TY - JOUR
T1 - Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors
AU - Khanfar, Mohammad A.
AU - Quinti, Luisa
AU - Wang, Hua
AU - Choi, Soo Hyuk
AU - Kazantsev, Aleksey G.
AU - Silverman, Richard B.
N1 - Funding Information:
The authors are grateful to the National Institutes of Health (Grant U01 NS066912 ) for financial support of this research.
PY - 2014/4/9
Y1 - 2014/4/9
N2 - Inhibitors of sirtuin-2 deacetylase (SIRT2) 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 neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in α-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate.
AB - Inhibitors of sirtuin-2 deacetylase (SIRT2) 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 neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in α-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate.
KW - 3-(Benzylsulfonamido)benzamides
KW - ADME
KW - Huntington's disease
KW - Polyglutamine aggregation
KW - SIRT2
UR - http://www.scopus.com/inward/record.url?scp=84895532960&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84895532960&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2014.02.003
DO - 10.1016/j.ejmech.2014.02.003
M3 - Article
C2 - 24602787
AN - SCOPUS:84895532960
SN - 0223-5234
VL - 76
SP - 414
EP - 426
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -
