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PubMed Journal Database | ChemMedChem RSS

18:50 EDT 19th March 2019 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage PubMed.gov which comprises of more than 29 million records, papers, reports for biomedical literature, including MEDLINE, life science and medical journals, articles, reviews, reports and  books.

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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 308 from ChemMedChem

Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity.

The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which s...

" Synthesis and Biological Evaluation of RGD and isoDGR - Monomethyl Auristatin Conjugates Targeting Integrin αVβ3.

This work reports the synthesis of a series of small molecule-drug conjugates containing the αVβ3-integrin ligand cyclo[DKP-RGD] or cyclo[DKP-isoDGR], a lysosomally cleavable Val-Ala (VA) linker or an "uncleavable" version devoid of this sequence, and monomethyl Auristatin E (MMAE) or F (MMAF) as cytotoxic agent. The conjugates were obtained via a straightforward synthetic scheme taking advantage of a copper-catalyzed azide-alkyne cycloaddition as key-step. The conjugates were tested for their binding aff...

Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors.

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly suited to serve as platform for diversity. Among many other therapeutic areas, the indole scaffold has been utilized to design aromatic compounds useful to interfere with enzymes engaged in regulation of substrate acylation status such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when a decoration with aromatic side-chains is required. Replacem...

Design of CK2β-mimicking peptides as tools to study the CK2α/CK2β interaction in cancer cells.

The ubiquitously expressed Ser/Thr kinase CK2 is a key regulator in a variety of key processes in normal and malignant cells. Due to its distinctive anti-apoptotic and tumor-driving properties, elevated levels of CK2 have frequently been found in tumors of different origin. In recent years, development of CK2 inhibitors has largely been focused on ATP-competitive compounds; however, targeting the CK2α/CK2β interface has emerged as a further concept that might avoid selectivity issues. In order to address ...

DUckCov: a Dynamic Undocking-based Virtual Screening Protocol for Covalent Binders.

Thanks to recent guidelines, the design of safe and effective covalent drugs has gained significant interest. Other than targeting non-conserved nucleophilic residues, optimizing the non-covalent binding framework is important to improve potency and selectivity of covalent binders towards the desired target. Strong efforts have been made in extending the computational toolkits to include a covalent mechanism of protein targeting, like in the development of covalent docking methods for binding mode predictio...

Towards second generation cardiomyogenic and anti-cardiofibrotic 1,4-dihydropyridine-class of TGFβ inhibitors.

Innovative therapeutic modalities for pharmacological intervention of TGFβ-dependent diseases are of great value. b-Annelated 1,4-dihydropyridines (DHPs) might be such a class as they induce TGFβ receptor type-II degradation. However, intrinsic drawbacks are associated with this compound class and were systematically addressed in the presented study. It was possible to install polar functionalities and bioisosteric moieties at distinct sites of the molecules while keeping TGFβ inhibiting activities. The ...

Ionic Liquids and salts from Ibuprofen as promising innovative formulations of an old drug.

Herein we report the synthesis of novel ionic liquids (ILs) by combination of Ibuprofen as anion with biocompatible ammonium, imidazolium and pyridinium cations. The synthetic methodology consisted in the acid-base reaction of neutral Ibuprofen with cation hydroxides, which were previously prepared by anion exchange from the corresponding halide salts with Amberlyst A-26(OH). In comparison with the parent drug, the plethora of synthesized compounds display very attractive physicochemical properties such as ...

Improvement of Aglycone π-Stacking Yields Nano- to Subnanomolar FimH Antagonists.

Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind pred...

Discovery of small molecule antibiotics against a unique tRNA-mediated regulation of transcription in Gram-positive bacteria.

The emergence of multi-drug resistant bacteria necessitates identifying unique targets of intervention and compounds that inhibit their function. Gram-positive bacteria use a well-conserved tRNA-responsive transcriptional regulatory element in mRNAs, the T-box, to regulate transcription of multiple operons controlling amino acid metabolism. T-box regulatory elements are found only in the 5'UTR of mRNAs of Gram-positive bacteria, not Gram-negative bacteria or the human host. Using the structure of the 5'-unt...

Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors.

Herein we report the discovery of a novel series of highly potent and selective mitogen-activated protein kinase kinase 4 (MEK4) inhibitors. MEK4 is an upstream kinase in MAPK signalling pathways that phosphorylates p38 MAPK and JNK in response to mitogenic and cellular stress queues. MEK4 is over-expressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have...

Design, synthesis, and evaluation of lipopeptide conjugates of mercaptoundecahydrododecaborate for boron neutron capture therapy.

We developed new 10B carriers for boron neutron capture therapy (BNCT) that can effectively transport and accumulate boron clusters into cells. These carriers consist of lipopeptide, mercaptoundecahydrododecaborate (BSH) and a disulfide linker. The carriers were conceived according to the structure of pepducine, a membrane-penetrating lipopeptide targeting protease-activated receptor 1 (PAR1). To improve the membrane permeability of BSH, the structure was optimised using various lipopeptides possessing diff...

Hydrophilic Carbon Nanomaterial: Characterization by Physical-Chemical and Biologic Assays.

A highly hydrophilic carbon nanomaterial was generated by an electrochemical approach, and its structure, chemical composition, redox properties, antioxidant activity and cells effects were characterized. It was found that the nanomaterial possesses a structure dominated by sp2 carbons in a non-order carbon network formed by small clusters (< 2 nm) of a carbonaceous material. This nanomaterial has an outstanding capability for electron-donating and an unusual ability to retain cations. Antioxidant activity ...

Synthesis and structure-activity relationship studies of benzob1,4oxazin-3(4H)-one analogues as inhibitors of mycobacterial thymidylate synthase X.

Since the discovery of a flavin-dependent thymidylate synthase (ThyX or FDTS), that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous screening efforts and report here an optimization campaign...

Diamondoid Amino Acid-based Peptide Kinase A Inhibitor Analogues.

The incorporation of diamondoid amino acids (DAAs) into peptide-like drugs is a general strategy to improve lipophilicity, membrane permeability and metabolic stability of peptidomimetic pharmaceuticals. We designed and synthesized five novel peptidic DAA-containing kinase inhibitors of protein kinase A using a sophisticated molecular dynamics protocol and solid phase peptide synthesis. By means of a thermophoresis binding assay, NMR, and crystal structure analysis, we determined the influence of the DAAs o...

Encapsulation of the dinuclear trithiolato-bridged arene ruthenium complex diruthenium-1 in an apoferritin nanocage: structure and cytotoxicity.

The effects of the encapsulation of the cytotoxic dinuclear trithiolato-bridged arene Ru complex [(η6-p-MeC6H4Pri)2Ru2(μ2-S-p-C6H4But)3]Cl (DiRu-1) within the apoferritin (AFt) nanocage were investigated. The DiRu-1-AFt nanocarrier was characterized by UV-Vis spectroscopy, ICP MS, CD and X-ray crystallography. In contrast to previously reported Au- and Pt- based drug-loaded AFt carriers, no direct interactions between DiRu-1 and AFt were evidenced. DiRu-1-AFt is cytotoxic towards immortalized murine fibro...

Discovery of sustainable drugs for neglected tropical diseases: cashew nut shell liquid (CNSL)-based hybrids target mitochondrial function and ATP production in Trypanosoma brucei.

In a search for effective and sustainable treatments for trypanosomiasis, we developed a library of hybrid compounds by merging the structural features of a previously synthesized quinone hit (4) with those of long-chain phenolic constituents from cashew nut shell liquid (CNSL). CNSL is an agro-waste product from cashew nut processing factories with great potential as a precursor for the production of drugs. The synthesized compounds were tested against Trypanosoma brucei brucei, including three multi-drug ...

Structure-Activity and Structure-Toxicity Relationships of Novel Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity.

Novel malaria intervention strategies are of great importance due to the development of drug resistance in malaria endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity. Based on a previously discovered peptoid-based hit compound, we modified all regions of the peptoid scaffold by utilizing a one-pot multicomponent...

Identification of the binding site of apical membrane antigen 1 (AMA1) inhibitors using a paramagnetic probe.

Apical membrane antigen 1 (AMA1) is essential for the invasion of host cells by malaria parasites. Several small-molecule ligands have been shown to bind to a conserved hydrophobic cleft in Plasmodium falciparum AMA1. However, a lack of detailed structural information on the binding pose of these molecules has hindered their further optimisation as inhibitors. We have developed a spin-labelled peptide based on RON2, the native binding partner of AMA1, to probe the binding sites of compounds on PfAMA1. The c...

Advancements in the Development of non-BET Bromodomain Chemical Probes.

The bromodomain and extra terminal (BET) family of bromodomain containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known hu...

Search for shorter portions of the proline-rich antimicrobial peptide fragment Bac5(1-25) that retain antimicrobial activity by blocking protein synthesis.

The spreading of antibiotic-resistant pathogens boosted the search for new antimicrobial drugs. Proline-rich antimicrobial peptides are promising lead compounds for the development of next-generation antibiotics, due to their very low cytotoxicity and their good antimicrobial activity targeting the bacterial ribosome. Bac5(1-25) is a N-terminal fragment of the bovine proline-rich antimicrobial peptide Bac5 whose mode of action has been recently described. In this work we tested a number of Bac5(1-25) fragme...

Investigation of the pentathiepin functionality as an inhibitor of Feline Immunodeficiency Virus (FIV) via a potential zinc ejection mechanism, as a model for HIV infection.

A small diverse library of pentathiepin derivatives were prepared to evaluate their efficacy against the nucleocapsid protein function of the Feline Immunodeficiency Virus (FIV) as a model for HIV, using an in-vitro cell culture approach. This approach led to the development of nanomolar active compounds with low toxicity.

Targeting Asexual and Sexual Blood Stages of Human Malaria Parasite P. falciparum with 7-Chloroquinoline based 1,2,3-Triazoles.

Novel 4-amino-7-chloroquinoline and [1,2,3]-triazole based hybrids were synthesized in good to excellent yields via Cu[I] catalysed Huisgen 1,3-dipolar cycloaddition of 2-azido-N-(7-chloroquinolin-4-ylaminoalkyl)acetamides with various terminal alkynes in 50% t-butanol in water containing a catalytic amount of CuSO4 and sodium ascorbate at ambient temperature. After spectroscopic characterization, the newly synthesized hybrids were screened for their in vitro antimalarial activity against asexual stages of ...

An Overview, Advantages and Therapeutic Potential of Non-peptide Positive Allosteric Modulators of Glucagon-like Peptide-1 Receptor.

Due to uncomfortable injection regimens of peptidic agonists of glucagon-like peptide 1 receptor (GLP-1R), orally available non-peptide positive allosteric modulators (PAMs) of GLP-1 receptors are foreseen as the possible future mainstream therapy of diabetes type 2. In this article we review current GLP-1R PAMs. Based on the effectiveness and in silico predicted physico-chemical properties, pharmacokinetics and toxicity, possible candidates for further development as oral drugs were selected. Our suggestio...

Synthesis, Biological Evaluation and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1-Activated Prodrugs as Antiviral Agents.

Recent studies indicate that tubulin can be a host factor for vector borne flaviviruses like dengue (DENV) and Zika (ZIKV) and inhibitors of tubulin polymerization like colchicine have been demonstrated to reduce virus replication. However, toxicity limits the application of these compounds. Herein, we report prodrugs based on combretastatin and colchicine derivatives that contain anan ester cleavage site for human carboxylesterase, a highly abundant enzyme in monocytes and hepatocytes targeted by DENV. Com...

Novel 8-aminoquinolines containing an aminoxyalkyl side chain exert in vitro dual-stage antiplasmodial activity.

A series of novel 8-aminoquinolines (8-AQs) with an aminoxyalkyl side chain was synthesized and evaluated for its in vitro antiplasmodial properties against asexual blood stages, liver stages, and sexual stages. 8-AQs bearing a 2-alkoxy- and a 5-phenoxy-substituent at the quinoline ring system were the most promising compounds under study, exhibiting potent blood schizontocidal and moderate tissue schizontocidal in vitro activity.


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