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

Abstract

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 10 proved to be the most efficient SIRT1 activator. An evaluation of the effects caused by focused structural variations revealed that its para-hydroxy-substituted diphenyl moiety of 10 was the fundamental structural requirement for achieving good SIRT1 activation. Compound 10 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 10 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.

Sirtuin 1-Activating Compounds: Discovery of a Class of Thiazole-Based Derivatives

“…The activation of SIRT1 by resveratrol was set at 100% and the percentage of SIRT1 activation obtained by compounds 8–11 at 100 µM was evaluated in comparison with that of resveratrol ( Table 1 ). In order to speculate on their potency of activation, we also reported the activation of SIRT1 shown by compound 7 (according to a previous publication [ 24 ]).…”

“…SIRT1 is a well-described target to effectively obtain anti-ischemic cardioprotective effects [ 19 , 24 , 37 , 38 , 39 ]. The procedure of in vivo coronary artery occlusion/reperfusion led to reproducible damage at the myocardium level; indeed, the ischemic area was 46 ± 2 % of the whole area of the left ventricle (A I /A LV , Figure 5 ).…”

“…Resveratrol is characterized by a poor bioavailability, which is mainly caused by an extensive in vivo conversion into its sulfate and gluconate metabolites [ 22 ]. Furthermore, the central double bond of resveratrol is one of the various molecular portions undergoing fast chemical and metabolic transformations [ 23 ]; therefore, we previously synthesized novel resveratrol analogues, where its double bond was replaced by an aniline scaffold [ 24 ]. Another example of a natural SIRT1 activator is quercetin (3,3′,4′,5,7-pentahydroxyflavone 2 , Figure 1 ), a flavone molecule widely common in fruits and vegetables, that has been proven to reduce the myocardial ischemia/reperfusion-induced cardiomyocyte apoptosis via SIRT1/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) signaling in a dose-dependent manner [ 25 ].…”

“…Indeed, compound 7 shares the same antipodal phenolic rings of natural polyphenols 1–3 , which are connected through a three-substituted anilino portion. Diarylamine 7 displays a notable SIRT1 activation ability and has been demonstrated to exert a cardioprotective effect in an ex vivo ischemia/reperfusion (I/R) model [ 24 ].…”

“…Taking into account the promising results achieved in our previous work [ 24 ], we decided to further investigate the effects due to the variations in the central core of the diarylamine derivative 7 , in order to find more potent SIRT1 activators. Therefore, we decided to maintain the two pharmacophoric peripheral phenolic rings, with hydroxyl groups in the meta and/or para position, and to replace the central 1,3-disubstituted phenyl ring with a 2,4-disubstituted thiazole ring ( Figure 2 ).…”