title: Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors.
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.
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA; Department of Pharmaceutical Sciences, The University of Jordan, Amman, Jordan.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Khanfar
authors.affiliation: Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA 02129-4404, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Quinti
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
authors.forename: Soo Hyuk
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA 02129-4404, USA. Electronic address: akazantsev@mgh.harvard.edu.
authors.forename: Aleksey G
authors.initials: AG
authors.lastname: Kazantsev
authors.affiliation: Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA. Electronic address: Agman@chem.northwestern.edu.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000107:Acetylation; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D018696:Neuroprotective Agents; C474199:SIRT2 protein, human; D056565:Sirtuin 2
keywords: 3-(Benzylsulfonamido)benzamides; ADME; Huntington's disease; Polyglutamine aggregation; SIRT2