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PubMed Journal Database | Journal of medicinal chemistry RSS

19:01 EDT 27th July 2016 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage PubMed.gov which comprises of more than 21 million records, papers, reports for biomedical literature, including MEDLINE, life science and medical journals, articles, reviews, reports and  books.  BioPortfolio aims to publish relevant information on published papers, clinical trials and news associated with users selected topics.

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

Showing PubMed Articles 1–25 of 2,400+ from Journal of medicinal chemistry

Synthesis of Fluorescent Binaphthyl Amines That Bind c-MYC G-Quadruplex DNA and Repress c-MYC Expression.

Two novel binaphthyl amines have been designed and synthesized using Buchwald amination and oxidative homocoupling as key steps. The binaphthyl amine containing two triazole rings shows higher affinity for c-MYC G-quadruplex, exhibits fluorescence "turn-on" response with c-MYC, and stains the nucleus in cells. The triazolyl binaphthyl amine shows cytotoxicity for cancer cells by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, both ligands can downregulate c-MYC expression at transcriptional a...

Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.

The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) were investigated using surface plasmon resonance and isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid electrostatically driven process. Off-rates were generally slow partly because of reversible covalent bond formation by some gliptins, and partly because of strong and extensive interactions. Binding of all gliptins is enthalpy-dominated due to strong ionic interactions and strong solvent-...

Structure-Based Design of β5c Selective Inhibitors of Human Constitutive Proteasomes.

This work reports the development of highly potent and selective inhibitors of the β5c catalytic activity of human constitutive proteasomes. The work details the design principles - large hydrophobic P3 residue, small hydrophobic P1 residue - that led to the synthesis of a panel of peptide epoxyketones; their evaluation and the selection of the most promising compounds for further analyses. Structure-activity-relationships detail how in a logical order the β1c/i, β2c/i and β5i activities became resistan...

Discovery of (R,E)-N-(7-Chloro-1-(1-4-(dimethylamino)but-2-enoylazepan-3-yl)-1H-benzodimidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers.

Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816...

The Medicinal Chemistry of Therapeutic Oligonucleotides.

Oligonucleotide-based therapeutic have made rapid progress in the clinic for treatment of a variety of disease indications. Unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Over the past two decades medicinal chemists have identified a number of chemical modification and conjugation strategies which can improve the nuclease stability, RNA-binding affinity and pharmacokinetic properties of oligonucleotides for therapeutic applications. In this chapter we present a su...

Substrate-Guided Design of Potent and Selective FXIIa Inhibitors Based on the Plant-Derived Momordica cochinchinensis Trypsin Inhibitor-II (MCoTI-II) Scaffold.

Thrombosis is a leading cause of morbidity and mortality associated with cardiovascular diseases. Inhibition of Factor XIIa (FXIIa) provides thrombus protection without bleeding complications. Here, we defined the extended substrate specificity of FXIIa and its close homolog Factor Xa and used these data, together with inhibitor-based and structure-guided methods, to engineer potent and selective FXIIa inhibitors based on Momordica cochinchinensis trypsin inhibitor-II.

Structure Activity Relationship and Signaling of New Chimeric CXCR4 Agonists.

The CXCR4 receptor binds with meaningful affinities only CXCL12 and synthetic antagonists/inverse agonists. We recently described high affinity synthetic agonists for this chemokine receptor, obtained by grafting the CXCL12 N-terminus onto the inverse agonist T140. While those chimeric molecules behave as agonists for CXCR4, their binding and activation mode is unknown. The present SAR of those CXCL12-oligopeptide grafts reveals the key determinants involved in CXCR4 activation. Position 3 (Val) controls af...

Evolution of a novel orally bioavailable series of PI3K δ inhibitors from an inhaled lead for the treatment of respiratory disease.

A four step process of high quality modelling of existing data, deconstruction, identification of replacement cores and an innovative synthetic re-growth strategy led to the rapid discovery of a novel oral series of PI3K δ inhibitors with promising selectivity and excellent in vivo characteristics.

Allosteric Sensing of Fatty Acid Binding by NMR: Application to Human Serum Albumin.

Human serum albumin (HSA) serves not only as a physiological oncotic pressure regulator and a ligand carrier, but also as a biomarker for pathologies ranging from ischemia to diabetes. Moreover, HSA is a biopharmaceutical with a growing repertoire of putative clinical applications from hypovolemia to Alzheimer's disease. A key determinant of the physiological, diagnostic and therapeutic functions of HSA is the amount of long chain fatty acids (LCFAs) bound to HSA. Here, we propose to utilize 13C-Oleic acid ...

Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure.

Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent...

An Update on Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors: Opportunities and Challenges in Cancer Therapy.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a critical DNA repair enzyme in the base excision repair pathway. Inhibitors of this enzyme comprise a new type of anticancer drug that selectively kills cancer cells by targeting homologous recombination repair defects. Since 2010, various important advances have been achieved in PARP-1 inhibitors. Specifically, the approval of olaparib in 2014 for the treatment of ovarian cancer with BRCA mutations validated PARP-1 as an anticancer target and established its clini...

South (S)- and North (N)-Methanocarba-7-Deazaadenosine Analogues as Inhibitors of Human Adenosine Kinase.

Adenosine kinase (AdK) inhibitors raise endogenous adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. On the basis of the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3.1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5'-Hydroxy (34, MRS4202 (...

Design, Synthesis, and Identification of 4"α-azidoethyl-Cyclic ADP-Carbocyclic-Ribose as a Highly Potent Analogue of Cyclic ADP-Ribose, a Ca2+-mobilizing Second Messenger.

Cyclic adenosine diphosphate-carbocyclic-ribose (cADPcR, 2) is a stable equivalent of cyclic adenosine diphosphate-ribose (cADPR, 1), a Ca2+-mobilizing second messenger. Based on the structure-activity relationship of cADPR-related compounds, and the three-dimensional structural modeling of cADPcR, we designed and synthesized cyclic-ADP-4"α-azidoethyl carbocyclic-ribose (N3-cADPcR, 3) to demonstrate that it has a highly potent Ca2+-mobilizing activity (IC50 = 24 nM). N3-cADPcR will be a useful precursor fo...

Correction to Structural Investigation of B-Raf Paradox Breaker and Inducer Inhibitors.

Fragment-based discovery of dual JC virus and BK virus helicase inhibitors.

There are currently no treatment for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 μM for the early 6-(2-methoxy...

Inhibitors of the cysteine synthase CysM with antibacterial potency against dormant Mycobacterium tuberculosis.

Cysteine is an important amino acid in the redox defense of Mycobacterium tuberculosis, primarily as a building block of mycothiol. Genetic studies have implicated de novo cysteine biosynthesis in pathogen survival in infected macrophages, in particular for persistent M. tuberculosis. Here, we report on the identification and characterization of potent inhibitors of CysM, a critical enzyme in cysteine biosynthesis during dormancy. A screening campaign of 17312 compounds identified ligands that bind to the a...

Discovery and Characterization of a Class of Pyrazole Inhibitors of Bacterial Undecaprenyl Pyrophosphate Synthase.

Undecaprenyl pyrophosphate synthase (UppS) is an essential enzyme in bacterial cell wall synthesis. Here we report the discovery of Staphylococcus aureus UppS inhibitors from an Encoded Library Technology screen and demonstrate binding to the hydrophobic substrate site through co-crystallography studies. The use of bacterial strains with regulated uppS expression and inhibitor resistant mutant studies confirmed that the whole cell activity was the result of UppS inhibition, validating UppS as a druggable an...

4-Oxo-1, 4-Dihydroquinoline-3-Carboxamide Derivatives as New Axl Kinase Inhibitors.

Axl is a new potential target for anticancer drug discovery. A series of 4-oxo-1, 4-dihydroquinoline-3-carboxamides were designed and synthesized as highly potent Axl kinase inhibitors. One of the most promising compounds 9im tightly bound with Axl protein and potently inhibited its kinase function with a Kd value of 2.7 nM and an IC50 value of 4.0 nM, respectively, while was obviously less potent against most of the 403 wild-type kinases evaluated at a relatively high concentration. The compound dose-depen...

Novel C-Ring-Hydroxy-substituted Controlled Deactivation Cannabinergic Analogues.

In pursuit of safer controlled-deactivation cannabinoids with high potency and short duration of action we report the design, synthesis, and pharmacological evaluation of novel C9- and C11-hydroxy-substituted hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC) analogues in which a seven atom long side chain, with or without 1'-substituents, carry a metabolically labile 2',3'-ester group. Importantly, in vivo studies validated our controlled deactivation approach in rodents and nonhuman primates. The le...

G Protein-coupled Receptor Kinase 2 (GRK2) Inhibitors: Current Trends and Future Perspectives.

G Protein-coupled Receptor Kinase 2 (GRK2) is a G protein-coupled receptor kinase that is ubiquitously expressed in many tissues and regulates various intracellular mechanisms. The up- or down-regulation of GRK2 correlates with several pathological disorders. GRK2 plays an important role in the maintenance of heart structure and function; thus, this kinase is involved in many cardiovascular diseases. GRK2 up-regulation can worsen cardiac ischemia; furthermore, increased kinase levels occur during the early ...

New Insights into Human 17β-Hydroxysteroid Dehydrogenase Type 14: First Crystal Structures in Complex with a Steroidal Ligand and with a Potent Non-Steroidal Inhibitor.

17β-HSD14 is a SDR enzyme, able to oxidize estradiol and 5-androstenediol using NAD(+). We determined the crystal structure of this human enzyme as the holo form and as ternary complexes with estrone and with the first potent, non-steroidal inhibitor. The structures reveal a conical, rather large and lipophilic binding site and are the starting point for structure-based inhibitor design. The two natural variants (S205 and T205) were characterized and adopt a similar structure.

Targeting the Translesion Synthesis Pathway for the Development of Anti-Cancer Chemotherapeutics.

Human cells possess tightly controlled mechanisms to rescue DNA replication following DNA damage caused by environmental and endogenous carcinogens using a set of low-fidelity translesion synthesis (TLS) DNA polymerases. These polymerases can copy over replication blocking DNA lesions while temporarily leaving them unrepaired, preventing cell death at the expense of increasing mutation rates and contributing to the onset and progression of cancer. In addition, TLS has been implicated as a major cellular mec...

Therapeutic Potential of Foldamers: From Chemical Biology Tools to Drug Candidates?

Over the last decade, Foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino-acid based backbones, have been the most studied from a therapeutic perspective. Separetely, polyaromatic foldamers have barely evolved from its nascencey and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targ...

Antibacterial and Solubility Optimization of Thiomuracin A.

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) provided access to analogs in the Northern region (C2-C10). Selective hydrolysis of the C10 amide of lead compound 2 and subsequent derivatization led to novel carbon and nitrogen-linked analogs (e.g., 3) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster C. difficile mo...

Discovery, pharmacokinetic and pharmacological properties of the potent and selective MET kinase inhibitor, 1-{6-6-(4-Fluoro-phenyl)-1,2,4triazolo4,3-bpyridazin-3-ylsulfanyl-benzothiazol-2-yl}-3-(2-morpholin-4-yl-ethyl)-urea (SAR125844).

The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant....


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