A scaffold replacement approach towards new sirtuin 2 inhibitors

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Seifert , T , Malo , M , Kokkola , T , Steen , E J L , Meinander , K , Wallen , E A A , Jarho , E M & Luthman , K 2020 , ' A scaffold replacement approach towards new sirtuin 2 inhibitors ' , Bioorganic & Medicinal Chemistry , vol. 28 , no. 2 , 115231 . https://doi.org/10.1016/j.bmc.2019.115231

Title: A scaffold replacement approach towards new sirtuin 2 inhibitors
Author: Seifert, Tina; Malo, Marcus; Kokkola, Tarja; Steen, E. Johanna L.; Meinander, Kristian; Wallen, Erik A. A.; Jarho, Elina M.; Luthman, Kristina
Contributor: University of Helsinki, Division of Pharmaceutical Chemistry and Technology
University of Helsinki, Pharmaceutical Design and Discovery group
Date: 2020-01-15
Language: eng
Number of pages: 12
Belongs to series: Bioorganic & Medicinal Chemistry
ISSN: 0968-0896
URI: http://hdl.handle.net/10138/309149
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.
Subject: Scaffold
1182 Biochemistry, cell and molecular biology
116 Chemical sciences
317 Pharmacy

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