title: Novel inhibitors of the mitochondrial respiratory chain: oximes and pyrrolines isolated from Penicillium brevicompactum and synthetic analogues.
abstract: The capacity of inhibition of the mammalian mitochondrial respiratory chain of brevioxime 5a, a natural insecticide compound isolated from Penicillium brevicompactum culture broth, and another 15 analogue compounds, other oximes 5b and 5c; two diastereomeric pyrrolidines 1c' and 1c' '; five pyrrolines 3c', 3c' ' (diastereomers between them), 3a, 3b, and 6; two oxazines 4c' and 4c' ' (also diastereomers between them); and four pyrrol derivatives 7-10, are analyzed in this paper. Compounds 3b, 3c', 3c' ', 4c', 4c' ', 5b, 5c, 6, and 10 were found to be inhibitors of the integrated electron transfer chain (NADH oxidase activity) in beef heart submitochondrial particles (SMP), establishing that all of them except compound 3b and 6 only affected to complex I of the mitochondrial respiratory chain. The most potent product was 5b, with an IC50 of 0.27 microM, similar to the IC50 values of other known complex I inhibitors. The diastereomeric pairs 1c'/1c' ', 3c'/3c' ', 4c'/4c' ', and 5c have not been previously described. Chemical characterization, on the basis of spectral data, is also shown.
authors.affiliation: Centro de Ecología Química Agrícola, Universidad Politécnica de Valencia, Campus de Vera, Edificio 9B, Laboratorio 111, 46022 Valencia, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Cantín
authors.forename: M Pilar
authors.initials: MP
authors.lastname: López-Gresa
authors.forename: M Carmen
authors.initials: MC
authors.lastname: González
authors.forename: Pilar
authors.initials: P
authors.lastname: Moya
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Miranda
authors.forename: Jaime
authors.initials: J
authors.lastname: Primo
authors.forename: Vanessa
authors.initials: V
authors.lastname: Romero
authors.forename: Eva
authors.initials: E
authors.lastname: Peris
authors.forename: Ernesto
authors.initials: E
authors.lastname: Estornell
mesh_terms: D000818:Animals; D002417:Cattle; D004579:Electron Transport / Q000187:drug effects*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000187:drug effects; D010091:Oximes / Q000138:chemical synthesis / Q000302:isolation & purification* / Q000494:pharmacology*; D010407:Penicillium / Q000737:chemistry*; D011758:Pyrroles / Q000138:chemical synthesis / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D010091:Oximes; D011758:Pyrroles; C013231:pyrroline; D042967:Electron Transport Complex I