Abstract
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.
Original language | English (US) |
---|---|
Pages (from-to) | 607-611 |
Number of pages | 5 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 6 |
Issue number | 5 |
DOIs | |
State | Published - May 14 2015 |
Externally published | Yes |
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Keywords
- 3-(benzylthio)benzamide
- docking
- Huntington's disease
- polyglutamine aggregation
- SIRT2
ASJC Scopus subject areas
- Organic Chemistry
- Drug Discovery
- Biochemistry
Cite this
Design and evaluation of 3-(benzylthio)benzamide derivatives as potent and selective SIRT2 inhibitors. / Khanfar, Mohammad A.; Quinti, Luisa; Wang, Hua; Nobles, Johnathan; Kazantsev, Aleksey G.; Silverman, Richard B.
In: ACS Medicinal Chemistry Letters, Vol. 6, No. 5, 14.05.2015, p. 607-611.Research output: Contribution to journal › Article
}
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.
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 - docking
KW - Huntington's disease
KW - polyglutamine aggregation
KW - SIRT2
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UR - http://www.scopus.com/inward/citedby.url?scp=84929323269&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.5b00075
DO - 10.1021/acsmedchemlett.5b00075
M3 - Article
AN - SCOPUS:84929323269
VL - 6
SP - 607
EP - 611
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 5
ER -