Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors

Mohammad A. Khanfar, Luisa Quinti, Hua Wang, Soo Hyuk Choi, Aleksey G. Kazantsev, Richard B. Silverman

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)414-426
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume76
DOIs
StatePublished - Apr 9 2014
Externally publishedYes

Fingerprint

Sirtuin 2
Benzamides
Assays
Huntington Disease
Cells
Cell Line
Agglomeration
Sirtuins
Pharmacology
Acetylation
Pathology
Tubulin
Bioactivity
Human Activities
Scaffolds
Acids

Keywords

  • 3-(Benzylsulfonamido)benzamides
  • ADME
  • Huntington's disease
  • Polyglutamine aggregation
  • SIRT2

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology
  • Medicine(all)

Cite this

Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors. / Khanfar, Mohammad A.; Quinti, Luisa; Wang, Hua; Choi, Soo Hyuk; Kazantsev, Aleksey G.; Silverman, Richard B.

In: European Journal of Medicinal Chemistry, Vol. 76, 09.04.2014, p. 414-426.

Research output: Contribution to journalArticle

Khanfar, Mohammad A. ; Quinti, Luisa ; Wang, Hua ; Choi, Soo Hyuk ; Kazantsev, Aleksey G. ; Silverman, Richard B. / Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors. In: European Journal of Medicinal Chemistry. 2014 ; Vol. 76. pp. 414-426.
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