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13:35 EDT 25th May 2015 | BioPortfolio

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For example view all recent relevant publications on Epigenetics and associated publications and clincial trials.

Showing PubMed Articles 1–25 of 2,100+ from Journal of medicinal chemistry

Friday 4th March 1244

Privileged Structures Meet Human T-Cell Leukemia Virus-1 (HTLV-1): C2-Symmetric 3,4-Disubstituted Pyrrolidines as Nonpeptidic HTLV-1 Protease Inhibitors.

3,4-disubstituted pyrrolidines originally designed to inhibit the closely related HIV-1 protease were evaluated as privileged structures against HTLV-1 protease (HTLV-1 PR). The most potent inhibitor of this series exhibits two-digit nanomolar affinity and represents, to the best of our knowledge, the most potent nonpeptidic inhibitor of HTLV-1 PR described so far. The X-ray structures of two representatives bound to HTLV-1 PR were determined, and the structural basis of their affinity is discussed.

Wednesday 7th January 1243

Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health.

In 1994, following work from this laboratory, it was reported that estrone-3-O-sulfamate irreversibly inhibits a new potential hormone-dependent cancer target steroid sulfatase (STS). Subsequent drug discovery projects were initiated to develop the core aryl O-sulfamate pharmacophore that, over some twenty years, have led to steroidal and non-steroidal drugs in numerous pre-clinical and clinical trials, with promising results in oncology and women's health, including endometriosis. Drugs have been designed ...

1242914

Synthesis and Biological Evaluation of Novel Olean-28,13?-lactams as Potential Anti-prostate Cancer Agents.

γ-Lactam is an important structural motif in a large number of biologically active natural products and synthetic small pharmaceutical molecules. However, there is currently no effective approach to construct γ-lactam ring directly from natural rigid polycyclic amides. Herein, we report a facile methodology for synthesis of a new group of olean-28,13β-lactams (10a-j) from their corresponding amides, promoted by an easily available reagent 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), through an intramolecu...

1242830

Structure-Activity Relationship Studies of a Series of Semi-synthetic Lipopeptides Leading to the Discovery of Surotomycin, a Novel Cyclic Lipopeptide Being Developed for the Treatment of Clostridium difficile-Associated Diarrhea.

Novel cyclic lipopeptides with different acyl tails were synthesized via a semi-synthetic approach. Structure-activity relationship studies revealed that lipophilicity, chain length, and the location of key aromatic functionalities of the tail modulated activity. The lead compound surotomycin exhibited significantly improved in vitro activity compared with daptomycin (MIC90 0.5 μg/mL vs 2 μg/mL) against C. difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animal...

1242621

Novel Bioactive Hybrid Compounds Dual Targeting Estrogen Receptor and Histone Deacetylase for Treatment of Breast Cancer.

A strategy to develop chemotherapeutic agents by combining several active groups into a single molecule as a conjugate that can modulate multiple cellular pathways may produce compounds having higher efficacy compared to single-target drugs. In this paper, we describe the synthesis and evaluation of an array of dual-acting ER and histone deacetylase inhibitors. These novel hybrid compounds combine an indirect antagonism structure motif of ER (OBHS, oxabicycloheptene sulfonate) with the HDAC inhibitor subero...

1242496

Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.

Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role o...

Friday 27th April 1240

Structure-guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2.

The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, non-covalent, ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) which act via a covalent mechanism of...

Friday 27th January 1240

Synthesis and Biological Evaluation of Cyclopentaquinoline Derivatives as Nonsteroidal Glucocorticoid Receptor Antagonists.

The steroidal glucocorticoid antagonist mifepristone has been reported to improve the symptoms of depression. We report the discovery of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one 3d (QCA-1093) as a novel nonsteroidal glucocorticoid receptor antagonist. The compound displayed potent in vitro activity, high selectivity over other steroid hormone receptors, and significant antidepressant-like activity in vivo.

1238827

Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF.

TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumours and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD-bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TRIM24 dual in...

1238563

Novel orthosteric antagonist of ASIC1a prevents NMDAR-dependent LTP induction.

Acid sensing ion channels 1a (ASIC1a) are of crucial importance in numerous physiological and pathological processes in the brain. Using molecular modeling approach, we have designed a novel 2-oxo-2H-chromene-3-carboxamidine derivative 5b targeting pH sensor of ASIC1a. It inhibits ASIC1a currents with an apparent IC50 of 27 nM when measured at pH 6.7. The mode of action of compound 5b suggests that it binds to pH sensor of ASIC1a acting as orthosteric noncompetitive antagonist. At 100 nM 5b abolishes induct...

1238479

A Dual-Mode HDAC Prodrug for Covalent Modification and Subsequent Inhibitor Release.

Histone deacetylase inhibitors (HDACi) target abnormal epigenetic states associated with a variety of pathologies including cancer. Here, the development of a prodrug of the canonical broad-spectrum HDACi suberoylanilide hydroxamic acid (SAHA) is described. Although hydroxamic acids are utilized universally in the development of metalloenzyme inhibitors, they are considered poor pharmacophores with reduced activity in vivo. We developed a prodrug of SAHA by appending a promoiety, sensitive to thiols, to the...

1237904

Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido2,3-dpyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells.

The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer...

1237814

New Monocyclic, Bicyclic, and Tricyclic Ethynylcyanodienones as Activators of the Keap1/Nrf2/ARE Pathway and Inhibitors of Inducible Nitric Oxide Synthase.

A monocyclic compound 3 (3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarbonitrile) is a highly reactive Michael acceptor leading to reversible adducts with nucleophiles, which displays equal or greater potency than the pentacyclic triterpenoid CDDO in inflammation and carcinogenesis related assays. Recently, reversible covalent drugs, which bind with protein targets but not permanently, have been gaining attention because of their unique features. To explore such reversible covalent drugs, we have synthesize...

Thursday 26th February 1237

Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-inflammatory Therapeutics.

Microsomal prostaglandin-E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin-E2 (PGE2) from prostaglandin-H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by ...

1236983

Structure-Activity Relationship and Pharmacokinetic Studies of 1,5-Diheteroarylpenta-1,4-dien-3-ones: A Class of Promising Curcumin-Based Anti-Cancer Agents.

Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner-Wadsworth-Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities towards both androgen-insensitive and androgen-sensitive prostate cancer cell lines, and an aggressive cervical cancer cell line. Most of the synthesi...

1236904

Detailed biological profiling of a photoactived and apoptosis inducing pdppz Ruthenium (II) polypyridyl complex in cancer cells.

Ruthenium complexes are currently showing great promise in clinical application. Their polypyridyl derivatives have been deemed promising candidates as a new class of photodynamic therapy (PDT) agent due to their water solubility, stability and well-studied photochemical properties. However, a significant drawback to their development is the lack of detailed studies and understanding of their mode of internalisation and mechanism of therapeutic action in cells. With this in mind, we have developed a new wat...

1236374

N-Substitued Quinolinonyl Diketo Acid Derivatives as HIV Integrase Strand Transfer Inhibitors and their Activity against RNase H Function of Reverse Transcriptase.

Bifunctional quinolinonyl DKA derivatives were firstly described as non-selective inhibitors of 3'-processing (3'-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuclease H (RNase H). In this study we describe the design, synthesis and biological evaluation of new quinolinonyl diketo acid (DKA) derivatives caracterized by variously substituted alkylatin...

1232905

Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products.

Cyclic peptide natural products contain a variety of conserved, non-proteinogenic structural elements such as D-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation. Here we report the synthes...

1232828

Discovery of a High Affinity and Selective Pyridine Analog as a Potential PET Imaging Agent for Cannabinoid Type 2 Receptor.

As part of our efforts to develop CB2 PET imaging agents, we investigated 2,5,6-substituted pyridines as a novel class of potential CB2 PET ligands. A total of 21 novel compounds were designed, synthesized and evaluated for their potency and binding properties towards human and rodent CB1 and CB2. The most promising ligand 6a was radiolabeled with carbon-11 to yield 16 ([(11)C]RSR-056). Specific binding of 16 to CB2-positive spleen tissue of rats and mice was demonstrated by in vitro autogadiography and ver...

Sunday 19th September 1232

Differential targeting of human topoisomerase II isoforms with small molecules.

The TOP2 poison etoposide has been implicated in the generation of secondary malignancies during cancer treatment. Structural similarities between TOP2 isoforms challenge the rational design of isoform-specific poisons to further delineate these processes. Herein, we describe the synthesis and biological evaluation of a focused library of etoposide analogues, with the identification of two novel small molecules exhibiting TOP2B-dependent toxicity. Our findings pave the way towards studying isoform-specific ...

1227674

A Novel Micelle-Forming Material Used for Preparing a Theranostic Vehicle Exhibiting Enhanced in Vivo Therapeutic Efficacy.

A new micelle-forming material, folic acid-conjugated carboxymethyl lauryl chitosan (FA-CLC), and superparamagnetic iron oxide (SPIO) nanoparticles were used for preparing an imaging-guided drug vehicle (the FA-CLC/SPIO hybrid micelle) that demonstrates targeted delivery, imaging, and controlled release of hydrophobic agents. We found that the ratio of viable normal cells to tumor cells was increased prominently after delivery of camptothecin (CPT)-loaded FA-CLC/SPIO micelles and therapeutic sonication. In ...

1227578

Correction to Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity.

1227392

Design, Synthesis, and Biological Evaluation of Hexacyclic Tetracyclines as Potent, Broad Spectrum Antibacterial Agents.

A series of novel hexacyclic tetracycline analogs ("hexacyclines") was designed, synthesized, and evaluated for antibacterial activity against a wide range of clinically important bacteria isolates, including multidrug-resistant, Gram-negative pathogens. Valuable structure-activity relationships were identified and several hexacyclines displayed potent, broad spectrum antibacterial activity, including promising anti-Pseudomonas aeruginosa activity in vitro and in vivo.

Tuesday 14th December 1227

Voltage-Gated Sodium Channels: Structure, Function, Pharmacology and Clinical Indications.

The tremendous therapeutic potential of voltage-gated sodium channels (Navs) has been the subject of many studies in the past and is of intense interest today. Nav1.7 channels in particular have received much attention recently because of strong genetic validation of their involvement in nociception. Here we summarize the current status of research in the Nav field and present the most relevant recent developments with respect to the molecular structure, general physiology, and pharmacology of distinct Nav ...

Saturday 8th August 1226

Synthesis and Evaluation of 1,2,4-Triazolo1,5-apyrimidines as Antibacterial Agents Against Enterococcus faecium.

Rapid emergence of antibiotic resistance is one of the most challenging global public health concerns. In particular, vancomycin-resistant Enterococcus faecium infections have been increasing in frequency, representing 25% of enterococci infections in intensive care units. A novel class of 1,2,4-triazolo[1,5-a]pyrimidines active against E. faecium is reported herein. We used a three-component Biginelli-like heterocyclization reaction for the synthesis of a series of these derivatives based on reactions of a...


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