Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
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Graphical contents list ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12
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Chemistry and biology of protein and inositol phosphorylation ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Maja Köhn
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Molecular mechanisms of protein kinase regulation by calcium/calmodulin ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Bertrand Simon , Anne-Sophie Huart , Matthias Wilmanns Many human protein kinases are regulated by the calcium-sensor protein calmodulin, which binds to a short flexible segment C-terminal to the enzyme’s catalytic kinase domain. Our understanding of the molecular mechanism of kinase activity regulation by calcium/calmodulin has been advanced by the structures of two protein kinases—calmodulin kinase II and death-associated protein kinase 1—bound to calcium/calmodulin. Comparison of these two structures reveals a surprising level of diversity in the overall kinase—calcium/calmodulin arrangement and functional readout of activity, as well as complementary mechanisms of kinase regulation such as phosphorylation. Graphical abstract image
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Design of a selenylsulfide-bridged EGFR dimerization arm mimic ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Laura E. Hanold , Christopher P. Watkins , Norman T. Ton , Peter Liaw , Aaron M. Beedle , Eileen J. Kennedy The epidermal growth factor receptor (EGFR) dimerization arm is a key feature that stabilizes dimerization of the extracellular receptor, thereby mediating activation of the tyrosine kinase domain. Peptides mimicking this β-loop feature can disrupt dimer formation and kinase activation, yet these peptides lack structural constraints or contain redox sensitive disulfide bonds which may limit their stability in physiological environments. Selenylsulfide bonds are a promising alternative to disulfide bonds as they maintain much of the same structural and chemical behavior, yet they are inherently less prone to reduction. Herein, we describe the synthesis, stability and activity of selenylsulfide-bridged dimerization arm mimics. The synthesis was accomplished using an Fmoc-based strategy along with C-terminal labeling for improved overall yield. This selenylsulfide-bridged peptide displayed both proteolytic stability and structural stability even under reducing conditions, demonstrating the potential application of the selenylsulfide bond to generate redox stable β-loop peptides for disruption of protein-protein interactions. Graphical abstract image
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Structure-based design and synthesis of covalent-reversible inhibitors to overcome drug resistance in EGFR ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Debjit Basu , André Richters , Daniel Rauh The clinical success of covalent kinase inhibitors in the treatment of EGFR-dependent non-small cell lung cancer (NSCLC) has rejuvenated the appreciation of reactive small molecules. Acquired drug resistance against first-line EGFR inhibitors remains the major bottleneck in NSCLC and is currently addressed by the application of fine-tuned covalent drugs. Here we report the design, synthesis and biochemical evaluation of a novel class of EGFR inhibitors with a covalent yet reversible warhead. A series of WZ4002 analogs, derived from anilinopyrimidine and 3-substituted-2-cyanoacrylamide scaffolds, exhibit strong and selective inhibitory activity against clinically relevant EGFRL858R and EGFRL858R/T790M. Graphical abstract image
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Strategies to make protein serine/threonine (PP1, calcineurin) and tyrosine phosphatases (PTP1B) druggable: Achieving specificity by targeting substrate and regulatory protein interaction sites ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Wolfgang Peti , Rebecca Page The established dogma is that protein serine/threonine (PSPs) and tyrosine (PTPs) phosphatases are unattainable drug targets. This is because natural product inhibitors of PSP active sites are lethal, while the active sites of PTPs are exceptionally conserved and charged, making it nearly impossible to develop PTP inhibitors that are selective. However, due to a series of recent structural and functional studies, this view of phosphatases is about to undergo a radical change. Rather than target active sites, these studies have demonstrated that targeting PSP/PTP protein (substrate/regulatory) interaction sites, which are distal from the active sites, are highly viable and suitable drugs targets. This is especially true for calcineurin (CN), in which the blockbuster immunosuppressant drugs FK506 and cyclosporin A were recently demonstrated to bind and block one of the key CN substrate interaction sites, the LxVP site. Additional studies show that this approach—targeting substrate and/or regulatory protein interaction sites—also holds incredible promise for protein phosphatase 1 (PP1)-related diseases. Finally, domains outside PTP catalytic domains have also recently been demonstrated to directly alter PTP activity. Collectively, these novel insights offer new, transformative perspectives for the therapeutic targeting of PSPs by interfering with the binding of PIPs or substrates and PTPs by targeting allosteric sites outside their catalytic domains. Graphical abstract image
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Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Lutz Tautz , Yotis A. Senis , Cécile Oury , Souad Rahmouni Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. Moreover, there remains a considerable incidence of arterial thrombosis in a subset of patients receiving currently available drugs. Thus, there is a pressing medical need for novel antiplatelet agents with a more favorable safety profile and less patient resistance. The discovery of novel antiplatelet targets is the matter of intense ongoing research. Recent findings demonstrate the potential of targeting key signaling molecules, including kinases and phosphatases, to prevent platelet activation and aggregation. Here, we offer perspectives to targeting members of the protein tyrosine phosphatase (PTP) superfamily, a major class of enzymes in signal transduction. We give an overview of previously identified PTPs in platelet signaling, and discuss their potential as antiplatelet drug targets. We also introduce VHR (DUSP3), a PTP that we recently identified as a major player in platelet biology and thrombosis. We review our data on genetic deletion as well as pharmacological inhibition of VHR, providing proof-of-principle for a novel and potentially safer VHR-based antiplatelet therapy. Graphical abstract image
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A potent and selective inhibitor for the UBLCP1 proteasome phosphatase ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Yantao He , Xing Guo , Zhi-Hong Yu , Li Wu , Andrea M. Gunawan , Yan Zhang , Jack E. Dixon , Zhong-Yin Zhang The ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1) has been implicated as a negative regulator of the proteasome, a key mediator in the ubiquitin-dependent protein degradation. Small molecule inhibitors that block UBLCP1 activity would be valuable as research tools and potential therapeutics for human diseases caused by the cellular accumulation of misfold/damaged proteins. We report a salicylic acid fragment-based library approach aimed at targeting both the phosphatase active site and its adjacent binding pocket for enhanced affinity and selectivity. Screening of the focused libraries led to the identification of the first potent and selective UBLCP1 inhibitor 13. Compound 13 exhibits an IC50 of 1.0μM for UBLCP1 and greater than 5-fold selectivity against a large panel of protein phosphatases from several distinct families. Importantly, the inhibitor possesses efficacious cellular activity and is capable of inhibiting UBLCP1 function in cells, which in turn up-regulates nuclear proteasome activity. These studies set the groundwork for further developing compound 13 into chemical probes or potential therapeutic agents targeting the UBLCP1 phosphatase. Graphical abstract image
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Synthesis and biological evaluation of 3-aminoisoquinolin-1(2H)-one based inhibitors of the dual-specificity phosphatase Cdc25B ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Kara M. George Rosenker , William D. Paquette , Paul A. Johnston , Elizabeth R. Sharlow , Andreas Vogt , Ahmet Bakan , John S. Lazo , Peter Wipf The cell division cycle 25B dual specificity phosphatase (Cdc25B) regulates the normal progression of the mammalian cell cycle by dephosphorylating and activating cyclin-dependent kinase (Cdk) complexes, particularly in response to DNA damage. Elevated Cdc25B levels enable a bypass of normal cell cycle checkpoints, and the overexpression of Cdc25B has been linked to a variety of human cancers. Thus, Cdc25B is an attractive target for the development of anticancer therapeutics. Herein we describe the synthesis and biological evaluation of a series of non-quinoid inhibitors of Cdc25B containing the 3-aminoisoquinolin-1(2H)-one pharmacophore. In addition to several strategies that address specific substitution patterns on isoquinolines, we have applied a regioselective Pd-catalyzed cross-coupling methodology to synthesize a new lead structure, 6-(3-aminophenyl)-3-(phenylamino)isoquinolin-1(2H)-one (13), which proved to be a reversible, competitive Cdc25B inhibitor with a K i of 1.9μM. Compound 13 prevented human cancer cell growth and blocked Cdc25B-mediated mitotic checkpoint bypass. Molecular docking studies support binding near the catalytic site. Graphical abstract image
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Synthesis of hydrolysis-resistant pyridoxal 5′-phosphate analogs and their biochemical and X-ray crystallographic characterization with the pyridoxal phosphatase chronophin ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Gunnar Knobloch , Nauras Jabari , Sven Stadlbauer , Hermann Schindelin , Maja Köhn , Antje Gohla A set of phosphonic acid derivatives (1–4) of pyridoxal 5′-phosphate (PLP) was synthesized and characterized biochemically using purified murine pyridoxal phosphatase (PDXP), also known as chronophin. The most promising compound 1 displayed primarily competitive PDXP inhibitory activity with an IC50 value of 79μM, which was in the range of the K m of the physiological substrate PLP. We also report the X-ray crystal structure of PDXP bound to compound 3, which we solved to 2.75Å resolution (PDB code 5AES). The co-crystal structure proves that compound 3 binds in the same orientation as PLP, and confirms the mode of inhibition to be competitive. Thus, we identify compound 1 as a PDXP phosphatase inhibitor. Our results suggest a strategy to design new, potent and selective PDXP inhibitors, which may be useful to increase the sensitivity of tumor cells to treatment with cytotoxic agents. Graphical abstract image
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Rational design of allosteric-inhibition sites in classical protein tyrosine phosphatases ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Cynthia M. Chio , Xiaoling Yu , Anthony C. Bishop Protein tyrosine phosphatases (PTPs), which catalyze the dephosphorylation of phosphotyrosine in protein substrates, are critical regulators of metazoan cell signaling and have emerged as potential drug targets for a range of human diseases. Strategies for chemically targeting the function of individual PTPs selectively could serve to elucidate the signaling roles of these enzymes and would potentially expedite validation of the therapeutic promise of PTP inhibitors. Here we report a novel strategy for the design of non-natural allosteric-inhibition sites in PTPs; these sites, which can be introduced into target PTPs through protein engineering, serve to sensitize target PTPs to potent and selective inhibition by a biarsenical small molecule. Building on the recent discovery of a naturally occurring cryptic allosteric site in wild-type Src-homology-2 domain containing PTP (Shp2) that can be targeted by biarsenical compounds, we hypothesized that Shp2’s unusual sensitivity to biarsenicals could be strengthened through rational design and that the Shp2-specific site could serve as a blueprint for the introduction of non-natural inhibitor sensitivity in other PTPs. Indeed, we show here that the strategic introduction of a cysteine residue at a position removed from the Shp2 active site can serve to increase the potency and selectivity of the interaction between Shp2’s allosteric site and the biarsenical inhibitor. Moreover, we find that ‘Shp2-like’ allosteric sites can be installed de novo in PTP enzymes that do not possess naturally occurring sensitivity to biarsenical compounds. Using primary-sequence alignments to guide our enzyme engineering, we have successfully introduced allosteric-inhibition sites in four classical PTPs—PTP1B, PTPH-1, FAP-1, and HePTP—from four different PTP subfamilies, suggesting that our sensitization approach can likely be applied widely across the classical PTP family to generate biarsenical-responsive PTPs. Graphical abstract image
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Light-switched inhibitors of protein tyrosine phosphatase PTP1B based on phosphonocarbonyl phenylalanine as photoactive phosphotyrosine mimetic ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Stefan Wagner , Anja Schütz , Jörg Rademann Phosphopeptide mimetics containing the 4-phosphonocarbonyl phenylalanine (pcF) as a photo-active phosphotyrosine isoster are developed as potent, light-switchable inhibitors of the protein tyrosine phosphatase PTP1B. The photo-active inhibitors 6–10 are derived from phosphopeptide substrates and are prepared from the suitably protected pcF building block 12 by Fmoc-based solid phase peptide synthesis. All pcF-containing peptides are moderate inhibitors of PTP1B with K I values between 10 and 50μM. Irradiation of the inhibitors at 365nm in the presence of the protein PTP1B amplify the inhibitory activity of pcF-peptides up to 120-fold, switching the K I values of the best inhibitors to the sub-micromolar range. Photo-activation of the inhibitors results in the formation of triplet intermediates of the benzoylphosphonate moiety, which deactivate PTP1B following an oxidative radical mechanism. Deactivation of PTP1B proceeds without covalent crosslinking of the protein target with the photo-switched inhibitors and can be reverted by subsequent addition of reducing agent dithiothreitol (DTT). Graphical abstract image
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Azide–alkyne cycloaddition-mediated cyclization of phosphonopeptides and their evaluation as PTP1B binders and enrichment tools ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Christoph Meyer , Birgit Hoeger , Jayanta Chatterjee , Maja Köhn Protein tyrosine phosphatases (PTPs) are important enzymes in health and disease, and chemical tools are crucial to understand and modulate their biological roles. PTP1B is involved in diabetes, obesity and cancer. One of the main challenges for the design of chemical tools for PTP1B is the homology to TCPTP, making tool selectivity a highly challenging task. Here, we aimed to study if azide–alkyne cycloaddition-mediated cyclization of a peptide inhibitor could increase its selectivity toward PTP1B over TCPTP, and if cyclic and linear peptide binders can be applied as enrichment tools of endogenous PTP1B. While the cyclization of the peptide binders did not improve the selectivity toward PTP1B over TCPTP, it enhanced strongly the efficiency to co-precipitate endogenous PTP1B out of cell lysates. Our results show that fine-tuning the molecular structure of peptidic pull-down baits can greatly enhance their efficiency compared to the parental peptide sequences. Graphical abstract image
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Desymmetrization of myo-inositol derivatives by lanthanide catalyzed phosphitylation with C2-symmetric phosphites ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Michael Duss , Samanta Capolicchio , Anthony Linden , Nisar Ahmed , Henning J. Jessen Desymmetrization by phosphorylation represents a promising method with potential impact in many different areas of research. C 2-Symmetric phosphoramidites have been used to desymmetrize myo-inositol derivatives by functionalization at different positions. With this method, 1:1 mixtures of diastereomers are obtained that can be separated subsequently. In this work, activation of a C 2-symmetric phosphoramidite is achieved by addition of pentafluorophenol (PFP) and leads to a reactive PFP phosphite, which can then be coupled to protected myo-inositol derivatives with reactive OH groups at the 1, 3, 4 and 6 positions. This strategy enhances the diastereoselectivity of the coupling reaction with a preference towards phosphitylation at position 6 (up to 3:1) or position 3 (up to 2:1). The concept of attenuative activation of phosphoramidites via in situ generated pentafluorophenol phosphite triesters is thus proven in these studies. It is further shown that Lewis–Acid catalysis enhances the rate of phosphite triester coupling without affecting the diastereoselectivity. This novel strategy improves access to different phosphorylated myo-inositol derivatives and will thus enable further studies into the function of these important intracellular second messengers. Graphical abstract image
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Reversible chemical dimerizer-induced recovery of PIP2 levels moves clathrin to the plasma membrane ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Martina Schifferer , Suihan Feng , Frank Stein , Christian Tischer , Carsten Schultz Chemical dimerizers are powerful non-invasive tools for bringing molecules together inside intact cells. We recently introduced a rapidly reversible chemical dimerizer system which enables transient translocation of enzymes to and from the plasma membrane (PM). Here we have applied this system to transiently activate phosphatidylinositol 4,5-bisphosphate (PIP2) breakdown at the PM via translocation of phosphoinositide 5-phosphatase (5Ptase). We found that the PIP2 sensor phospholipase C-δ PH domain (PLCδ-PH) is released from the PM upon addition of the reversible chemical dimerizer rCD1. By outcompeting rCD1, rapid release of the 5Ptase from the PM is followed by PIP2 recovery. This permits the observation of the PIP2-dependent clathrin assembly at the PM. Graphical abstract image
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A single-cell model of PIP3 dynamics using chemical dimerization ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Aidan MacNamara , Frank Stein , Suihan Feng , Carsten Schultz , Julio Saez-Rodriguez Most cellular processes are driven by simple biochemical mechanisms such as protein and lipid phosphorylation, but the sum of all these conversions is exceedingly complex. Hence, intuition alone is not enough to discern the underlying mechanisms in the light of experimental data. Toward this end, mathematical models provide a conceptual and numerical framework to formally evaluate the plausibility of biochemical processes. To illustrate the use of these models, here we built a mechanistic computational model of PI3K (phosphatidylinositol 3-kinase) activity, to determine the kinetics of lipid metabolizing enzymes in single cells. The model is trained to data generated upon perturbation with a reversible small-molecule based chemical dimerization system that allows for the very rapid manipulation of the PIP3 (phosphatidylinositol 3,4,5-trisphosphate) signaling pathway, and monitored with live-cell microscopy. We find that the rapid relaxation system used in this work decreased the uncertainty of estimating kinetic parameters compared to methods based on in vitro assays. We also examined the use of Bayesian parameter inference and how the use of such a probabilistic method gives information on the kinetics of PI3K and PTEN activity. Graphical abstract image
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Towards the computational design of protein post-translational regulation ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Marta Strumillo , Pedro Beltrao Protein post-translational modifications (PTMs) are a fast and versatility mechanism used by the cell to regulate the function of proteins in response to changing conditions. PTMs can alter the activity of proteins by allosteric regulation or by controlling protein interactions, localization and abundance. Recent advances in proteomics have revealed the extent of regulation by PTMs and the different mechanisms used in nature to exert control over protein function via PTMs. These developments can serve as the foundation for the rational design of protein regulation. Here we review the advances in methods to determine the function of PTMs, protein allosteric control and examples of rational design of PTM regulation. These advances create an opportunity to move synthetic biology forward by making use of a level of regulation that is of yet unexplored. Graphical abstract image
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Semisynthesis and initial characterization of sortase A mutants containing selenocysteine and homocysteine ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Lena Schmohl , Felix Roman Wagner , Michael Schümann , Eberhard Krause , Dirk Schwarzer The bacterial transpeptidase sortase A is a well-established tool in protein chemistry and catalyzes the chemoselective ligation of peptides and proteins. During catalysis sortase A cleaves the conserved Leu-Pro-X-Thr-Gly sorting motif at the Thr residue under concomitant thioester formation at active site Cys184. We have used expressed protein ligation (EPL) to generate sortase mutants with Cys184 replaced by selenocysteine (Sec) and homocysteine (Hcy). Sec-sortase showed a moderate 2–3-fold reduction in catalytic activity in contrast to Hcy-sortase which is a poor catalyst with less than 1% of wild-type activity. The sensitivity of the active site nucleophiles towards an alkylation reagent correlated with the pK a values of the mutated residues. Furthermore, the pH-profile of Sec-sortase was shifted to more acidic conditions when compared to the wild-type enzyme. These observations provide information on sortase catalysis and the semisynthetic enzymes might represent useful tools for further biochemical investigations and engineering approaches of sortases A. Graphical abstract image
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Native chemical ligation between asparagine and valine: Application and limitations for the synthesis of tri-phosphorylated C-terminal tau ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Oliver Reimann , Maria Glanz , Christian P.R. Hackenberger We present the successful native chemical ligation (NCL) at an Asn-Val site employing β-mercaptovaline and subsequent desulfurization in the synthesis of native phosphorylated C-terminal tau, relevant for Alzheimer’s disease related research. Despite recent progress in the field of NCL we illustrate limitations of this ligation site that stem from thioester hydrolysis and predominantly aspartimide formation. We systematically investigated the influence of pH, temperature, peptide concentration and thiol additives on the outcome of this ligation and identified conditions under which the ligation can be driven toward complete conversion, which required the deployment of a high surplus of thioester. Application of the optimized conditions allowed us to gain access to challenging tri-phosphorylated C-terminal tau peptide in practical yields. Graphical abstract image
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Biology-oriented synthesis of benzopyrano[3,4-c]pyrrolidines ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Marco Potowski , Christopher Golz , Carsten Strohmann , Andrey P. Antonchick , Herbert Waldmann A natural product inspired synthesis of 6,6,5-tricyclic compounds via a silver(I)-catalyzed formal 1,3-dipolar cycloaddition of coumarins with α-iminoesters was developed. The reaction proceeds in a stepwise reaction course under formation of the trans-substituted diastereomer with respect to the 1,3-dipole and shows a broad substrate scope. Graphical abstract image
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Structure–activity studies in the development of a hydrazone based inhibitor of adipose-triglyceride lipase (ATGL) ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Nicole Mayer , Martina Schweiger , Michaela-Christina Melcher , Christian Fledelius , Rudolf Zechner , Robert Zimmermann , Rolf Breinbauer Adipose triglyceride lipase (ATGL) catalyzes the degradation of cellular triacylglycerol stores and strongly determines the concentration of circulating fatty acids (FAs). High serum FA levels are causally linked to the development of insulin resistance and impaired glucose tolerance, which eventually progresses to overt type 2 diabetes. ATGL-specific inhibitors could be used to lower circulating FAs, which can counteract the development of insulin resistance. In this article, we report about structure–activity relationship (SAR) studies of small molecule inhibitors of ATGL based on a hydrazone chemotype. The SAR indicated that the binding pocket of ATGL requests rather linear compounds without bulky substituents. The best inhibitor showed an IC50 =10μM in an assay with COS7-cell lysate overexpressing murine ATGL. Graphical abstract image
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Developing new chemical tools for DNA methyltransferase 1 (DNMT 1): A small-molecule activity-based probe and novel tetrazole-containing inhibitors ()
Publication date: 15 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 12 Author(s): Biwei Zhu , Jingyan Ge , Shao Q. Yao DNA methylation is an important epigenetic modification catalyzed by DNA methyltransferases (DNMTs). Abnormal expression of endogenous DNMTs in human causes alterations in the genome methylation patterns which subsequently lead to the development of cancers. Thus detection of endogenous DNMT activities and efficient inhibition of DNMTs have important therapeutic significance. In this work, a small molecule activity-based probe (ABP) of DNA methyltransferase 1 (DNMT1), T1, was developed. The probe was a clickable analog of tryptophan and was able to covalently label endogenous DNMT1 and inhibit its enzymatic activity more effectively than previously known DNMT1 inhibitors (RG108 and its maleimide analog 1149). In addition, we also discovered a new type of small molecule DNMT inhibitors based on tetrazole-containing compounds which were analogs of 1149. Among these compounds, which we called Gn, one of them (G6) possessed reasonable inhibitory activity against DNMT1 in both in vitro enzymatic assays and cell growth proliferation experiments. Both T1 and G6 showed effective labeling of endogenous DNMT1 from mammalian cells by using in vitro competitive pull-down and live-cell bioimaging experiments. Graphical abstract image
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Editorial board ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
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Graphical contents list ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11
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Innovative approaches to the design and synthesis of small molecule libraries ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Adam Nelson , Didier Roche
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Stereoselective synthesis of a natural product inspired tetrahydroindolo[2,3-a]-quinolizine compound library ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Muthukumar G. Sankar , Luca Mantilli , James Bull , Fabrizio Giordanetto , Jonathan O. Bauer , Carsten Strohmann , Herbert Waldmann , Kamal Kumar A natural product-inspired synthesis of a compound collection embodying the tetrahydroindolo[2,3-a]quinolizine scaffold was established with a five step synthesis route. An imino-Diels–Alder reaction between Danishefsky’s diene and the iminoesters derived from tryptamines was used as a key reaction. Reductive amination of the ketone function and amide synthesis with the carboxylic acid derived from the ethyl ester, were used to decorate the core scaffold. Thus a compound library of 530 tetrahydroindolo[2,3-a]quinolizines was generated and submitted to European lead factory consortium for various biological screenings. Graphical abstract image
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Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp3-rich library ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Thomas E. Storr , Sarah J. Cully , Michael J. Rawling , William Lewis , Daniel Hamza , Geraint Jones , Robert A. Stockman The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp3-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp3-rich natural product-like library. Graphical abstract image
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Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Philip Craven , Anthony Aimon , Mark Dow , Nicolas Fleury-Bregeot , Rachel Guilleux , Remy Morgentin , Didier Roche , Tuomo Kalliokoski , Richard Foster , Stephen P. Marsden , Adam Nelson The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory. Graphical abstract image
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Synthesis of a hexahydropyrrolo indole (HPI) compound library ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Sabrina Nickel , Philipp Nickel , Marco Hellmert , Silvia Ernst , Robert Jewell , Christopher A. Pearce , Geraint Jones , Daniel Hamza , Markus Kaiser Scaffolds of natural products represent promising starting points for the development of focused compound libraries. Here, we describe the development of a synthetic route to a compound library based on the hexahydropyrrolo indole (HPI) scaffold, the denoting structural motif of the HPI natural product family. To this end, a two-step approach consisting of a batch synthesis of an advanced functionalizable HPI intermediate followed by the establishment of reaction conditions that allow derivatization of this scaffold at three different positions is described. Subsequently, the optimized methods were applied to the synthesis of a 276-member library. Graphical abstract image
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Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet–Spengler cyclization/metal-catalyzed cross coupling/amidation sequence ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Rico Petersen , A. Emil Cohrt , Michael Åxman Petersen , Peng Wu , Mads H. Clausen , Thomas E. Nielsen Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet–Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields. Graphical abstract image
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Cyclopentitol as a scaffold for a natural product-like compound library for drug discovery ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Jalindar D. Padwal , Dmitri V. Filippov , Bharat D. Narhe , Sjoerd Aertssen , Remmelt Jan Beuving , Jorg C.J. Benningshof , Gijsbert A. van der Marel , Herman S. Overkleeft , Mario van der Stelt A concise and efficient synthesis of cyclopentitols as a scaffold for a two-dimensional compound library for drug discovery is described. Starting from d-mannose, the key steps are Wittig olefination and ring-closing metathesis (RCM) followed by a [3,3]-sigmatropic Overmann rearrangement to form an sp3-rich, natural product-like scaffold from which a focused compound library with different functionalities is prepared. Graphical abstract image
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Branching cascades provide access to two amino-oxazoline compound libraries ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Annamalai Murali , Federico Medda , Matthias Winkler , Fabrizio Giordanetto , Kamal Kumar An efficient synthetic access to two amino-oxazoline compound libraries was developed employing the branching cascades approach. A common precursor, that is, chromonylidene β-ketoester was transformed into two different ring-systems, that is, the pyridine and the benzopyrane substituted hydroxyphenones. In further two steps, the ketone moiety in two ring-systems was transformed into an amino-oxazoline ring. The functional groups on the two amino-oxazoline scaffolds were exploited further to generate, a compound collection of ca. 600 amino-oxazolines which are being exposed to various biological screenings within the European Lead Factory consortium. Graphical abstract image
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Studies towards the synthesis of indolizin-5(3H)-one derivatives and related 6,5-azabicyclic scaffolds by ring-closing metathesis ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Michelle S. Frei , Matthew K. Bilyard , Thomas A. Alanine , Warren R.J.D. Galloway , Jamie E. Stokes , David R. Spring Herein, we report on work towards the development of a new strategy for the synthesis of rare and biologically interesting indolizin-5(3H)-ones, which is based around the use of ring-closing metathesis to construct the carbocyclic ring system. This study has provided insights into the general stability of indolizin-5(3H)-ones and their tendency to exist as the tautomeric indolizin-5-ols. Furthermore, this approach has allowed access to other novel structurally related compounds based around unusual 6,5-azabicyclic scaffolds, which are also difficult to generate using typical methods. The azabicyclic compounds synthesized in this study reside in attractive regions of heterocyclic chemical space that are underexploited in current drug and agrochemical discovery efforts. Graphical abstract image
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Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Monique Lüthy , Mary C. Wheldon , Chehasnah Haji-Cheteh , Masakazu Atobe , Paul S. Bond , Peter O’Brien , Roderick E. Hubbard , Ian J.S. Fairlamb Synthetic routes to six 3-D scaffolds containing piperazine, pyrrolidine and piperidine cores have been developed. The synthetic methodology focused on the use of N-Boc α-lithiation-trapping chemistry. Notably, suitably protected and/or functionalised medicinal chemistry building blocks were synthesised via concise, connective methodology. This represents a rare example of lead-oriented synthesis. A virtual library of 190 compounds was then enumerated from the six scaffolds. Of these, 92 compounds (48%) fit the lead-like criteria of: (i) −1⩽ A log P ⩽3; (ii) 14⩽number of heavy atoms⩽26; (iii) total polar surface area⩾50Å2. The 3-D shapes of the 190 compounds were analysed using a triangular plot of normalised principal moments of inertia (PMI). From this, 46 compounds were identified which had lead-like properties and possessed 3-D shapes in under-represented areas of pharmaceutical space. Thus, the PMI analysis of the 190 member virtual library showed that whilst scaffolds which may appear on paper to be 3-D in shape, only 24% of the compounds actually had 3-D structures in the more interesting areas of 3-D drug space. Graphical abstract image
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Synthesis of 1,4,5 trisubstituted γ-lactams via a 3-component cascade reaction ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Michael Åxman Petersen , Michael A. Mortensen , A. Emil Cohrt , Rico Petersen , Peng Wu , Nicolas Fleury-Brégeot , Rémy Morgentin , Claude Lardy , Thomas E. Nielsen , Mads H. Clausen A three component one-pot cascade reaction was developed for the synthesis of 1,4,5-trisubstituted γ-lactams. The resulting scaffold can be modified independently at three positions, two of which are conveniently accessed by changing the components of the one-pot reaction. The phases of building block generation, scaffold synthesis and subsequent appendage modification were adapted to library production, which resulted in a screening library of 500 compounds. Graphical abstract image
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MCR synthesis of a tetracyclic tetrazole scaffold ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Pravin Patil , Kareem Khoury , Eberhardt Herdtweck , Alexander Dömling Scaffold diversity is key in the ongoing exercise of discovery of novel bioactive compounds using high throughput screening (HTS). Based on the Ugi tetrazole synthesis we have designed novel bi- and tri-cyclic scaffolds featuring interesting pharmacophore properties. The compounds of the scaffold (B) are synthesizable in large diversity and numbers in two steps using (hetero)phenylethylamines, HN3, oxo components and iscyanoacetaldehyde(dimethylacetale). The chemistry is amenable to parallel synthesis and is used to enhance and fill the screening decks of the European Lead factory (ELF). Here, we are reporting full experimental details, scope and limitations of the reaction, cheminformatic analysis and the 3D structures of selected compounds. Graphical abstract image
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Design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Raquel Ortega , Jorge Sanchez-Quesada , Christoph Lorenz , Grzegorg Dolega , Anna Karawajczyk , Miguel Sanz , Graham Showell , Fabrizio Giordanetto The introduction of silicon in biologically-relevant molecules represents an interesting medicinal chemistry tactic. Its use is mainly confined to the fine-tuning of specific molecular properties and organosilicon compounds are underrepresented in typical screening libraries. As part of the European Lead Factory efforts to generate novel, drug discovery-relevant chemical matter, the design and synthesis of 1,1-disubstituted-1-silacycloalkane-based compound libraries is described. Graphical abstract image
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Synthesis and functionalization of bicyclic N,O-acetal scaffolds from furfural ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Ferdi van der Pijl , Floris L. van Delft , Floris P.J.T. Rutjes We have synthesized biologically relevant 6-aza-8-oxa[3.2.1]bicyclooctane scaffolds in a five-step procedure starting from furfural. Besides showing that these scaffolds are amenable to decoration via standard functional group interconversions, we also describe investigations for further functionalization via Lewis acid-mediated N,O-acetal opening, followed by nucleophilic trapping of the resulting intermediate cation. By using different nucleophiles, we have successfully prepared a modest library of 2,6-trans-disubstituted pyrans in good yields and in a highly diastereoselective manner. Graphical abstract image
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Seven-membered ring scaffolds for drug discovery: Access to functionalised azepanes and oxepanes through diazocarbonyl chemistry ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Andrew Nortcliffe , Christopher J. Moody Functionalised azepane and oxepane scaffolds were prepared using diazocarbonyl chemistry and elaborated to show their potential use in library synthesis. Key dicarbonyl containing seven-membered rings were functionalised via diastereoselective Luche reduction of the ketone followed by manipulation of the ester and amine groups. Further scaffolds could be accessed by C-alkylation of the dicarbonyl compounds. In addition, an oxepane containing amino acid could be prepared via a diastereoselective enamine reduction. Graphical abstract image
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Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries ()
Publication date: 1 June 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 11 Author(s): Ignacio Colomer , Ololade Adeniji , George M. Burslem , Philip Craven , Martin Ohsten Rasmussen , Anthony Willaume , Tuomo Kalliokoski , Richard Foster , Stephen P. Marsden , Adam Nelson The application of [4+2] cycloadditions between alkenes and an N-benzoyl iminium species, generated in situ under acidic conditions, is described in the synthesis of diverse molecular scaffolds. The key reaction led to the formation of cyclic imidates in good yield and with high regioselectivity. It was demonstrated that the cyclic imidates may be readily converted into 1,3-amino alcohols. Incorporation of orthogonally-reactive functionality, such as aryl and alkyl bromides, into the cycloaddition substrates enabled the synthesis of additional scaffolds. For one scaffold, the synthesis of exemplar screening compounds was undertaken to demonstrate potential value in small molecule library production. Graphical abstract image
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Synthesis and Bioevaluation of Heterocyclic Derivatives of Cleistanthin-A ()
Publication date: Available online 27 May 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Yu Zhao , Rui Zhang , Yapeng Lu , Jinlong Ma , Li Zhu The vacuolar H+-ATPase (V-ATPase) was proposed as a key target for new strategies in cancer treatment recently. We have synthesized a novel class of derivatives of Cleistanthin-A bearing heterocyclic moieties. Most of these compounds displayed potent antiproliferative effects on four cancer cells at submicromolar concentration, and they have no cytotoxicity on normal WRL-68 cells at 200 nM. The most potent compound 3a has been shown to inhibit the activity of vacuolar H+-ATPase at submicromolar concentration, and it could also significantly decrease the cytosolic pH values in HepG2 cells. The current findings provide valuable insights for future development of novel V-ATPase inhibitors as anticancer agents. Graphical abstract image
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Discovery of a 1-Isopropyltetrahydroisoquinoline Derivative as an Orally Active N-type Calcium Channel Blocker for Neuropathic Pain ()
Publication date: Available online 27 May 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Takashi Ogiyama , Koichi Yonezawa , Makoto Inoue , Toshihiro Watanabe , Yukihito Sugano , Takayasu Gotoh , Tetsuo Kiso , Akiko Koakutsu , Shuichiro Kakimoto , Jun-ichi Shishikura N-type calcium channel blockade is a promising therapeutic approach for the treatment of neuropathic pain. Starting from lead compound (S)-1, we focused our optimization efforts on potency for N-type calcium channel inhibition and improvement of CYP inhibition profile. 2-{[(1-Hydroxycyclohexyl)methyl]amino}-(1R)-(1-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethanone oxalate ((R)-5r) was identified as a novel orally active small-molecule N-type calcium channel inhibitor with reduced CYP inhibition liability. Oral administration of (R)-5r improved mechanical allodynia in a spinal nerve ligation model of neuropathic pain in rats with an ED50 value of 2.5 mg/kg. Graphical abstract image
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Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3 ()
Publication date: Available online 27 May 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Yutaka Nakajima , Takayuki Inoue , Kazuo Nakai , Koichiro Mukoyoshi , Hisao Hamaguchi , Keiko Hatanaka , Hiroshi Sasaki , Akira Tanaka , Fumie Takahashi , Shigeki Kunikawa , Hiroyuki Usuda , Ayako Moritomo , Yasuyuki Higashi , Masamichi Inami , Shohei Shirakami Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model. Graphical abstract image
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Lipocarbazole, an efficient lipid peroxidation inhibitor anchored in the membrane ()
Publication date: Available online 27 May 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Gabin Fabre , Anne Hänchen , Claude Calliste , Karel Berka , Srinivas Banala , Michal Otyepka , Roderich D. Süssmuth , Patrick Trouillas Lipid peroxidation is a major deleterious effect caused by oxidative stress. It is involved in various diseases such as atherosclerosis, rheumatoid arthritis and neurodegenerative diseases. In order to inhibit lipid peroxidation, antioxidants must efficiently scavenge free radicals and penetrate inside biological membranes. Lipocarbazole has recently been shown to be a powerful antioxidant in solution. Here, we show its powerful capacity as lipid peroxidation inhibitor. Its mechanism of action is rationalized based on molecular dynamics simulations on a biomembrane model, quantum calculations and experimental evaluation. The role of the lipocarbazole side chain is particularly highlighted as a critical chemical feature responsible for its antioxidant activity. Graphical abstract image
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Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors ()
Publication date: Available online 23 May 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Hiroaki Yamagishi , Shohei Shirakami , Yutaka Nakajima , Akira Tanaka , Fumie Takahashi , Hisao Hamaguchi , Keiko Hatanaka , Ayako Moritomo , Masamichi Inami , Yasuyuki Higashi , Takayuki Inoue Because Janus kinases (JAKs) play a crucial role in cytokine-mediated signal transduction, JAKs are an attractive target for the treatment of organ transplant rejection and autoimmune diseases such as rheumatoid arthritis (RA). To identify JAK inhibitors, we focused on the 1H-pyrrolo[2,3-b]pyridine derivative 3, which exhibited moderate JAK3 and JAK1 inhibitory activities. Optimization of 3 identified the tricyclic imidazo-pyrrolopyridinone derivative 19, which exhibited potent JAK3 and JAK1 inhibitory activities (IC50 = 1.1 nM, 1.5 nM, respectively) with favorable metabolic stability. Graphical abstract image
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Synthesis and in vitro kinetic evaluation of N-thiazolylacetamide monoquaternary pyridinium oximes as reactivators of sarin, O-ethylsarin and VX inhibited human acetylcholinesterase (hAChE) ()
Publication date: Available online 22 May 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Aditya Kapil Valiveti , Uma M. Bhalerao , Jyotiranjan Acharya , Hitendra N. Karade , Badrinarayan Acharya , G. Raviraju , Anand K. Halve , Mahabir Parshad Kaushik Presently available medications for treatment of organophosphate poisoning are not sufficiently effective due to various pharmacological and toxicological reasons. In this regard, herein we report the synthesis of a series of N-thiazolylacetamide monoquaternary pyridinium oximes and its analogues (1a-1b to 6a-6b) with diversely substituted thiazole ring and evaluation of their in vitro reactivation efficacies against nerve agent (sarin, O-ethylsarin and VX) inhibited human erythrocyte acetylcholinesterase (hAChE). Reactivation kinetics was performed to determine dissociation constant (K D), reactivity rate constant (k r) and the second order rate constant (k r2) for all the compounds and compared their efficacies with commercial antidotes viz. 2-PAM and obidoxime. All the newly synthesized oximes were evaluated for their physicochemical parameters (pKa) and correlated with their respective reactivation efficacies to assess the capability of the oxime reactivator. Three of these novel compounds showed promising reactivation efficacies toward OP inhibited hAChE. Further molecular docking studies were performed in order to correlate the reactivation efficacies with their interactions in the active site of the AChE. Graphical abstract image
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6-Phenoxy-2-phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE) ()
Publication date: Available online 21 May 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Kwanghyun Choi , Kwang Su Lim , Juhee Shin , Seo Hee Kim , Young-Ger Suh , Hyun-Seok Hong , Hee Kim , Hee-Jin Ha , Young-Ho Kim , Jiyoun Lee , Jeewoo Lee Receptor for advanced glycation end products (RAGE) is known to be involved in the transportation of amyloid β (Aβ) peptides and causes the accumulation of Aβ in the brain. Moreover, recent studies suggest that the interactions between RAGE and Aβ peptides may be the culprit behind Alzheimer’s disease (AD). Inhibitors of the RAGE-Aβ interactions would not only prevent the accumulation of toxic Aβ in the brain, and but also block the progress of AD, therefore, have the potential to provide a ‘disease-modifying therapy’. In this study, we have developed a series of 6-phenoxy-2-phenylbenzoxazole analogs as novel inhibitors of RAGE. Among these derivatives, we found several effective inhibitors that block the RAGE-Aβ interactions without causing significant cellular toxicity. Further testing showed that compound 48 suppressed Aβ induced toxicity in mouse hippocampal neuronal cells and reduced Aβ levels in the brains of a transgenic mouse model of AD after oral administration. Graphical abstract image
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Synthesis of (2-amino)ethyl derivatives of quercetin 3-O-methyl ether and their antioxidant and neuroprotective effects ()
Publication date: Available online 21 May 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Young Hun Lee , Hyoung Ja Kim , Ho Yoo , Seo Yun Jung , Bong Jin Kwon , Nam-Jung Kim , Changbae Jin , Yong Sup Lee Reactive oxygen species have been implicated in several diseases, particularly in ischemia-reperfusion injury. Quercetin 3-O-methyl ether has been reported to show potent antioxidant and neuroprotective activity against neuronal damage induced by reactive oxygen species. Several aminoethyl-substituted derivatives of quercetin 3-O-methyl ether have been synthesized to increase water solubility while retaining antioxidant and neuroprotective activity. Among such derivatives, compound 3a shows potent and well-balanced antioxidant activity in three types of cell-free assay systems and has in vivo neuroprotective effects on transient focal ischemic injury induced by the occlusion of the middle cerebral artery in rats. Graphical abstract image
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Synthesis, molecular docking and biological evaluation of 3-Arylfuran-2(5H)-ones as anti-gastric ulcer agent ()
Publication date: Available online 21 May 2015 Source:Bioorganic & Medicinal Chemistry Author(s): Xu-Dong Wang , Wei Wei , Peng-Fei Wang , Li-Cheng Yi , Wei-Kang Shi , Yong-Qiang Xie , Lang-Zhou Wu , Nian Tang , Liang-Song Zhu , Jia Peng , Chan Liu , Xian-Hui Li , Shi Tang , Zhu-Ping Xiao , Hai-Liang Zhu 3-Arylfuran-2(5H)-one derivatives show good antibacterial activity and were determined as tyrosyl-tRNA synthetase (TyrRS) inhibitors. In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to treat infections caused by Helecobacter pylori. Twenty 3-arylfuran-2(5H)-ones were synthesized and evaluated for anti-H. pylori, antioxidant and anti-urease activities which are closely interconnected with H. pylori infection. The results displayed that some of the compounds show excellent antioxidant activity, and good anti-H. pylori and urease inhibitory activities. Out of these compounds, 3-(3-methylphenyl)furan-2(5H)-one (b9) showed the most potent antioxidant activity (IC50=8.2 μM) and good anti-H. pylori activity (MIC50=2.6 μg/mL), and it can be used as a good candidate for discovering novel anti-gastric ulcer agent. Graphical abstract image
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