Enrichment and Viability Inhibition of Circulating Tumor Cells on a Dual Acid-responsive Composite Nanofiber Film
The formation and metastatic colonization of circulating tumor cells (CTCs) are responsible for the vast majority of cancer-related deaths. Over the last decade, drug delivery system (DDS) has been
rapidly developed with nanotechnology arising, however, most of the reported tumor-targeting DDSs were just able to deliver drugs to the solid tumor cells but not CTCs. In here, a novel drug delivery
system was constructed with composite nanofiber film to inhibit the viability of circulating tumor cells (CTCs). In this system, gold nanoparticles (Au NPs) were functionalized with doxorubicin (DOX)
through an acid-responsive cleavable linker to get the Au-DOX NPs. Then, the Au-DOX NPs were mixed in the solution of the acid-responsive polymer (PDMAEMA) to synthesize the nanofiber film through
electrospinning technology. After that, the nanofiber film was modified with the specific antibody (anti-EpCAM) to enrich CTCs on the film. Finally, the Au-DOX NPs could release from the nanofiber
film and inhibit the viability of CTCs through delivering the DOX to the enriched CTCs. This composite nanofiber film can significantly reduce the viability of CTCs at the suspending or fluid state,
and it will be expected to limit the migration and proliferation of tumor cells.
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Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates
Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib
(pan-CDK inhibitor), BAY 1143572 (PTEFb inhibitor), and AZD 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug
discovery is clearly on the rise, there remains an incomplete understanding of the medicinal chemistry relevant properties of sulfoximines. Herein, we report the synthesis and in vitro
characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug
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Synthesis and antiproliferative effect of ethyl 4-(4-substitutedpiperidin-1-yl)]benzylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives on human leukemic cells
Acute leukemia is a hematological malignancy with high incidence and recurrence rates, and is characterized by an accumulation of blasts in bone marrow due to proliferation of immature lymphoid or
myeloid cells associated with a blockade of differentiation. The heterogeneity of leukemia led to look for new specific molecules for leukemia subtypes or even for therapy-resistant cases. Among
heterocyclic derivatives that attracted attention due to their large spread biological activities, we have focused our interest towards the pyrrolo[1,2-a]quinoxaline heterocyclic framework that has
been previously identified as an interesting scaffold for antiproliferative activities against various human cancer cell lines. In this work, new ethyl
4-[4-(4-substitutedpiperidin-1-yl)]benzylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives 1a-o have been designed, synthesized and evaluated against five different leukemia cell lines, including
Jurkat and U266 (lymphoid cell lines), and K562, U937, HL60 (myeloid cell lines), and also on normal human peripheral blood mononuclear cells (PBMNCs). These new pyrrolo[1,2-a]quinoxaline series
showed interesting cytotoxic potential against all tested leukemia cell lines. In particular, pyrroloquinoxalines 1a and 1m-n seem to be interesting due to their high activity against leukemia and
their low activity against normal hematopoietic cells leading to high index of selectivity.
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Optimization of bicyclic lactam derivatives as NMDA receptor antagonists
N-Methyl-D-aspartate (NMDA) receptors are fundamental for the normal function of the central nerve system, and play an important role in memory and learning. An overactivation of these receptors will
lead to neuronal loss associated with major neurological disorders, such as Parkinson's disease, Alzheimer's disease, schizophrenia, and epilepsy. Herein, twenty two novel enantiopure bicyclic
lactams were designed, synthesized, and evaluated as NMDA receptor antagonists. Most of the new compounds displayed NMDA receptor antagonism and, the most promising compound showed IC50 value in the
same order of magnitude of memantine, a NMDA receptor antagonist used in the clinic for the treatment of Alzheimer's disease. Further biological evaluation indicated that this compound is
brain-permeable (determined by an in vitro assay) and non-hepatotoxic. All of these results indicate that compound 5b is a potential candidate for the treatment of pathologies associated with the
overactivation of NMDA receptors.
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"Theranostic" nanoparticles loaded with imaging probes and rubrocurcumin for a combined cancer therapy by folate receptor targeting.
The combination of different therapeutic modalities is a promising option to combat tumour recurrence. PolyLactic and Glycolic Acid nanoparticles are exploited for the simultaneous delivery of a
boron-curcumin complex (RbCur) and an amphiphilic Gd complex into tumour cells with the aim of performing Boron and Gadolinium Neutron Capture Therapy (NCT) in combination with an additional curcumin
anti-proliferative effect. Furthermore, the use of Gd complexes allows the MRI assessment of the amount of B and Gd internalized by tumour cells. PLGA nanoparticles are targeted to ovarian cancer
cells (IGROV-1) through folate receptors, by including in the formulation a pegylated phospholipid functionalized with the folate moiety. NCT is performed on IGROV-1 cells internalizing 6.4 and 78.6
µg/g of 10B and 157Gd, respectively. The synergic action of neutron treatment and curcumin cytotoxicity results in a significant therapeutic improvement.
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Synthesis and Pharmacological Evaluation of Identified and Putative Metabolites of the A1 Adenosine Receptor Antagonist Cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX)
The A1 adenosine receptor (A1AR) antagonist [18F]cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([18F]CPFPX), used in imaging human brain A1ARs by PET, is stable in the brain but rapidly undergoes
transformation into one major (M1) and several minor metabolites in blood. This report describes the synthesis of putative metabolites of CPFPX as standards for the identification of those
metabolites. Analysis by (radio)HPLC revealed that extracts of human liver microsomes incubated with n.c.a.[18F]CPFPX contained the major metabolite, M1, as well as radioactive metabolites
corresponding to derivatives functionalized at the cyclopentyl moiety, but no N1-despropyl species or metabolites resulting from functionalizations of the N3-fluoropropyl chain. The putative
metabolites displaced the binding of [3H]CPFPX to the A1AR in pig brain cortex at Kis between 1.9 and 380 nM and the binding of [3H]ZM 241385 to the A2AAR in pig striatum at Kis greater than 180 nM.
One metabolite, a derivative functionalized at the omega-position of the N1-propyl chain, showed high affinity (Ki 2 nM) to and very good selectivity (> 9000) for the A1AR.
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Probing the interactions of cytotoxic [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] and its Pt(IV) derivatives with human serum.
The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS, prompted us to look into its interactions and those of its Pt(IV) derivatives with human serum, HSA,
lipoproteins and serum supplemented cell culture medium. The Pt(II) complex, Pt56MeSS, binds non-covalently and reversibly to slow tumbling proteins in human serum and in cell culture medium and
interacts through the phenanthroline with HSA with a Kd of about 1.5 × 10-6. All Pt(IV) complexes were stable to reduction in HS but those with axial carboxylate ligands,
cct-[Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenantroline)(acetato)2](TFA)2 (Pt56MeSS(OAc)2) and cct-[Pt(1S,2S-DACH)(5,6-dimehtyl-1,10-phenantroline)(phenylbutyrate)2](TFA)2 (Pt56MeSS(PhB)2), were
spontaneously reduced at pH=7 or higher in phosphate buffer, but not in tris buffer (pH=8). HS also retarded the rate of reduction by ascorbate of the Pt(IV) complexes compared with the rates of
reduction in phosphate buffer suggesting that for this class of compounds, phosphate buffer is not a good model for HS.
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Synthesis of 5α,8α-ergosterol peroxide 3-carbamate derivatives and fluorescent mitochondria-targeting conjugate for enhanced anticancer activities
By inspiration of significant anticancer activity of our previously screened natural ergosterol peroxide (1), a series of novel ergosterol peroxide 3-carbamate derivatives were synthesized and
characterized. The anti-proliferative activity of synthesized compounds against human hepatocellular carcinoma cells (HepG2, SK-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were
investigated. Compound 3d, 3f and their hydrochloride exhibited significant in vitro anti-proliferative activity against the tested tumor cell lines, with IC50 values ranging from 0.85 to 4.62 μM.
Furthermore, fluorescence mitochondria-targeting images showed that the designed coumarin-3d conjugate (5) localized mainly in mitochondria, leading to enhanced anticancer activities over the parent
structure (1). As a whole, it appeared that substituent changes to the C-3 position could serve as a promising launch point for further design of this type of steroidal anticancer agents.
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Discovery of Cdc25A lead inhibitors with novel chemotype by virtual screening: application of pharmacophore modeling based on training set with unique limited components
Cdc25 phosphatase has been studied as an attractive target for cancer therapy. Multiple pharmacophore models with unique core features of classic quinone inhibitors and novel inhibitors were used to
discover novel lead inhibitor. 21 compounds with qualified physical properties were screened out from Maybridge hitfinderTM database containing 14400 compounds by pharmacophore models. 4 compounds
inhibit the Cdc25A activity more than 50% at concentration of 100 μM. Among them, compound KM10389 (N-(2-((furan-2-ylmethyl)thio)ethyl)-2-((4-hydroxy-6-propylpyrimidin-2-yl)thio)acetamide) shows high
enzyme inhibition activity with IC₅₀ of 7.9 μM. Selective cytotoxicity for Hela cells was observed with IC₅₀ values of 66.3 μM. While IC₅₀ values for Hek293 cells was higher than 100 μM. Blocking of
G1/S transition was also observed for Hela cells in the presence of the compound by increasing G1 phase of 16.15%. Together with compound HTS02435 and HTS01205, novel lead inhibitor structure was
identified and analyzed using molecular docking study. Implication of virtual screening using different pharmacophore models representing for different features was fully discussed.
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Trachycladines and Analogues: Synthesis and Anti-cancer Activity Evaluation
The synthesis of four new analogues of marine nucleoside trachycladine A was accomplished via direct regio- and stereoselective Vorbrüggen glycosylations of 2,6-dichloropurine and 2-chloropurine with
a D-ribose derived chiron. Naturally occurring trachycladines (A and B) and a series of analogues were examined for their cytotoxic activity against a number of cancer cell lines (glioblastoma, lung
and cervical cancer). Parent trachycladine A and two analogues (the diacetate of 2,6-dichloropurine derivative and N-cyclopropyl trachycladine A) were found to result in a significant reduction of
cell viability, with the latter exhibiting a stronger effect. The same compounds enhance the cytotoxic effect of docetaxel in lung cancer cell lines whereas additional experiments revealed that their
mode of action relies on mitotic catastrophe rather than DNA damage. Moreover their activity as autophagic flux blockers has been postulated.
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Recent advances in the discovery of PqsD inhibitors as antimicrobial agents
The treatment of the infections caused by Pseudomonas aeruginosa, an opportunistic Gram-negative bacterium, is very difficult. High intrinsic tolerance towards common antibiotics and the development
of new resistant strains challenge us to find a new treatment as soon as possible. PqsD is an enzyme essential for Pseudomonas aeruginosa quorum sensing apparatus, which catalyzes the last and key
step in the biosynthesis of HHQ that is a signal molecule of the P. aeruginosa quorum sensing system. In this review, following an outline on their structures, we present a brief introduction of the
PqsD inhibitors including their mechanisms of action, inhibitory activity and structure-activity relationships.
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Synthesis, biological evaluations and molecular docking studies on DNA binding interaction of platinum(II) rollover complexes containing phosphorus donor ligands
A series of cyclometalated rollover complexes [PtMe(κ²N,C-bipyO-H)(L)], 2a-2c, bipyO-H = cyclometalated 2,2'-bipyridine N-oxide, L = PCy₃ (2a), PPh₂py (2-(diphenylphosphino)pyridine, 2b), P(OPh)₃
(2c), was synthesized by reacting of complex [PtMe(κ²N,C-bipyO-H)(SMe₂)], 1, with various monodentate phosphine and phosphite ligands. These complexes were characterized by means of NMR spectroscopy
and the structures of 2a confirmed by single-crystal X-ray diffraction. 1 was treated with bis(diphenylphosphino)methane (dppm) in a 1 : 1 ratio to give corresponding complex
[PtMe(κ²N,C-bipyO-H)(η¹P-dppm)], 3b, in which dppm ligand acts as a monodentate pendant ligand. Biological activities of these complexes were evaluated against a panel of four standard cancer cell
lines: lung carcinoma (A549), ovarian carcinoma (OV-90 and SKOV3) and breast carcinoma (MCF-7). 2c and especially 3b indicated an effective potent cytotoxic activity regarding to the cell lines.
Electrophoresis mobility shift assay and molecular modeling investigations have been performed to determine the specific binding mode or the binding orientation of these alkylating agents to DNA.
Cellular reactive oxygen species (ROS) detection was also determined.
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How selective are heat shock protein 90 (Hsp90) inhibitors for cancer cells over normal cells?
Selectively inhibiting target proteins in cancer cells over normal cells is one of the most critical features of a successful protein inhibitor for clinical applications. By evaluating and comparing
the impact of a clinical N-terminal Hsp90 inhibitor, AUY922, on Hsp90 inhibition-associated cellular events in cancer cells versus normal cells, we find that it produces similar phenotype
characteristics in both cell types, indicating that AUY922 is not selective for targeting tumor Hsp90. By comparison, the C-terminal Hsp90 modulator SM258 suppresses cell proliferation, triggers
apoptosis, regulates the expression of Hsp90-associated heat shock proteins, and enhances the degradation of Hsp90's client proteins preferentially in cancer cells over normal cells. Herein our work
supports a new paradigm that AUY922 is not tumor selective, whereas SM258 is relatively more selective and likely acting via a Hsp90-dependent mechanism.
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Medicinal Chemistry Profiling of Monocyclic 1,2-Azaborines
The first examples of biologically active monocyclic 1,2-azaborines have been synthesized and demonstrated to exhibit not only improved in vitro aqueous solubility in comparison with their
corresponding carbonaceous analogues, but in the context of a CDK2 inhibitor, also improved biological activity and better in vivo oral bioavailability. This proof-of-concept study establishes the
viability of monocyclic 1,2-azaborines as a novel pharmacophore with distinct pharmacological profiles that can help address challenges associated with solubility in drug development research.
BOR-ing? NO! Monocyclic 1,2-azaborines can serve as a novel pharmacophore with improved in vitro aqueous solubility, improved bioactivity, and better in vivo oral availability than their carbonaceous
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Design, Synthesis, and Biological Evaluation of Chalcone-Containing Shikonin Derivatives as Inhibitors of Tubulin Polymerization
The biological importance of microtubules in mitosis makes them an interesting target for the development of anticancer agents. In this study, a series of novel chalcone-containing shikonin
derivatives was designed, synthesized, and evaluated for biological activities. Among them, derivative PMMB-259 [(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl
(E)-2-(4-(3-oxo-3-(3-(trifluoromethoxy)phenyl)prop-1-en-1-yl)phenoxy)acetate] was identified as a potent inhibitor of tubulin polymerization. Further investigation confirmed that PMMB-259 can induce
MCF-7 cell apoptosis, reduce the mitochondrial transmembrane potential, and arrest the cell cycle at the G2/M phase. Moreover, the morphological variation of treated cells was visualized by confocal
microscopy. The results, along with docking simulations, further indicated that PMMB-259 can bind well to tubulin at the colchicine site. Overall, these studies may provide a new molecular scaffold
for the further development of antitumor agents that target tubulin. Combined effect: A series of chalcone-containing shikonin derivatives were designed, synthesized, and evaluated as potential
inhibitors of tubulin polymerization. Most showed potent antiproliferative activity, and studies into the mechanism of action revealed induction of apoptosis, reduction of mitochondrial membrane
potential, accumulation of cells in the G2/M phase, and severe disruption of the microtubule system to an extent similar to that of the reference compound colchicine.
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A Molecular Dynamics–Shared Pharmacophore Approach to Boost Early-Enrichment Virtual Screening: A Case Study on Peroxisome Proliferator-Activated Receptor α
Molecular dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins and study them in a dynamic way. Furthermore, the use of multiple crystal structures of the
same protein containing different co-crystallized ligands can help elucidate the role of the ligand on a protein′s active conformation, and then explore the most common interactions between small
molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial
ligand–protein interactions within the complexes. The study was carried out on peroxisome proliferator-activated receptor α (PPARα). Findings derived from the dynamic analysis of interactions were
then used as features for pharmacophore generation and constraints for generating the docking grid for use in virtual screening. We found that information derived from short multiple MD simulations
using different molecules within the binding pocket of the target can improve the early enrichment of active ligands in the virtual screening process for this receptor. In the end we adopted a
consensus scoring based on docking score and pharmacophore alignment to rank our dataset. Our results showed an improvement in virtual screening performance in early recognition when screening was
performed with the Molecular dYnamics SHAred PharmacophorE (MYSHAPE) approach. The MYSHAPE approach is a new way of studying ligand–receptor interactions. In this method, a pharmacophore model is
created that exploits information derived from multiple short MD simulations, using different molecules within the binding pocket of the target. Conformational information is retrieved from the full
trajectory and not only from clustered frames. This approach can help improve virtual screening performance, especially for the early enrichment of active ligands in the virtual screening process.
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Aqueous Instability of δ-Fluorobutylpiperidines
In a series of partially fluorinated N-propyl- and N-butylpiperidine derivatives, three compounds were found to exhibit unexpected instability under mild biophysical assay conditions. These compounds
carry a single terminal fluorine in the δ-position of an N-butyl group as a common structural feature. An adjacent fluorine substituent at the γ-position significantly slows down the reactivity. All
other compounds, having either no or more than one fluorine substituent at the δ-position are chemically inert under all assay conditions. The reactivity of the labile compounds is traced to an
intramolecular ring-closing fluorine substitution reaction by the moderately basic piperidine unit, leading to a spiro-pyrrolidinium salt. The chemical lability of δ-monofluorinated or
γ,δ-difluorinated N-butylpiperidine derivatives even under very mild biophysical assay conditions constitutes a caveat to the molecular design of partially fluorinated alkylamines. Don't go alone at
δ. Among many N-fluoroalkylpiperidines, those with a single fluorine substituent at the δ-position proved to be unstable under very mild biophysical assay conditions. This is a caveat to molecular
design in drug discovery.
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Unconventional Coupling between Ligand Recognition and Allosteric Control in the Multidrug Resistance Gene Regulator, BmrR
BmrR is a multidrug resistance (MDR) regulator that responds to diverse ligands. To obtain insight into signal recognition, allosteric control, and cooperativity, we used a quantitative in vitro
transcription assay to determine the ligand-dependent activation profiles for a diverse set of cations, zwitterions, and uncharged ligands. As for many other biological switch systems, the data are
well described by a modified Hill equation. Parameters extracted from curve fits to the data include L50, RMAX and N. We found that L50 values correlate directly with ΔGBIND values, suggesting that
the parameter reflects binding, whereas RMAX and N reflect allosteric control and cooperativity, respectively. Our results suggest unconventional coupling between ligand binding and allosteric
control, with weakly interacting ligands exhibiting the highest levels of activation. Such properties are in stark contrast to those often exhibited by biological switch proteins, whereby ligand
binding and allostery are tightly coupled, yielding both high selectivity and ultrasensitivity. We propose that weakened coupling, as observed for BmrR, may be important for providing robust
activation responses to unrelated ligands. We also propose that other MDR proteins and other polyspecific switch systems will show similar features. To gain insight into signal recognition,
allosteric control, and cooperativity in the multidrug-sensing regulator BmrR, we used a quantitative in vitro transcription assay to determine the activation profiles for a diverse set of ligands.
Comparisons with signal-specific systems suggest weakened coupling between signal recognition and allostery in BmrR. This type of coupling may be important for providing robust responses to unrelated
ligands. We propose that other MDR proteins and other polyspecific systems will show similar features.
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Development of Highly Potent GAT1 Inhibitors: Synthesis of Nipecotic Acid Derivatives with N-Arylalkynyl Substituents
A new scaffold of highly potent and mGAT1-selective inhibitors has been developed. Compounds in this class are characterized by an alkyne-type spacer connecting nipecotic acid with an aromatic
moiety. Preliminary evaluations made it apparent that a nipecotic acid derivative with an N-butynyl linker and a terminal 2-biphenyl residue exhibiting a binding affinity (pKi) of 7.61±0.03 to mGAT1
and uptake inhibition (pIC50) of 7.00±0.06 selective for mGAT1 could serve as a hit compound. Docking calculations for compounds based on this structure in an hGAT1 homology modeling study indicated
binding affinities similar to or even higher than that of the well-known mGAT1 inhibitor tiagabine. Synthesis of the designed compounds was readily carried out by two consecutive cross-coupling
reactions, giving flexible access to variously substituted biphenyl subunits. With an appropriate substitution pattern of the biphenyl moiety, the binding affinity of enantiopure (R)-nipecotic acid
derivatives to mGAT1 increased to pKi=8.33±0.01, and the uptake inhibitory potency up to pIC50=7.72±0.02. Stable alkyne-type spacer: A series of N-substituted nipecotic acid derivatives with various
2-biphenyl moieties attached via an N-alkynyl linker were synthesized as potential GAT1 inhibitors. Some 2′,4′-disubstituted derivatives were found to be highly potent in binding and uptake assays
and display high subtype selectivity for GAT1.
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A Dual Topoisomerase Inhibitor of Intense Pro-Apoptotic and Antileukemic Nature for Cancer Treatment
Classic cytotoxic drugs remain indispensable instruments in antitumor therapy due to their effectiveness and a more prevalent insensitivity toward tumor resistance mechanisms. Herein we describe the
favorable properties of 6-(N,N-dimethyl-2-aminoethoxy)-11-(3,4,5-trimethoxyphenyl)pyrido[3,4-c][1,9]phenanthroline (P8-D6), a powerful inducer of apoptosis caused by an equipotent inhibition of human
topoisomerase I and II activities. A broad-spectrum effect against human tumor cell lines at nanomolar concentrations, as well as strong antileukemic effects, were shown to be superior to those of
marketed topoisomerase-targeting drugs and dual topoisomerase inhibitors in clinical trials. The facile four-step synthesis, advantageous drugability properties, and initial in vivo data encourage
the application of P8-D6 in appropriate animal tumor models and further drug development. A significant lead! P8-D6 is a novel designed drug candidate for antineoplastic chemotherapy that acts as a
highly pro-apoptotic dual inhibitor of topoisomerases I and II. Its broad-spectrum effect against human tumor cell lines, potent antileukemic activity, facile synthetic access, advantageous
drugability properties, as well as initial in vivo data encourage the application of P8-D6 in appropriate in vivo efficacy studies and further drug development.
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Inhibitor Selectivity for Cyclin-Dependent Kinase 7: A Structural, Thermodynamic, and Modelling Study
Deregulation of the cell cycle by mechanisms that lead to elevated activities of cyclin-dependent kinases (CDK) is a feature of many human diseases, cancer in particular. We identified small-molecule
inhibitors that selectively inhibit CDK7, the kinase that phosphorylates cell-cycle CDKs to promote their activities. To investigate the selectivity of these inhibitors we used a combination of
structural, biophysical, and modelling approaches. We determined the crystal structures of the CDK7-selective compounds ICEC0942 and ICEC0943 bound to CDK2, and used these to build models of
inhibitor binding to CDK7. Molecular dynamics (MD) simulations of inhibitors bound to CDK2 and CDK7 generated possible models of inhibitor binding. To experimentally validate these models, we
gathered isothermal titration calorimetry (ITC) binding data for recombinant wild-type and binding site mutants of CDK7 and CDK2. We identified specific residues of CDK7, notably Asp155, that are
involved in determining inhibitor selectivity. Our MD simulations also show that the flexibility of the G-rich and activation loops of CDK7 is likely an important determinant of inhibitor specificity
similar to CDK2. Selectivity structured: We have solved crystal structures of CDK7-selective inhibitors bound to CDK2. We used a combination of structural, biophysical, and modelling approaches to
model the binding of these inhibitors to CDK7, and used this information to explain their selectivity. We identify specific CDK7 residues that contribute to the specificity of these inhibitors.
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Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid
A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated
at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N-substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on
eight cancer cell lines and two non-cancer fibroblasts. 2-Bromoallobetulone (2 b) methyl 2-bromobetulonate (3 b), 2-bromooleanonic acid (5 b), and 2-thiocyanooleanonic acid (5 c) were best, with IC50
values less than 10 μm against CCRF-CEM cells (e.g., 3 b: IC50=2.9 μm) as well as 2′-(diethylamino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 f, IC50=9.7 μm) and
2′-(N-methylpiperazino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 k, IC50=11.4 μm). Compound 5 c leads to the accumulation of cells in the G2 phase of the cell cycle and inhibits RNA and DNA
synthesis significantly at 1×IC50. The G2/M cell-cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycin D. Compound 5 c is new,
active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2-bromobetulonate (3 b) and methyl 2-thiocyanometulonate (3 c) were found to
inhibit nucleic acid synthesis only at 5×IC50. We assume that in 3 b and 3 c (unlike in 5 c), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1×IC50
or lower concentration. SAR & MOA of cytotoxic triterpenes: Aminothiazoles were prepared from four triterpenic scaffolds. Diethylamino- and N-methylpiperidinothiazoles of oleanonic acid were
best; however, the much better candidate is intermediate thiocyanate 5 c, as it is new, active, nontoxic, and induces apoptosis selectively in cancer cells via cell-cycle arrest in the G2/M phase and
inhibits DNA/RNA synthesis.
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Old Drug Scaffold, New Activity: Thalidomide-Correlated Compounds Exert Different Effects on Breast Cancer Cell Growth and Progression
Thalidomide was first used for relief of morning sickness in pregnant women and then withdrawn from the market because of its dramatic effects on normal fetal development. Over the last decades, it
has been used successfully for the treatment of several pathologies, including cancer. Many analogues with improved activity have been synthesized and tested. Herein we report some effects on the
growth and progression of MCF-7 and MDA-MB-231 breast cancer cells by a small series of thalidomide-correlated compounds, which are very effective at inducing cancer cell death by triggering
TNFα-mediated apoptosis. The most active compounds are able to drastically reduce the migration of breast cancer cells by regulation of the two major proteins involved in epithelial–mesenchymal
transition (EMT): vimentin and E-cadherin. Moreover, these compounds diminish the intracellular biosynthesis of vascular endothelial growth factor (VEGF), which is primarily involved in the promotion
of angiogenesis, sustaining tumor progression. The multiple features of these compounds that act on various key points of the tumorigenesis process make them good candidates for preclinical studies.
Thalidomide redirected! Compounds 3 and 8 act on different key points of the tumorigenesis process by drastically reducing the migration of breast cancer cells, through the regulation of vimentin and
E-cadherin and by diminishing the intracellular biosynthesis of vascular endothelial growth factor (VEGF).
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Cover Picture: Innocent But Deadly: Nontoxic Organoiridium Catalysts Promote Selective Cancer Cell Death (ChemMedChem 4/2017)
The front cover picture shows the ability of nontoxic organoiridium complexes to selectively chemosensitize cancer cells toward clinically used platinum anticancer agents. It is demonstrated that
cancer cells that are pretreated with the Ir compounds exhibit higher levels of reactive oxygen species (ROS) as well as oxidized nicotinamide adenine dinucleotide (NAD+) than in noncancer cells.
Mechanistic studies into the biochemical effects of the organoiridium compounds on cancer cell biology are currently underway. This work provides new guiding principles for the application of
inorganic complexes in medicinal chemistry. More information can be found in the Full Paper by Loi H. Do et al. on page 292 in Issue 4, 2017 (DOI: 10.1002/cmdc.201600638).
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The Development of Next-Generation Pyridinium-Based multiQAC Antiseptics
A series of 18 bis- and tris-pyridinium amphiphiles were prepared and tested for both antimicrobial activity and lytic capability, in comparison with the commercially available pyridinium antiseptic
cetylpyridinium chloride (CPC). Assessments were made against Gram-positive and Gram-negative bacteria, including two methicillin-resistant Staphylococcus aureus (MRSA) strains. While 2Pyr-11,11 was
identified as one of the most potent antimicrobial quaternary ammonium compounds (QACs) reported to date, boasting nanomolar inhibition against five of six bacteria tested, no significant improvement
in bioactivity of tris-pyridinium amphiphiles over their bis-pyridinium counterparts was observed. However, the multicationic QACs (multiQACs) presented herein did display significant advantages over
the monocationic CPC; while similar red blood cell lysis was observed, superior activity against both Gram-negative bacteria and resistant S. aureus strains led to the discovery of four
pyridinium-based multiQACs with advantageous therapeutic indices. Killing bacteria with pyridinium QACs: Quaternary ammonium compounds (QACs) have long been used as disinfectants due to their
amphiphilic structure, leading to their ability to lyse bacterial cells. Most commercial QACs are simple in structure—monocationic with either alkyl or aryl QACs—with much potential for improvement.
This work examines the combination of pyridinium-based QACs with multiple head groups toward developing novel antiseptics with enhanced antibacterial activity.
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Visible-Light-Triggered Activation of a Protein Kinase Inhibitor
A photoresponsive small molecule undergoes a ring-opening reaction when exposed to visible light and becomes an active inhibitor of the enzyme protein kinase C. This “turning on” of enzyme inhibition
with light puts control into the hands of the user, creating the opportunity to regulate when and where enzyme catalysis takes place. Control comes to light: Visible light turns on an inhibitor of
protein kinase C by ring-opening a photoresponsive compound, thereby shutting down enzyme activity. This capacity to turn on enzyme inhibition with light puts control into the hands of the user, a
significant advantage over traditional inhibitors, which, once administered, give the user little to no control over the activity profile.
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Synthesis and Biological Evaluation of Amidinourea and Triazine Congeners as Inhibitors of MDA-MB-231 Human Breast Cancer Cell Proliferation
A series of novel amidinourea derivatives was synthesized, and the compounds were evaluated as inhibitors of MDA-MB-231 human breast cancer cell proliferation. In addition, a second series of
triazine derivatives designed as rigid congeners of the amidinoureas was synthesized, and the compounds were evaluated for their antiproliferative activity. Among the two series, amidinourea 3 d
(N-[N-[8-[[N-(morpholine-4-carbonyl)carbamimidoyl]amino]octyl]carbamimidoyl]morpholine-4-carboxamide) emerged as a potent anticancer hit compound with an IC50 value of 0.76 μm, similar to that of
tamoxifen. New class in the fight: Breast cancer is currently the second most lethal cancer among women, preceded only by lung cancer. Novel amidinourea derivatives were synthesized and evaluated as
inhibitors of MDA-MB-231 breast cancer cell proliferation. Amidinourea 3 d was found to be active against MDA-MB-231 breast cancer cells with an IC50 value of 0.76 μm, close to the activity of
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Innocent But Deadly: Nontoxic Organoiridium Catalysts Promote Selective Cancer Cell Death
We demonstrate that nontoxic organoiridum complexes can selectively chemosensitize cancer cells toward platinum antiproliferative agents. Treatment of human cancer cells (breast, colon, eye/retina,
head/neck, lung, ovary, and blood) with the iridium chemosensitizers led to lowering of the 50 % growth inhibition concentration (IC50) of the Pt drug carboplatin by up to ∼30–50 %. Interestingly,
non-cancer cells were mostly resistant to the chemosensitizing effects of the iridium complexes. Cell culture studies indicate that cancer cells that were administered with Ir show significantly
higher reactive oxygen species concentrations as well as NAD+/NADH ratios (oxidized vs. reduced nicotinamide adenine dinucleotide) than Ir-treated non-cancer cells. These biochemical changes are
consistent with a catalytic transfer hydrogenation cycle involving the formation of iridium-hydride species from the reaction of the iridium catalysts with NADH and subsequent oxidation in air to
generate hydrogen peroxide. Organometallic compounds repurposed: Iridium complexes that have been considered to be ineffective anticancer agents are shown to be highly selective cancer cell
chemosensitizers when co-administered with clinically used platinum drugs. This discovery opens up new opportunities in combination drug therapy that can be aided by small-molecule synthetic
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Finely Tuned Asymmetric Platinum(IV) Anticancer Complexes: Structure–Activity Relationship and Application as Orally Available Prodrugs
Platinum(IV) bis-carboxylates are highly versatile prodrug scaffolds with different axial ligands that can be functionalized while keeping the platinum(II) pharmacophore intact. Using a sequential
acylation strategy, we developed a class of PtIV prodrugs of cisplatin with contrasting lipophilic and hydrophilic ligands. We investigated their stability, reduction rates, lipophilicity, aqueous
solubility, and antiproliferative efficacies, and assessed for correlations among the parameters that could be useful in drug design. We showed that compounds with high lipophilicity result in better
antiproliferative effects in vitro and in vivo, with one of the three compounds tested showing better efficacy than satraplatin against an animal model of colorectal cancer, owing to its higher
solubility and lower reduction rates. Our asymmetric PtIV prodrugs may pave the way for a highly predictable, fine-tuned class of orally available PtIV prodrugs for the treatment of colorectal
cancer. Beauty in asymmetry: A series of asymmetric PtIV bis-carboxylates based on the cisplatin template was investigated to establish the correlation between various pharmacological parameters that
would be useful for the development of this class of compounds as orally available anticancer prodrugs for colorectal cancer.
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Lysine-Based α-Peptide/β-Peptoid Peptidomimetics: Influence of Hydrophobicity, Fluorination, and Distribution of Cationic Charge on Antimicrobial Activity and Cytotoxicity
Multidrug-resistant bacteria pose a serious threat to public health worldwide. Previously, α-peptide/β-peptoid hybrid oligomers were found to display activity against Gram-negative
multidrug-resistant bacteria. In the present work, the influence of hydrophobicity, fluorination, and distribution of cationic/hydrophobic residues on antimicrobial, hemolytic, and cytotoxic
properties of α-peptide/β-peptoid hybrids were investigated. An array of 22 peptidomimetics was tested. Analogues with enhanced hydrophobicity were found to exhibit increased activity against
Gram-positive bacteria. Incorporation of fluorinated residues into the peptidomimetics conferred increased potency against Gram-positive bacteria, while hemolytic properties and activity against
Gram-negative bacteria depended on the degree and type of fluorination. Generally, shorter oligomers were less potent than the corresponding longer analogues. However, some short analogues exhibited
equal or higher antimicrobial activity. The alternating hydrophobic/cationic design proved superior to other distribution patterns of cationic side chains and hydrophobic moieties. Alternating
alternatives: From a structure–activity relationship study comprising an array of α-peptide/β-peptoid hybrids with an alternating cationic/hydrophobic design, displaying variation in length and side
chains, it was found that fluorination of the hydrophobic residues led to increased antibacterial activity. For the longer oligomers, concomitantly increased cytotoxicity toward human cells was
observed, whereas some 12-mers exhibited an acceptable activity profile.
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Synthesis and Biological Evaluation of Novel 2-Aminonicotinamide Derivatives as Antifungal Agents
Based on the structures of the reported compounds G884 [N-(3-(pentan-2-yloxy)phenyl)nicotinamide], E1210 [3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine], and 10 b
[2-amino-N-((5-(3-fluorophenoxy)thiophen-2-yl)methyl)nicotinamide], which inhibit the biosynthesis of glycosylphosphatidylinositol (GPI)-anchored proteins in fungi, a series of novel
2-aminonicotinamide derivatives were designed, synthesized, and evaluated for in vitro antifungal activity. Most of these compounds were found to exhibit potent in vitro antifungal activity against
Candida albicans, with MIC80 values ranging from 0.0313 to 4.0 μg mL−1. In particular, compounds 11 g [2-amino-N-((5-(((2-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] and 11 h
[2-amino-N-((5-(((3-fluorophenyl)amino)methyl)thiophen-2-yl)methyl)nicotinamide] displayed excellent activity against C. albicans, with MIC80 values of 0.0313 μg mL−1, and exhibited broad-spectrum
antifungal activity against fluconazole-resistant C. albicans, C. parapsilosis, C. glabrata, and Cryptococcus neoformans, with a MIC80 range of 0.0313–2.0 μg mL−1. Further studies by electron
microscopy and laser confocal microscopy indicated that compound 11 g targets the cell wall and decreases GPI anchor content on the cell surface of C. albicans. Infections unanchored! A series of
novel 2-aminonicotinamide derivatives were designed, synthesized, and evaluated for in vitro antifungal activity. Compounds 11 g and 11 h have excellent activity against Candida albicans, with MIC80
values of 0.0313 μg mL−1, and exhibit broad-spectrum antifungal activity against fluconazole-resistant C. albicans, C. parapsilosis, C. glabrata, and Cryptococcus neoformans, with a MIC80 range of
0.0313–2.0 μg mL−1. Further investigation suggested that compound 11 g targets the cell wall and decreases glycosylphosphatidylinositol anchor content on the cell surface of C. albicans.
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Synthesis and Evaluation of Anti-inflammatory N-Substituted 3,5-Bis(2-(trifluoromethyl)benzylidene)piperidin-4-ones
A total of 24 N-substituted 3,5-bis(2-(trifluoromethyl)benzylidene)piperidin-4-one derivatives were synthesized via aldol condensation, and their anti-inflammatory activities were evaluated. These
compounds were found to have no significant cytotoxicity against mouse bone marrow cells in vitro. However, some compounds, such as c6
(N-(3-methylbenzoyl)-3,5-bis-(2-(trifluoromethyl)benzylidene)piperidin-4-one) and c10 (N-(2-chlorobenzoyl)-3,5-bis-(2-(trifluoromethyl)benzylidene)piperidin-4-one), displayed potent anti-inflammatory
activity by inhibiting lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), IL-1β, prostaglandin E2 (PGE2), and nitric oxide (NO) production in RAW 264.7 cells.
Treatment with c6 or c10 at 2.5 or 10 mg kg−1 significantly decreased the paw edema induced by carrageenan in rats, and the anti-inflammatory effects of these compounds were found to be better than
those of celecoxib or indomethacin as well as their parent compound C66 (2,6-bis-(2-(trifluoromethyl)benzylidene)cyclohexanone). Pharmacokinetic analysis indicated that c6 has better bioavailability
than curcumin. Therefore, these compounds may be valuable leads for the development of new anti-inflammatory drugs. Taking the heat off: The 24 curcumin analogues in this study were found to have no
toxicity toward mouse bone marrow cells, and some of them showed potent anti-inflammatory activity by inhibiting LPS-stimulated TNFα, IL-6, IL-1β, PGE2, and NO production in rat macrophages.
Pharmacokinetic studies indicated that compound c6 has better bioavailability than curcumin in vivo. Both c6 and c10 may be valuable leads for the development of new anti-inflammatory agents.
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Form Matters: Stable Helical Foldamers Preferentially Target Human Monocytes and Granulocytes
Some hybrid foldamers of various length, all containing the (4R,5S)-4-carboxy-5-methyloxazolidin-2-one (d-Oxd) moiety alternating with an l-amino acid (l-Val, l-Lys, or l-Ala), were prepared in order
to study their preferred conformations and to evaluate their biological activity. Surprisingly, only the longer oligomers containing l-Ala fold into well-established helices, whereas all the other
oligomers give partially unfolded turn structures. Nevertheless, they all show good biocompatibility, with no detrimental effects up to 64 μm. After equipping some selected foldamers with the
fluorescent tag rhodamine B, a quantitative analysis was performed by dose– and time–response fluorescence-activated cell sorting (FACS) assays with human HeLa cells and primary blood lymphocytes,
granulocytes, and monocytes. Among the cell types analyzed, the oligomers associated with monocytes and granulocytes with greatest efficacy, still visible after 24 h incubation. This effect is even
more pronounced for foldamers that are able to form stable helices. Where form is function: Hybrid peptide oligomers with helical frameworks can associate preferentially with inflammatory cells,
regardless of their charge or chemical nature. Such foldamers can thus act as targeting agents for small-molecule drugs, as they are intrinsically non-cytotoxic at relatively high doses. Moreover,
with sufficient length, they show a particular cell targeting preference; they are rapidly and more effectively internalized in human blood myeloid cells, such as monocytes and granulocytes.
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