs of baicalein according to formula (I): where R5 is H, (CI-C12)alkyl, (C2-C13)acyl, or an optionally substituted phenyl or benzyl group, an acyl group, a C1-C20 alkyl or ether group, a phosphate, diphosphate, triphosphate or phosphodiester group; R6 and R7 are each independently H, (C1-C12)alkyl, (C2-C13)acyl, or an optionally substituted phenyl or benzyl or together form a -OCR1R20- group wherein each of R1 and R2 is independently H, a C1-C3 alkyl group or an optionally substituted phenyl or benzyl group; and R8 is H, OH, an O-acyl group, a C1,-C4 alkyl or alkoxy group, F, Cl, Br or I, or a pharmaceutically acceptable salt thereof, which exhibit anti-P-glycoprotein activity and methods of enhancing the bioavailability of active compounds, especially orally administered compounds, by inhibition of P-glycoprotein 170 (P-gp 170) and/or CYP450 enzyme, especially CYP450 3A4 enzyme. Pharmaceutical compositions based upon these novel derivatives according to the present invention are also described herein.
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PROTEIN BINDING MINIATURE PROTEINS (Fri, 20 May 2005)
The present invention provides a protein scaffold, such as an avian pancreatic polypeptide, that can be modified by substitution of two or more amino acid residues that are exposed on the alpha helix domain of the polypeptide when the polypeptide is in a tertiary form.
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PROTEIN BINDING MINIATURE PROTEINS (Fri, 20 May 2005)
The present invention provides a protein scaffold, such as an avian pancreatic polypeptide, that can be modified by substitution of two or more amino acid residues that are exposed on the alpha helix domain of the polypeptide when the polypeptide is in a tertiary form. </p>
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Riboswitches, methods for their use, and compositions for use with riboswitches (Fri, 11 Mar 2005)
<p id="p-0001-en" num="0000">It has been discovered that certain natural mRNAs serve as metabolite-sensitive genetic switches wherein the RNA directly binds a small organic molecule. This binding process changes the conformation of the mRNA, which causes a change in gene expression by a variety of different mechanisms. Modified versions of these natural “riboswitches” (created by using various nucleic acid engineering strategies) can be employed as designer genetic switches that are controlled by specific effector compounds. Such effector compounds that activate a riboswitch are referred to herein as trigger molecules. The natural switches are targets for antibiotics and other small molecule therapies. In addition, the architecture of riboswitches allows actual pieces of the natural switches to be used to construct new non-immunogenic genetic control elements, for example the aptamer (molecular recognition) domain can be swapped with other non-natural aptamers (or otherwise modified) such that the new recognition domain causes genetic modulation with user-defined effector compounds. The changed switches become part of a therapy regimen—turning on, or off, or regulating protein synthesis. Newly constructed genetic regulation networks can be applied in such areas as living biosensors, metabolic engineering of organisms, and in advanced forms of gene therapy treatments.</p>
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MinK-related genes, formation of potassium channels and association with cardiac arrhythmia (Wed, 09 Mar 2005)
<p id="p-00001-en" num="00001">The present invention is directed to genes and gene products related to Min-K which form ion channels and to a process for diagnosis of ion channel disorders, including long QT syndrome (LQT). For example, KCNE2 forms I<sub>Kr </sub>potassium channels and is associated with LQT. LQT is diagnosed in accordance with the present invention by analyzing the DNA sequence of KCNE2 of an individual to be tested and comparing the respective DNA sequence to the known DNA sequence of a normal KCNE2 gene. Alternatively, these MinK-related genes of an individual to be tested can be screened for mutations which cause ion channel disorders, including LQT. Prediction of ion channel disorders, including LQT, will enable practitioners to prevent the disorders using existing medical therapy. This invention is further directed to the discovery that the HERG and KCNE2 (also known as MiRP1) proteins coassemble to form a cardiac I<sub>Kr </sub>potassium channel.</p>
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AGENTS AND METHODS FOR TREATMENT OF DISEASE BY OLIGOSACCHARIDE TARGETING AGENTS (Fri, 25 Feb 2005)
A method for targeting, treating, or diagnosing malignant mammalian tumor cells, comprising administering an effective amount of a β1,6-branched oligosaccharide specific binding agent to the mammal. As a treatment, the binding agent may be intrinsically cytotoxic, initiate an endogenous cytotoxic cascade, or play a role in a cytotoxic cascade involving exogenous factors. A preferred binding agent is Bordetella pertussis, which is both specific for the β1,6-branched oligosaccharide and well tolerated. Genetically engineered organisms may also be employed. Pharmaceutical compositions may also serve as binding agents.
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AGENTS AND METHODS FOR TREATMENT OF DISEASE BY OLIGOSACCHARIDE TARGETING AGENTS (Fri, 25 Feb 2005)
A method for targeting, treating, or diagnosing malignant mammalian tumor cells, comprising administering an effective amount of a .beta.1,6-branched oligosaccharide specific binding agent to the mammal. As a treatment, the binding agent may be intrinsically cytotoxic, initiate an endogenous cytotoxic cascade, or play a role in a cytotoxic cascade involving exogenous factors. A preferred binding agent is Bordetella pertussis, which is both specific for the .beta.1,6-branched oligosaccharide and well tolerated. Genetically engineered organisms may also be employed. Pharmaceutical compositions may also serve as binding agents. </p>
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Method of identifying molecules that bind to the large ribosomal subunit (Fri, 18 Feb 2005)
<p id="p-0001-en" num="0000">The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism.</p>
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ANTI-VIRAL NUCLEOSIDE ANALOGS AND METHODS FOR TREATING VIRAL INFECTIONS, ESPECIALLY HIV INFECTIONS (Fri, 11 Feb 2005)
The present invention relates to novel compounds according to the general Formulae (I, II, III, IV or V); wherein B is nucleoside base according to the structure Formula (VI); R is H, F, Cl, Br, I, C1-C4 alkyl (preferably CH3), -C≡N, -C≡C-Ra, Formula (VII); X is H, C1-C4 alkyl (preferably, CH3), F, Cl, Br or 1; Z is 0 or CH2, with the proviso that Z is CH2 and not O when the compound is according to general formula II, R3 is -C≡C-H and R2 is H or a phosphate, diphosphate, triphosphate or phosphotriester group; R1 is H, an acyl group, a C1-C20 alkyl or an ether group; R2 is H, an acyl group, a CI-C20 alkyl or ether group, a phosphate, diphosphate, triphosphate, phosphodiester group or a Formula;(VIII) or Formula (IX) group; Nu is a radical of a biologically active antiviral compound such that an amino group or hydroxyl group from said biologically active antiviral compound forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety; R8 is H, or a C1-C20 alkyl or ether group, preferably a C1-C12 alkyl group; k is 0-12, preferably, 0-2; R3 is selected from a C1-C4 alkyl (preferably, CH3), -(CH2)n-C≡C-Ra, Formula (X) or Formula (XI); R3a and R3b are independently selected from H, F, C1, Br or I ; R4 and R5 are independently selected from H, F, C1, Br, I, OH, C1-C4 alkyl (preferably, CH3),-(CH2)n-C≡C-Ra, Formula(XII) or Formula(XIII) with the proviso that R4 and R5 are not both H; Ra is H, F, Cl, Br, I, or -C1-C4 alkyl, preferably H or CH3; Y is H, F, C1, Br, I or -C1-C4 alkyl, preferably H or CH3; and n is 0, 1, 2,3, 4 or 5, preferably 0, 1 or 2; and their anomers, pharmaceutically acceptable salts, solvates, or polymorphs thereof.
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ANTI-VIRAL NUCLEOSIDE ANALOGS AND METHODS FOR TREATING VIRAL INFECTIONS, ESPECIALLY HIV INFECTIONS (Fri, 11 Feb 2005)
The present invention relates to novel compounds according to the general Formulae (I, II, III, IV or V); wherein B is nucleoside base according to the structure Formula (VI); R is H, F, Cl, Br, I, C1-C4 alkyl (preferably CH3),- C.ident.N, -C.ident.C-Ra, Formula (VII); X is H, C1-C4 alkyl (preferably, CH3), F, Cl, Br or 1; Z is 0 or CH2, with the proviso that Z is CH2 and not O when the compound is according to general formula II, R3 is -C.ident.C-H and R2 is H or a phosphate, diphosphate, triphosphate or phosphotriester group; R1 is H, an acyl group, a C1-C20 alkyl or an ether group; R2 is H, an acyl group, a CI-C20 alkyl or ether group, a phosphate, diphosphate, triphosphate, phosphodiester group or a Formula;(VIII) or Formula (IX) group; Nu is a radical of a biologically active antiviral compound such that an amino group or hydroxyl group from said biologically active antiviral compound forms a phosphate, phosphoramidate, carbonate or urethane group with the adjacent moiety; R8 is H, or a C1-C20 alkyl or ether group, preferably a C1-C12 alkyl group; k is 0-12, preferably, 0-2; R3 is selected from a C1-C4 alkyl (preferably, CH3), -(CH2)n-C.ident.C-Ra, Formula (X) or Formula (XI); R3a and R3b are independently selected from H, F, C1, Br or I ; R4 and R5 are independently selected from H, F, C1, Br, I, OH, C1-C4 alkyl (preferably, CH3),-(CH2)n-C.ident.C-Ra, Formula(XII) or Formula(XIII) with the proviso that R4 and R5 are not both H; Ra is H, F, Cl, Br, I, or -C1-C4 alkyl, preferably H or CH3; Y is H, F, C1, Br, I or -C1-C4 alkyl, preferably H or CH3; and n is 0, 1, 2,3, 4 or 5, preferably 0, 1 or 2; and their anomers, pharmaceutically acceptable salts, solvates, or polymorphs thereof. </p>
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Methods of detecting interactions between proteins, peptides or libraries thereof using fusion proteins (Fri, 26 Nov 2004)
<p id="p-0001-en" num="0000">The present invention provides a method for identifying a polypeptide that interacts with a known protein, which method uses fusion proteins with GFP fragments.</p>
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15α-substituted estradiol carboxylic acid esters as locally active estrogens (Fri, 08 Oct 2004)
<p id="p-0001-en" num="0000">The present invention relates to analogs of estradiol, which, in their most preferred embodiment, act as locally active estrogens without significant systemic action. A series of 15α-estradiol ester compounds is presented which exhibit excellent biological activity for use in pharmaceutical compositions for the treatment of symptomology associated with menopause. The present invention is therefore directed to compounds according to the structure: <chemistry id="chem-us-00001-en" num="00001"><img id="emi-c00001-en" he="25.57mm" wi="42.93mm" file="US07015211-20060321-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/></chemistry> where X is <chemistry id="chem-us-00002-en" num="00002"><img id="emi-c00002-en" he="8.13mm" wi="12.62mm" file="US07015211-20060321-C00002.TIF" alt="embedded image" img-content="chem" img-format="tif"/></chemistry><ul id="ul0001-en" list-style="none"><li>R is H, a C<sub>1 </sub>to C<sub>5 </sub>alkyl group, optionally substituted with at least one halogen group, such as CH<sub>2</sub>CH<sub>2</sub>F, or other group (e.g., CH<sub>2</sub>CHF<sub>2</sub>, CH<sub>2</sub>CF<sub>3 </sub>or CF<sub>3 </sub>group); and</li><li>m is from 0–5, preferably from 0–2.</li></ul></p>
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MinK-related genes, formation of potassium channels and association with cardiac arrhythmia (Fri, 08 Oct 2004)
<p id="p-a-0001-en">The present invention is directed to genes and gene products related to Min-K which form ion channels and to a process for diagnosis of ion channel disorders, including long QT syndrome (LQT). For example, KCNE2 forms I<sub>Kr </sub>potassium channels and is associated with LQT. LQT is diagnosed in accordance with the present invention by analyzing the DNA sequence of KCNE2 of an individual to be tested and comparing the respective DNA sequence to the known DNA sequence of a normal KCNE2 gene. Alternatively, these MinK-related genes of an individual to be tested can be screened for mutations which cause ion channel disorders, including LQT. Prediction of ion channel disorders, including LQT, will enable practitioners to prevent the disorders using existing medical therapy. This invention is further directed to the discovery that the HERG and KCNE2 (also known as MiRP1) proteins coassemble to form a cardiac I<sub>Kr </sub>potassium channel. </p>
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15α-SUBSTITUTED ESTRADIOL CARBOXYLIC ACID ESTERS AS LOCALLY ACTIVE ESTROGENS (Fri, 08 Oct 2004)
The present invention relates to analogs of estradiol, which, in their most preferred embodiment, act as locally active estrogens without significant systemic action. A series of 15α-estradiol ester compounds is presented which exhibit excellent biological activity for use in pharmaceutical compositions for the treatment of symptomology associated with menopause. The present invention is therefore directed to compounds according to the structure: where X is (CH2)m , R is H, a C1 to C5 alkyl group, optionally substituted with at least one halogen group, such as CH2CH2F, or other group (e.g., CH2CHF2, CH2CF3 or CF3 group); and m is from 0-5, preferably from 0-2.
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RAG POLYPEPTIDES, NUCLEIC ACIDS, AND THEIR USE (Fri, 03 Sep 2004)
The present invention relates generally to regeneration associated genes (RAGs). More specifically, the invention relates to structure-based methods and compositions useful in designing, identifying, and producing molecules which act as functional modulators of RAGs and RAG polypeptides. The invention further relates to methods of detecting, preventing, and treating RAG-associated disorders.
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Anti-viral nucleoside analogs and methods for treating viral infections, especially HIV infections (Fri, 27 Aug 2004)
<p id="p-0001-en" num="0000">The present invention relates to compounds according to the general formula:</p> <p id="p-0002-en" num="0000"> <chemistry id="chem-us-00001-en" num="00001"> <img id="emi-c00001" he="18.63mm" wi="23.79mm" file="US07589078-20090915-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> wherein B is </p> <p id="p-0003-en" num="0000"> <chemistry id="chem-us-00002-en" num="00002"> <img id="emi-c00002" he="29.21mm" wi="21.34mm" file="US07589078-20090915-C00002.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> or </p> <p id="p-0004-en" num="0000"> <chemistry id="chem-us-00003-en" num="00003"> <img id="emi-c00003" he="29.72mm" wi="21.93mm" file="US07589078-20090915-C00003.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> and the remaining variables are defined in the specification, and compositions comprising the compounds. The compounds are useful as anti-viral agents in viral therapy. </p>
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Molecular scale electronic devices (Wed, 30 Jun 2004)
<p id="p-00001-en">Molecular scale electronic devices are disclosed. Such devices include at least two conductive contacts, and a conductive path bridging the contacts. The conductive path is able to be written into a perturbed state by a voltage pulse, which can be of high or low conductivity, relative to an initial state. The conductive path comprises organic molecules including at least one electron-withdrawing group. Room temperature negative differential resistance is exhibited by the devices.</p>
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Nucleosides and related processes, pharmaceutical compositions and methods (Fri, 18 Jun 2004)
<p id="p-0001-en" num="0000">The invention provides novel nucleosides and related processes, pharmaceutical compositions, and methods. The novel nucleosides are useful in a wide variety of antiviral, antineoplastic, and antibacterial applications. Preferred embodiments of the instant invention include novel 2 halogen-substituted, 3 halogen-substituted, and 2′,3′dihalogen-substituted analogues of 3-deazaadenosine, and novel 3 halogen-substituted analogues of 3-deazaguanosine. Compounds of the instant invention, including 4-Amino-6-fluoro-1-(β-D-ribofuranosyl)imidazo[4,5-c]pyridine and 6-Amino-7-bromo-1,5-dihydro-1-β-<smallcaps>D</smallcaps>-ribofuranosylimidazo[4,5-c]pyridin-4-one, have exhibited potent antiviral and anticancer activity in vitro. The compounds are also useful in the concomitant treatment of bacterial infections associated with viral infections such as AIDS.</p>
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RIBOSWITCHES, METHODS FOR THEIR USE, AND COMPOSITIONS FOR USE WITH RIBOSWITCHES. (Fri, 02 Apr 2004)
It has been discovered that certain natural mRNAs serve as metabolite-sensitive genetic switches wherein the RNA directly binds a small organic molecule. This binding process changes the conformation of the mRNA, which causes a change in gene expression by a variety of different mechanisms. Modified versions of these natural 'riboswitches' (created by using various nucleic acid engineering strategies) can be employed as designer genetic switches that are controlled by specific effector compounds. Such effector compounds that activate a riboswitch are referred to herein as trigger molecules. The natural switches are targets for antibiotics and other small molecule therapies. In addition, the architecture of riboswitches allows actual pieces of the natural switches to be used to construct new non­immunogenic genetic control elements, for example the aptamer (molecular recognition) domain can be swapped with other non-natural aptamers (or otherwise modified) such that the new recognition domain causes genetic modulation with user-defined effector compounds. The changed switches become part of a therapy regimen-turning on, or off, or regulating protein synthesis. Newly constructed genetic regulation networks can be applied in such areas as living biosensors, metabolic engineering of organisms, and in advanced forms of gene therapy treatments.
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RIBOSWITCHES, METHODS FOR THEIR USE, AND COMPOSITIONS FOR USE WITH RIBOSWITCHES. (Fri, 02 Apr 2004)
It has been discovered that certain natural mRNAs serve as metabolite- sensitive genetic switches wherein the RNA directly binds a small organic molecule. This binding process changes the conformation of the mRNA, which causes a change in gene expression by a variety of different mechanisms. Modified versions of these natural "riboswitches" (created by using various nucleic acid engineering strategies) can be employed as designer genetic switches that are controlled by specific effector compounds. Such effector compounds that activate a riboswitch are referred to herein as trigger molecules. The natural switches are targets for antibiotics and other small molecule therapies. In addition, the architecture of riboswitches allows actual pieces of the natural switches to be used to construct new non~immunogenic genetic control elements, for example the aptamer (molecular recognition) domain can be swapped with other non-natural aptamers (or otherwise modified) such that the new recognition domain causes genetic modulation with user-defined effector compounds. The changed switches become part of a therapy regimen-turning on, or off, or regulating protein synthesis. Newly constructed genetic regulation networks can be applied in such areas as living biosensors, metabolic engineering of organisms, and in advanced forms of gene therapy treatments. </p>
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ENANTIOSELECTIVE AMINATION AND ETHERIFICATION (Fri, 26 Mar 2004)
The present invention is directed to a catalyst composition, comprising: (1) a catalyst precursor having the general structure MSXn wherein M is a transition metal selected from the group consisting of iridium, molybdenum, and tungsten; S is a coordinating ligand; X is a counterion; and n is an integer from 0 to 5; and (2) a phosphoramidite ligand having the structure wherein O-Cn-O is an aliphatic or aromatic diolate and wherein R1, R2, R3 and R4 are selected from the group consisting of substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted aliphatic groups, and combinations thereof, with the proviso that at least one of R1, R2, R3, or R4 must be a substituted or unsubstituted aryl or heteroaryl group. The present invention is also directed to activated catalysts made from the above catalyst composition, as well as methods of allylic amination and etherification using the above catalysts.
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Purification of oligomers (Fri, 05 Mar 2004)
<p id="p-0001-en" num="0000">Compositions and methods are disclosed which facilitate purification of oligomers and other compounds. The disclosed compositions are silyl compositions that can be directly coupled, or coupled through a linking group, to a compound of interest, preferably to an oligomer at the end of oligomer synthesis. The silicon atom includes between one and three sidechains that function as capture tags. In one embodiment, the capture tags are lipophilic, which allows a derivatized oligomer to be separated from failure sequences by reverse phase chromatography. In another embodiment, the capture tags are compounds with a known affinity for other compounds, which other compounds are preferably associated with a solid support to allow chromatographic separation. Examples include haptens, antibodies, and ligands. Biotin, which can bind to or interact with a streptavidin-bound solid support, is a preferred capture tag of this type.</p>
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Proteolysis targeting chimeric pharmaceutical (Fri, 27 Feb 2004)
<p id="p-0001-en" num="0000">The present invention is based on the discovery of a composition that provides targeted ubiquitination. Specifically the composition contains a ubiquitin pathway protein binding moiety which recognizes a ubiquitin pathway protein and a targeting moiety which recognizes a target protein. In addition, the present invention provides libraries of compositions, where each composition contains a ubiquitin pathway protein binding moiety and a member of a molecular library. The libraries of the present invention can be used to identify proteins involved in a predetermined function of cells.</p>
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Excitatory glycine receptors and methods (Fri, 20 Feb 2004)
<p id="p-0001-en" num="0000">The invention provides isolated N-methyl-D-aspartate type 3B (NR3B) polypeptides, functional fragments and peptides, encoding nucleic acid molecules and polynucleotides, and specific antibodies. Also provided are excitatory glycine receptors, containing either NR3B or NR3A polypeptides. Further provided are methods for detecting excitatory glycine receptor ligands, agonists and antagonists. The invention also provides related diagnostic and therapeutic methods.</p>
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SELECTIVE, CATALYSTIC, THERMAL FUNCTIONALIZATION OF SECONDARY OR AROMATIC C-H CYCLIC HYDROCARBON BONDS (Thu, 01 Jan 2004)
</p> <p>at a secondary or aromatic C-H cyclic hydrocarbon bond compris <br> thermally reacting a functionalizing reagent and the cyclic hydrocar <br> in the presence of a catalyst, said catalyst comprising: a) a sou <br> of rhodium; b) a source of a 3 to 8, cyclic or non-cyclic, aromatic <br> non-aromatic, neutral, cationic or anionic, substituted or unsubstitut <br> electron donor moiety which does not dissociate under thermal react <br> conditions; and c) a source of ligands capable of formally donating <br> electron pair to rhodium and which dissociate thermally; and wher <br> said functionalizing reagent comprises a source of boron.</p> <p> <BR> <br> Second Stage : HBpin as reagent
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Determination and uses of the atomic structures of ribosomes and ribosomal subunits and their ligand complexes (Fri, 19 Dec 2003)
<p id="p-0001-en" num="0000">The present invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as the crystals produced by such methods. The x-ray diffraction patterns of the crystals provided by the present invention are of sufficiently high resolution for determining the three-dimensional structure of ribosomes and ribosomal subunits, for identifying ligand binding sites on ribosomes and ribosomal subunits, and for molecular modeling of ligands which interact with ribosomes and ribosomal subunits. The present invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties. Thus, the methods of the present invention may be used to produce ligands which are designed to kill or inhibit any specific target organism(s).</p>
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5-(E)-Bromovinyl uracil analogues and related pyrimidine nucleosides as anti-viral agents and methods of use (Wed, 26 Nov 2003)
<p id="p-00001-en">The present invention relates to pyrimidine nucleoside compounds and their use to treat viral infections of Varicella Zoster virus and Epstein Barr Virus, as well as cancers which are complications of Epstein Barr virus.</p>
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Crystals of the large ribosomal subunit (Wed, 29 Oct 2003)
<p id="p-00001-en">The present invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as the crystals produced by such methods. The x-ray diffraction patterns of the crystals provided by the present invention are of sufficiently high resolution for determining the three-dimensional structure of ribosomes and ribosomal subunits, for identifying ligand binding sites on ribosomes and ribosomal subunits, and for molecular modeling of ligands which interact with ribosomes and ribosomal subunits. The present invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties. Thus, the methods of the present invention may be used to produce ligands which are designed to kill or inhibit any specific target organism(s).</p>
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Use of the crystal structure of Staphylococcus aureus isoleucyl-tRNA synthetase in antibiotic design (Wed, 08 Oct 2003)
<p id="p-00001-en">The present invention provides the atomic coordinates derived from high resolution x-ray diffraction of the cocrystal complex comprising mupirocin with its target enzyme, isoleucyl-tRNA synthetase from<i>Staphylococcus aureus</i>, and the cognate tRNA<sup>ile</sup>from<i>Escherichia coli</i>. The present invention further provides methods of using the atomic coordinates to identify and design new agents which modulate protein synthesis as well as the agents themselves.</p>
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Crystals of the large ribosomal subunit (Fri, 12 Sep 2003)
<p id="p-0001-en" num="0000">The present invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as the crystals produced by such methods. The x-ray diffraction patterns of the crystals provided by the present invention are of sufficiently high resolution for determining the three-dimensional structure of ribosomes and ribosomal subunits, for identifying ligand binding sites on ribosomes and ribosomal subunits, and for molecular modeling of ligands which interact with ribosomes and ribosomal subunits. The present invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties. Thus, the methods of the present invention may be used to produce ligands which are designed to kill or inhibit any specific target organism(s).</p>
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Modified avian pancreatic polypeptide miniature binding proteins (Fri, 05 Sep 2003)
<p id="p-0001-en" num="0000">The present invention provides a protein scaffold, such as an avian pancreatic polypeptide, that can be modified by substitution of two or more amino acid residues that are exposed on the alpha helix domain of the polypeptide when the polypeptide is in a tertiary form.</p>
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NOVEL TYLOINDICINES AND RELATED PROCESSES, PHARMACEUTICAL COMPOSITIONS AND METHODS (Fri, 29 Aug 2003)
The invention provides novel tyloindicines analogues and related processes, pharmaceutical compositions, and methods. The novel tyloindicines are useful in a wide variety of antiviral, antineoplastic, antibacterial, and anti-inflammatory applications. Preferred embodiments of the instant invention include the novel tyloindicine designated herein as compound IT-3 (NSC-716802). Compounds of the instant invention have exhibited potent antiviral and anticancer activity in vitro. The invention further provides novel methods of treating neoplastic, bacterial, viral, and anti-inflammatory disorders using tyloindicines including the novel tyloindicine analogues of the instant invention. The invention also provides novel syntheses of tyloindicines including the novel tyloindicines analogues of the instant invention.
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NOVEL TYLOINDICINES AND RELATED PROCESSES, PHARMACEUTICAL COMPOSITIONS AND METHODS (Fri, 29 Aug 2003)
The invention provides novel tyloindicines analogues and related processes, pharmaceutical compositions, and methods. The novel tyloindicines are useful in a wide variety of antiviral, antineoplastic, antibacterial, and anti- inflammatory applications. Preferred embodiments of the instant invention include the novel tyloindicine designated herein as compound IT-3 (NSC- 716802). Compounds of the instant invention have exhibited potent antiviral and anticancer activity in vitro. The invention further provides novel methods of treating neoplastic, bacterial, viral, and anti-inflammatory disorders using tyloindicines including the novel tyloindicine analogues of the instant invention. The invention also provides novel syntheses of tyloindicines including the novel tyloindicines analogues of the instant invention. </p>
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SELECTIVE,CATALYTIC, AND THERMALLY INDUCED FUNCTIONALIZATION OF PRIMARY C-H BONDS IN HYDROCARBONS (Thu, 28 Aug 2003)
</p> <p>a primary C-H hydrocarbon bond comprising thermally reacting a functionalizing reagent and the hydrocarbon in the presence of a catalyst, said catalyst comprising: a) a source of a transition metal; b) a source of a 3 to 8, cyclic or non-cyclic, aromatic or non-aromatic, neutral, cationic or anionic, substituted or unsubstituted, electron donor moiety which does not dissociate under thermal reaction conditions, wherein said moiety (i) lacks aromatic C-H bonds on the moiety directly bonded to the transition metal, or (ii) contains sterically hindered aromatic C-H bonds on the moiety directly bonded to the transition metal; and c) a source of ligands capable of formally donating an electron pair to the transition metal of a) and which dissociate thermally; and wherein said
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Modulators of ribosomal function and identification thereof (Fri, 15 Aug 2003)
<p id="p-0001-en" num="0000">The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism.</p>
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Methods for selectively modulating survivin apoptosis pathways (Fri, 01 Aug 2003)
<p id="p-0001-en" num="0000">The present invention, based on the discovery of a new biological phenomena, provides methods and compositions for use in identifying agents that modulate the phosphorylation of survivin, the interaction between survivin and p34<sup>cdc2</sup>-cyclin B1 kinase complex, and the interaction between survivin and caspase-9. Related methods and compositions can be used to modulate survivin regulated apoptosis.</p>
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PIPERAZINONE COMPOUNDS AS ANTI-TUMOR AND ANTI-CANCER AGENTS AND METHODS OF TREATMENT (Fri, 07 Mar 2003)
The present invention relates to piperazinone compounds, pharmaceutical compositions containing those compounds and methods of treating tumors and cancer, among other disease states and conditions in mammalian patients, especially including humans.
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PIPERAZINONE COMPOUNDS AS ANTI-TUMOR AND ANTI-CANCER AGENTS AND METHODS OF TREATMENT (Fri, 07 Mar 2003)
The present invention relates to piperazinone compounds, pharmaceutical compositions containing those compounds and methods of treating tumors and cancer, among other disease states and conditions in mammalian patients, especially including humans. The compounds according to the structure: (see formula I) or (see formula II). </p>
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BORINIC ACID PROTEASE INHIBITORS (Fri, 28 Feb 2003)
The invention provides compounds of formula I: wherein R?1-R4, A, A1¿, and X have any the values described in the specification, as well as pharmaceutical compositions comprising such compounds, and methods of inhibiting proteases with such compounds. The invention also provides synthetic intermediates and processes useful for preparing compounds of formula (I).
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EXCITATORY GLYCINE RECEPTORS AND METHODS (Fri, 28 Feb 2003)
The invention provides isolated N-methyl-D- aspartate type 3B (NR3B) polypeptides, functional fragments and peptides, encoding nucleic acid molecules and polynucleotides, and specific antibodies. Also provided are excitatory glycine receptors, containing either NR3B or NR3A polypeptides. Further provided are methods for detecting excitatory glycine receptor ligands, agonists and antagonists. The invention also provides related diagnostic and therapeutic methods.
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EXCITATORY GLYCINE RECEPTORS AND METHODS (Fri, 28 Feb 2003)
The invention provides isolated N-methyl-D- aspartate type 3B (NR3B) polypeptides, functional fragments and peptides, encoding nucleic acid molecules and polynucleotides, and specific antibodies. Also provided are excitatory glycine receptors, containing either NR3B or NR3A polypeptides. Further provided are methods for detecting excitatory glycine receptor ligands, agonists and antagonists. The invention also provides related diagnostic and therapeutic methods. </p>
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RIBOSOME STRUCTURE AND PROTEIN SYNTHESIS INHIBITORS (Tue, 04 Feb 2003)
The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome- related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism. </p>
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JNK3 modulators and methods of use (Fri, 31 Jan 2003)
<p id="p-0001-en" num="0000">The c-Jun NH<sub>2</sub>-terminal kinase (JNK) group of MAP kinases are activated by exposure of cells to environmental stress. The role of JNK in the brain was examined by targeted disruption of the gene that encodes the neuronal isoform JNK3. It was found that JNK3 is required for the normal response to seizure activity. Methods of screening for molecules and compounds that decrease JNK3 expression or activity are described. Such molecules or compounds are useful for treating disorders involving excitotoxicity such as seizure disorders, Alzheimer's disease, Huntington disease, Parkinson's disease, and ischaemia.</p>
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MC4-R as target for the identification of compounds used to treat drug addiction (Fri, 24 Jan 2003)
<p id="p-a-0001-en">The present invention relates to drug screening assays and therapeutic methods for the treatment of addictive behavior disorders, such as cocaine and morphine addiction utilizing the melanocortin 4-receptor (MC4-R) as the target for intervention. The invention also relates to compounds that antagonize the activity or expression of the MC4-R, and the use of such compounds in the treatment of addictive behavior disorders. </p>
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2-amino-9H-purin-9-yl compounds and methods for inhibiting/treating HIV infections and AIDS related symptoms (Fri, 24 Jan 2003)
<p id="p-0001-en" num="0000">The present invention relates to novel compounds, compositions and methods for inhibiting the growth, elaboration and/or replication of HIV in human patients and to the prevention and treatment of human acquired immunodeficiency syndrome (AIDS) and other diseases caused by retroviral infection. More particularly, in preferred aspects, the present invention provides a method for the use of novel prodrug forms of 9-(2,3-Dideoxy-β-D-glycero-pent-2-enofuranosyl) guanine (d4G) for the prevention and treatment of both wild type and drug-resistant Human Immunodeficiency Virus (HIV), the causative pathogen of AIDS. Compounds according to the present invention are based upon the chemical formula: <chemistry id="chem-us-00001-en" num="00001"><img id="emi-c00001-en" he="28.02mm" wi="42.93mm" file="US06900315-20050531-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/></chemistry> where X is OCH<sub>3</sub>, N<sub>3</sub>, NHCH<sub>3</sub>, N(CH<sub>3</sub>)<sub>2 </sub>or an aminocyclopropyl group; <ul id="ul0001-en" list-style="none"><li><ul id="ul0002-en" list-style="none"><li>R<sup>1 </sup>is H or a C<sub>1 </sub>to C<sub>20 </sub>acyl or ether group, a phosphate, diphosphate, triphosphate or phosphodiester group; and</li><li>R<sup>2 </sup>is H or a C<sub>1 </sub>to C<sub>20 </sub>acyl or alkyl group.</li></ul></li></ul></p>
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CATALYTIC METHOD TO CONVERT ARYL COMPOUNDS TO ARYL AMINES (Fri, 24 Jan 2003)
The present invention is directed to a method of converting an aryl compound to an aniline compound, comprising the steps of (1)providing an aryl compound containing a halide group or a sulfur-containing group; (2) reacting the aryl compound with an a reactant having the structure wherein R1,R2, and R3 are each independently selected from the group consisting substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroarylakyl, and combinations thereof; R4 is selected from the group consisting hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, and SiR1R2R3; and A is H or an alkali metal; the reacting step taking place in the presence of a Group 8 transition metal catalyst under reaction conditions that form an aryl silylamine intermediate, with the proviso that when A is H in the reactant, the reacting step further comprises a base; and (3) converting the aryl silylamine intermediate to the aniline compound.
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COMPOUNDS AND METHODS FOR THE INHIBITION OF TRYPANOSOMA CRUZ I (Fri, 24 Jan 2003)
The present invention relates to compounds according to the formula (I): Where RA is a C¿1?-C10 substituted or unsubstituted linear, branch-chained or cyclic alkyl or alkenyl group or a phenyl group according to the formula (II): R?B¿ is a C¿1?-C10 substituted or unsubstituted linear, branch-chained or cyclic alkyl or alkenyl group or a phenyl group of the formula (III): R?1, R2 , R3, R4, R5, R6, R7, R8, R9 and R10¿ are each independently selected from H, C¿1?-C10(preferably a C1-C4)alkyl or alkenyl group, CF3, F, Cl, Br, I, CN, NO2, NH2, NHR, NRR, COR (acyl group), OR (hydroxyl or ether group), CO2R (carboxylic acid or ester group ), or COSR (thioester group) where R is H or a C1-C10(preferably a C1-C4)alkyl or alkenyl group, an unsubstituted or substituted aryl (preferably, phenyl) or heterocycle group, or a (IV) group, where R3 is H, a C1-C10 (preferably a C1-C4) alkyl, alkenyl, ether or a thioether group; and R?11 and R12¿ are independently selected from H or a C¿1?-C3 alkyl or alkenyl group, or a pharmaceutically acceptable salt thereof and methods for treating infections caused by protozoal, fungal and/or bacterial agents such as Trypanosoma cruzi, Mycobacterium spp., Leishmania spp., Cryptococcus spp., Aspergillus spp., Histoplasma spp., Candida spp. especially Candida albicans, Pneumocystis carinii, Trichophyton spp., Microsporum spp., Malassezia spp., Rhizopus spp., Pseudallescheria spp., Blastomyces dermatitidis and Coccidiodes spp., among others.
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COMPOUNDS AND METHODS FOR THE INHIBITION OF TRYPANOSOMA CRUZI (Fri, 24 Jan 2003)
The present invention relates to compounds according to the formula (I): Where RA is a C1-C10 substituted or unsubstituted linear, branch-chained or cyclic alkyl or alkenyl group or a phenyl group according to the formula (II): RB is a C1-C10 substituted or unsubstituted linear, branch-chained or cyclic alkyl or alkenyl group or a phenyl group of the formula (III): R1, R2 , R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from H, C1- C10(preferably a C1-C4)alkyl or alkenyl group, CF3, F, Cl, Br, I, CN, NO2, NH2, NHR, NRR, COR (acyl group), OR (hydroxyl or ether group), CO2R (carboxylic acid or ester group ), or COSR (thioester group) where R is H or a C1-C10(preferably a C1-C4)alkyl or alkenyl group, an unsubstituted or substituted aryl (preferably, phenyl) or heterocycle group, or a (IV) group, where R3 is H, a C1-C10 (preferably a C1-C4) alkyl, alkenyl, ether or a thioether group; and R11 and R12 are independently selected from H or a C1-C3 alkyl or alkenyl group, or a pharmaceutically acceptable salt thereof and methods for treating infections caused by protozoal, fungal and/or bacterial agents such as Trypanosoma cruzi, Mycobacterium spp., Leishmania spp., Cryptococcus spp., Aspergillus spp., Histoplasma spp., Candida spp. especially Candida albicans, Pneumocystis carinii, Trichophyton spp., Microsporum spp., Malassezia spp., Rhizopus spp., Pseudallescheria spp., Blastomyces dermatitidis and Coccidiodes spp., among others. </p>
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Methods for selectively modulating survivin apoptosis pathways (Wed, 22 Jan 2003)
<p id="p-00001-en">The present invention, based on the discovery of a new biological phenomena, provides methods and compositions for use in identifying agents that modulate the phosphorylation of survivin, the interaction between survivin and p34<sup>cdc2</sup>-cyclin B1 kinase complex, and the interaction between survivin and caspase-9. Related methods and compositions can be used to modulate survivin regulated apoptosis.</p>
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Proteomimetic compounds and methods (Fri, 10 Jan 2003)
<p id="p-00001-en" num="00001">The present invention relates to compounds and pharmaceutical compositions which are proteomimetic and to methods for inhibiting the interaction of an alpha-helical protein with another protein or binding site. Methods for treating diseases or conditions which are modulated through interactions between alpha helical proteins and their binding sites are other aspects of the invention.</p>
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Catalyst for aromatic C—O, C—N, and C—C bond formation (Fri, 10 Jan 2003)
<p id="p-00001-en">The present invention is directed to a transition metal catalyst, comprising a Group 8 metal and a ligand having the structure<chemistry id="chem-us-00001-en"><img he="N/A" wi="N/A" img-format="tif" id="emi-c00001-en" file="US06562989-20030513-C00001.TIF" img-content="chem" alt="embedded image"/></chemistry></p> <p id="p-00002-en">wherein R, R′ and R″ are organic groups having 1-15 carbon atoms, n=1-5, and m=0-4. The present invention is also directed to a method of forming a compound having an aromatic or vinylic carbon-oxygen, carbon-nitrogen, or carbon-carbon bond using the above catalyst. The catalyst and the method of using the catalyst are advantageous in preparation of compounds under mild conditions of approximately room temperature and pressure.</p>
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Antiviral agents and methods of treating viral infections (Fri, 13 Dec 2002)
<p id="p-0001-en" num="0000">The present invention relates to methods of treating viral or fungal infections using 3-aminopyridine-2-carboxyaldehyde thiosemicarbazone (3-AP) and 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone (3-AMP) and its prodrug forms and to pharmaceutical compositions comprising these compounds.</p>
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PROTEOMIMETIC COMPOUNDS AND METHODS (Fri, 15 Nov 2002)
The present invention relates to compounds and pharmaceutical compositions which are proteomimetic and to methods for inhibiting the interaction of an alpha-helical protein with another protein or binding site. Methods for treating diseases or conditions which are modulated through interactions between alpha helical protein and their binding sites are other aspects of the invention.
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PROTEOMIMETIC COMPOUNDS AND METHODS (Fri, 15 Nov 2002)
The present invention relates to compounds and pharmaceutical compositions which are proteomimetic and to methods for inhibiting the interaction of an alpha-helical protein with another protein or binding site. Methods for treating diseases or conditions which are modulated through interactions between alpha helical protein and their binding sites are other aspects of the invention. </p>
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ANTIVIRAL AGENTS AND METHODS OF TREATING VIRAL INFECTIONS (Fri, 01 Nov 2002)
The present invention relates to methods of treating viral or fungal infections using 3-aminopyridine-2-carboxyaldehyde thiosemicarbazone (3-AP) and 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone (3-AMP) and its prodrug forms and to pharmaceutical compositions comprising these compounds.
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Methods of detecting interactions between proteins, peptides or libraries thereof using fusion proteins (Fri, 11 Oct 2002)
<p id="p-00001-en">The present invention provides assays using fusion proteins with GFP fragments and test polypeptides for investigating protein-protein interactions.</p>
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Estradiol-16α-carboxylic acid esters as locally active estrogens (Fri, 04 Oct 2002)
<p id="p-00001-en">The present invention relates to analogs of estradiol, which, in their most preferred embodiment, act as locally active estrogens without significant systemic action. A series of 16α-carboxylic acid substituted steroids and their esters is presented which exhibit excellent biological activity for use in pharmaceutical compositions for the treatment of symptomology associated with menopause. The present invention is therefore directed to compounds according to the structure:<chemistry id="chem-us-00001-en"><img he="N/A" wi="N/A" img-format="tif" id="emi-c00001-en" file="US06476012-20021105-C00001.TIF" img-content="chem" alt="embedded image"/></chemistry></p> <p id="p-00002-en">Where R is H, a C<sub>1</sub>to C<sub>5</sub>alkyl, vinyl, CF<sub>3</sub>, CH<sub>2</sub>CH<sub>2</sub>F, CH<sub>2</sub>CHF<sub>2</sub>or CH<sub>2</sub>CF<sub>3</sub>; and</p> <p id="p-00003-en">m is from 0-2, or a pharmaceutically acceptable salt thereof. Preferably, R is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, neo-pentyl, vinyl, CF<sub>3</sub>, CH<sub>2</sub>CH<sub>2</sub>F, CH<sub>2</sub>CHF<sub>2</sub>or CH<sub>2</sub>CF<sub>3</sub>and m is 0. More preferably, R is methyl, ethyl, CH<sub>2</sub>CH<sub>2</sub>F, CH<sub>2</sub>CHF<sub>2</sub>or CH<sub>2</sub>CF<sub>3</sub>and m is 0.</p>
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Selective, catalytic, thermal functionalization of primary C-H hydrocarbon bonds (Wed, 18 Sep 2002)
<p id="p-00001-en">A process for the catalytic coupling of aliphatic or alkyl branched alicyclic hydrocarbons with a functionalizing reagent under thermal conditions to selectively functionalize the hydrocarbon at its primary C—H site.</p>
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Method for the treatment of psoriasis and genital warts (Wed, 21 Aug 2002)
<p id="p-00001-en">The present invention relates to the use of prodrug forms of (−)-(2S,4S)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl)cytosine to treat psoriasis, genital warts and other hyperproliferative keratinocyte diseases such as hyperkeratosis, ichthyosis, keratoderma or lichen planus.</p>
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NOVEL COMPOUNDS AND METHODS FOR INHIBITING/TREATING HIV INFECTIONS AND AIDS RELATED SYMPTOMS (Fri, 16 Aug 2002)
The present invention relates to novel compounds, compositions and methods for inhibiting the growth, elaboration and/or replication of HIV in human patients and to the prevention and treatment of human acquired immunodeficiency syndrome (AIDS) and other diseases caused by retroviral infection. More particularly, in preferred aspects, the present invention provides a method for the use of novel prodrug forms of 9-(2,3-Dideoxy-β-D-glycero-pent-2-enofuranosyl)guanine (d4G) for the prevention and treatment of both wild type and drug-resistant Human Immunodeficiency Virus (HIV), the causative pathogen of AIDS.
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ESTRADIOL-16α-CARBOXYLIC ACID ESTERS AS LOCALLY ACTIVE ESTROGENS (Fri, 02 Aug 2002)
The present invention relates to analogs of estradiol, which, in their most preferred embodiment, act as locally active estrogens without significant systemic action. A series of 16α-carboxylic acid substituted steroids sand their esters is presented which exhibit excellent biological activity for use in pharmaceutical compositions for the treatment of symptomology associated with menopause. The present invention is therefore directed to compounds according to the structure: I Where R is H, a C1 to C5 alkyl, vinyl, CF3, CH2CH2F, CH2CHF2 or CH2CF3; and m is from 0-2, or a pharmaceutically acceptable salt thereof. Preferably, R is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, neo-pentyl, vinyl, CF3, CH2CH2F, CH2CHF2 or CH2CF ?3? and m is 0. More preferbly, R is methyl, ethyl, CH2CH2F, CH2CHF2 or CH2CF2 and m is 0.
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Purification of oligomers (Fri, 26 Jul 2002)
<p id="p-00001-en">Compositions and methods are disclosed which facilitate purification of oligomers and other compounds. The disclosed compositions are silyl compositions that can be directly coupled, or coupled through a linking group, to a compound of interest, preferably to an oligomer at the end of oligomer synthesis. The silicon atom includes between one and three sidechains that function as capture tags. In one embodiment, the capture tags are lipophilic, which allows a derivatized oligomer to be separated from failure sequences by reverse phase chromatography. In another embodiment, the capture tags are compounds with a known affinity for other compounds, which other compounds are preferably associated with a solid support to allow chromatographic separation. Examples include haptens, antibodies, and ligands. Biotin, which can bind to or interact with a streptavidin-bound solid support, is a preferred capture tag of this type.</p>
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Covalent conjugates of topoisomerase I and topoisomerase II inhibitors (Wed, 17 Jul 2002)
<p id="p-00001-en">The present invention provides covalent conjugates of topoisomerase I and topoisomerase II inhibitors. Such compounds have a structure according to formula I:</p> <p id="p-00002-en">T<sub>I</sub>—L—T<sub>II</sub>  (I)</p> <p id="p-00003-en">wherein:</p> <p id="p-00004-en">T<sub>I</sub>is a topoisomerase I inhibitor such as a camptothecin group;</p> <p id="p-00005-en">T<sub>II</sub>is a topoisomerase II inhibitor such as an amsacrine, ellipticine, epipodophyllotoxin, or anthracycline antibiotic group; and</p> <p id="p-00006-en">L is a linking group.</p> <p id="p-00007-en">The compounds are useful for inhibiting topoisomerase I and II enzymes, for promoting cellular differentiation, and for treating cancer.</p>
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Modulators of ribosomal function and identification thereof (Fri, 05 Jul 2002)
<p id="p-0001-en" num="0000">The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism.</p>
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STERICALLY HINDERED PHOSPHINE LIGANDS AND USES THEREOF (Fri, 21 Jun 2002)
The present invention is directed to a catalyst composition, comprising a Group 8 metal; and a ligand having a structure selected from the group consisting of: (a) wherein R, R' and R' are selected from the group consisting of H, a 1-10 carbon moiety, OR1, and NR2R3, wherein R1, R2, and R3 are each individually a 1-10 carbon moiety, with the proviso that one of R, R', or R' is not H, and that R, R', and R' together do not form an adamantyl moiety; and (b) wherein L is selected from the group consisting of a 1-30 carbon moiety with a tertiary carbon bound to phosphorous The present invention is also directed to a method of forming carbon-carbon, carbon-oxygen, carbon-sulfur, and carbon-nitrogen bonds between substrates using the above catalysts.
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Binuclear non-heme iron catalysts (Wed, 29 May 2002)
<p id="p-00001-en">The subject invention provides a binuclear metal complex having structure (I) wherein M<sub>1</sub>, and M<sub>2</sub>are independently selected from the group consisting of Fe, Co, Mn and Ru; wherein m and n are independently +2 or +3; wherein R<sub>1</sub>, R<sub>2</sub>, R<sub>3</sub>, R<sub>4</sub>, R<sub>5</sub>and R<sub>6</sub>are independently a linear C<sub>1</sub>-C<sub>6</sub>alkyl, C<sub>5</sub>-C<sub>6</sub>cycloalkyl, phenyl, etc.; wherein (i) R<sub>1</sub>and R<sub>2</sub>, (ii) R<sub>3</sub>and R<sub>4</sub>, or (iii) R<sub>5</sub>and R<sub>6</sub>independently and optionally are linked covalently and together with the respective adjoining C atom comprise a spirocyclic ring; wherein i, j and k are integers such that 2≦i+j+k≦4; wherein p is 1 or 2, and q is 0, 1 or 2 such that m+n−4=p×q; wherein (i) R<sub>1</sub>or R<sub>2</sub>and R<sub>3</sub>or R<sub>4</sub>, (ii) R<sub>3</sub>or R<sub>4</sub>and R<sub>4</sub>or R<sub>5</sub>, or (iii) R<sub>1</sub>or R<sub>2</sub>and R<sub>5</sub>or R<sub>6</sub>independently and optionally are linked covalently and together with the respective adjoining C atoms comprise a fused ring; wherein Ar is 1,2-phenylene, 1,2- or 2,3-naphthylene, etc., wherein said Ar is optionally substitued by C<sub>1</sub>-C<sub>6</sub>alkyl or alkoxy; wherein L is N-methylimidazole, N-ethylimidazole, etc.; and wherein X is fluorine, chlorine, bromine, etc. Also provided are methods of oxidation of alkanes, arenes, and sulfides using the binuclear metal complex as a catalyst and a method of preparing said complex.<chemistry id="chem-us-00001-en"><img he="N/A" wi="N/A" img-format="tif" id="emi-c00001-en" file="US06395904-20020528-C00001.TIF" img-content="chem" alt="embedded image"/></chemistry></p>
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Methods and compositions utilizing Rad51 (Wed, 22 May 2002)
<p id="p-00001-en">Compositions and methods are provided for identifying and diagnosing individuals at risk for a disease state associated with aberrant Rad41 foci.</p>
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PROTEOLYSIS TARGETING CHIMERIC PHARMACEUTICAL (Fri, 15 Mar 2002)
The present invention is based on the discovery of a composition that provides targeted ubiquitination. Specifically the composition contains an ubiquitin pathway protein binding moiety which recognizes an ubiquitin pathway protein and a targeting moiety which recognizes a target protein. In addition, the present invention provides libraries of compositions, where each composition contains an ubiquitin pathway protein binding moiety and a member of a molecular library. The libraries of the present invention can be used to identify proteins involved in a predetermined function of cells.
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CATALYST FOR AROMATIC C-O, C-N, and C-C BOND FORMATION (Fri, 15 Feb 2002)
The present invention is directed to a transition metal catalyst, comprising a Group 8 metal and a ligand having the structure (I), wherein R', R' and R'' are organic groups having 1-15 carbon atoms, n = 1-5, and m = 0-4. The present invention is also directed to a method of forming a compound having an aromatic or vinylic carbon-oxygen, carbon-nitrogen, or carbon-carbon bond using the above catalyst. The catalyst and the method of using the catalyst are advantageous in preparation of compounds under mild conditions of approximately room temperature and pressure.
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CATALYST FOR AROMATIC C-O, C-N, AND C-C BOND FORMATION (Fri, 15 Feb 2002)
The present invention is directed to a transition metal catalyst, comprising a Group 8 metal and a ligand having the structure (I), wherein R', R' and R'' are organic groups having 1-15 carbon atoms, n = 1-5, and m = 0-4. The present invention is also directed to a method of forming a compound having an aromatic or vinylic carbon-oxygen, carbon-nitrogen, or carbon-carbon bond using the above catalyst. The catalyst and the method of using the catalyst are advantageous in preparation of compounds under mild conditions of approximately room temperature and pressure. </p>
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RIBOSOME STRUCTURE AND PROTEIN SYNTHESIS INHIBITORS (Sun, 10 Feb 2002)
The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome- related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism. </p>
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Transition metal-catalyzed process for addition of amines to carbon-carbon double bonds (Fri, 08 Feb 2002)
<p id="p-00001-en">The present invention is directed to a process for addition of amines to carbon-carbon double bonds in a substrate, comprising: reacting an amine with a compound containing at least one carbon-carbon double bond in the presence a transition metal catalyst under reaction conditions effective to form a product having a covalent bond between the amine and a carbon atom of the former carbon-carbon double bond. The transition metal catalyst comprises a Group 8 metal and a ligand containing one or more 2-electron donor atoms. The present invention is also directed to enantioselective reactions of amine compounds with compounds containing carbon-carbon double bonds, and a calorimetric assay to evaluate potential catalysts in these reactions.</p>
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METHODS OF DETECTING INTERACTIONS BETWEEN PROTEINS, PEPTIDES OR LIBRARIES THEREOF USING FUSION PROTEINS (Fri, 23 Nov 2001)
The present invention discloses a method of reconstituting, folding, or reassembling peptides or other binding pairs into a functionally active protein or other complex using an antiparallel leucine zipper. The present invention also provides assays using fusion proteins comprising GFP fragments and test polypeptides for investigating protein-protein interactions.
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METHODS OF DETECTING INTERACTIONS BETWEEN PROTEINS, PEPTIDES OR LIBRARIES THEREOF USING FUSION PROTEINS (Fri, 23 Nov 2001)
The present invention discloses a method of reconstituting, folding, or reassembling peptides or other binding pairs into a functionally active protein or other complex using an antiparallel leucine zipper. The present invention also provides assays using fusion proteins comprising GFP fragments and test polypeptides for investigating protein-protein interactions. </p>
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DNA & PROTEIN BINDING MINIATURE PROTEINS (Fri, 02 Nov 2001)
The present invention provides a protein scaffold, such as an avian pancreatic polypeptide, that can be modified by substitution of two or more amino acid residues that are exposed on the alpha helix domain of the polypeptide when the polypeptide is in a tertiary form.
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DNA & PROTEIN BINDING MINIATURE PROTEINS (Fri, 02 Nov 2001)
The present invention provides a protein scaffold, such as an avian pancreatic polypeptide, that can be modified by substitution of two or more amino acid residues that are exposed on the alpha helix domain of the polypeptide when the polypeptide is in a tertiary form. </p>
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SELECTIVE, CATALYTIC, THERMAL FUNCTIONALIZATION OF SECONDARY OR AROMATIC C-H CYCLIC HYDROCARBON BONDS (Sat, 08 Sep 2001)
A process for functionalizing a cyclic hydrocarbon at a secondary or aromatic C-H cyclic hydrocarbon bond comprising thermally reacting a functionalizing reagent and the cyclic hydrocarbon in the presence of a catalyst, said catalyst comprising: a) a source of rhodium; b) a source of a 3 to 8, cyclic or non-cyclic, aromatic or non-aromatic, neutral, cationic or anionic, substituted or unsubstituted, electron donor moiety which does not dissociate under thermal reaction conditions; and c) a source of ligands capable of formally donating an electron pair to rhodium and which dissociate thermally; and wherein said functionalizing reagent comprises a source of boron.
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METHODS FOR SELECTIVELY MODULATING SURVIVIN APOPTOSIS PATHWAYS (Sat, 08 Sep 2001)
The present invention, based on the discovery of a new biological phenomena, provides methods and compositions for use in identifying agents that modulate the phosphorylation of survivin, the interaction between survivin and p34cdc2-cyclin B1 kinase complex, and the interaction between survivin and caspase-9. Related methods and compositions can be used to modulate survivin regulated apoptosis.
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SELECTIVE, CATALYTIC, AND THERMALLY INDUCED FUNCTIONALIZATION OF PRIMARY C-H BONDS IN HYDROCARBONS (Sat, 08 Sep 2001)
A process for selectively functionalizing an aliphatic hydrocarbon and/or alkyl branched alicyclic hydrocarbon at a primary C-H hydrocarbon bond comprising thermally reacting a functionalizing reagent and the hydrocarbon in the presence of a catalyst, said catalyst comprising: a) a source of a transition metal; b) a source of a 3 to 8, cyclic or non-cyclic, aromatic or non-aromatic, neutral, cationic or anionic, substituted or unsubstituted, electron donor moiety which does not dissociate under thermal reaction conditions, wherein said moiety (i) lacks aromatic C-H bonds on the moiety directly bonded to the transition metal, or (ii) contains sterically hindered aromatic C-H bonds on the moiety directly bonded to the transition metal; and c) a source of ligands capable of formally donating an electron pair to the transition metal of a) and which dissociate thermally; and wherein said functionalizing reagent comprises a source of boron.
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TRANSITION METAL-CATALYZED PROCESS FOR ADDITION OF AMINES TO CARBON-CARBON DOUBLE BONDS (Sat, 08 Sep 2001)
The present invention is directed to a process for addition of amines to carbon-carbon double bonds in a substrate, comprising: reacting an amine with a compound containing at least one carbon-carbon double bond in the presence a transition metal catalyst catalyst under reaction conditions effective to form a product having a covalent bond between the amine and the carbon-carbon double bond. The transition metal catalyst comprises a Group 8 metal and a ligand containing one or more 2-electron donor atoms. The present invention is also directed to enantioselective reactions of amine compounds with compounds containing carbon-carbon double bonds, and a colorimetric assay to evauluate potential catalysts in these reactions.
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METHODS FOR SELECTIVELY MODULATING SURVIVIN APOPTOSIS PATHWAYS (Sat, 08 Sep 2001)
The present invention, based on the discovery of a new biological phenomena, provides methods and compositions for use in identifying agents that modulate the phosphorylation of survivin, the interaction between survivin and p34cdc2- cyclin B1 kinase complex, and the interaction between survivin and caspase-9. Related methods and compositions can be used to modulate survivin regulated apoptosis. </p>
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SELECTIVE, CATALYTIC, THERMAL FUNCTIONALIZATION OF SECONDARY OR AROMATIC C-H CYCLIC HYDROCARBON BONDS (Sat, 08 Sep 2001)
A process for functionalizing a cyclic hydrocarbon at a secondary or aromatic C-H cyclic hydrocarbon bond comprising thermally reacting a functionalizing reagent and the cyclic hydrocarbon in the presence of a catalyst, said catalyst comprising: a) a source of rhodium; b) a source of a 3 to 8, cyclic or non-cyclic, aromatic or non-aromatic, neutral, cationic or anionic, substituted or unsubstituted, electron donor moiety which does not dissociate under thermal reaction conditions; and c) a source of ligands capable of formally donating an electron pair to rhodium and which dissociate thermally; and wherein said functionalizing reagent comprises a source of boron. </p>
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SELECTIVE, CATALYTIC, AND THERMALLY INDUCED FUNCTIONALIZATION OF PRIMARY C-H BONDS IN HYDROCARBONS (Sat, 08 Sep 2001)
A process for selectively functionalizing an aliphatic hydrocarbon and/or alkyl branched alicyclic hydrocarbon at a primary C-H hydrocarbon bond comprising thermally reacting a functionalizing reagent and the hydrocarbon in the presence of a catalyst, said catalyst comprising: a) a source of a transition metal; b) a source of a 3 to 8, cyclic or non-cyclic, aromatic or non-aromatic, neutral, cationic or anionic, substituted or unsubstituted, electron donor moiety which does not dissociate under thermal reaction conditions, wherein said moiety (i) lacks aromatic C-H bonds on the moiety directly bonded to the transition metal, or (ii) contains sterically hindered aromatic C-H bonds on the moiety directly bonded to the transition metal; and c) a source of ligands capable of formally donating an electron pair to the transition metal of a) and which dissociate thermally; and wherein said functionalizing reagent comprises a source of boron. </p>
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TRANSITION METAL-CATALYZED PROCESS FOR ADDITION OF AMINES TO CARBON-CARBON DOUBLE BONDS (Sat, 08 Sep 2001)
The present invention is directed to a process for addition of amines to carbon-carbon double bonds in a substrate, comprising: reacting an amine with a compound containing at least one carbon-carbon double bond in the presence a transition metal catalyst catalyst under reaction conditions effective to form a product having a covalent bond between the amine and the carbon-carbon double bond. The transition metal catalyst comprises a Group 8 metal and a ligand containing one or more 2-electron donor atoms. The present invention is also directed to enantioselective reactions of amine compounds with compounds containing carbon-carbon double bonds, and a colorimetric assay to evauluate potential catalysts in these reactions. </p>
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L-beta-dioxolane uridine analogs and methods for treating and preventing virus infections (Fri, 31 Aug 2001)
<p id="p-a-0001-en">The present invention relates to the discovery that certain P-L-dioxolane nucleoside analogs which contain a uracil base, and preferably, a 5-halosubstituted uracil base, exhibit unexpectedly high activity against Epstein-Barr virus (EBV), Varciella-Zoster virus (VZV) and Herpes Virus 8 (HV-8). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus (viral growth) in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds are useful for treating EBV, VZV and HV-8 infections in humans. </p>
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L-β-dioxolane uridine analogs and their pharmaceutical compositions (Wed, 15 Aug 2001)
<p id="p-00001-en">The present invention relates to the discovery that certain β-L-dioxolane nucleoside analogs which contain a uracil base, and preferably, a 5-halosubstituted uracil base, exhibit unexpectedly high activity against Epstein-Barr virus (EBV), Varciella-Zoster virus (VZV) and Herpes Virus 8 (HV-8). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus (viral growth) in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds are useful for treating EBV, VZV and HV-8 infections in humans.</p>
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TRANSITION METAL-CYCLOPENTADIENYL-TROPANE CONJUGATES (Fri, 08 Jun 2001)
Transition metal-cyclopentadienyl-tropane conjugate compounds are described. Methods for preparing transition metal-cyclopentadienyl-tropane conjugate compounds are also described. Transition metal-cyclopentadienyl-tropane conjugate compounds of the invention exhibit an affinity for monoamine transporters and are useful as diagnostic and/or therapeutic agents.
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TRANSITION METAL-CYCLOPENTADIENYL-TROPANE CONJUGATES (Fri, 08 Jun 2001)
Transition metal-cyclopentadienyl-tropane conjugate compounds are described. Methods for preparing transition metal-cyclopentadienyl-tropane conjugate compounds are also described. Transition metal-cyclopentadienyl-tropane conjugate compounds of the invention exhibit an affinity for monoamine transporters and are useful as diagnostic and/or therapeutic agents. </p>
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Transition metal-catalyzed process for preparing N-aryl amine compounds (Wed, 23 May 2001)
<p id="p-00001-en">The present invention is directed to a process for the preparation of N-aryl amine compounds. The process of the present invention involves reacting a compound having an amino group with an arylating compound in the presence of a base and a transition metal catalyst under reaction conditions effective to form an N-aryl amine compound, the transition metal catalyst comprising a Group 8 metal and at least one chelating ligand selected from the group consisting of bisphosphines having at least one stearically hindered alkyl substituent. The formed products are valuable intermediates in the pharmaceutical and polymer fields.</p>
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MOLECULAR SCALE ELECTRONIC DEVICES (Fri, 20 Apr 2001)
Molecular scale electronic devices (1) are disclosed. Such devices include at least two conductive contacts (9 and 11), and a conductive path (13) bridging the contacts. The conductive path is able to be written into a perturbed state by a voltage pulse, which can be of high or low conductivity, relative to an initial state. The conductive path comprises organic molecules including at least one electron-withdrawing group. Room temperature negative differential resistance is exhibited by the devices.
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MOLECULAR SCALE ELECTRONIC DEVICES (Fri, 20 Apr 2001)
Molecular scale electronic devices (1) are disclosed. Such devices include at least two conductive contacts (9 and 11), and a conductive path (13) bridging the contacts. The conductive path is able to be written into a perturbed state by a voltage pulse, which can be of high or low conductivity, relative to an initial state. The conductive path comprises organic molecules including at least one electron-withdrawing group. Room temperature negative differential resistance is exhibited by the devices. </p>
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Covalent conjugates of topoisomerase I and topoisomerase II inhibitors (Wed, 28 Mar 2001)
<p id="p-00001-en">The present invention provides covalent conjugates of topoisomerase I and topoisomerase II inhibitors. Such compounds have a structure according to formula I:</p> <p id="p-00002-en">T<sub>I</sub>—L—T<sub>II</sub>  (I)</p> <p id="p-00003-en">wherein:</p> <p id="p-00004-en">T<sub>I</sub>is a topoisomerase I inhibitor such as a camptothecin group;</p> <p id="p-00005-en">T<sub>II</sub>is a topoisomerase II inhibitor such as an amsacrine, ellipticine, epipodophyllotoxin, or anthracycline antibiotic group; and</p> <p id="p-00006-en">L is a linking group.</p> <p id="p-00007-en">The compounds are useful for inhibiting topoisomerase I and II enzymes, for promoting cellular differentiation, and for treating cancer.</p>
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USE OF THE CRYSTAL STRUCTURE OF STAPHYLOCOCCUS AUREUS ISOLEUCYL-tRNA SYNTHETASE IN ANTIBIOTIC DESIGN (Fri, 09 Feb 2001)
The present invention provides the atomic coordinates derived from high resolution x-ray diffraction of the cocrystal complex comprising mupirocin with its target enzyme, isoleucyl-tRNA synthetase form Staphylococcus aureus, and the cognate tRNAile from Escherichia coli. The present invention further provides methods of using the atomic coordinates to identify and design new agents which modulate protein synthesis as well as the agents themselves.
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USE OF THE CRYSTAL STRUCTURE OF STAPHYLOCOCCUS AUREUS ISOLEUCYL-TRNA SYNTHETASE IN ANTIBIOTIC DESIGN (Fri, 09 Feb 2001)
The present invention provides the atomic coordinates derived from high resolution x-ray diffraction of the cocrystal complex comprising mupirocin with its target enzyme, isoleucyl-tRNA synthetase form Staphylococcus aureus, and the cognate tRNAile from Escherichia coli. The present invention further provides methods of using the atomic coordinates to identify and design new agents which modulate protein synthesis as well as the agents themselves. </p>
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5-(E)-BROMOVINYL URACIL ANALOGUES AND RELATED PYRIMIDINE NUCLEOSIDES AS ANTI-VIRAL AGENTS AND METHODS OF USE (Fri, 02 Feb 2001)
The present invention relates to pyrimidine nucleoside compounds and their use to treat viral infections of Varicella Zoster Virus, Epstein Barr Virus and Kaposi's Sarcoma virus, also known as HV-8 and related complications of these viral infections. In another aspect of the present invention, the use of one or more nucleoside compound to increase the retention or half-life of 5-fluorouracil (FU) in patients is also described.
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5-(E)-BROMOVINYL URACIL ANALOGUES AND RELATED PYRIMIDINE NUCLEOSIDES AS ANTI-VIRAL AGENTS AND METHODS OF USE (Fri, 02 Feb 2001)
The present invention relates to pyrimidine nucleoside compounds and their use to treat viral infections of Varicella Zoster Virus, Epstein Barr Virus and Kaposi's Sarcoma virus, also known as HV- 8 and related complications of these viral infections. In another aspect of the present invention, the use of one or more nucleoside compound to increase the retention or half-life of 5-fluorouracil (FU) in patients is also described. </p>
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MinK-RELATED GENES, FORMATION OF POTASSIUM CHANNELS AND ASSOCIATION WITH CARDIAC ARRHYTHMIA (Fri, 27 Oct 2000)
The present invention is directed to genes and gene products related to Min-K which form ion channels and to a process for diagnosis of ion channel disorders, including long QT syndrome (LQT). For example, KCNE2 forms IKr potassium channels and is associated with LQT. LQT is diagnosed in accordance with the present invention by analyzing the DNA sequence of KCNE2 of an individual to be tested and comparing the respective DNA sequence to the known DNA sequence of a normal KCNE2 gene. Alternatively, these MinK-related genes of an individual to be tested can be screened for mutations which cause ion channel disorders, including LQT. Prediction of ion channel disorders, including LQT, will enable practitioners to prevent the disorders using existing medical therapy. This invention is further directed to the discovery that the HERG and KCNE2 (also known as MiRP1) proteins coassemble to form a cardiac IKr potassium channel.
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MINK-RELATED GENES, FORMATION OF POTASSIUM CHANNELS AND ASSOCIATION WITH CARDIAC ARRHYTHMIA (Fri, 27 Oct 2000)
The present invention is directed to genes and gene products related to Min-K which form ion channels and to a process for diagnosis of ion channel disorders, including long QT syndrome (LQT). For example, KCNE2 forms IKr potassium channels and is associated with LQT. LQT is diagnosed in accordance with the present invention by analyzing the DNA sequence of KCNE2 of an individual to be tested and comparing the respective DNA sequence to the known DNA sequence of a normal KCNE2 gene. Alternatively, these MinK-related genes of an individual to be tested can be screened for mutations which cause ion channel disorders, including LQT. Prediction of ion channel disorders, including LQT, will enable practitioners to prevent the disorders using existing medical therapy. This invention is further directed to the discovery that the HERG and KCNE2 (also known as MiRP1) proteins coassemble to form a cardiac IKr potassium channel. </p>
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Transition metal-catalyzed process for preparing N-aryl amine compounds (Wed, 09 Aug 2000)
<p>Disclosed is a process for the preparation of N-aryl amine compounds, comprising reacting an amine compound with an arylating compound in the presence of a base and a transition metal catalyst under reaction conditions effective to form an N-aryl amine compound, the transition metal catalyst comprising a Group 8 metal and P(t-Bu).sub.3 as a ligand, and wherein the ratio of the ligand to the Group 8 metal is in the range of about 3:1 to about 0.25:1, and wherein the reaction temperature is less than 100.degree. C. The process of the present invention provides a useful general method of N-arylation for the manufacture of pharmaceuticals, polymers, and the like. -GOVT PAC STATEMENT OF GOVERNMENT SUPPORT PAR This application was made with United States Government support under Award Number 1-R29-GM382-01 from the National Institutes of Health. The U.S. Government has certain rights in this invention.</p>
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Methods and compositions utilizing Rad51 (Wed, 19 Jul 2000)
<p>Compositions and methods are provided for identifying agents which bind to or modulate Rad51.</p>
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ASSOCIATION OF COMPOUNDS IN CARBON DIOXIDE AND THE GELS AND/OR FOAMS FORMED THEREFROM (Fri, 23 Jun 2000)
The invention relates to a method of increasing the viscosity of supercritical CO2 by combining a compound having a CO2-philic functional group and an aggregating functional group which enables the compound to form a supramolecular network in solution with supercritical CO2 to form a solution. The compound is then aggregated in solution to form a supramolecular network such that the viscosity of the supercritical CO2 with the supramolecular network is greater than that of the starting supercritical CO2. The invention also relates to a method of making a microcellular foam by combining a compound having a CO2-philic functional group and an aggregating functional group which enables the compound to form a supramolecular network in solution, with supercritical CO2 to form a solution. The compound is aggregated to form a supramolecular network in solution. Then the CO2 is removed under conditions sufficient to form a microcellular foam.
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Carbonyl arylations and vinylations using transition metal catalysts (Wed, 07 Jun 2000)
<p>The invention is directed to a process for preparing an alpha-arylated or vinylated carbonyl-containing compounds, comprising reacting a compound having a carbonyl group with an arylating or vinylating compound in the presence of a base and a transition metal catalyst. The transition metal catalyst has the formula X.sub.n M(ER.sub.1-4).sub.m, wherein X is an optional ligand, M is a group 8 transition metal, E is an element bearing a nonbonding electron pair when E is not bonded to the metal, and R is a substituent bonded to E through a carbon, nitrogen, oxygen, or sulfur atom, with the proviso that R.sub.3 cannot contain 3 aryl groups, n is an integer from 0 to 4, and m is an integer from 1-4. The process of the invention is useful for preparation of alpha-arylated or vinylated carbonyl-containing compounds which are significant in the development of pharmacologically active compounds and polymers and oligomers.</p>
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Methods for the treatment of psoriasis and genital warts (Wed, 17 May 2000)
<p>The present invention relates to the use of (-)-(2S,4S)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl) cytosine to treat psoriasis, genital warts and other hyperproliferative keratinocyte diseases such as hyperkeratosis, ichthyosis, keratoderma or lichen planus.</p>
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Stabilized external guide sequences (Wed, 03 May 2000)
<p>Modified external guide sequence (EGS) molecules that mediate cleavage of specific target RNAs have been constructed. The modified molecules are external guide sequence molecules for RNAse P which are designed to specifically bind to and promote RNAse P-mediated cleavage of target RNA molecules and to have enhanced nuclease resistance. Specific regions are modified to achieve enhanced stability while maintaining RNAse P activity. Modified external guide sequence molecules suitable for use in the treatment of hepatitis B viral infections have been constructed.</p>
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N,n-bis(sulfonyl)hydrazines useful as antineoplastic agents (Wed, 22 Mar 2000)
<p>The present invention relates to a compound of the formula wherein R.sup.1 and R.sup.2 are selected from lower alkyl groups having 1-6 carbon atoms, substituted or unsubstituted aryl groups, and unsaturated alkyl groups having 1-6 carbon atoms; R.sup.3 is a substituted or unsubstituted lower alkyl group having 1-6 carbons; and R.sup.4 is selected from substituted or unsubstituted lower alkyl groups having 1-6 carbon atoms, substituted or unsubstituted aryl groups, and unsaturated alkyl groups having 1-6 carbon atoms. The present invention also relates to a pharmaceutical composition comprising the above compound, as well as a method of treating tumor cells with the compound. -GOVT PAC STATEMENT OF GOVERNMENT SUPPORT PAR This invention was made in part with government support under grant number CA-53340 from the National Cancer Institute. The government has certain rights in this invention.</p>
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MC4-R AS TARGET FOR THE IDENTIFICATION OF COMPOUNDS USED TO TREAT DRUG ADDICTION (Fri, 17 Mar 2000)
The present invention relates to drug screening assays and therapeutic methods for the treatment of addictive behavior disorders, such as cocaine and morphine addiction utilizing the melanocortin 4-receptor (MC4-R) as the target for intervention. The invention also relates to compounds that antagonize the activity or expression of the MC4-R, and the use of such compounds in the treatment of addictive behavior disorders. </p>
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Glycosylated indolocarbazole synthesis (Wed, 15 Mar 2000)
<p>Tertiary alcohols containing the structural features illustrated in 3 or 4 below (Scheme I) are prepared by reacting at least one diazo carbonyl compound, e.g., 1 in Scheme I) and at least one allylic alcohol (e.g., 2 in Scheme I) in a coupling reaction run under conditions that produce carbene or carbenoid intemediates from the diazo containing substrate such as transition metal catalysis or either thermal or photochemical decomposition. In some preferred embodiments, Rh.sub.2 (OAc).sub.4 is employed to catalyze the coupling reaction. ##STR1## Indolocarbazoles (e.g., 7 below) are prepared by coupling of diazo carbonyl compounds (e.g., 5) and biindoles (e.g., 6). Indolocarbazoles are furanosylated (e.g., 7) with acetals (e.g., 8) or their open chain congeners (e.g., 9) under conditions known to promote acetal exchange or formation, such as protic or Lewis acids. Furanosylated indolocarbazoles (e.g., 10) are also prepared via ring contraction of pyranosylated indolocarbazoles (e.g., 11) under conditions know to effect oxidation and benzylic acid type rearrangements, and pyranosylated indolocarbazoles (e.g., 11) are prepared via ring expansion of the furanosylated congeners (e.g., 10). ##STR2##</p>
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Urinary screening for down syndrome and other aneuploidies (Wed, 16 Feb 2000)
<p>This invention represents a significant advance in prenatal diagnosis by providing urinary screening to detect fetal aneuploidies. Herein disclosed are methods for prenatally assessing risks of a pregnancy being affected by Down syndrome and other aneuploidies by testing maternal urine samples for levels of .beta.-core-hCG. Levels of maternal urinary .beta.-core-hCG above normal indicate a risk that the pregnancy is affected with Down syndrome, and in general risks of other fetal aneuploidies are indicated by either lower than normal or higher than normal maternal urinary .beta.-core-hCG levels. Assessments can be made based on urinary .beta.-core-hCG levels alone or in conjunction with levels of other urinary and/or serum markers, ultrasound parameters and other factors, such as, maternal age.</p>
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L-.beta.-dioxolane uridine analogs and methods for treating and preventing Epstein-Barr virus infections (Wed, 09 Feb 2000)
<p>The present invention relates to the discovery that certain .beta.-L-dioxolane nucleoside analogs which contain a uracil base, and preferably, a 5-halosubstituted uracil base, exhibit unexpectedly high activity against Epstein-Barr virus (EBV), Varciella-Zoster virus (VZV) and Herpes Virus 8 (HV-8). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus (viral growth) in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds are useful for treating EBV, VZV and HV-8 infections in humans. -GOVT PAR The United States Government has retained certain rights in this invention arising out of NIH Grant No. R01-A133655.</p>
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Regulation of gene expression (Wed, 09 Feb 2000)
<p>The present invention relates to utrons, RNA molecules which contain promoter regulatory motif(s) and DNA analogs thereof and DNA molecules that can be transcribed to produce the foregoing. In particular, the invention provides gene promoter suppressing nucleic acids which suppress transcription from a promoter of interest. In a preferred embodiment, the invention provides the TSU gene, nucleotide sequences of the TSU gene and RNA, as well as fragments, homologs and derivatives thereof. Methods of isolating TSU genes are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are also provided. In particular, the invention relates to methods for cell replacement therapy, gene therapy or organ transplantation wherein TSU nucleic acids suppress MHC class I and II gene expression, thus preventing immuno-rejection of non-autologous cells or organs. The invention also provides methods for treatment of diseases or disorders by suppression of MHC class I, MHC class II, ICAM-1, B7-1, B7-2, and/or Fc.gamma.R expression by provision of TSU function.</p>
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Use of 2',3'-dideoxycytidin-2'-ene (2'- ,3'-dideoxy-2'3'-didehydrocytidine) in treating patients infected with retroviruses (Wed, 15 Dec 1999)
<p>This invention relates to the use of 2',3'-dideoxycytidin-2'-ene (2',3'-dideoxy-2',3'-didehydrocytidine) in treating patients infected with a retrovirus. -GOVT PAC GOVERNMENT RIGHTS PAR This invention was made with United States government support under Grant CA-28852 from the NIH. The United States Government has certain rights in this invention.</p>
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MULTIPARAMETRIC FLUORESCENCE IN SITU HYBRIDIZATION (Fri, 10 Dec 1999)
The invention relates to a set of combinatorially labeled oligonucleotide probes each member thereof: (i) having a predetermined label distinguishable from the label of any other member of said set, and (ii) being capable of specifically hybridizing with a predetermined chromosome or nucleic acid molecule, and to the use of such molecules, alone or in concert with nucleic acid amplification methods. </p>
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Composition of L-oddC Compound derivatives and methods of use as antineoplastic agents. (Thu, 18 Nov 1999)
(-)-(2S,4S)—1-(2—Hydroxymsthy i-i,o-diaxo1 an—4—y1)cytosine (also referred to as L-OddC) according to the formula : or its ancer,cells derivative, and its use tumors, including or other abnormal or undesired proliferation of in animals, including humans.
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Transition metal-catalyzed process for preparing N-aryl compounds (Wed, 03 Nov 1999)
<p>The present invention is directed to a process for the preparation of N-aryl compounds containing at least one unsaturated nitrogen atom, comprising reacting a compound having at least one unsaturated nitrogen atom with an arylating compound in the presence of a base and a transition metal catalyst under reaction conditions effective to form an N-aryl compound containing at least one unsaturated nitrogen atom, wherein the aryl moiety of the N-aryl compound is bonded to the at least one unsaturated nitrogen atom, the transition metal catalyst comprising a Group 8 metal and at least one chelating ligand selected from the group consisting of Group 15-substituted metallocenes, Group 15-substituted arylenes, unsaturated Group 15 heterocycles, Group 15-substituted alkanes, and combinations thereof. The process of the present invention a useful general method of N-arylation for the manufacture of pharmaceuticals, polymers, and the like. -GOVT PAC STATEMENT OF GOVERNMENT SUPPORT PAR This application was made with United States Government support under Award Number 1-R29-GM382-01 from the National Institutes of Health. The U.S. Government has certain rights in this invention.</p>
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METHOD TO IDENTIFY MODULATORS OF SURVIVIN - TUBULIN INTERACTION (Fri, 08 Oct 1999)
The present invention, based on the discovery of a new biological phenomena, provides methods and compositions for use in identifying agents which modulate the interaction between Survivin and polymerized tubulin or the mitotic spindles. Related methods and compositions can be used to modulate the interactions between Survivin and polymerized tubulin or the mitotic spindles, thereby modulating Survivin regulated apoptosis.
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N,N'-BIS(SULFONYL)HYDRAZINES USEFUL AS ANTINEOPLASTIC AGENTS (Sat, 15 May 1999)
The present invention relates to a compound of formula (I) wherein R?1 and R2¿ are selected from lower alkyl groups having 1-6 carbon atoms, substituted or unsubstituted aryl groups, and unsaturated alkyl groups having 1-6 carbon atoms; R3 is a substituted or unsubstituted lower alkyl group having 1-6 carbons; and R4 is selected from substituted or unsubstituted lower alkyl groups having 1-6 carbon atoms, substituted or unsubstituted aryl groups, and unsaturated alkyl groups having 1-6 carbon atoms. The present invention also relates to a pharmaceutical composition comprising the above compound, as well as a method of treating tumor cells with the compound.
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N,N'-BIS(SULFONYL)HYDRAZINES USEFUL AS ANTINEOPLASTIC AGENTS (Sat, 15 May 1999)
The present invention relates to a compound of formula (I) wherein R1 and R2 are selected from lower alkyl groups having 1-6 carbon atoms, substituted or unsubstituted aryl groups, and unsaturated alkyl groups having 1-6 carbon atoms; R3 is a substituted or unsubstituted lower alkyl group having 1-6 carbons; and R4 is selected from substituted or unsubstituted lower alkyl groups having 1-6 carbon atoms, substituted or unsubstituted aryl groups, and unsaturated alkyl groups having 1-6 carbon atoms. The present invention also relates to a pharmaceutical composition comprising the above compound, as well as a method of treating tumor cells with the compound. </p>
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JNK3 MODULATORS AND METHODS OF USE (Fri, 16 Apr 1999)
The c-Jun NH2-terminal kinase (JNK) group of MAP kinases are activated by exposure of cells to environmental stress. The role of JNK in the brain was examined by targeted disruption of the gene that encodes the neuronal isoform JNK3. It was found that JNK3 is required for the normal response to seizure activity. Methods of screening for molecules and compounds that decrease JNK3 expression or activity are described. Such molecules or compounds are useful for treating disorders involving excitotoxicity such as seizure disorders, Alzheimer's disease, Huntington disease, Parkinson's disease, and ischaemia. </p>
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A METHOD FOR SELECTIVELY CONTROLLING MEMBRANE PROTEIN DISPLAY AND PROTEIN SECRETION IN EUKARYOTIC CELLS (Fri, 09 Apr 1999)
A method and related compositions are disclosed that modulate the presence on a cell surface membrane of selected integral membrane proteins, or modulate the secretion of selected secretory proteins, by increasing or decreasing the intracellular transport of the protein form the endoplasmic reticulum to and through the cis-Golgi apparatus. Associated methods are disclosed to identify whether the intracellular transport of a specific protein is mediated by the spectrin-ankyrin-adapter protein trafficking system (SAATS). Related methods to determine whether a candidate compound inhibits or enhances the intracellular transport of a selected protein from the endoplasmic reticulum to the cis-Golgi apparatus by SAATS also are disclosed. Disclosed agents and methods are applicable for a variety of uses, including as immunoregulators, ion transport inhibitors, vascular modulators and cancer chemotherapeutics.
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A METHOD FOR SELECTIVELY CONTROLLING MEMBRANE PROTEIN DISPLAY AND PROTEIN SECRETION IN EUKARYOTIC CELLS (Fri, 09 Apr 1999)
A method and related compositions are disclosed that modulate the presence on a cell surface membrane of selected integral membrane proteins, or modulate the secretion of selected secretory proteins, by increasing or decreasing the intracellular transport of the protein form the endoplasmic reticulum to and through the cis-Golgi apparatus. Associated methods are disclosed to identify whether the intracellular transport of a specific protein is mediated by the spectrin-ankyrin-adapter protein trafficking system (SAATS). Related methods to determine whether a candidate compound inhibits or enhances the intracellular transport of a selected protein from the endoplasmic reticulum to the cis-Golgi apparatus by SAATS also are disclosed. Disclosed agents and methods are applicable for a variety of uses, including as immunoregulators, ion transport inhibitors, vascular modulators and cancer chemotherapeutics. </p>
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RADIATION DOSIMETRY WITH MAGNETIC RESONANCE DETECTABLE COMPOUNDS (Fri, 19 Mar 1999)
A method for radiation dosimetry utilizes magnetic resonance spectroscopy and/or imaging of radiation-sensitive compounds in irradiated tissue or samples. Typical embodiments employ coated or uncoated superparamagnetic iron oxide particles which are administered to a patient to provide a means to assess the amount of radiation which a tumor target receives during radiotherapy.
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BINUCLEAR NON-HEME IRON CATALYSTS (Fri, 05 Mar 1999)
The subject invention provides a binuclear metal complex having structure (I) wherein M1, and M2 are independently selected from the group consisting of Fe, Co, Mn and Ru; wherein m and n are independently +2 or +3; wherein R1, R2, R3, R4, R5 and R6 are independently a linear C1-C6 alkyl, C5-C6 cycloalkyl, phenyl, etc.; wherein (i) R1 and R2, (ii) R3 and R4, or (iii) R5 and R6 independently and optionally are linked covalently and together with the respective adjoining C atom comprise a spirocyclic ring; wherein i, j and k are integers such that 2≤i + j + k≤4; wherein p is 1 or 2, and q is 0, 1 or 2 such that m + n-4=p x q; wherein (i) R1 or R2 and R3 or R4, (ii) R3 or R4 and R4 or R5, or (iii) R1 or R2 and R5 or R6 independently and optionally are linked covalently and together with the respective adjoining C atoms comprise a fused ring; wherein Ar is 1,2-phenylene, 1,2- or 2,3-naphthylene, etc., wherein said Ar is optionally substitued by C1-C6 alkyl or alkoxy; wherein L is N-methylimidazole, N-ethylimidazole, etc.; and wherein X is fluorine, chlorine, bromine, etc. Also provided are methods of oxidation of alkanes, arenes, and sulfides using the binuclear metal complex as a catalyst and a method of preparing said complex.
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SYNTHETIC METALLOPROTEINS AND METHOD OF PREPARATION THEREOF (Fri, 04 Dec 1998)
The subject invention provides synthetic metalloproteins containing at least one metal binding site consisting of a metal ion and ligands associated therewith. Such metalloproteins are prepared by using protein structure coordinate arrays to determine a set of primary sequence mutations in a preselected host protein, and constructing the synthetic metalloproteins by methods of recombinant genetics, protein expression and purification. Particular applications include synthetic superoxide dismutases and monooxidases. Also provided is a method of oxidizing an alkane using a synthetic metalloprotein in which a monooxygenase active site is installed. Other uses of synthetic metalloproteins include a method of treating a subject suffering from reperfusion type tissue damage and from ischemia.
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(Cyanomethylene) phosphoranes as carbonyl 1,1-dipole synthons for use in constructing combinatorial libraries (Wed, 11 Nov 1998)
<p>The invention is directed to systematic synthetic and testing strategies for .alpha.-keto acids, esters and amides. The method of synthesis comprises (A) reacting (cyanomethylene)triphenylphosphorane with a carbonyl compound selected from carboxylic acids (RCOOH) and acyl chlorides (RCOCl) to make a cyano keto phosphorane, (B) oxidizing said phosphorane and (C) reacting the oxidized product with a nucleophile (NuH) to make the product .alpha.-keto acid, ester or amide. Systematic synthesis and testing are achieved by a modular approach in which arrays of molecules are generated by variation of R and Nu.</p>
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L-2'3',dideoxy nucleoside analogs as anti-hepatitus B (HBV) agents (Wed, 04 Nov 1998)
<p>The present invention relates to the surprising discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D- configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV. -GOVT PAR This work is supported by National Institutes of Health Grants CA44358 and AI25899. The United States Government retains a certain rights in the invention.</p>
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Method of resolution of 1,3-oxathiolane nucleoside enantiomers (Wed, 28 Oct 1998)
<p>A process for the resolution of a racemic mixture of nucleoside enantiomers that includes the step of exposing the racemic mixture to an enzyme that preferentially catalyzes a reaction in one of the enantiomers. The nucleoside enantiomer (-)-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane is an effective antiviral agent against HIV, HBV, and other viruses replicating in a similar manner. In particular, deaminase, PPL, PLE and subtilisn are used to resolve 1,3-oxathiolane nucleoside enantiomers. -GOVT PAR The U.S. Government has rights in this invention arising out of the partial funding of work leading to this invention through the National Institutes of Health Grant Nos. NIH 5-21935 and NIH AI-26055, as well as a Veteran's Administration Merit Review Award.</p>
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Compounds and methods for the treatment of cancer (Wed, 07 Oct 1998)
<p>(-)-(2S,4S)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)cytosine (also referred to as (-)-OddC) and its use to treat cancer in animals, including humans. -GOVT PAC GOVERNMENT RIGHTS PAR The U.S. government has rights in this invention by virtue of Grant No. CA-44358 from the National Cancer Institute (NIH).</p>
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Metal-catalyzed amination of organic sulfonates to organic amines (Wed, 07 Oct 1998)
<p>A process of preparing an organic amine having at least one unsaturated group, such as an arylamine, involving contacting an unsaturated organic sulfonate, such as an aryl sulfonate, with a reactant amine, such as an alkyl or aryl amine, in the presence of a base and a transition metal catalyst under reaction conditions. The transition metal catalyst contains a Group 8 metal and a chelating ligand, for example a Group 15-substituted arylene or Group 15-substituted metallocene, such as 1,1'-bis(diphenylphosphino)-2,2'-binaphthyl or 1,1'-bis(diphenylphosphino)-ferrocene, respectively. The aryl sulfonate can be prepared from a phenol and sulfonating agent. -GOVT PAR This application was made with United States Government support under Award Number CHE-9457672 awarded by The National Science Foundation.</p>
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COVALENT CONJUGATES OF TOPOISOMERASE I AND TOPOISOMERASE II INHIBITORS (Fri, 18 Sep 1998)
The present invention provides covalent conjugates of topoisomerase I and topoisomerase II inhibitors. Such compounds have a structure according to the formula (I): TI-L-TII wherein: TI is a topoisomerase I inhibitor such as a camptothecin group; TII is a topoisomerase II inhibitor such as an amsacrine, ellipticine, epipodophyllotoxin, or anthracycline antibiotic group; and L is a linking group. The compounds are useful for inhibiting topoisomerase I and II enzymes, for promoting cellular differentiation, and for treating cancer.
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L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides (Wed, 16 Sep 1998)
<p>A method for stabilizing an oligonucleotide by including a .beta.-L-2'-deoxy-2'-fluoro-arabinofuranosyl nucleoside at the 5'-terminus, the 3'-terminus, or in the interior of the oligonucleotide. The oligonucleotide can be used in the modulation of gene expression through a process wherein a synthetic oligonucleotide is hybridized to a complementary nucleic acid sequence to inhibit transcription or replication of DNA or to inhibit translation or processing of RNA.</p>
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L-.beta.-dioxolane uridine analog administration for treating Epstein-Barr virus infection (Wed, 12 Aug 1998)
<p>The present invention relates to the discovery that certain .beta.-L-dioxolane nucleoside analogs which contain a uracil base, and preferably, a 5-halosubstituted uracil base, exhibit unexpectedly high activity against Epstein-Barr virus (EBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus (viral growth) in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds are useful for treating EBV infections in humans.</p>
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DIAGNOSTIC METHODS AND COMPOSITIONS BASED ON THE DISTRIBUTION OF RAD51 (Fri, 07 Aug 1998)
Method of diagnosing individual at risk for a disease comprising determining the distribution of RAD51 foci in a tissue type of a first individual; and comparing said distribution of RAD51 foci form a second normal tissue type from said first individual or a second unaffected individual.
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DIAGNOSTIC METHODS AND COMPOSITIONS BASED ON THE DISTRIBUTION OF RAD51 (Fri, 07 Aug 1998)
Method of diagnosing individual at risk for a disease comprising determining the distribution of RAD51 foci in a tissue type of a first individual; and comparing said distribution of RAD51 foci form a second normal tissue type from said first individual or a second unaffected individual. </p>
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SURVIVIN, A PROTEIN THAT INHIBITS CELLULAR APOPTOSIS, AND ITS MODULATION (Fri, 29 May 1998)
The present invention provides the amino acid of a protein that inhibits cellular apoptosis, herein termed the Survivin protein and nucleic acid molecules that encode Survivin. Based on this disclosure, the present invention provides isolated Survivin protein, isolated Survivin encoding nucleic acid molecules, methods of isolating other members of the Survivin family of proteins, methods for identifying agent that blocks Survivin mediated inhibition of cellular apoptosis, methods of using agent that block Survivin mediated inhibition or Survivin expression to modulate biological and pathological processes, and methods of assaying Survivin activity.
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L-β-DIOXOLANE URIDINE ANALOGS AND METHODS FOR TREATING AND PREVENTING VIRUS INFECTIONS (Sat, 23 May 1998)
The present invention relates to the discovery that certain β-L-dioxolane nucleoside analogs which contain a uracil base, and preferably, a 5-halosubstituted uracil base, exhibit unexpectedly high activity against Epstein-Barr virus (EBV), Varicella-Zoster virus (VZV) and Human Herpes Virus 8 (HV-8). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus (viral growth) in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds are useful for treating EBV, VZV and HV-8 infections in humans.
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L-.BETA.-DIOXOLANE URIDINE ANALOGS AND METHODS FOR TREATING AND PREVENTING VIRUS INFECTIONS (Sat, 23 May 1998)
The present invention relates to the discovery that certain .beta.-L-dioxolane nucleoside analogs which contain a uracil base, and preferably, a 5- halosubstituted uracil base, exhibit unexpectedly high activity against Epstein-Barr virus (EBV), Varicella-Zoster virus (VZV) and Human Herpes Virus 8 (HV-8). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus (viral growth) in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds are useful for treating EBV, VZV and HV-8 infections in humans. </p>
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Oligonucleotides containing L-nucleosides (Wed, 20 May 1998)
<p>Oligonucleotides that include a 2'-fluoro .beta.-L-arabinofuranosyl nucleoside at the 3'-terminus, the 5'-terminus or in the interior of the oligomer. A preferred nucleoside is 2'-fluoro-5-methyl-.beta.-L-arabinofuranosyluridine (also referred to as L-FMAU). This compound is a potent antiviral agent against HBV and EBV and exhibits low cytotoxicity. Other specific examples of active compounds include N.sub.1 -(2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl)-5-ethyluracil, N.sub.1 -(2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl)-5-iodocytosine), and N.sub.1 -(2'-deoxy-2'-fluoro-.beta.-L-arabinofuranosyl)-5-iodouracil.</p>
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Nucleic acids encoding ancylostoma secreted protein (Wed, 20 May 1998)
<p>A protein, Ancylostoma Secreted Protein (ASP), that is released by hookworm larvae following infection, and which is highly immunogenic in experimental animals, is disclosed. Nucleic acids encoding ASP, antibodies recognizing ASP, and methods of detecting ASP, nucleic acids encoding ASP, and antibodies recognizing ASP, in a sample are also disclosed. ASP is useful in a vaccine for hookworm as well as other soil-transmitted human and veterinary nematodiases. ASP is also useful as a target for specific treatment of hookworm, and can be used in a diagnostic assay for hookworm, using standard protein detection techniques, especially those based on antibodies. DNA encoding ASP is useful both for producing ASP recombinantly and in a diagnostic assay for hookworm. Antibodies recognizing ASP are useful in diagnostic assays to detect protein produced during hookworm infection. -GOVT PAR This invention was made with government support under Grant Numbers R29-AI32726 awarded by the Department of Health and Human Services. The government has certain rights in the invention.</p>
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MONOPHOSPHATE PRODRUGS OF β-L-FD4C AND β-L-FddC AS POTENT ANTIVIRAL AGENTS (Fri, 01 May 1998)
The present invention relates to certain prodrug forms of the L-dideoxynucleoside analogs β-L-FD4C and β-L-FddC, especially β-L-Fd4C, which preferably contain S-acyl-2-thioethyl-bearing 5'monophosphate groups which exhibit excellent activity against hepatitis B virus (HBV) and human immunodeficiency virus (HIV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e, animal or human tissue) and unexpectedly high therapeutic indices. The prodrug form of β-L-FD4C exhibits particularly effective inhibition of HBV in comparison to β-L-FD4C and markedly improved therapeutic index.
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Method of using 2-formylpyridine thiosemicarbazone compounds (Wed, 25 Feb 1998)
<p>A method of treatment of tumors is provided based upon a compound of the formula ##STR1## wherein one of R.sup.1 is NHR.sup.4 or NR.sup.4 R.sup.5 or R.sup.3 is NHR.sup.4, NR.sub.4 R.sup.5 or OH, and the other is hydrogen; PA1 R.sup.2 is hydrogen or C.sub.1-4 lower alkyl; PA1 R.sup.4 is hydrogen, hydroxyl or C.sub.1-4 lower alkyl; and PA1 R.sup.5 is C.sub.1-4 lower alkyl; or PAL a pharmaceutically acceptable salt or hydrate thereof. PAL In a further aspect there is provided a method for the treatment of a tumor in a mammal which comprises administration of a compound which is 3- or 5-hydroxy-4-methyl-2-formylpyridine thiosemicarbazone to said mammal. -GOVT PAR Some aspects of the invention were supported in part by U.S. Public Health Service Grant CA-02817 from the National Cancer Institute and support from the Northeast NMR Facility at Yale University insofar as the use of high resolution NMR spectra is concerned that was made possible by a grant from the Chemical Division of the National Science Foundation (Grant No. CHE-7916210).</p>
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REGULATION OF GENE EXPRESSION (Fri, 28 Nov 1997)
The present invention relates to utrons, RNA molecules which contain promoter regulatory motif(s) and DNA analogs thereof and DNA molecules that can be transcribed to produce the foregoing. In particular, the invention provides gene promoter suppressing nucleic acids which suppress transcription from a promoter of interest. In a preferred embodiment, the invention provides the TSU gene, nucleotide sequences of the TSU gene and RNA, as well as fragments, homologs and derivatives thereof. Methods of isolating TSU genes are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are also provided. In particular, the invention relates to methods for cell replacement therapy, gene therapy or organ transplantation wherein TSU nucleic acids suppress MHC class I and II gene expression, thus preventing immuno-rejection of non-autologous cells or organs. The invention also provides methods for treatment of diseases or disorders by suppression of MHC class I, MHC class II, ICAM-1, B7-1, B7-2, and/or FcηR expression by provision of TSU function.
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Sterol modified oligonucleotide duplexes having anticancer activity (Wed, 09 Jul 1997)
<p>Oligonucleotides having approximately 8 to 18 nucleotide units and a 3'-tail which includes asteroid structure attached to the 3'-end through the A ring of the steroid skeleton and which form substantially stable duplexes at physiological temperature, have selective cytotoxic activity against certain tumor cell lines.</p>
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Antitumor 2-aminocarbonyl-1, 2-bis(methylsulfonyl)-1-(substituted)hydrazines (Wed, 11 Jun 1997)
<p>The present invention relates to novel 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines and 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-methylhydrazines, and their use to treat malignant tumors. The agents are especially useful in the treatment of animal and human cancers. Two preferred agents in this class, especially for use in the treatment of tumors are 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(2-chloroethyl)aminocarbonylhy drazine and 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-methylaminocarbonylhydrazine. These agents are characterized by the following: they are incapable of undergoing inactivation by the denitrosation mechanism proposed for the inactivation of the CNUs; they are incapable of generating a hydroxyethylating species by the mechanism proposed for the CNUs; and they are capable of chloroethylation or methylation and carbamoylation. -GOVT PAR This invention was made with government support under grant number CA-53340 awarded by the Department of Health and Human Services.</p>
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Three-dimensional detection, dosimetry and imaging of an energy field by formation of a polymer in a gel (Wed, 28 May 1997)
<p>A visible and/or MRI visualizable permanent image is formed in a gel in a container which maintains the gel a dimensionally stable shape, which gel contains uniformly dispersed therein in storage stable form at least one radiant energy, e.g., ionizing radiation, or mechanical, e.g., ultrasonic or sonic shock wave, polymerizable monomer in a concentration effective to form a polymer in the gel which alters the NMR relaxation time of the solvent in any area thereof in which the polymer is formed, e.g., a mixture of (a) a linearly homopolymerizable monomer and (b) a comonomer which is cross-linkably copolymerizable with the monomer, the polymerization of the monomer initiated by the radiant or mechanical energy being restricted to any area of the gel which receives that energy, which image is representative of the dose distribution of the energy to which the gel is exposed, by exposing the gel to a non-uniform dose of the energy until a polymer which produces a permanent image representative of the dose of the energy received by the gel is formed therein. The image can be used for dosimetric purposes; to provide reference standards for quality control of magnetic resonance imaging techniques and equipment; and as a three- or two-dimensional array detector in industrial radiography (nondestructive testing techniques).</p>
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L-2',3'-dideoxy nucleoside analogs as anti-Hepatitis B (HBV) agents (Wed, 21 May 1997)
<p>The present invention relates to the surprising discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D- configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV. -GOVT PAR This work is supported by National Institutes of Health Grants CA44358 and AI29430. The United States Government retains certain rights in the invention.</p>
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L-2',3'-dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents (Wed, 07 May 1997)
<p>The present invention relates to the surprising discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D-configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV. The compound 1-(2,3-dideoxy-beta-L-ribofuranosyl)-5-fluorocytosine is shown to be a potent anti-HIV agent with low toxicity to host cells. -GOVT PAR This work is supported by National Institutes of Health Grants AI29430 and CA44358. The United States Government retains certain rights in the invention.</p>
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GLYCOSYLATED INDOLOCARBAZOLE SYNTHESIS (Fri, 28 Feb 1997)
Tertiary alcohols containing the structural features illustrated in 3 or 4 (Scheme I) are prepared by reacting at least one diazo carbonyl compound, (e.g., 1 in Scheme I) and at least one allylic alcohol (e.g., 2 in Scheme I) in a coupling reaction run under conditions that produce carbene or carbenoid intermediates from the diazo-containing substrate such as transition metal catalysis or either thermal or photochemical decomposition. In some preferred embodiments, Rh2(OAc)4 is employed to catalyze the coupling reaction. In Scheme I R represents a substituent comprised of any number and combination of the elements H, C, N, S, Si, O, Cl, Br, I, and F. Indolocarbazoles (e.g., 7 in Scheme II) are prepared by coupling of diazo carbonyl compounds (e.g., 5 Scheme II) and biindoles (e.g., 6 in Scheme II). Indolocarbazoles are furanosylated (e.g., 7 in Scheme II) with acetals (e.g., 8 in Scheme II) or their open chain congeners (e.g., 9 in Scheme II) under conditions known to promote acetal exchange or formation, such as protic or Lewis acids. Furanosylated indolocarbazoles (e.g., 10 in Scheme II) are also prepared via ring contraction of pyranosylated indolocarbazoles (e.g., 11 in Scheme II) under conditions know to effect oxidation and benzylic acid type rearrangements, and pyranosylated indolocarbazoles (e.g., 11 in Scheme II) are prepared via ring expansion of the furanosylated congeners (e.g., 10 in Scheme II).
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ANTITUMOR 2-AMINOCARBONYL-1,2-BIS(METHYLSULFONYL)-1-(SUBSTITUTED)HYDRAZINES (Fri, 24 Jan 1997)
The present invention relates to novel 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines and 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-methylhydrazines, and their use to treat malignant tumors. The agents are especially useful in the treatment of animal and human cancers. Two preferred agents in this class, especially for use in the treatment of tumors are 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(2-chloroethyl)aminocarbonylhydrazine and 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-methylaminocarbonylhydrazine. These agents are characterized by the following: they are incapable of undergoing inactivation by the denitrosation mechanism proposed for the inactivation of the CNUs roethylation or methylation and carbamoylation.
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ANTITUMOR 2-AMINOCARBONYL-1,2-BIS(METHYLSULFONYL)-1-(SUBSTITUTED)HYDRAZINES (Fri, 24 Jan 1997)
A compound of the formula: CH3SO2N(Y)N(CONHR)SO2CH3 where Y is -CH3 or --CH2CH2Cl; and R is C1-C7 alkyl, cyclohexyl, methylcyclohexyl, -CH2CH=CH2 ,--CH2CH2Cl, -CH2CH2CH2Cl, -CH2COOC2H5, -CH(CH3)COOC2H5 or - CH(CH2C6H5)COOC2H5. The present invention relates to novel 2-aminocarbonyl--1,2-bis(methylsulfonyl)-1-(2-chloroeghyl)hydrazines and 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-methylhydrazines, and their use to treat malignant tumors. The agents are especially useful in the treatment of animal and human cancers. Two preferred agents in this class, especially for use in the treatment of tumors are 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(2- chloroethyl)aminocarbonylhydrazine and 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-methylaminocarbonylhydrazine. These agents are characterized by the following: They are incapable of undergoing inactivation by the denitrosation mechanism proposed for the inactivation of the CNUs roethylation or methylation and carbamoylation. </p>
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L-nucleosides (Wed, 25 Dec 1996)
<p>A compound, and a pharmaceutical composition comprising an effective mount to treat HBV or EBV of a compound, of the formula: ##STR1## wherein R is selected from the group consisting of 5-methyluracil, adenine and cytosine, and R' is hydrogen, acyl, or alkyl or a monophosphate, diphosphate or triphosphate ester, or its pharmaceutically acceptable salt. -GOVT PAR This invention was supported in part by the United States Department of Health and Human Services under grant numbers NIH R01-AI-33655 AND NCI CA44358. PAR This invention is in the area of methods for the treatment of hepatitis B virus (also referred to as "HBV") and Epstein-Bar Virus (referred to as "EBV") that includes administering an effective amount of one or more of the active compounds disclosed herein, or a pharmaceutically acceptable derivative or prodrug of one of these compounds.</p>
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L-nucleosides for the treatment of hepatitis B-virus (Wed, 23 Oct 1996)
<p>A method for the treatment of a human infected with HBV that includes administering an HBV-treatment amount of an L-nucleoside of the formula: ##STR1## wherein R is selected from the group consisting of 5-methyluracil, adenine and cytosine, and R' is hydrogen, acyl, alkyl or a monophosphate, diphosphate or triphosphate ester, or its pharmaceutically acceptable salt. -GOVT PAR This invention was supported in part by the United States Department of Health and Human Services under grant numbers NIH R01AI-33655 AND NCI CA44358.</p>
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HOOKWORM VACCINE (Fri, 18 Oct 1996)
Proteins that are released by hookworm larvae following infection, and which are highly immunogenic in experimental animals, are disclosed. Data indicates that these polypeptides are useful in a vaccine for hookworm as well as other soil-transmitted human and veterinary nematodiases. The proteins are also useful as a target for specific treatment of hookworm, and can be used in a diagnostic assay for hookworm, using standard protein detection techniques, especially those based on antibodies. DNA encoding the proteins has been isolated. The proteins can be made by recombinant means in a variety of hosts. The recombinant proteins, or fragments thereof, can be formulated as a vaccine. The recombinant proteins can also be used in an assay to detect antibodies to the protein produced in a previous hookworm infection. The recombinant proteins can also be used to produce antibodies which recognize the proteins. DNA encoding all or immunogenic parts of the proteins can be used as probes to detect the presence of hookworm nucleic acid. Such probes are useful in assays of tissue samples, body fluid samples, and hookworm infection sources. Antibodies to the proteins can be produced using standard immunological techniques. Such antibodies are useful in diagnostic assays to detect proteins produced during hookworm infection.
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L-nucleosides for the treatment of epstein-bar virus (Wed, 16 Oct 1996)
<p>A method for the treatment of a human infected with EBV that includes administering an EBV-treatment amount of an L-nucleoside of the formula: ##STR1## wherein R is 5-methyluracil, and R' is hydrogen, acyl, alkyl or a monophosphate, diphosphate or triphosphate ester, or its pharmaceutically acceptable salt.</p>
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Method for treating HBV infections with L-2',3'-didehydro-dideoxy-5-fluorocytidine (Wed, 02 Oct 1996)
<p>The present invention relates to the surprising discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D- configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV. -GOVT PAR This work is supported by National Institutes of Health Grants CA44358 and AI25899. The United States Government retains certain rights in the invention.</p>
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4.beta.-amino podophyllotoxin analog compounds and methods (Wed, 31 Jul 1996)
<p>Novel podophyllotoxin compounds and their use in treating tumors are disclosed. The analogs have the general formula: ##STR1## wherein NH--R is a selected aryl amine, dialkylaminoalkyleneamino, or dialkylaminoanilino group.</p>
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COMPOUNDS AND METHODS FOR THE TREATMENT OF CANCER (Fri, 15 Mar 1996)
(-)-(2S,4S)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)cytosine (also referred to as L-OddC) or its derivative and its use to treat tumors, including cancer, or other abnormal or undesired proliferation of cells, in animals, including humans.
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COMPOUNDS AND METHODS FOR THE TREATMENT OF CANCER (Fri, 15 Mar 1996)
(-)-(2S,4S)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)cytosine (also referred to as L-OddC) or its derivative and its use to treat tumors, including cancer, or other abnormal or undesired proliferation of cells, in animals, including humans. </p>
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Modified nucleotides and polynucleotides and complexes form therefrom (Wed, 20 Dec 1995)
<p>Compounds having the structure: ##STR1## wherein B represents a purine, 7-deazapurine, or pyrimidine moiety covalently bonded to the C.sup.1' -position of the sugar moiety, provided that when B is purine or 7-deazapurine, it is attached at the N.sup.9 -position of the purine or 7-deazapurine and when B is pyrimidine, it is attached at the N.sup.1 -position; PA1 wherein A represents a moiety consisting of at least three carbon atoms which is capable of forming a detectable complex with a polypeptide when the compound is incorporated into a double-stranded ribonucleic acid, deoxyribonucleic acid duplex, or DNA-RNA hybrid; PA1 wherein the dotted line represents a chemical linkage joining B and A, provided that if B is purine, the linkage is attached to the 8-position of the purine, if B is 7-deazapurine, the linkage is attached to the 7-position of the deazapurine, and if B is pyrimidine, the linkage is attached to the 5-position of the pyrimidine; and PA1 wherein each of x, y and z represents ##STR2## either directly, or when incorporated into oligo- and polynucleotides, provide probes which are widely useful. PAL Applications include detection and localization of polynucleotide sequences in chromosomes, fixed cells, tissue sections, and cell extracts. Specific applications include chromosomal karyotyping, clinical diagnosis of nucleic acid-containing etiological agents, e.g. bacteria, viruses, or fungi, and diagnosis of genetic disorders. -GOVT PAR This invention was made with government support under grant numbers P50 GM 20124, T32 GM 07499 and T32 CA 09159 awarded by the National Institutes of Health of the Department of Health and Human Services. The Government has certain rights in the invention.</p>
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Immune system modulation using psoralens activated with visible light (Wed, 01 Nov 1995)
<p>Methods and pharmaceutical compositions for modifying the immune response of a mammal are provided. The pharmaceutical compositions include a pharmaceutically acceptable carrier and a plurality of cells containing psoralen-DNA monoadducts and substantially no psoralen-DNA crosslinks. The preparation is formed by irradiating a suspension of cells with visible light radiation in the presence of psoralen. -GOVT PAC GOVERNMENT SUPPORT PAR This invention was made with government support under Contract. No. 2R01CA43058-09A1 awarded by the National Institutes of Health. The government has certain rights in the invention.</p>
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Modified polynucleotides and methods of preparing same (Wed, 13 Sep 1995)
<p>Compounds having the structure: ##STR1## wherein B represents 7-deazapurine, or pyrimidine moiety covalently bonded to the C.sup.1 '-position of the sugar moiety, provided that when B is 7-deazapurine, it is attached at the N.sup.9 -position of the 7-deazapurine and when B is pyrimidine, it is attached at the N.sup.1 -position; PA0 wherein A represents a moiety consisting of at least three carbon atoms which is capable of forming a detectable complex with a polypeptide when the compound is incorporated into a double-stranded ribonucleic acid, deoxyribonucleic acid duplex, or DNA-RNA hybrid; PA0 wherein the dotted line represents a chemical linkage joining B and A, provided that if B is 7-deazapurine, the linkage is attached to the 7-position of the deazapurine, and if B is pyrimidine, the linkage is attached to the 5-position of the pyrimidine; and PA0 wherein each of x, y and z represents ##STR2## either directly, or when incorporated into oligo- and polynucleotides, provide probes which are widely useful. -GOVT PAR The invention disclosed and/or claimed in this application was made in the course of work carried out under grants from the Public Health Service, National Institute of General Medical Research Grant No. P50-GM20124; Public Health Service, National Cancer Institute Training Grant No. T32-CA09159; and Public Health Service, National Institute of General Medical Science Grant No. T32-GM07499. The Government has certain rights in the invention.</p>
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MODIFIED OLIGONUCLEOTIDE DUPLEXES HAVING ANTICANCER ACTIVITY (Fri, 01 Sep 1995)
Oligonucleotides having approximately 8 to 18 nucleotide units and a 3'-tail which includes a steroid structure attached to the 3'-end through the A ring of the steroid skeleton and which form substantially stable duplexes at physiological temperature, have selective cytotoxic activity against certain tumor cell lines.
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L-NUCLEOSIDES FOR THE TREATMENT OF HEPATITIS B-VIRUS AND EPSTEIN-BAR VIRUS (Fri, 04 Aug 1995)
A method for the treatment of a host, and in particular, a human, infected with HBV or EBV is provided that includes administering an HBV- or EBV- treatment amount of an L-nucleoside of formula(I) wherein R is a purine or pyrimidine base. In one preferred embodiment, the active compound is 2'-fluoro-5-methyl-β-L-arabinofuranosyluridine (also referred to as L-FMAU). This compound is a potent antiviral agent against HBV and EBV and exhibits low cytotoxicity. Other specific examples of active compounds include N1-(2'-deoxy-2'-fluoro-β-L-arabinofuranosyl)-5-ethyluracil, N1-(2'-deoxy-2'-fluoro-β-L-arabinofuranosyl)-5-iodocytosine), and N1-(2'-deoxy-2'-fluoro-β-L-arabinofuranosyl)-5-iodouracil.
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L-NUCLEOSIDES FOR THE TREATMENT OF HEPATITIS B-VIRUS AND EPSTEIN-BAR VIRUS (Fri, 04 Aug 1995)
A method for the treatment of a host, and in particular, a human, infected with HBV or EBV is provided that includes administering an HBV- or EBV- treatment amount of an L-nucleoside of formula(I) wherein R is a purine or pyrimidine base. In one preferred embodiment, the active compound is 2'-fluoro- 5-methyl-.beta.-L-arabinofuranosyluridine (also referred to as L-FMAU). This compound is a potent antiviral agent against HBV and EBV and exhibits low cytotoxicity. Other specific examples of active compounds include N1-(2'-deoxy- 2'-fluoro-.beta.-L-arabinofuranosyl)-5-ethyluracil, N1-(2'-deoxy-2'-fluoro- .beta.-L-arabinofuranosyl)-5-iodocytosine), and N1-(2'-deoxy-2'-fluoro-.beta.- L-arabinofuranosyl)-5-iodouracil. </p>
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Conversion of amines to hydroxylamines (Wed, 03 May 1995)
<p>Oxidation of primary amines to primary hydroxylamines using a dialkyl dioxirane is described. This new method is utilized to prepare aliphatic non-axial hydroxylamines from corresponding primary amino-substituted sugar derivatives and hydroxylamino acid derivatives. -GOVT PAR This invention was made with government support under Grant numbers CA 28824 and CA 08641 awarded by the Department of Health and Human Services and CHE 7916210 awarded by the National Science Foundation. The government has certain rights in the invention.</p>
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Synthesis of inhibitors of calmodulin-mediated enzymes including KS-501, KS-502 and their enantiomers (Wed, 01 Feb 1995)
<p>The total synthesis of a group of compounds with inhibitory effects on calmodulin-mediated enzyme activities has been accomplished. Among these synthesized compounds are KS-501 and KS-502. Other compounds that have been synthesized by the described scheme are ent-KS-501 and ent-KS-502 which are enantiomers of KS-501 and KS-502 and which also have inhibitory effects on calmodulin-mediated enzyme activities. -GOVT PAC GOVERNMENT SUPPORT PAR This invention was made with U.S. Government support under PHS Grant HL25858 awarded by the NIH. The U.S. Government has certain rights in the invention.</p>
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L-2',3'-DIDEOXY NUCLEOSIDE ANALOGS AS ANTI-HEPATITIS B (HBV) AND ANTI-HIV AGENTS (Fri, 09 Dec 1994)
The present invention relates to the discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D-configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV. The compound 1-(2,3-dideoxy-beta-L-ribofuranosyl)-5-fluorocytosine is shown to be a potent anti-HIV agent with low toxicity to host cells.
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L-2',3'-DIDEOXY NUCLEOSIDE ANALOGS AS ANTI-HEPATITIS B (HBV) AND ANTI-HIV AGENTS (Fri, 09 Dec 1994)
The present invention relates to the discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D-configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV. The compound 1-(2,3-dideoxy-beta-L- ribofuranosyl)-5-fluorocytosine is shown to be a potent anti-HIV agent with low toxicity to host cells. In a preferred embodiment a .beta.-L nucleoside compound according to the following structure is provided: <img he="0" wi="0" file="" alt="" img-content="undefined" img-format="jpg" inline="yes" orientation="portrait"/> </p>
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IMMUNE SYSTEM MODULATION USING PSORALENS ACTIVATED WITH VISIBLE LIGHT (Fri, 19 Aug 1994)
Methods and pharmaceutical compositions for modifying the immune response of a mammal are provided. The pharmaceutical compositions include a pharmaceutically acceptable carrier and a plurality of cells containing psoralen-DNA monoadducts and substantially no psoralen-DNA crosslinks. The preparation is formed by irradiating a suspension of cells with visible light radiation in the presence of psoralen.
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Methods of using labeled nucleotides (Wed, 13 Jul 1994)
<p>Compounds having the structure: ##STR1## wherein B represents a purine, 7-deazapurine, or pyrimidine moiety covalently bonded to the C.sup.1' -position of the sugar moiety, provided that when B is purine or 7-deazapurine, it is attached at the N.sup.9 -position of the purine or 7-deazapurine and when B is pyrimidine, it is attached at the N.sup.1 -position; PA1 wherein A represents a moiety consisting of at least three carbon atoms which is capable of forming a detectable complex with a polypeptide when the compound is incorporated into a double-stranded ribonucleic acid, deoxyribonucleic acid duplex, or DNA-RNA hybrid; PA1 wherein the dotted line represents a chemical linkage joining B and A, provided that if B is purine, the linkage is attached to the 8-position of the purine, if B is 7-deazapurine, the linkage is attached to the 7-position of the deazapurine, and if B is pyrimidine, the linkage is attached to the 5-position of the pyrimidine; and PA1 wherein each of x, y and z represents ##STR2## either directly, or when incorporated into oligo- and polynucleotides, provide probes which are widely useful. PAL Applications include detection and localization of polynucleotide sequences in chromosomes, fixed cells, tissue sections, and cell extracts. Specific applications include chromosomal karyotyping, clinical diagnosis of nucleic acid-containing etiological agents, e.g. bacteria, viruses, or fungi, and diagnosis of genetic disorders. -GOVT PAR The invention disclosed and/or claimed in this application was made in the course of work carried out under grants from the Public Health Service, National Institute of General Medical Science Research Grant P50-GM20124; Public Health Service, National Cancer Institute Training Grant T32-CA09159; and Public Health Service, National Institute of General Medical Science Grant T32-GM07499. The Government has certain rights in the invention.</p>
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Three-dimensional detection, dosimetry and imaging of an energy field by formation of a polymer in a gel (Wed, 15 Jun 1994)
<p>A visible and/or MRI visualizable permanent image is formed in a gel in a container which maintains the gel a dimensionally stable shape, which gel contains uniformly dispersed therein in storage stable form at last one radiant energy, e.g., ionizing radiation, polymerizable monomer in a concentration effective to form an insoluble polymer in the gel which alters the relaxation time of the solvent in any area thereof in which the polymer is formed, e.g., a mixture of (a) a linearly homopolymerizable monomer and (b) a comonomer which is cross-linkably copolymerizable with the monomer, the polymerization of the monomer initiated by the radiant energy being restricted to any area of the gel which receives the radiant energy, which image is representative of the dose distribution of the radiant energy to which the gel is exposed, by exposing the gel to a non-uniform dose of radiant energy until a polymer which produces a permanent image representative of the dose of radiant energy received by the gel is formed therein. -GOVT PAR This invention was made with government support under grant numbers NCI T32 CA09549, 1R01 CA40675 and 1R01 CA44605 awarded by the Department of Health and Human Services. The government has certain rights in the invention.</p>
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4 beta-amino podophyllotoxin analog compounds and methods (Wed, 06 Apr 1994)
<p>Novel podophyllotoxin compounds and their use in treating tumors are disclosed. In one embodiment, the compounds have the general formula: ##STR1## wherein NH-R is a selected from the from the group consisting of: ##STR2##</p>
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DOSIMETRY AND IMAGING OF RADIANT ENERGY BY FORMATION OF A POLYMER IN A GEL (Fri, 18 Feb 1994)
A visible and/or mr1 visualizable permanent image is formed in a gel in a container which maintains the gel in a dimensionally stable shape. The gel contains uniformly dispersed therein in storage stable form at least one radiant energy polymerizable monomer. The monomer is in a concentration effective to form an insoluble polymer in the gel. The polymerization of the monomer is restricted to the area of the gel that receives radiant energy. The relaxation rate (R1) measured at 20 MHz is shown as a function of radiant dose (Gy). This corresponds to an 8 % aqueous solution of 50 % comonomers in the absence and presence of agarose. Agarose makes the gel respond to radiation gradually.
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2-formylpyridine thiosemicarbazone compounds (Wed, 26 Jan 1994)
<p>A method of treatment of tumors is provided based upon a compound of the formula ##STR1## PAR Some aspects of the invention were supported in part by U.S. Public Health Service Grant CA-02817 from the National Cancer Institute and support from the Northeast NMR Facility at Yale University insofar as the use of high resolution NMR spectra is concerned that was made possible by a grant from the Chemical Division of the National Science Foundation (Grant No. CHE-7916210). -GOVT PAC RESEARCH GRANT PAR Some aspects of the invention were supported in part by U.S. Public Health Service Grant CA-02817 from the National Cancer Institute and support from the Northeast NMR Facility at Yale University insofar as the use of high resolution NMR spectra is concerned that was made possible by a grant from the Chemical Division of the National Science Foundation (Grant No. CHE-7916210).</p>
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Route to glycals in the allal and gulal series (Wed, 12 Jan 1994)
<p>Axial anomeric sulfoxides generated via thiophenol Ferrier rearrangement of glucal and galactal derivatives are used to synthesize glycals of the gulal and allal series. An application of the method led to the synthesis of the esperamicin thiosugar. -GOVT PAR This invention was made with government support under Contract Nos. CA 28824 and CA 08641 awarded by the Department of Health and Human Services and CHE 7916210 awarded by the National Science Foundation. The government has certain rights in the invention.</p>
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1-alkyl-2-acyl-1,2-disulfonylhydrazines (Wed, 27 Oct 1993)
<p>Novel antineoplastic 1-alkyl-2-acyl-1,2-disulfonylhydrazine having the following formula and methods of therapy using those antineoplastic compounds: ##STR1## where R.sub.1 and R.sub.2 are (independently) alkyl, cycloalkyl, aryl, aralkyl or heteroaryl. X is an acyl group, and Z is an alkyl or a haloalkyl group. -GOVT PAR This research was supported in part by a U.S. Public Health Service grant (CA-02817) from the National Cancer Institute. The U.S. Government has certain rights in this invention.</p>
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SYNTHESIS OF INHIBITORS OF CALMODULIN-MEDIATED ENZYMES (Fri, 23 Jul 1993)
The total synthesis of a group of compounds with inhibitory effects on calmodulin-mediated enzyme activities has been accomplished. Among these synthesized compounds are KS-501 and KS-502. Other compounds that have been synthesized by the described scheme are e^_n^_t^_KS-501 and e^_n^_t^_KS-502 which are enantiomers of KS-501 and KS-502 and which also have inhibitory effects on calmodulin-mediated enzyme activities.
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Sulfonylhydrazines and their use as antineoplastic agents and as antitrypanosomal agents (Wed, 26 May 1993)
<p>Sulfonylhydrazines of the formula RSO.sub.2 N(CH.sub.2 CH.sub.2 X)N(SO.sub.2 CH.sub.3).sub.2, wherein R is an alkyl or an aryl and X is a halogen or OSO.sub.2 Y, wherein Y is an alkyl or an aryl. Such sulfonylhydrazines are useful in treating cancer. PAL Methylating agents of the formula PA1 (a) R'SO.sub.2 N(CH.sub.3)N(SO.sub.2 CH.sub.3).sub.2, wherein R' is an alkyl or an aryl and PA1 (b) R"SO.sub.2 N(CH.sub.3)N(CH.sub.3)SO.sub.2 R", wherein R" is an alkyl or an aryl. PAL Such methylating agents are useful as antitrypanosomal and anticancer agents. -GOVT PAC GOVERNMENT RIGHTS PAR This invention was made with United States government support under Grant CA-02817 from the United States Public Health Service. The United States government may have certain rights in the present invention.</p>
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PHARMACEUTICAL COMPOSITIONS CONTAINING 3'-DEOXYTHYMIDIN-2'-ENE (3'-DEOXY-2',3'-DIDEHYDROTHYMIDINE)FOR TREATING PATIENTS INFECTED WITHRETROVIRUS (Tue, 16 Mar 1993)

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Pyrazinone N-oxide nucleosides and analogs thereof (Wed, 10 Mar 1993)
<p>This invention relates to nucleoside and acyclo analogs containing 5- or 6-substituted 2-pyrazinone-4-N-oxide. These compounds are useful for treating various conditions including viral infections, cancer, fungal infections, bacterial infections, microbial infections and related disease states. This invention also relates to pharmaceutical formulations containing these compounds. In addition, this invention relates to methods of treating the above-described conditions in animals and in particular, humans. -GOVT PAR This work is supported by the National Cancer Institute, National Institutes of Health, grant numbers CA-44358 and CA-06695 and National Institute of Arthritis and Infectious Diseases, National Institutes of Health, grant number AI-29430. The government retains certain rights in the invention.</p>
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PHARMACEUTICAL COMPOSITION CONTAINING 2',3'-DIDEOXYCYTIDIN-2'-ENE(2',3'-DDEOXY-2',3'-DIDEHYDROCYTIDINE) FOR TREATING P (Mon, 01 Feb 1993)

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NOVEL PYRAZINONE N-OXIDE NUCLEOSIDES AND ANALOGS THEREOF (Fri, 11 Dec 1992)
This invention relates to nucleoside and acyclo analogs containing 5- and 6- substituted 2-pyrazinone-4-N-oxide. These compounds are useful for treating various conditions including viral infections, cancer, fungal infections, bacterial infections, microbial infections and related disease states. This invention also relates to pharmaceutical formulations containing these compounds. In addition, this invention relates to methods of treating the above-described conditions in animals and in particular, humans.
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METHOD OF TREATING OR PREVENTING HEPATITIS B VIRUS (Fri, 30 Oct 1992)
Anti-hepatitis B virus compounds (-)3'-thia-2',3'-dideoxycytidine, (-)5-fluoro-3'-thia-2',3'-dideoxycytidine, (±) β-dioxolane cytosine and (-)-L-β-dioxolane cytosine. A method of treating a patient suffering from hepatitis B virus or preventing hepatitis B virus infection comprising administering to the patient an effective amount of an active compound selected from the group consisting of (a) (-)3'-thia-2',3'-dideoxycytidine, (b) (±)3'-thia-2',3'-dideoxycytidine, (c) (-)5-fluoro-3'-thia-2',3'-dideoxycytidine, (d) (±)5-fluoro-3'-thia-2,3-dideoxycytidine, (e) (±) β-dioxolane cytosine and (f) (-)-L-β-dioxolane cytosine, or a salt or an ester thereof, either alone or in admixture within a diluent.
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Decreasing the melanin content in mammalian skin and hair using 5,6-dihydroxindole derivatives (Wed, 01 Jul 1992)
<p>A method of decreasing the melanin content in mammalian skin and hair by administering to a mammal a composition comprising an effective amount of one or more derivatives of 5,6-dihydroxyindole, the derivatives having one or more substituents which are capable of being removed enzymatically, in admixture with a pharmaceutically acceptable carrier, the amount being 0.5% to 20% wt/wt based on the composition.</p>
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