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PubMed Journal Database | Journal of medicinal chemistry RSS

19:48 EDT 5th May 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

Novel cephalosporins selectively active on non-replicating Mycobacterium tuberculosis.

We report two series of novel cephalosporins that are bactericidal to Mycobacterium tuberculosis alone of the pathogens tested, that only kill M. tuberculosis when its replication is halted by conditions resembling those believed to pertain in the host, and whose bactericidal activity is not dependent on or enhanced by clavulanate, a β-lactamase inhibitor. The two classes of cephalosporins bear an ester or, alternatively, an oxadiazole isostere, at C-2 of the cephalosporin ring system, a position that is a...

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.

In the treatment of EML4-ALK+ non-small-cell lung cancer (NSCLC), secondary mutations within the anaplastic lymphoma kinase (ALK) kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine...

PEGylated bis-sulfonamide carbonic anhydrase inhibitors can efficiently control the growth of several carbonic anhydrase IX-expressing carcinomas.

A series of aromatic/heterocyclic bis-sulfonamides were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores, coupled with either ethyleneglycol oligomeric or polymeric diamines to yield bis-sulfonamides with short or long (polymeric) linkers. Testing of novel inhibitors and their precursors against a panel of membrane-bound CA isoforms, including tumor-overexpressed CA IX and CA XII and cytosolic isozymes, identified nanomolar-potent inhibitors ag...

2-(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists.

Constitutive androstane receptor (CAR) is a key regulator of xenobiotic and endobiotic metabolism. Together with Pregnane X (PXR) and Aryl hydrocarbon (AHR) receptors, it is referred to as "xenobiotic receptor". The unique properties of human CAR, such as its high constitutive activity, both direct (ligand-binding domain-dependent) and indirect activation have hindered the discovery of direct selective human CAR ligands. Herein, we report a novel class of direct human CAR agonists in a group of 2-(3-methoxy...

Chlorin p6-based Water-soluble Amino Acid Derivatives as Potent Photosensitizers for Photodynamic Therapy.

The development of novel photosensitizer with high phototoxicity, low dark-toxicity and good water solubility is a challenging task for photodynamic therapy (PDT). A series of chlorin p6-based water-soluble amino acid conjugates were synthesized and investigated for antitumor activity. Among them, aspartylchlorin p6 dimethylester (7b) showed highest phototoxicity against melanoma cells with weakest dark-toxicity, which was more phototoxic than verteporfin while with less dark-toxicity. It also exhibited bet...

5'-Substituted amiloride derivatives as allosteric modulators binding in the sodium ion pocket of the adenosine A2A receptor.

The sodium ion site is an allosteric site conserved amongst many G protein-coupled receptors (GPCRs). Amiloride 1 and 5-(N,N-hexamethylene)amiloride 2 (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high resolution X-ray crystal structure of the human adenosine A2A receptor (hA2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report th...

From Companion Diagnostics to Theranostics: A New Avenue for Alzheimer's Disease?

The recent literature signals a growing paradigm shift towards integrating therapeutics and diagnostics, rather than developing and deploying them separately. In this gradual move towards more effective and personalized medications, companion diagnostics are an intermediate stage. The next step may be "theranostics", in which single chemical entities are developed to deliver therapy and diagnosis simultaneously. This strategy has been successfully exploited in oncology and is now emerging as a possibility f...

Challenges and opportunities for the application of boron clusters in drug design.

There are two branches in boron medicinal chemistry: the first focuses on single boron atom compounds, and the second utilizes boron clusters. Boron clusters and their heteroatom counterparts belong to the family of cage compounds. A subset of this extensive class of compounds includes dicarbadodecaboranes, which have the general formula C2B10H12, and their metal biscarboranyl complexes, metallacarboranes, with the formula [M(C2B10H12)2-2]. The unique properties of boron clusters have resulted in their util...

Design principles for fragment libraries - Maximizing the value of learnings from Pharma fragment based drug discovery (FBDD) programs for use in academia.

Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function: it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry, but is sometimes used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in acad...

Identification and development of 2,3-dihydropyrrolo1,2-aquinazolin-5(1H)-one inhibitors targeting bromodomains within the Switch/Sucrose Non-Fermenting complex.

Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors targeting these proteins, which display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KDs of 262 and 417 nM respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4.

Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70.

HSP70 is a molecular chaperone and a key component of the heat shock response. Due to its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge, which induces a conformational change in the protein, leading to high affinity li...

Crystal structure of human E-cadherin-EC1EC2 in complex with a peptidomimetic competitive inhibitor of cadherin homophilic interaction.

Cadherins are transmembrane cell adhesion proteins whose aberrant expression often correlates with cancer development and proliferation. We report the crystal structure of an E-cadherin extracellular fragment in complex with a peptidomimetic compound that was previously shown to partially inhibit cadherin homophilic adhesion. The structure reveals an unexpected binding mode and allows the identification of a druggable cadherin interface, thus paving the way to a future structure-guided design of cell adhesi...

Rational design of potent and selective inhibitors of an epoxide hydrolase virulence factor from Pseudomonas aeruginosa.

The virulence factor cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is secreted by Pseudomonas aeruginosa and is the founding member of a distinct class of epoxide hydrolases (EHs) that triggers the catalysis-dependent degradation of the CFTR. We describe here the development of a series of potent and selective Cif inhibitors by structure-based drug design. Initial screening revealed 1a (KB2115), a thyroid hormone analog, as a lead compound with low micromolar potency. St...

H2S-Donating Doxorubicins may overcome Cardiotoxicity and Multidrug Resistance.

Doxorubicin (DOXO) is one of the most effective antineoplastic agents in clinical practice. Its use is limited by acute and chronic side effects, in particular by its cardiotoxicity and by the rapid development of resistance to it. As part of a program aimed at developing new DOXO derivatives endowed with reduced cardiotoxicity and active against DOXO-resistant tumor cells, a series of H2S-releasing DOXOs (H2S-DOXOs) were obtained by combining DOXO with appropriate H2S-donor substructures. The resulting com...

Passive membrane permeability of macrocycles can be controlled by exocyclic amide bonds.

We have developed a strategy to synthesize passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecul...

Synthesis and Anti-Influenza Activity of Pyridine, Pyridazine, and Pyrimidine C-Nucleosides as Favipiravir (T-705) Analogues.

Influenza viruses are responsible for seasonal epidemics and occasional pandemics which cause significant morbidity and mortality. Despite available vaccines, only partial protection is achieved. Currently, there are two classes of widely approved anti-influenza drugs: M2 ion channel blockers and neuraminidase inhibitors. However, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs, particularly with a different mechanism of action. Favipiravir (T-705), a ...

An Advanced Tool To Interrogate BRD9.

Selective inhibitors of bromodomain-containing protein 9 (BRD9) may have therapeutic potential in the treatment of human malignancies and inflammatory diseases. A selective small molecule inhibitor that is well tolerated and has proper pharmacokinetic properties is required to explore the function of BRD9 in diseases. BI-9564 (2) is a cell permeable and noncytotoxic BRD9 inhibitor provided to the scientific community to explore BRD9 biology and determine its potential as a drug target.

Novel 3-Aminothiazolquinolones: Design, Synthesis, Bioactive Evaluation, SARs and Preliminary Antibacterial Mechanism.

A series of novel 3-aminothiazolquinolones as analogs of quinolone antibacterial agents were designed and synthesized in an effort to circumvent quinolone resistance. Among these 3-aminothiazolquinolones, 3-(2-aminothiazol-4-yl)-7-chloro-6-(pyrrolidin-1-yl) quinolone 12b exhibited potent antibacterial activity, low cytotoxicity to hepatocyte cells, strong inhibitory potency to DNA gyrase and a broad antimicrobial spectrum including against multidrug-resistant strains. This active molecule 12b also induced b...

Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines that Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase.

Novel pyrazolopyrimidines displaying high potency and selectivity towards SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure-activity relationships that biased subsequent designs...

Preclinical characterization of 3β-(N-acetyl L-cysteine methyl ester)-2aβ,3-dihydrogaliellalactone (GPA512), a prodrug of a direct STAT3 inhibitor for the treatment of prostate cancer.

The transcription factor STAT3 is a potential target for the treatment of castration-resistant prostate cancer. Galiellalactone (1), a direct inhibitor of STAT3, prevents the transcription of STAT3 regulated genes. In this study we characterized 6 (GPA512, Johansson, M.; Sterner, O. Patent WO 2015/132396 A1, 2015), a prodrug of 1. In vitro studies showed that 6 is rapidly converted to 1 in plasma and is stable in a buffer solution. The pharmacokinetics of 6 following a single oral dose indicated that the...

Big Data from Pharmaceutical Patents: A Computational Analysis of Medicinal Chemists' Bread and Butter.

Multiple recent studies have focused on unraveling the content of the medicinal chemist's toolbox. Here, we present an investigation of chemical reactions and molecules retrieved from US patents over the last 40 years (1976-2015). We used a sophisticated text-mining pipeline to extract 1.1 million unique whole reaction schemes, including reaction roles and yields, from pharmaceutical patents. The reactions were assigned to well-known reaction types such as Wittig olefination or Buchwald-Hartwig amination us...

Gram Scale Syntheses of (-)-Incarvillateine and Its Analogs, Discovery of Potent Analgesics for Neuropathic Pain.

(-)-Incarvillateine (INCA) is the major antinociceptive component of Incarvillea sinensis, which has been used to treat rheumatism and relieve pain in Traditional Chinese Medicine. We have developed a concise and general synthetic approach for INCA, which enabled gram-scale asymmetric syntheses of (-)-INCA, (-)-incarvilline, (-)-isoincarvilline, and six other INCA analogues. The synthesis of isoincarvilline was reported for the first time. Three structurally simplified analogues of INCA were also synthesize...

Zinc(II)-thiosemicarbazone complexes are localized to the lysosomal compartment where they transmetallate with copper ions to induce cytotoxicity.

As the di-2-pyridylketone thiosemicarbazone (DpT) and 2-acetylpyridine thiosemicarbazone (ApT) series show potent anti-tumor activity in vitro and in vivo, we synthesized their fluorescent zinc(II) complexes to assess their intracellular distribution. The Zn(II) complexes generally showed significantly greater cytotoxicity than the thiosemicarbazones alone in several tumor cell-types. Notably, specific structure-activity relationships demonstrated the importance of the di-2-pyridyl pharmacophore in their ac...

Identification of a Human Toll-like Receptor (TLR) 8-specific Agonist and a Functional Pan-TLR Inhibitor in 2-Aminoimidazoles.

Activation of human toll-like receptor-8 (TLR8), expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells, evokes a distinct cytokine profile which favors the development of Type 1 helper T cells. Part-structures of the 2-aminobenzimidazole scaffold were examined with a view to identifying structural requisites corresponding to the smallest possible fragment of the benzimidazole core that would allow for retention of TLR8-agonistic activity. TLR8-specific agonistic activity was ...

Total Synthesis of Laspartomycin C and Characterization of its Antibacterial Mechanism of Action.

Laspartomycin C is a lipopeptide antibiotic with activity against a range of Gram-positive bacteria including drug-resistant pathogens. We report the first total synthesis of laspartomycin C as well as a series of structural variants. Laspartomycin C was found to specifically bind undecaprenyl phosphate (C55-P) and inhibit formation of the bacterial cell wall precursor lipid II. While several clinically-used antibiotics target the lipid II pathway, there are no approved drugs that act on its C55-P precursor...


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