Study of 1,4-Dihydropyridine Structural Scaffold: Discovery of Novel Sirtuin Activators and Inhibitors

Abstract

NAD(+)-dependent sirtuin deacetylases have emerged as potential therapeutic targets for treatment of human illnesses such as cancer, metabolic, cardiovascular, and neurodegenerative diseases. The benefits of sirtuin modulation by small molecules have been demonstrated for these diseases. In contrast to the discovery of inhibitors of SIRT1, -2, and -3, only activators for SIRT1 are known. Here, we rationalized the potential of the previously unexplored dihydropyridine scaffold in developing sirtuin ligands, thus we prepared a series of 1,4-dihydropyridine-based derivatives 1-3. Assessment of their SIRT1-3 deacetylase activities revealed the importance of the substituent at the N1 position of the dihydropyridine structure on sirtuin activity. Placement of cyclopropyl, phenyl, or phenylethyl groups at N1 conferred nonselective SIRT1 and SIRT2 inhibition activity, while a benzyl group at N1 conferred potent SIRT1, -2, and -3 activation. Senescence assays performed on hMSC and mitochondrial function studies conducted with murine C2C12 myoblasts confirmed the compounds' novel and unique SIRT-activating properties.

Ex-527 inhibits Sirtuins by exploiting their unique NAD + -dependent deacetylation mechanism

“…The identified mechanism and technical approaches will allow further identification of ECS inhibitors and solving of their Sirtuin complex structures to obtain further information on how to optimize binding to this site and how to add specific interactions. Obvious candidates, besides AGK2 and GW5074, are nicotinamide-related, Sirtuin-inhibiting 2-anilinobenzamides and dihydropyridin amides (26,40,41). Nonaromatic carbamides might in fact be favorable ECS ligands for two reasons.…”

A Nitric Oxide-dependent Cross-talk between Class I and III Histone Deacetylases Accelerates Skin Repair

“…Of note is that Resv is capable of promoting WH, activating SIRT1, and stimulating NO synthesis (16,17). This work describes how, similarly to Resv, SIRT activation by the novel synthetic compound MC2562 (15) led to accelerated wound repair. Remarkably, the same effect was obtained with the class I pan-inhibitor trichostatin A (TSA), suggesting a concerted action for these molecules in wound repair.…”

“…Although their role is still poorly characterized, SIRTs seem important in this process because SIRT1 regulates keratinocyte proliferation (13,14). We recently synthesized novel SIRT activators with effects comparable with those of resveratrol (Resv) but on the basis of a different chemistry (15). Of note is that Resv is capable of promoting WH, activating SIRT1, and stimulating NO synthesis (16,17).…”

Mitochondrial dysfunction in the pathophysiology of renal diseases

“…The SIRT1 activator resveratrol, which is present in red grapes and red wine, improves mitochondrial function and lipid levels (136) and promotes and maintains PGC-1␣ expression, consequently protecting podocyte integrity (153). Besides resveratrol, other novel SIRT1 agonists have also been reported (88,94,144). NAD ϩ , the enzymatic cofactor, is critical for SIRT1 signaling.…”