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https://www.readbyqxmd.com/read/28346821/structure-activity-relationships-on-cynnamoyl-derivatives-as-inhibitors-of-p300-histone-acetyltransferase
#1
Valentina Noemi Madia, Rosaria Benedetti, Maria Letizia Barreca, Liza Ngo, Luca Pescatori, Antonella Messore, Giovanni Pupo, Francesco Saccoliti, Sergio Valente, Antonello Mai, Luigi Scipione, Yujun George Zheng, Cristina Tintori, Maurizio Botta, Violetta Cecchetti, Lucia Altucci, Roberto Di Santo, Roberta Costi
Human p300 is a polyhedric transcriptional coactivator, playing a crucial role by acetylating histones on specific lysine residues. A great deal of evidences shows that p300 is involved in several diseases as leukemia, tumors and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale as to how its modulation could represent an amenable drug target. Several p300 inhibitors (HATi) have been described so far, but all suffer from low potency, lack of specificity or low cell-permeability, highlighting the need to find more effective inhibitors...
March 27, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28342294/benzylphenylpyrrolizinones-with-anti-amyloid-and-scavenging-effects-potentially-useful-in-alzheimer-s-disease-treatment
#2
Jean-Pierre Gabriel Jourdan, Marc Since, Laîla El Kihel, Cédric Lecoutey, Sophie Corvaisier, Rémi Legay, Jana Sopkova-de Oliveira Santos, Thierry Cresteil, Aurélie Malzert-Fréon, Christophe Rochais, Patrick Dallemagne
This article describes the drug design steps developed to try to increase the scavenging and Aβ aggregation inhibition activities of a previously described series of benzylidenephenyl-pyrrolizinones. Among the novel synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities and first druggability parameters which confer to these compounds a potential therapeutic interest in Alzheimer's disease.
March 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28334511/elongated-and-shortened-peptidomimetic-inhibitors-of-the-proprotein-convertase-furin
#3
Kornelia Hardes, Teodora Ivanova, Bastian Thaa, Gerald M McInerney, Tove Irene Klokk, Kirsten Sandvig, Sebastian Künzel, Iris Lindberg, Torsten Steinmetzer
Novel elongated and shortened derivatives of the peptidomimetic furin inhibitor phenylacteyl-Arg-Val-Arg-4-amidinobenzylamide were synthesized. The most potent compounds, e.g., Nα(carbamidoyl)Arg-Arg-Val-Arg-4-amidinobenzylamide (Ki = 6.2 pM), contain additional basic residues at the N-terminus and inhibit furin in the low picomolar range. Furthermore, to decrease the molecular weight of this inhibitor type, compounds lacking the P5-moiety were prepared. The best inhibitors of this series, 5-(guanidino)-valeroyl-Val-Arg-4-amidinobenzylamide and its P3 tert...
March 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28334506/molecular-features-of-the-yap-inhibitor-verteporfin-synthesis-of-hexasubstituted-dipyrrins-as-potential-inhibitors-of-yap-taz-the-downstream-effectors-of-the-hippo-pathway
#4
Floriane Gibault, Fabrice Bailly, Matthieu Corvaisier, Mathilde Coevoet, Guillemette Huet, Patricia Melnyk, Philippe Cotelle
Porphyrin derivatives, and in particular Verteporfin (VP), a photosensitizer initially designed for cancer therapy, have been identified as inhibitors of YAP-TEAD interaction and transcriptional activity. We herein report the efficient convergent synthesis of the dipyrrin western half-part of protoporphyrin IX dimethyl ester (PPIX-DME) where the sensitive vinyl group was created at the final stage by a dehydroiodation reaction. Two other dipyrrin derivatives were synthesized including dipyrrin 19 containing two vinyl groups...
March 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28333400/an-improved-model-of-the-trypanosoma-brucei-ctp-synthetase-glutaminase-domain-acivicin-complex
#5
Juliana Oliveira de Souza, Alice Dawson, William Nigel Hunter
The natural product acivicin inhibits the glutaminase activity of CTP synthetase and is a potent lead compound for drug discovery in the area of neglected tropical diseases, specifically trypanosomaisis. A 2.1 Å resolution crystal structure of the acivicin adduct with the glutaminase domain from Trypanosoma brucei CTP synthetase has been deposited in the Protein Data Bank and provides a template for structure-based approaches to design new inhibitors. However, our assessment of that data identified deficiencies in the model...
March 23, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28328074/the-13-th-winter-conference-on-medicinal-and-bioorganic-chemistry
#6
Scott D Williams
The Medicinal and Bioorganic Chemistry Foundation (MBCF) hosted its 13(th) biannual Winter Conference on Medicinal and Bioorganic Chemistry (WCMBC) this past January 22(nd) -26(th) in Steamboat Springs, Colorado (USA). The gathering this year kept true to the tradition of this conference series, with an impressive lineup of presenters from both academia and industry. With about 125 delegates, the conference took all the advantages of a mid-sized gathering: a sufficiently wide spectrum of scientists in attendance, yet an intimate atmosphere conducive to solid networking and frank, open discussions...
March 22, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28328014/n-guanidino-derivatives-of-1-5-dideoxy-1-5-imino-d-xylitol-are-potent-selective-and-stable-inhibitors-of-%C3%AE-glucocerebrosidase
#7
Alen Sevšek, Luka Šrot, Jakob Rihter, Maša Čelan, Linda Quarles van Ufford, Ed E Moret, Nathaniel I Martin, Roland J Pieters
A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant β-glucocerebrosidase with IC50 values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for β-galactosidase from bovine liver...
March 22, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28324644/synthesis-of-the-t-705-ribonucleoside-and-ribonucleotide-and-studies-on-the-chemical-stability
#8
Johanna Huchting, Matthias Winkler, Hiba Nasser, Chris Meier
T-705 (favipiravir) is a fluorinated hydroxypyrazine carboxamide that exhibits antiviral activities against a variety of RNA viruses. Due to the lack of potent agents to combat these infections caused by a large number of these high-impacting pathogens, huge emphasis has been put on the studies of T-705's antiviral properties and its mechanism of action. T-705 acts as a nucleobase analogue; hence, it is metabolized to the corresponding ribonucleoside triphosphate intracellularly. We herein report a reliable synthesis of T-705-ribonucleoside and its 5'-monophosphate...
March 21, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28322513/site-of-metabolism-prediction-based-on-ab-initio-derived-atom-representations
#9
Arndt R Finkelmann, Andreas H Göller, Gisbert Schneider
Machine learning models for site of metabolism (SoM) prediction offer the ability to identify metabolic soft spots in low molecular weight drug molecules at low computational cost and enable data-based reactivity prediction. SoM prediction is an atom classification problem. Successful construction of machine learning models requires atom representations that capture the reactivity-determining features of a potential reaction site. We have developed a descriptor scheme that characterizes an atom's steric and electronic environment and its relative location in the molecular structure...
March 21, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28319646/improving-non-specific-binding-and-solubility-bicycloalkyls-and-cubanes-as-p-phenyl-bioisosteres
#10
Yves P Auberson, Cara Brocklehurst, Markus Furegati, Thomas Fessard, Guido Koch, Andrea Decker, Luigi La Vecchia, Emmanuelle Briard
Bicycloalkyl groups have previously been described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction in complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl group improves solubility by at least 50-fold, and markedly decreases non-specific binding (NSB) as measured using CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes...
March 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28296270/analogues-of-dehydroacetic-acid-as-selective-and-potent-agonists-of-an-ectopic-odorant-receptor-through-a-combination-of-hydrophilic-and-hydrophobic-interactions
#11
Bernie Byunghoon Park, NaHye Lee, YunHye Kim, YoonGyu Jae, Seunghyun Choi, NaNa Kang, Yu Ri Hong, Kiwon Ok, Jeonghee Cho, Young Ho Jeon, Eun Hee Lee, Youngjoo Byun, JaeHyung Koo
Identification of potent agonists of odorant receptors (ORs), a major class of G protein-coupled receptors, remains challenging due to complex receptor-ligand interactions. ORs are present in both olfactory and non-chemosensory tissues, indicating roles beyond odor detection that may include modulating physiological functions in non-olfactory tissues. Selective and potent agonists specific for particular ORs can be used to investigate physiological functions of ORs in non-chemosensory tissues. In this study, we designed and synthesized novel synthetic dehydroacetic acid analogues as agonists of odorant receptor 895 (Olfr895) expressed in bladder...
March 15, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28296145/synthesis-and-opioid-activity-of-tyr1-z-cf-ch-gly2-and-tyr1-s-r-cf3ch-nh-gly2-leu-enkephalin-fluorinated-pep-tidomimetics
#12
Somnath N Karad, Mohan Pal, Thomas E Prisinzano, Rachel Saylor Crowley, Ryan A Altman
We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1-ψ[(Z)CF=CH]-Gly2) and trifluoroethylamine (Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2) analogs of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exihibited low nanomolar functional activity (5.0 ± 2 nM and 60 ± 15 nM for δ- and μ-opioid receptors, respectively) with a μ/δ-selectivity ratio that mimicked the natural peptide. However, the trifluoroethyl-amine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, which suggest that bulky CF3 substitu-ents are not tolerated at this position...
March 14, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28296169/pyrrole-based-macrocyclic-small-molecule-inhibitors-targeting-oocyte-maturation
#13
Jeong Kyu Bang, Pethaiah Gunasekaran, So Rim Lee, Seung-Min Jeong, Jeong-Woo Kwon, Toshiki Takei, Yuya Asahina, Geul Bang, Seongnyeon Kim, Mija Ahn, Eun Kyung Ryu, Hak Nam Kim, Ki-Yub Nam, Song Yub Shin, Hironobu Hojo, Suk Namgoong, Nam-Hyung Kim
Polo-like kinase 1 (PLK1) plays crucial roles in various stages of oocyte maturation. Recently, we reported that the peptidomimetic AB103-8 that targets polo box domain (PBD) of PLK1 affected oocyte meiotic maturation and meiosis resumption. However, to overcome the peptidic drawbacks, we designed and synthesized a series of pyrrole-based small-molecule inhibitors and screened against porcine oocyte maturation rates. Among them, compound 4 showed the highest inhibitory activity with enhanced inhibition against the embryos blastocyst formation...
March 12, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28276645/design-synthesis-in-vitro-and-in-vivo-evaluation-of-z-3-4-5-trimethoxystyryl-benzenesulfonamides-sulfonates-as-highly-potent-tubulin-polymerization-inhibitors
#14
Ahmed Kamal
Newer therapeutics can be developed in drug discovery by adopting the strategy of scaffold hopping of the privileged scaffolds from known bioactive compounds. This strategy has been widely employed in drug discovery process. Structure based docking studies illustrates the basic underlying concepts, which have been carried out, reveal interactions of sulfonamide group and hydrophobic interactions are crucial. Based on this strategy over 60 synthetic analogues were synthesized and evaluated for their cytotoxicity against the NCI panel of sixty human cancer cell lines, majority of these compounds exhibited promising cytotoxicity with GI50 values ranging between 18-50 nM, and among them compounds 7a and 9a were found to be potent...
March 9, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28266812/anticancer-activity-of-stilbene-based-derivatives
#15
Barbara De Filippis, Alessandra Ammazzalorso, Marialuigia Fantacuzzi, Letizia Giampietro, Cristina Maccallini, Rosa Amoroso
Anticancer Activity of Stilbene-based Derivatives Barbara De Filippis,* Alessandra Ammazzalorso, Marialuigia Fantacuzzi, Letizia Giampietro, Cristina Maccallini, Rosa Amoroso Dipartimento di Farmacia, Università "G. d'Annunzio", via dei Vestini 31, 66100 Chieti, Italy; * E-mail: barbara.defilippis@unich.it Stilbene is a very present structural scaffold in nature and stilbene-based compounds are largely described for their biological activity such as cardioprotective, potent antioxidant, anti-inflammatory, and anticancer agents...
March 7, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28264138/structure-based-design-and-synthesis-of-harmine-derivatives-with-different-selectivity-profiles-in-kinase-vs-monoamine-oxidase-inhibition
#16
Balazs Balint, Csaba Weber, Francisco Cruzalegui, Mike Burbridge, Andras Kotschy
DYRK1A is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design we have synthesized a collection of harmine analogs with tunable selectivity towards these two enzymes...
March 6, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28263042/1-3-5-trisubstituted-pyrazoles-as-potent-negative-allosteric-modulators-of-the-mglu2-3-receptors
#17
Michiel Van Gool, Sergio Alvar Alonso De Diego, Oscar Delgado, Andrés A Trabanco, Fabrice Jourdan, Gregor J Macdonald, Marijke Somers, Luc Ver Donck
The metabotropic glutamate subtype 2 (mGlu2) receptor is a presynaptic membrane receptor distributed widely in brain that provides feedback inhibitory control of glutamate release. Inhibition of the mGlu2 receptor function with a negative allosteric modulator (NAM) enhances activity dependent glutamate release which may be of therapeutic benefit for treatment of neurological and psychiatric disorders. An attractive pyrazole hit was identified after a high throughput screening (HTS) campaign. The evolution of this hit is described by structure-activity relationship (SAR) study on specific parts of the molecule...
March 6, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28263035/identifying-protein-allosteric-transitions-for-drug-discovery-using-1d-nmr
#18
Isabelle Krimm
Allosteric drugs present many advantages over orthosteric drugs and represent therefore an attractive approach in drug discovery, yet highly challenging. First, the binding of ligands in protein allosteric pockets do not ensure allosteric effect and second, allosteric ligands can possess diverse modes of pharmacology even within a compound family. Here we report a new method (1) to detect allosteric communication between protein binding sites and (2) to compare the effect of allosteric ligands on the allosteric transitions of the protein target...
March 6, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28261964/synthesis-and-cytotoxicity-evaluation-of-c4-and-c5-modified-analogs-of-the-%C3%AF-%C3%AF-%C3%AF-unsaturated-lactone-of-pironetin
#19
Gunda Ingrid Georg, David Huang, Henry Wong
Twelve analogs of the α-tubulin binding natural product pironetin were prepared by total synthesis for a systematic evaluation of structure-activity relationships at the C4 and C5 positions of the α,β-unsaturated lactone of the natural product. Modifications of the stereochemistry at the C4 and/or C5 positions of the α,β-unsaturated lactone of pironetin resulted in loss of antiproliferative activity in OVCAR5 ovarian cancer cells. Moreover, substitutions of the C4 ethyl substituent with groups such as methyl, propyl, cyclopropyl, and isobutyl were tolerated, however, isopropyl and benzyl groups were not...
March 6, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28258688/synthesis-of-novel-4-4-disubstituted-3-methylidenechroman-2-ones-as-potent-anticancer-agents
#20
Rafał Jakubowski, Dorota Pomorska, Angelika Długosz, Anna Janecka, Urszula Krajewska, Marek Różalski, Marek Mirowski, Tomasz Bartosik, Tomasz Janecki
The synthesis of new library of 4,4-disubstituted 3-methylidene-3,4-dihydro-2H-chroman-2-ones applying Horner-Wadsworth-Emmons methodology for the construction of egzo-methylidene moiety is reported. Corresponding 3-diethoxyphosphorylchroman-2-ones were synthesized in a three step reaction sequence consisting of O-methylation of ethyl 2-diethoxyphosphoryl-3-oxoalkanoates, followed by reaction of obtained 2-diethoxyphosphoryl-3-methoxy-2-alkenoates with phenols or 1-naphthol. Obtained 3-diethoxyphosphorylochromen-2-ones proved to be effective Michael acceptors in the reaction with various Grignard reagents...
March 4, 2017: ChemMedChem
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