title: N-nitrosoanilines: a new class of caspase-3 inhibitors.
abstract: Caspases are a family of cysteine proteases activated during apoptosis. In cultured human endothelial cells, physiological levels of NO prevent apoptosis and interfere with the activation of the caspase cascade. Previous studies have demonstrated that NO inhibits the activity of caspase-3 by S-nitrosylation of the enzyme. In this study, the inhibitory effect of a new class of NO donors. N-nitrosoaniline derivatives, were examined against caspase-3. Initially eight small molecule inhibitors bearing N-nitroso moieties were assayed. It was found that the presence of an electron-donating group on the phenyl ring led to better inhibitory potency, a trend consistent with the results from the previous papain studies. Based on the analysis of the enzyme and substrates' structures, two peptidyl N-nitrosoaniline inhibitors [Ac-DVAD-NNO (1) and Ac-DV-AMO (2)] were designed and synthesized. Both compounds exhibited enhanced inhibitory potency against caspase-3.
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, MI 48202, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Guo
authors.forename: M
authors.initials: M
authors.lastname: Xian
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: McGill
authors.forename: P G
authors.initials: PG
authors.lastname: Wang
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis*; D053148:Caspase 3; D061945:Caspase Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D009602:Nitrosamines / Q000737:chemistry; D009603:Nitroso Compounds / Q000138:chemical synthesis*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D009602:Nitrosamines; D009603:Nitroso Compounds; D011994:Recombinant Proteins; C505407:CASP3 protein, human; D053148:Caspase 3