1159276-01-3Relevant academic research and scientific papers
Inhibition of human sirtuins by in situ generation of an acetylated lysine-ADP-ribose conjugate
Asaba, Tomomi,Suzuki, Takayoshi,Ueda, Rie,Tsumoto, Hiroki,Nakagawa, Hidehiko,Miyata, Naoki
supporting information; experimental part, p. 6989 - 6996 (2009/09/29)
A new type of small-molecular slrtuln Inhibitor was designed on the basis of the proposed catalytic mechanism for deacetylatlon of acetylated lysine substrates by sirtuins. Among the compounds thus designed and synthesized, we found that 2k, which contains an ethoxycarbonyl group at the a position to the acetamlde of acetylated lysine substrate analogue 1, showed potent Inhibitory activity In an In vitro assay using recombinant SIRT1, with high selectivity over SIRT2 and SIRT3. Mechanistic study by means of kinetic analysis, mass spectroscopy, and computation Indicated that the enol form of compound 2k nucleophlllcally attacks NAD+ In the active site of SIRTs to afford the stable compound 2k-ADP-rlbose conjugate 5, leading to Inhibition of the enzyme activity. Compound 2k also caused a dose-dependent Increase of p53 acetylatlon In human colon cancer HCT116 cells, Indicating Inhibition of SIRT1 In the cells. These results have Implications for the development of selective slrtuln Inhibitors by means of mechanismbased drug design.
