New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds

• Main Authors: Giulia Bononi (Author), Lorenzo Flori (Author), Valentina Citi (Author), Cecilia Acciai (Author), Viviana Nocilla (Author), Alma Martelli (Author), Giulio Poli (Author), Tiziano Tuccinardi (Author), Carlotta Granchi (Author), Lara Testai (Author), Vincenzo Calderone (Author), Filippo Minutolo (Author)
• Format: Book
• Published: MDPI AG, 2022-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph15030339; 1424-8247
• Keywords: sirtuin 1; activators; I/R injury; cardioprotection; diarylamine; molecular modeling; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 15, Iss 3, p 339 (2022)

NAD⁺-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so far devoted to finding new SIRT1 activators, both derived from natural sources or prepared by synthetic procedures. Herein, we discovered new SIRT1-activating derivatives, characterized by phenolic rings spaced by sulfur, nitrogen or oxygen-based central linkers. The newly synthesized derivatives were analyzed in enzymatic assays to determine their ability to activate SIRT1, as compared with that of resveratrol. Among the tested molecules, bisarylaniline compound <b>10</b> proved to be the most efficient SIRT1 activator. An evaluation of the effects caused by focused structural variations revealed that its <i>para</i>-hydroxy-substituted diphenyl moiety of <b>10</b> was the fundamental structural requirement for achieving good SIRT1 activation. Compound <b>10</b> was further investigated in ex vivo studies in isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R), where it showed significant protection of the myocardium against I/R injury. Molecular modeling studies suggest the binding mode of <b>10</b> within SIRT1 in the presence of the p53-AMC peptide. Our findings reveal that this chemical scaffold may be used as the starting point to develop a new class of more potent SIRT1 activators as cardioprotective agents.