title: Bivalent SIRT1 inhibitors.
abstract: In the current study, bivalent compounds 1-17 constructed by covalently linking the ɛ-amino group of lysine in a tripeptidic scaffold to a functionality via a linker were prepared and examined for their inhibitory potencies against SIRT1, a prototypical member of the β-nicotinamide adenine dinucleotide (β-NAD+)-dependent sirtuin family of protein Nε-acyl-lysine deacylases. A few of them were found to be stronger SIRT1 inhibitors than the Nɛ-acetyl-lysine-containing monovalent counterparts 18 and 19. As exemplified with compounds 6 and 18, a bivalent SIRT1 inhibitor could exhibit a greater degree of inhibitory selectivity among SIRT1/2/3 than the corresponding monovalent counterpart. This study has laid a foundation for the future development of superior bivalent inhibitors against the (patho)physiologically and therapeutically important sirtuin family of deacylase enzymes.
authors.affiliation: School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zang
authors.affiliation: School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China. Electronic address: wzheng@ujs.edu.cn.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zheng
mesh_terms: D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors
chemical_list: D056572:Histone Deacetylase Inhibitors; D009842:Oligopeptides; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; C466093:SIRT3 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D056566:Sirtuin 3
keywords: Bivalent; Inhibitor; SIRT1; Sirtuin