title: 3-(N-arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2).
abstract: Inhibition of sirtuin 2 (SIRT2) is known to be protective against the toxicity of disease proteins in Parkinson's and Huntington's models of neurodegeneration. Previously, we developed SIRT2 inhibitors based on the 3-(N-arylsulfamoyl)benzamide scaffold, including3-(N-(4-bromophenyl)sulfamoyl)-N-(4-bromophenyl)benzamide(C2-8, 1a), which demonstrated neuroprotective effects in a Huntington's mouse model, but had low potency of SIRT2 inhibition. Here we report that N-methylation of 1a greatly increases its potency and results in excellent selectivity for SIRT2 over SIRT1 and SIRT3 isoforms. Structure-activity relationships observed for 1a analogs and docking simulation data suggest that the para-substituted amido moiety of these compounds could occupy two potential hydrophobic binding pockets in SIRT2. These results provide a direction for the design of potent drug-like SIRT2 inhibitors.
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, United States.
authors.forename: Soo Hyuk
authors.initials: SH
authors.lastname: Choi
authors.forename: Luisa
authors.initials: L
authors.lastname: Quinti
authors.forename: Aleksey G
authors.initials: AG
authors.lastname: Kazantsev
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000215:Acylation; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology; D020033:Protein Isoforms; D056564:Sirtuin 1 / Q000737:chemistry; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D056566:Sirtuin 3 / Q000737:chemistry; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D020033:Protein Isoforms; D013450:Sulfones; D056564:Sirtuin 1; D056565:Sirtuin 2; D056566:Sirtuin 3