Syntéza stabilních analog O-acetyl-adenosin difosforibosy a inhibitorů sirtuinů

Dvořáková, Marcela

Acetylated adenosine diphosphoribose (OAADPR) is a product of protein deacetylation catalysed by class III of histone deacetylases called sirtuins. Sirtuins deacetylate histones and other proteins by unique mechanism coupled with consumption of stoichiometric amount of NAD+ . Sirtuins and OAADPR are implicated in the regulation of gene transcription, signalling and metabolic pathways and lifespan extension, thus preventing the development of age-related diseases. Even though, sirtuins are well studied, the exact biological role of OAADPR remains mainly unknown. Its further exploration is restricted by OAADPR's proneness to enzymatic hydrolysis. Therefore, non-hydrolysable analogues of OAADPR are needed to establish its biological function. These analogues are also expected to be competitive inhibitors of sirtuins, which may reveal their potential as therapeutic agents. A series of OAADPR analogues in which the acetate moiety was replaced with alkylcarbonate functionality has been synthesized. The studies of alkylcarbonate migration on furanoside scaffold have established the stability of alkylcarbonate vs. acetate under various conditions. Generally, alkylcarbonates are more stable than acetate under acidic or neutral conditions whereas under basic conditions they seem to be less stable....

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