2. Academic Validation
  3. Synthesis of indole inhibitors of silent information regulator 1 (SIRT1), and their evaluation as cytotoxic agents

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

  • Eur J Med Chem. 2020 Sep 15;202:112561. doi: 10.1016/j.ejmech.2020.112561.
Hanna Laaroussi 1,  Ying Ding 2,  Yuou Teng 2,  Patrick Deschamps 3,  Michel Vidal 4,  Peng Yu 2,  Sylvain Broussy 5
Affiliations

Affiliations

  • 1 Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, F-75006, Paris, France.
  • 2 China International Science and Technology, Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China.
  • 3 Université de Paris, CiTCoM, 8038 CNRS, Paris, F-75006, France.
  • 4 Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, F-75006, Paris, France; Service Biologie Du Médicament, Toxicologie, AP-HP, Hôpital Cochin, F-75014, Paris, France.
  • 5 Université de Paris, CiTCoM, 8038 CNRS, U 1268 INSERM, F-75006, Paris, France. Electronic address: sylvain.broussy@u-paris.fr.
PMID: 32711231 DOI: 10.1016/j.ejmech.2020.112561
Abstract

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.

Keywords

Bioactive conformation; Cancer; Cytotoxicity assays; Indoles; SIRT1 inhibitors.

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