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A scaffold replacement approach towards new sirtuin 2 inhibitors

Journal article
Authors Tina Seifert
Marcus Malo
T. Kokkola
Johanna Stéen
K. Meinander
E. A. A. Wallen
E. M. Jarho
Kristina Luthman
Published in Bioorganic & Medicinal Chemistry
Volume 28
Issue 2
Pages 12
ISSN 0968-0896
Publication year 2020
Published at Department of Chemistry and Molecular Biology
Pages 12
Language en
Links dx.doi.org/10.1016/j.bmc.2019.11523...
Keywords Scaffold, Sirtuin, SIRT2, Inhibitor, Benzothiazine-1,1-dioxide, Benzothiadiazine-1,1-dioxides, Saccharin, Quinolin-4-one, Docking, force-field, chroman-4-one, protein, brain, Biochemistry & Molecular Biology, Pharmacology & Pharmacy, Chemistry
Subject categories Pharmacology, Biochemistry and Molecular Biology

Abstract

Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD(+)-dependent protein deacylases regulating the acylation state of epsilon-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.

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