TY - JOUR
T1 - 3-(N-Arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2)
AU - Choi, Soo Hyuk
AU - Quinti, Luisa
AU - Kazantsev, Aleksey G.
AU - Silverman, Richard B.
N1 - Funding Information:
The authors are grateful to the National Institutes of Health ( 5U01NS066912 ) for financial support of this research.
Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/4/15
Y1 - 2012/4/15
N2 - Inhibition of sirtuin 2 (SIRT2) is known to be protective against the toxicity of disease proteins in Parkinson's and Huntington's models of neurodegeneration. Previously, we developed SIRT2 inhibitors based on the 3-(N-arylsulfamoyl)benzamide scaffold, including3-(N-(4-bromophenyl)sulfamoyl)- N-(4-bromophenyl)benzamide(C2-8, 1a), which demonstrated neuroprotective effects in a Huntington's mouse model, but had low potency of SIRT2 inhibition. Here we report that N-methylation of 1a greatly increases its potency and results in excellent selectivity for SIRT2 over SIRT1 and SIRT3 isoforms. Structure-activity relationships observed for 1a analogs and docking simulation data suggest that the para-substituted amido moiety of these compounds could occupy two potential hydrophobic binding pockets in SIRT2. These results provide a direction for the design of potent drug-like SIRT2 inhibitors.
AB - Inhibition of sirtuin 2 (SIRT2) is known to be protective against the toxicity of disease proteins in Parkinson's and Huntington's models of neurodegeneration. Previously, we developed SIRT2 inhibitors based on the 3-(N-arylsulfamoyl)benzamide scaffold, including3-(N-(4-bromophenyl)sulfamoyl)- N-(4-bromophenyl)benzamide(C2-8, 1a), which demonstrated neuroprotective effects in a Huntington's mouse model, but had low potency of SIRT2 inhibition. Here we report that N-methylation of 1a greatly increases its potency and results in excellent selectivity for SIRT2 over SIRT1 and SIRT3 isoforms. Structure-activity relationships observed for 1a analogs and docking simulation data suggest that the para-substituted amido moiety of these compounds could occupy two potential hydrophobic binding pockets in SIRT2. These results provide a direction for the design of potent drug-like SIRT2 inhibitors.
KW - 3-(N-Arylsulfamoyl)benzamides
KW - Hydrophobic pocket
KW - Neurodegenerative disease
KW - Sirtuin 2
KW - Sirtuin selectivity
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U2 - 10.1016/j.bmcl.2012.02.089
DO - 10.1016/j.bmcl.2012.02.089
M3 - Article
C2 - 22446090
AN - SCOPUS:84862817330
VL - 22
SP - 2789
EP - 2793
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 8
ER -