title: Structure-Activity Relationship Study of 3-Amino-2-indolyllactam Derivatives: Development of Inhibitors of Oxidative Stress-Induced Necrosis.
abstract: Modification of our previously reported selective inhibitor of oxidative stress-induced necrosis, 2-(1H-indol-3-yl)-3-pentylamino-maleimide (IM-54) by regioselective reduction of the C-4 carbonyl group afforded a 3-amino-2-indolyllactam (IL-1) with more potent activity. To examine the structure-activity relationship of IL derivatives, we developed new synthetic routes with flexibility to incorporate a range of substituents at a late stage. The synthesized IL derivatives were evaluated for activity to inhibit necrotic cell death induced by hydrogen peroxide. Among them, IL-12 showed the most potent activity (IC50=49 nM) among the IL and indolylmaleimide (IM) derivatives examined.
authors.affiliation: Synthetic Organic Chemistry Laboratory, RIKEN.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Dodo
authors.forename: Kenji
authors.initials: K
authors.lastname: Hayamizu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Mikiko
authors.initials: M
authors.lastname: Sodeoka
mesh_terms: D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009336:Necrosis / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000613660:3-amino-2-indolyllactam; D007211:Indoles; D007769:Lactams; D006861:Hydrogen Peroxide