期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 15, 页码 5616-5625出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.06.035
关键词
Histone deacetylases; NAD(+)-dependent deacetylation; Sirtuin inhibitors
资金
- Graduate School of Drug Discovery, Academy of Finland [127062]
- Orion Farmos Research Foundation
- Finnish Cultural Foundation
- Emil Aaltonen Foundation
- Saastamoinen Foundation
- Academy of Finland (AKA) [127062, 127062] Funding Source: Academy of Finland (AKA)
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. (C) 2010 Elsevier Ltd. All rights reserved.
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