Sirtuins activators

Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430 686-689. 

Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., Sinclair, D. A. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature, 430, 686-689. 

Several types of sirtuin activators have been reported. Resveratrol (38, Fig. 11), a triphenolic component of red wine, is one of the most intensely studied molecules it has been used as a tool compound in several neurodegenerative models and there is ample data suggesting a positive impact in metabolic, neurodegenerative, and oncology models. 

Fig. 11 Structure of resveratrol and other polyphenolic natural products with reported sirtuin-activating properties...

Fig. 13 Structures of sirtuin activators (a) pyrroloquinoxaline 48 (b) Structure and Sirtl activation data for dihydropyridines 49-51...

Mai A et al (2009) Study of 1, 4-dihydropyridine structural scaffold discovery of novel sirtuin activators and inhibitors. J Med Chem 52(17) 5496-5504... 

Sirtuins possess either histone deacetylase or mono-ribosyltransferase activity. The dependence of sirtuins activity upon NAD plays a major role in connecting their enzymatic activity to the grade of energy of the cell by means of the cellular NAD/NADH ratio. 

Wood JG, Rogina B, Lavu S, Howitz KT, Helfand SL, Tatar M, Sinclair DA (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430 686-689 Woodward RB, Doering WE (1944) The total synthesis of quinine. J Am Chem Soc 66 849 World Drug Report of the United Nations (2007)... 

The 1,4-dihydropyridines (DHPs) classes of privileged heterocyclic pharmacophores are well known for their calcium channel blocker activity. Other versatile biological profiles of 1,4-DHPs such as anticonvulsant activity, selective adenosine-A3 receptor antagonism, radioprotective activity, sirtuin activation, and inhibition, etc. have also been well known [186]. Conventionally, 1,4-DHPs could be accessed via the Hantzsch reaction, reduction of pyridines, addition to pyridines or cycloadditions, etc. As a facile and broadly tolerable protocol, the Hantzsch reaction consisting of cyclocondensation reaction of ethyl acetoacetate (2 equivalent) with an aldehyde and ammonia remains as a frequently employed tactic for the synthesis of 1,4-DHPs in a large number of areas such as stereoselective synthesis and green chemistry [187]. 

HYPOXIA-INDUCIBLE FACTOR (HIF)-STABILIZERS AND SIRTUIN ACTIVATORS... 

Figure 4.20 Structures of selected HIF-stabilizers (1-6) and sirtuin activators (7-9) isoquinoline model substance (1), isoquinoline model substance (2), 2-oxoglutarate (3), oxalyl glycine (4), 3,4-dihydroxybenzoic acid (5), L-mimosine (6), resveratrol (7), SRT-1720 (8), and SRT-1460 (9).

Scheme 4.12 Suggested dissociation pathways of (a) isoquinoline-derived HIF-stabilizer 1, and the sirtuin activators resveratrol (b) and SRT-1720...

Figure 4.22 ESI product ion mass spectra of (a) the deprotonated molecule [M-H] of resveratrol (mol wt = 228), recorded on an API2000 QTfap system and (b) the protonated molecule [M+H] of the sirtuin activator SRT-1720 (mol wt = 469), recorded on an LTQ-Orbitrap system.

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