3739-38-6Relevant articles and documents
Hit-to-lead optimization on aryloxybenzamide derivative virtual screening hit against SIRT
Yagci, Semih,Gozelle, Mahmut,Kaya, Selen Gozde,Ozkan, Yesim,Aksel, Ahmet Bugra,Bakar-Ates, Filiz,Dundar, Yasemin,Eren, Gokcen
, (2021/01/07)
Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein histone deacetylases (HDACs) that are evolutionarily conserved from bacteria to mammals. This group of enzymes catalyses the reversible deacetylation of lysine residues in the histones or non-histone substrates using NAD+ as a cosubstrate. Numerous studies have demonstrated that the aberrant enzymatic activity of SIRTs has been linked to various diseases like diabetes, cancer, and neurodegenerative disorders. Previously, we performed a pharmacophore-based virtual screening campaign and an aryloxybenzamide derivative (1) displaying SIRT1/2 inhibitory effect was identified as a hit compound. In the current study, the hit-to-lead optimization on the hit compound was explored in order to improve the SIRT binding and inhibition. Fourteen compounds, ten of which were new, have been synthesized and subjected to in vitro biological evaluation for their inhibitory activity against SIRT1-3. By the structural modifications performed, a significant improvement was observed in selective SIRT1 inhibition for ST01, ST02, and ST11 compared to that of the hit compound. The highest SIRT2 inhibitory activity was observed for ST14, which was designed according to compatibility with pharmacophore model developed for SIRT2 inhibitors and thus, providing the interactions required with key residues in SIRT2 active site. Furthermore, ST01, ST02, ST11, and ST14 were subjected to in vitro cytotoxicity assay against MCF-7 human breast cancer cell line to determine the influence of the improvement in SIRT1/2 inhibition along with the structural modifications on the cytotoxic properties of the compounds. The cytotoxicity of the compounds was found to be correlated with their SIRT inhibitory profiles indicating the effects of SIRT1/2 inhibition on cancer cell viability. Overall, this study provides structural insights for further inhibitor improvement.
Screening of by-products of esfenvalerate in aqueous medium using SBSE probe desorption GC-IT-MS technique
Colombo, Renata,Ferreira, Tanare C. R.,Yariwake, Janete H.,Lanza, Marcos R. V.
, p. 1831 - 1837 (2015/09/22)
The pyrethroids, their metabolites and by-products have been recognized as toxic to environment and human health. Despite several studies about esfenvalerate toxicity and its detection in water and sediments, information about its degradation products is still scanty. In this work, esfenvalerate degradation products were obtained by chemical oxidation with hydrogen peroxide and their structure was elucidated using a procedure known as stir bar sorptive extraction (SBSE) probe desorption gas chromatography-ion trap mass spectrometry (GC-IT-MS) analysis. This procedure consists of the thermal desorption of analytes extracted from a SBSE stir bar introduced by a probe into a gas chromatograph (GC) coupled to an ion trap mass spectrometry (IT-MS) system. Based on IT-MS data, a degradation pathway of esfenvalerate is proposed with ten products of chemical oxidation of esfenvalerate that are fully identified. Among these compounds, 3-phenoxybenzoic acid and 3-phenoxybenzaldehyde were detected, reported as being environmental metabolites of some pyrethroids, with endocrine-disrupting activity.
Aerobic oxidation at benzylic positions catalyzed by a simple Pd(OAc)2/bis-triazole system
Urgoitia, Garazi,Maiztegi, Ainhoa,Sanmartin, Raul,Herrero, María Teresa,Domínguez, Esther
, p. 103210 - 103217 (2015/12/23)
An efficient catalyst system for the Pd-catalyzed aerobic oxidation of benzylic positions has been developed. The combination of palladium(ii) acetate and 3,5-bis((1H-1,2,4-triazol-1-yl)methyl)benzoate ligand allows the selective oxidation at carbon adjacent to arene rings (primary and secondary benzylic alcohols, and other benzyl compounds) to provide the corresponding carbonyl and carboxy derivatives, employing molecular oxygen as oxidizing agent and a very low metal loading (10-5 mol%).
