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3-(N-arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2).

ABSTRACT: 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.

SUBMITTER: Choi SH

PROVIDER: S-EPMC3326608 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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3-(N-arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2).

Choi Soo Hyuk SH Quinti Luisa L Kazantsev Aleksey G AG Silverman Richard B RB

Bioorganic & medicinal chemistry letters 20120303 8

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 incre ...[more]

PMID: 22446090

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