N-epsilon-Modified lysine containing inhibitors for SIRT1 and SIRT2

作者：Huhtiniemi Tero^*; Suuronen Tiina; Lahtela Kakkonen Maija; Bruijn Tanja; Jaaskelainen Sanna; Poso Antti; Salminen Antero; Leppanen Jukka; Jarho Elina

来源：Bioorganic & Medicinal Chemistry, 2010, 18(15): 5616-5625.

DOI：10.1016/j.bmc.2010.06.035

• Histone deacetylases
• NAD(+)-dependent deacetylation
• Sirtuin inhibitors

Sirtuins catalyze the NAD(+) dependent deacetylation of N-epsilon-acetyl lysine residues to nicotinamide, O '-acetyl- ADP-ribose (OAADPR) and N-epsilon-deacetylated lysine. Here, an easy-to-synthesize Ac-Ala-Lys-Ala sequence has been used as a probe for the screening of novel N-epsilon-modified lysine containing inhibitors against SIRT1 and SIRT2. N-epsilon-Selenoacetyl and N-epsilon-isothiovaleryl were the most potent moieties found in this study, comparable to the widely studied N-epsilon-thioacetyl group. The N-epsilon-3,3-dimethylacryl and N-epsilon-isovaleryl moieties gave significant inhibition in comparison to the N-epsilon-acetyl group present in the substrates. In addition, the studied N-epsilon-alkanoyl, N-epsilon-alpha,beta-unsaturated carbonyl and N-epsilon-aroyl moieties showed that the acetyl binding pocket can accept rather large groups, but is sensitive to even small changes in electronic and steric properties of the N-epsilon-modification. These results are applicable for further screening of Ne-acetyl analogues.

• 出版日期2010-8-1