Synthesis of indole inhibitors of silent information regulator 1 (SIRT1), and their evaluation as cytotoxic agents

• DOI: 10.1016/j.ejmech.2020.112561
• Publication Date: 2020-07-02T06:17:39Z
• Authors: Hanna Laaroussi; Ying Ding; Yuou Teng; Patrick Deschamps; Michel Vidal; Peng Yu; Sylvain Broussy
• Keywords: 0303 health sciences; Indoles; Dose-Response Relationship, Drug; Molecular Structure; Cell Line; 3. Good health; Molecular Docking Simulation; Structure-Activity Relationship; 03 medical and health sciences; Sirtuin 1; [CHIM] Chemical Sciences; [CHIM]Chemical Sciences; Humans; Cell Proliferation

A series of achiral indole analogues of the selective sirtuin inhibitor EX-527 (a racemic, substituted 1,2,3,4 tetrahydrocarbazole) was designed to stabilize the bioactive conformation, and synthesized. These new indoles were evaluated against the isolated sirtuin enzymes SIRT1 and SIRT2, and against a panel of nine human cell lines. Structure-activity relationship studies demonstrated the influence of the substituent at position 3 of the indole. The most potent SIRT1 inhibitor 3h, bearing an isopropyl substituent, was as potent as EX-527, and more selective for SIRT1 over SIRT2. Compound 3g, bearing a benzyl substituent, inhibited both sirtuins at micromolar concentration and was more cytotoxic than EX-527 on several cancer cell lines.