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ChemMedChem

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https://www.readbyqxmd.com/read/30010248/design-and-synthesis-of-dna-interactive-%C3%AE-carboline-oxindole-hybrids-as-cytotoxic-and-apoptosis-inducing-agents
#1
Shankaraiah Nagula, Ramya Tokala, Sowjanya Thatikonda, Sravani Sana, Usha Sree Vanteddu, Chandraiah Godugu
A new series of (E)-3-((1-aryl-9H-pyrido[3,4-b]indol-3-yl)methylene)indolin-2-one hybrids have been synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines namely, HCT-15, HCT-116, A549, NCI-H460, MCF-7 including HFL. Among the tested compounds, 10s showed potent cytotoxicity against HCT-15 cancer cells with an IC50 value of 1.43 ± 0.26 μM and GI50 value of 0.89 ± 0.06 μM. Notably, induction of apoptosis by 10s on HCT-15 cell line was characterized by using different staining techniques such as acridine orange/ethidium bromide (AO/EB) and DAPI...
July 16, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30009544/progress-in-the-development-of-platelet-activating-factor-receptor-pafr-antagonists-and-applications-in-the-treatment-of-inflammatory-diseases
#2
Isabel Hyland, Ronan O'Toole, Jason Smith, Alex C Bissember
Platelet-Activating Factor (PAF) and its receptor (PAFr) have been implicated in a wide range of diseases and disorders that originate from the activation of inflammatory pathways. Although the exact structure of the binding site on the PAFr receptor remains unknown, the PAFr is a well-established therapeutic target and an array of structurally diverse PAFr antagonists have been identified. This ranges from compounds that are structurally similar to the natural PAF ligand, synthetic heterocycles, complex polycyclic natural products, and various metal complexes...
July 15, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30004647/exploiting-thiobarbituric-acid-scaffold-for-antibacterial-activity
#3
Fernando Albericio, Anamika Sharma, Sikabe Noki, Sizwe J Zamisa, Heba Hazzah, Zainab M Almarhoon, Ayman El-Faham, Beatriz G de la Torre
Thiobarbituric acid (TBA) has been considered as a privileged structure for developing antimicrobial agents. Diversity was obtained at position "N" and at "C-5" through acylation, Schiff base formation, Knoevenagel condensation, thioamide, and enamine formation. The present work describes the synthesis of small libraries based on TBA moiety and above mentioned reactions. The preliminary antimicrobial activity screening for the prepared compounds against some selected bacteria (Gram +ve and Gram -ve) showed the best results with Boc-Phe-TBA derivative...
July 13, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30004170/%C3%AF-phthalimidoalkyl-aryl-ureas-as-potent-and-selective-inhibitors-of-cholesterol-esterase
#4
Florian M Dato, Miriam Sheikh, Rocky Z Uhl, Alexandra W Schüller, Michaela Steinkrüger, Peter Koch, Jörg-Martin Neudörfl, Michael Gütschow, Bernd Goldfuss, Markus Pietsch
Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure-activity-relationship study applying a small library of ω-phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic character of the ω-phthalimide residue were most important for inhibitory activity...
July 13, 2018: ChemMedChem
https://www.readbyqxmd.com/read/30003691/decoding-the-rich-biological-properties-of-noble-gases-how-well-can-we-predict-noble-gas-binding-to-diverse-proteins
#5
David Alan Winkler, Ira Katz, Géraldine Farjot, Aaron Thornton, Andrew Warden
The chemically inert noble gases display a surprisingly rich spectrum of useful biological properties. Relatively little is known about molecular mechanisms behind these effects. It is clearly not feasible to conduct large numbers of pharmacological experiments on noble gases to identify activity. Computational studies of binding of noble gases and proteins can address this paucity of information and provide insight into mechanisms of action. We employed bespoke computational grid calculations to predict the positions of energy minima in the interactions of noble gases with diverse proteins...
July 12, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29985556/x-ray-structures-and-feasibility-assessment-of-clk2-inhibitors-for-phelan-mcdermid-syndrome
#6
Andreas Markus Lerchner, Joerg Kallen, Christian Bergsdorf, Bertrand Arnaud, Mario Bernhard, Murielle Brichet, Amanda Cobos-Correa, Azeddine Elhajouji, Felix Freuler, Ivan Galimberti, Christel Guibourdenche, Simon Haenni, Sandra Holzinger, Juerg Hunziker, Aude Izaac, Markus Kaufmann, Lukas Leder, Hans-Joerg Martus, Peter von Matt, Valery Polyakov, Patrik Roethlisberger, Guglielmo Roma, Nikolaus Stiefl, Marianne Uteng
CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, we report the discovery of a very potent indazole CLK inhibitor series, and the CLK2 X-ray structure of its most potent analog. This new indazole series was identified via a biochemical CLK2 Caliper assay screen with 30k compounds that were selected by an in silico approach. Novel high resolution X-ray structures of all CLKs, including the first CLK4 X-ray structure, bound to known CLK2 inhibitor tool compounds (e...
July 9, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29981273/cholesterol-a-key-in-the-pathogenesis-of-alzheimer-s-disease
#7
Samya Banerjee, Sanjoy Mukherjee
Cholesterol has been identified as a key component for catalyzed aggregation of Aβ42, which leads to the Alzheimer's disease. This Highlight discusses this work and its enormous potentials in understanding and addressing the inhibition of such processes.
July 7, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29979487/the-impact-of-adrenomedullin-thr22-on-selectivity-within-the-calcitonin-receptor-like-receptor-receptor-activity-modifying-protein-system
#8
Jan-Patrick Fischer, Sylvia Els-Heindl, Ria Schönauer, Donald Bierer, Johannes Koebberling, Bernd Riedl, Annette G Beck-Sickinger
Adrenomedullin (ADM) is a peptide hormone of the calcitonin gene-related peptide (CGRP) family. It is involved in the regulation of cardiovascular processes such as angiogenesis, vasodilation and the reduction of oxidative stress. ADM mediates its effects by activation of the ADM 1 and 2 receptors (AM1R/AM2R), but also activates the CGRP receptor (CGRPR) with reduced potency. It binds to the extracellular domains of the receptors with its C-terminal binding motif (residues 41-52). The activation motif, consisting of a disulfide-bonded ring structure (residues 16-21) and an adjacent helix (residues 22-30), binds to the transmembrane region and stabilizes the receptor conformation in the active state...
July 6, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29974635/synthesis-of-a-novel-series-of-structurally-different-mb327-derivatives-and-their-affinity-characterization-at-the-nicotinic-acetylcholine-receptor
#9
Klaus Theodor Wanner, Sebastian Rappenglück, Sonja Sichler, Georg Höfner, Thomas Wein, Karin V Niessen, Thomas Seeger, Franz F Paintner, Franz Worek, Horst Thiermann
A novel series of 30 symmetric bispyridinium and related N-heteroaromatic bisquaternary salts with a propane-1,3-diyl linker was synthesized and characterized for their binding affinity at the MB327 binding site of nAChR (nicotinic acetylcholine receptor) from Torpedo californica. Compounds targeting this binding site are of particular interest for the research into new antidotes against organophosphate poisoning, as therapeutically active 4-tert-butyl substituted bispyridinium salt MB327 was previously identified as nAChR resensitizer...
July 5, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29969537/brain-penetrant-triazolopyrimidine-and-phenylpyrimidine-microtubule-stabilizers-as-potential-leads-to-treat-human-african-trypanosomiasis
#10
Ludovica Monti, Steven C Wang, Killian Oukoloff, Amos B Smith, Kurt R Brunden, Conor Caffrey, Carlo Ballatore
In vitro whole-organism screens of T. brucei with representative examples of brain-penetrant microtubule (MT)-stabilizing agents identified lethal triazolopyrimidines and phenylpyrimidines with sub-µM potency. In mammalian cells, these anti-proliferative compounds disrupt MT-integrity and reduce total tubulin levels. Their parasiticidal potency, combined with their generally favorable pharmacokinetic properties, which include oral bioavailability and brain-penetration, suggest that these compounds are potential leads against African trypanosomiasis...
July 3, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29968968/nucleobase-modified-adefovir-pmea-analogues-as-potent-and-selective-inhibitors-of-adenylate-cyclases-from-bordetella-pertussis-and-bacillus-anthracis
#11
Michal Česnek, Jan Skácel, Petr Jansa, Martin Dračínský, Markéta Šmídková, Helena Mertlíková-Kaiserová, Monica P Soto-Velasquez, Val J Watts, Zlatko Janeba
A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was the most potent ACT inhibitor in the series (IC50 = 16 nM) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC50 values ranging from 0...
July 3, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29968426/hydroxypyridonecarboxylic-acids-as-inhibitors-of-human-cytomegalovirus-pul89-endonuclease
#12
Jayakanth Kankanala, Yan Wang, Robert J Geraghty, Zhengqiang Wang
Human cytomegalovirus (HCMV) infection poses a major health threat for immuno-compromised individuals. Until very recently treatment of HCMV infection has relied solely on polymerase inhibitors which suffer from safety and resistance issues. pUL89 provides the enzymatic functions for HCMV terminase complex in viral DNA packaging and represents an attractive target for developing a new class of HCMV drugs. However, inhibitors of the endonuclease activity of the C terminus of pUL89 (pUL89-C) were unknown prior to our recently characterized hydroxypyridonecarboxylic acid (HPCA) hit 7r (numbered as 10k in the original publication; Wang et al...
July 3, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29966045/quinone-fused-pyrazoles-through-regio-selective-1-3-dipolar-cycloadditions-synthesis-of-tricyclic-scaffolds-and-in-vitro-cytotoxic-activity-evaluation-on-glioblastoma-cancer-cells
#13
Mauro Comes Franchini, Giulio Bertuzzi, Mariafrancesca Fochi, Erica Locatelli, Ilaria Monaco, Elena Strocchi, Paolo Zani, Bianca Flavia Bonini, Pierpaolo Calandro, Mario Chiariello, Simone Crotti, Andrea Mazzanti
A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and the mild reaction conditions were suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues and two of them, after brief synthetic elaborations, were analysed by molecular docking studies in silico as potential anti-cancer drugs...
July 2, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29943432/synthesis-and-antiviral-evaluation-of-tripppro-abacavirtp-tripppro-carbovirtp-and-their-1-2-cis-disubstituted-analogues
#14
Simon Weising, Vicente Sterrenberg, Dominique Schols, Chris Meier
Herein we describe the synthesis of lipophilic triphosphate prodrugs of Abacavir, Carbovir and their 1',2'-cis-substituted carbocyclic analogues. The 1',2'-cis-carbocyclic nucleosides were prepared starting from enantiomerically pure (1R,2S)-2-((benzyloxy)methyl)cyclopent-3-en-1-ol by a microwave assisted Mitsunobu-type reaction with 2-amino-6-chloropurine. All four nucleoside analogues were prepared from their 2-amino-6-chloropurine precursors. The nucleosides were converted into their corresponding nucleoside triphosphate prodrugs (TriPPPro-approach) by application of the H-phosphonate route...
June 26, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29932312/towards-novel-angiogenesis-inhibitors-based-on-the-conjugation-of-organometallic-platinum-ii-complexes-to-rgd-peptides
#15
Vicente Marchan, Ana Zamora, Albert Gandioso, Anna Massaguer, Silvia Buenestado, Carme Calvis, Jose Luis Hernández, Francesc Mitjans, Venancio Rodríguez, Jose Ruiz
A novel conjugate between a cyclometalated platinum(II) complex with dual anti-angiogenic and antitumor activity and a cyclic peptide containing the RGD sequence (-Arg-Gly-Asp-) has been synthesized by combining solid- and solution-phase methodologies. Although peptide conjugation rendered a non-cytotoxic compound in all tested tumor cell lines (+/- αVβ3 and αVβ5 integrin receptors), the anti-angiogenic activity of the Pt-c(RGDfK) conjugate in HUVEC cells at sub-cytotoxic concentrations opens the way to the design of a novel class of angiogenesis inhibitors through conjugation of metallodrugs with high anti-angiogenic activity to cyclic RGD-containing peptides or peptidomimetic analogues...
June 22, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29931741/a-minimalist-approach-to-the-design-of-complexity-enriched-bioactive-small-molecules-discovery-of-phenanthrenoid-mimics-as-antiproliferative-agents
#16
Fernando Alonso, María Josefina Quezada, Gabriel Gola, Victoria Richmond, Gabriela Cabrera, Andrea Barquero, Javier Alberto Ramírez
Over the last decades, much effort has been devoted to the design of the "ideal" library for screening, the most promising strategies being those which draw inspiration from biogenic compounds, as they seek to add biological relevance to such libraries. On the other hand, there is a growing understanding of the role that molecular complexity plays in the discovery of new bioactive small molecules. Nevertheless, the introduction of molecular complexity must be balanced with synthetic accessibility...
June 21, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29928781/nvp-bhg712-effects-of-regioisomers-on-the-affinity-and-selectivity-towards-the-ephrin-family
#17
Harald Schwalbe, Alix Tröster, Stephanie Heinzlmeir, Benedict-Tilman Berger, Santosh L Gande, Krishna Saxena, Sridhar Sreeramulu, Verena Linhard, Amir H Nasiri, Michael Bolte, Susanne Müller, Bernhard Kuster, Guillaume Médard, Denis Kudlinzki
EPH receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates the intracellular kinase activity. EPHs are key players in bidirectional intercellular signaling, controlling cell morphology, adhesion and migration. They are increasingly recognized as cancer drug targets. We analyzed the binding of the Novartis inhibitor NVP-BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples turned out to be a regioisomer (NVPiso) of the inhibitor, initially described in a Novartis patent application...
June 21, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29927521/what-has-come-out-from-phytomedicines-and-herbal-edibles-for-the-treatment-of-cancer
#18
Srinivasa Reddy Bonam, Seng Wu Yuan, Lakshmi Tunki, Ranjithkumar Chellian, Sampath Kumar Halmuthur M, Sylviane Muller, Vijayapandi Pandy
Several modern treatment strategies have been adopted to combat cancer with the aim of minimizing toxicity. Medicinal plant-based compounds with the potential to treat cancer have been widely studied in preclinical research and have elicited many innovative ways of leading-edge clinical research. In parallel, researchers have eagerly tried to reduce the toxicity of current chemotherapeutic agents either by combining them with herbals or in using herbals alone. The focus of this article is to present an update of medicinal plants and their bioactive compounds, or mere changes in the bioactive compounds, and herbal edibles, which display efficacy against diverse cancer cells and in anticancer therapy...
June 21, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29927060/tertiary-amine-based-inhibitors-of-the-astacin-protease-meprin-alpha
#19
Kathrin Tan, Christian Jäger, Dagmar Schlenzig, Stephan Schilling, Mirko Buchholz, Daniel Ramsbeck
Metalloproteinases of the astacin family are more and more drawing attention as potential drug targets. However, the knowledge about inhibitors thereof is limited in most cases. Crucial for the development of metalloprotease inhibitors is a high selectivity to avoid side effects through the inhibition of off-target proteases and the interference with physiological pathways. Here we aimed at the design of novel selective inhibitors for the astacin proteinase meprin α. Based on a recently identified tertiary amine scaffold, a series of compounds was synthesized and evaluated...
June 21, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29926535/structure-based-design-of-a-monosaccharide-ligand-targeting-galectin-8
#20
Mohammad Bohari, Xing Yu, Chandan Kishor, Brijesh Patel, Rob-Marc Go, Hadieh Alsadat Eslampanah Seyedi, Yaron Vinik, Irwin Darren Grice, Yehiel Zick, Helen Blanchard
Galectin-8 is a β-galactoside-recognising protein that has a role in the regulation of bone remodelling and is an emerging new target for tackling diseases with associated bone-loss. We have designed and synthesised methyl 3-O-[1-carboxyethyl]-β-D-galactopyranoside (compound 6) as a ligand to target the N-terminal domain of galectin-8 (galectin-8N). Our design involved molecular dynamics (MD) simulations that predicted 6 to mimic the interactions made by the galactose ring as well as the carboxylic acid group of 3'-O-sialylated lactose (3'-SiaLac), with galectin-8N...
June 21, 2018: ChemMedChem
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