TY - JOUR
T1 - Design and evaluation of 3-(benzylthio)benzamide derivatives as potent and selective SIRT2 inhibitors
AU - Khanfar, Mohammad A.
AU - Quinti, Luisa
AU - Wang, Hua
AU - Nobles, Johnathan
AU - Kazantsev, Aleksey G.
AU - Silverman, Richard B.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/5/14
Y1 - 2015/5/14
N2 - Inhibitors of sirtuin-2 (SIRT2) deacetylase have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the 3-(benzylsulfonamido)benzamide scaffold and improving their metabolic stability. Molecular modeling and docking studies revealed an unfavorable role of the sulfonamide moiety for SIRT2 binding. This prompted us to replace the sulfonamide with thioether, sulfoxide, or sulfone groups. The thioether analogues were the most potent SIRT2 inhibitors with a two- to three-fold increase in potency relative to their corresponding sulfonamide analogues. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. Two thioether-derived compounds (17 and 18) increased α-tubulin acetylation in a dose-dependent manner in at least one neuronal cell line, and 18 was found to inhibit polyglutamine aggregation in PC12 cells.
AB - Inhibitors of sirtuin-2 (SIRT2) deacetylase have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the 3-(benzylsulfonamido)benzamide scaffold and improving their metabolic stability. Molecular modeling and docking studies revealed an unfavorable role of the sulfonamide moiety for SIRT2 binding. This prompted us to replace the sulfonamide with thioether, sulfoxide, or sulfone groups. The thioether analogues were the most potent SIRT2 inhibitors with a two- to three-fold increase in potency relative to their corresponding sulfonamide analogues. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. Two thioether-derived compounds (17 and 18) increased α-tubulin acetylation in a dose-dependent manner in at least one neuronal cell line, and 18 was found to inhibit polyglutamine aggregation in PC12 cells.
KW - 3-(benzylthio)benzamide
KW - Huntington's disease
KW - SIRT2
KW - docking
KW - polyglutamine aggregation
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U2 - 10.1021/acsmedchemlett.5b00075
DO - 10.1021/acsmedchemlett.5b00075
M3 - Article
C2 - 26005542
AN - SCOPUS:84929323269
SN - 1948-5875
VL - 6
SP - 607
EP - 611
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 5
ER -