Brevioxime

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.

The synthesis, in racemic form, of the insect juvenile hormone inhibitor brevioxime (1) is described, as well as exploratory studies that led to the related model compounds 14 and 15a. The route to 1 involves Ag(+)-mediated coupling of the amine derived from 20 with the beta-keto thioester 32. Acid treatment of the coupled product 33 led by acetal hydrolysis, cyclization, and desilylation to 34a,b, from which 1 was reached by oxidation and conversion into the oxime. In the synthesis of the amino component 20, a known, but unusual, reduction was used for converting a nitrile into an amine hydrochloride.