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ChemMedChem

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https://www.readbyqxmd.com/read/27921386/cytotoxicity-of-a-series-of-norcantharidin-inspired-tetrahydroepoxyisoindole-carboxamides
#1
Christopher Peter Gordon, Lawson K Spare, Pasquale Falsetta, Jayne Gilbert, David G Harman, Mark A Baker, Feng Li, Adam McCluskey, Jack K Clegg, Jennette A Sakoff, Janice R Aldrich-Wright
A series of 28 norcantharidin (NorC) inspired analogues were accessed via a robust two-step Ugi intramolecular Diels-Alder (IMDA) sequence. Four analogues displayed equipotent whole cell cytotoxicity to NorC and cisplatin against a number of cancer cell lines and a normal breast cell line (MCF10A). Notably (3S,3aS,6R)-2-benzyl-7-methyl-N-(naphthalen-2-yl)-1-oxo-1,2,3,6-tetrahydro-3a,6-epoxyisoindole-3-carboxamide (trans-27) displayed superior whole cell activity against breast (MCF-7, GI50 = 2.9 µM) and colon (HT29, GI50 = 6...
December 6, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27917615/design-synthesis-and-evaluation-of-2-9-bis-substituted-aminomethyl-phenyl-1-10-phenanthroline-derivatives-as-g-quadruplex-ligands
#2
Nassima Meriem Gueddouda, Miyanou Rosales Hurtado, Stéphane Moreau, Luisa Ronga, Rabindra Nath Das, Solène Savrimoutou, Sandra Rubio, Adrien Marchand, Oscar Mendoza, Mathieu Marchivie, Lilian Elmi, Albain Chansavang, Vanessa Desplat, Valérie Gabelica, Anne Bourdoncle, Jean-Louis Mergny, Jean Guillon
Genomic sequences able to form guanine quadruplexes (G4) are found in oncogene promoters, in telomeres and in 5' and 3' untranslated regions as well as introns of messenger RNAs. These regions are potential targets for drugs designed to treat cancer. In the present work, we present the design and syntheses of ten new phenantroline derivatives and characterization of their interactions with G4-forming oligonucleotides. We evaluated ligand-induced stabilization and specificity and selectivity of ligands for various G4 conformations using FRET-melting experiments...
December 4, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27914122/design-synthesis-and-structure-activity-relationships-of-bavachinin-analogues-as-peroxisome-proliferator-activated-receptor-%C3%AE-agonists
#3
Guoxin Du, Yuanyuan Zhao, Li Feng, Zhuo Yang, Jiye Shi, Cheng Huang, Bo Li, Fujiang Guo, Weiliang Zhu, Yiming Li
Bavachinin analogues with systematic modifications at the A-, B-, and C-rings were designed, synthesized, and subjected to in vitro bioevaluation as peroxisome proliferator-activated receptor γ (PPAR-γ) agonists. In total, 30 molecules, including flavanone and flavone analogues, were evaluated by reporter gene assays for the PPAR-γ agonist activity. Preliminary structure-activity relationships of PPAR-γ agonist activity of bavachinin analogues were initially summarized and analogues 2b, 3, 4a, 4b, 11c, 11d, and 12b were found with higher PPAR-γ agonist activities compared to bavachinin...
December 3, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27911045/anti-cancer-potential-of-ionic-liquids
#4
Ana Rita Dias, João Costa-Rodrigues, Maria Helena Fernandes, Ricardo Ferraz, Cristina Prudêncio
Nowadays, many of the challenges that pharmaceutical industry faces impose the need to innovative and effective therapies. The investigation of alternative and effective therapies at the level of cancer is an actual goal of pharmaceutical industry. Ionic Liquids (ILs) appear recently as potential target of study by pharmaceutical industry on search of new therapeutic agents. They are, by definition, organic salts with melting point below 100°C only composed by ions. Their man advantage, is the numerous combinations made between the cation and the anion, which allow adjustments in their physicochemical properties...
December 2, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27902884/synthesis-and-biological-evaluation-of-new-triazolo-and-imidazolopyridine-ror%C3%AE-t-inverse-agonists
#5
Samuel Hintermann, Christine Guntermann, Henri Mattes, David A Carcache, Juergen Wagner, Anna Vulpetti, Andreas Billich, Janet Dawson, Klemens Kaupmann, Joerg Kallen, Rowan Stringer, David Orain
Retinoic-acid-related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORγt inverse agonists was designed...
November 30, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27902882/glycated-99m-tc-tricarbonyl-labeled-peptide-conjugates-for-tumor-targeting-by-click-to-chelate
#6
Karolin Römhild, Christiane A Fischer, Thomas L Mindt
Attaching polar pharmacological modifiers to molecular imaging probes is a common strategy to modulate their pharmacokinetic profiles to improve such parameters as the clearance rate of radiotracers and/or metabolites, and to enhance signal-to-background ratios. We combined the tumor-targeting peptide sequence of bombesin (BBN) with glucuronic acid and the single-photon emission computed tomography (SPECT) radionuclide (99m) Tc by the "click-to-chelate" methodology. The (99m) Tc-tricarbonyl-labeled glucuronated BBN conjugate was compared with a reference compound lacking the carbohydrate...
November 30, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27902880/monoamine-oxidase-inhibitory-activity-methyl-versus-chlorochalcone-derivatives
#7
Bijo Mathew, Gülberk Uçar, Githa Elizabeth Mathew, Sincy Mathew, Praseedha Kalatharakkal Purapurath, Fasil Moolayil, Smrithy Mohan, Sheeba Varghese Gupta
Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase-B (MAO-B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO-B (hMAO-B) inhibitors, two series of twenty chalcones containing electron-donating and electron-withdrawing substituents were synthesized. All compounds were found to be competitive, selective, and reversible inhibitors of hMAO-B except (2E)-1-(4-methylphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P7) and (2E)-1-(4-chlorophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P17), which were found to be selective inhibitors of hMAO-A...
November 30, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27897427/structure-based-drug-design-of-mineralocorticoid-receptor-antagonists-to-explore-oxosteroid-receptor-selectivity
#8
Anneli Nordqvist, Gavin O'Mahony, Maria Fridén-Saxin, Marlene Fredenwall, Anders Hogner, Kenneth L Granberg, Anna Aagaard, Stefan Bäckström, Anders Gunnarsson, Tim Kaminski, Yafeng Xue, Anita Dellsén, Eva Hansson, Pia Hansson, Ida Ivarsson, Ulla Karlsson, Krister Bamberg, Majlis Hermansson, Jennie Georgsson, Bo Lindmark, Karl Edman
The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of non-steroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high-throughput screening (HTS) campaign. The compound bound to MR with a pKi=6.6, but displayed poor selectivity over the glucocorticoid receptor (GR) and the progesterone receptor (PR)...
November 29, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27886451/activity-of-fluorine-containing-analogues-of-wc-9-and-structurally-related-analogues-against-two-intracellular-parasites-trypanosoma-cruzi-and-toxoplasma-gondii
#9
María N Chao, Catherine Li, Melissa Storey, Bruno N Falcone, Sergio H Szajnman, Sergio M Bonesi, Roberto Docampo, Silvia N J Moreno, Juan B Rodriguez
Two obligate intracellular parasites, Trypanosoma cruzi, the agent of Chagas disease, and Toxoplasma gondii, an agent of toxoplasmosis, upregulate the mevalonate pathway of their host cells upon infection, which suggests that this host pathway could be a potential drug target. In this work, a number of compounds structurally related to WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, were designed, synthesized, and evaluated for their effect on T. cruzi and T. gondii growth in tissue culture cells...
November 25, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27885822/from-type%C3%A2-i-to-type%C3%A2-ii-design-synthesis-and-characterization-of-potent-pyrazin-2-ones-as-dfg-out-inhibitors-of-pdgfr%C3%AE
#10
Eugen Bethke, Boris Pinchuk, Christian Renn, Lydia Witt, Joachim Schlosser, Christian Peifer
Reversible protein kinase inhibitors that bind in the ATP cleft can be classified as type I or type II binders. Of these, type I inhibitors address the active form, whereas type II inhibitors typically lock the kinase in an inactive form. At the molecular level, the conformation of the flexible activation loop holding the key DFG motif controls access to the ATP site, thereby determining an active or inactive kinase state. Accordingly, type I and type II kinase inhibitors bind to so-called DFG-in or DFG-out conformations, respectively...
November 25, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27879063/carbazole-aminoalcohols-induce-antiproliferation-and-apoptosis-of-human-tumor-cells-by-inhibiting-topoisomerase%C3%A2-i
#11
Weisi Wang, Xiao Sun, Deheng Sun, Shizhu Li, Yang Yu, Tingyuan Yang, Junmin Yao, Zhuo Chen, Liping Duan
Novel carbazole aminoalcohols were designed and synthesized as anticancer agents. Among them, alkylamine-chain-substituted compounds showed the most promising antiproliferative activity, with IC50 values in the single-digit micromolar range against two human tumor cell lines. Topoisomerase I (topo I) is likely to be one of the targets of these compounds. Results of comet assays and molecular docking indicate that the representative compounds may act as topo I poisons, causing single-strand DNA damage by stabilizing the topo I-DNA cleavage complex...
November 23, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27875633/design-synthesis-and-evaluation-of-dasatinib-amino-acid-and-dasatinib-fatty-acid-conjugates-as-protein-tyrosine-kinase-inhibitors
#12
Rakesh K Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady Verkhivker, Keykavous Parang, Gongqin Sun
Derivatives of the tyrosine kinase inhibitor dasatinib were synthesized by esterification with 25 carboxylic acids, including amino acids and fatty acids, thereby extending the drug to interact with more diverse sites and to improve specificity. The dasatinib-l-arginine derivative (Das-R, 7) was found to be the most potent of the inhibitors tested, with IC50 values of 4.4, <0.25, and <0.45 nm against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src, belonged to compound 18 (Das-C10 ) with an IC50 value of 3...
November 22, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27875023/myxochelin-inspired-5-lipoxygenase-inhibitors-synthesis-and-biological-evaluation
#13
Sebastian Schieferdecker, Stefanie König, Simona Pace, Oliver Werz, Markus Nett
A total of 48 analogues of the natural product myxochelin A were prepared and evaluated for their inhibitory effects on human 5-lipoxygenase in both cell-free and cell-based assays. Structure-activity relationship analysis revealed that the secondary alcohol function and only chiral center of myxochelin A is not required for the biological activity. By expanding the diaminoalkane linker of the two aromatic residues it was possible to generate a myxochelin derivative with superior activity against 5-lipoxygenase in intact cells...
November 22, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27874262/a-deep-hydrophobic-binding-cavity-is-the-main-interaction-for-different-y2-r-antagonists
#14
Kerstin Burkert, Tristan Zellmann, René Meier, Anette Kaiser, Jan Stichel, Jens Meiler, Gopi K Mittapalli, Edward Roberts, Annette G Beck-Sickinger
The neuropeptide Y2 receptor (Y2 R) is involved in various pathophysiological processes such as epilepsy, mood disorders, angiogenesis, and tumor growth. Therefore, the Y2 R is an interesting target for drug development. A detailed understanding of the binding pocket could facilitate the development of highly selective antagonists to study the role of Y2 R in vitro and in vivo. In this study, several residues crucial to the interaction of BIIE0246 and SF-11 derivatives with Y2 R were investigated by signal transduction assays...
November 22, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27860401/probing-an-allosteric-pocket-of-cdk2-with-small-molecules
#15
Michael S Christodoulou, Fabiana Caporuscio, Valentina Restelli, Luca Carlino, Giuseppe Cannazza, Elisa Costanzi, Cinzia Citti, Leonardo Lo Presti, Pasquale Pisani, Roberto Battistutta, Massimo Broggini, Daniele Passarella, Giulio Rastelli
The availability of well characterized allosteric modulators is of crucial importance for investigating allosteric regulation of protein function. In a recently identified inactive conformation of CDK2 an open allosteric pocket has been detected and proposed as a site to accommodate allosteric inhibitors. Previous structure-based approaches allowed the identification of a hit compound expected to bind to this pocket. Here, we report the characterization of this compound by X-ray crystallography, which surprisingly provided a chemical structure different from the one previously reported...
November 18, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27863026/design-and-synthesis-of-selurampanel-a-novel-orally-active-and-competitive-ampa-receptor-antagonist
#16
David Orain, Engin Tasdelen, Samuel Haessig, Manuel Koller, Anne Picard, Celine Dubois, Kurt Lingenhoehl, Sandrine Desrayaud, Phillip Floersheim, David Carcache, Stephan Urwyler, Joerg Kallen, Henri Mattes
A series of potent quinazolinedione sulfonamide antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor were designed and synthesized. The structure-activity relationships (SAR) and in vivo activity of the series were investigated. In particular, compound 1 S (selurampanel; N-[7-isopropyl-6-(2-methylpyrazol-3-yl)-2,4-dioxo-1H-quinazolin-3-yl]methanesulfonamide) has shown excellent oral potency against maximal electroshock seizure (MES)-induced generalized tonic-clonic seizures in rodents as well as significant activity in patients suffering from various forms of epilepsy...
November 15, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27863116/a-quinacrine-analogue-selective-against-gastric-cancer-cells-insight-from-biochemical-and-biophysical-studies
#17
Ana Gomes, Iva Fernandes, Cátia Teixeira, Nuno Mateus, M J Sottomayor, Paula Gomes
One of the earliest synthetic antimalarial drugs, quinacrine, was recently reported as interesting for the treatment of acute myeloid leukemia. Inspired by this and similar findings, we evaluated a set of quinacrine analogues against gastric (MKN-28), colon (Caco-2), and breast (MFC-7) cancer cell lines and one normal human fibroblast cell line (HFF-1). All the compounds, previously developed by us as dual-stage antimalarial leads, displayed antiproliferative activity, and one of the set stood out as selective toward the gastric cancer cell line, MKN-28...
November 14, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27863031/discovery-of-a-novel-scaffold-as-an-indoleamine-2-3-dioxygenase%C3%A2-1-ido1-inhibitor-based-on-the-pyrrolopiperazinone-alkaloid-longamide%C3%A2-b
#18
Zenyu Shiokawa, Emi Kashiwabara, Daisuke Yoshidome, Koichi Fukase, Shinsuke Inuki, Yukari Fujimoto
Indoleamine 2,3-dioxygenase 1 (IDO1) has emerged as a key target for cancer therapy, as IDO1 plays a critical role in the capacity of tumor cells to evade the immune system. The pyrrolopiperazinone alkaloid longamide B and its derivatives were identified as novel IDO1 inhibitors based on docking studies and small library synthesis. The thioamide derivative showed higher IDO1 inhibitory activity than longamide B, and displayed an activity similar to that of a representative IDO1 inhibitor, 1-methyl-tryptophan...
November 11, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27863054/utility-of-the-2-nitrobenzenesulfonamide-group-as-a-chemical-linker-for-enhanced-extracellular-stability-and-cytosolic-cleavage-in-sirna-conjugated-polymer-systems
#19
Chih Hao Huang, Hiroyasu Takemoto, Takahiro Nomoto, Keishiro Tomoda, Makoto Matsui, Nobuhiro Nishiyama
Herein we report the 2-nitrobenzenesulfonamide group as a new chemical linker that responds to the difference in redox potential across the cellular membrane, toward the construction of siRNA-polymer conjugates. PEG-conjugated to siRNA via the 2-nitrobenzenesulfonamide group (PEG-sul-siRNA) exhibited highly selective siRNA release under intracellular conditions due to the exclusive presence of GSH/GST ratios in the cell. In addition, siRNA release from PEG-sul-siRNA under extracellular reductive conditions was dramatically suppressed relative to PEG-siRNA conjugates containing a conventional redox-sensitive disulfide linkage (PEG-disulfide-siRNA), indicating the enhanced extracellular stability of the 2-nitrobenzenesulfonamide group...
November 10, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27860402/characterization-of-a-cell-penetrating-peptide-with-potential-anticancer-activity
#20
Anja Gronewold, Mareike Horn, Ivan Ranđelović, József Tóvári, Sergio Muñoz Vázquez, Klaus Schomäcker, Ines Neundorf
Cell-penetrating peptides (CPPs) are still an interesting and viable alternative for drug delivery applications. CPPs contain considerably high amounts of positively charged amino acids, imparting them with cationic character. Tumor cells are characterized by an enhanced anionic nature of their membrane surface, a property that could be used by CPPs to target these cells. We recently identified a branched CPP that displays a high internalization capacity while exhibiting selectivity for certain tumor cell types...
November 8, 2016: ChemMedChem
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