Design and Synthesis of New 9‐Substituted Norharmane Derivatives as Potential Sirt5 Inhibitors. (21st July 2016)

• Record Type: Journal Article
• Authors: Yang, Ling‐Ling; He, Yan‐Ying; Chen, Quan‐Long; Qian, Shan; Wang, Zhou‐Yu
• Is Part Of: Journal of heterocyclic chemistry. Volume 54:Number 2(2017:Mar.)
• Page Start: 1457
• Page End: 1466
• Publication Date: 2016-07-21
• Subjects: Heterocyclic compounds -- Periodicals; 547.59
• DOI: 10.1002/jhet.2732
• Languages: English
• ISSNs: 0022-152X

Abstract

Abstract : Sirt5 is a potential new drug target for the treatment of cancer, Alzheimer's disease, and Parkinson's disease. Given that norharmane is an important chemical synthon for some biologically important compounds and 9‐substituted norharmane derivatives containing a negatively charged carboxyl group may accord with the characteristic of potential Sirt5 inhibitors, a series of novel 9‐substituted norharmane derivatives were synthesized. The chemical structures and purities of all the target compounds were characterized by 1 H NMR, 13 C NMR, MS, and HPLC. By in vitro SIRT5 inhibitory assays, three compounds (1a, 3a, and3b ) show over 30% inhibition ratios at concentration of 100 µ M, and the most active compound3b has 35% and 52% inhibition ratios at 30 µ M and 100 µ M, respectively. Docking analysis showed that compound3b is likely to fit very well on the substrate binding site of Sirt5, and hence, we believe that compound3b can serve as a lead compound for further efforts to develop specific Sirt5 inhibitors. Abstract :