In vitro oxidative metabolism study of (-)-rhazinilam.
Metabolism studies were conducted in order to investigate the reasons for the in vivo lack of activity of (-)-rhazinilam 1, an original poison of the mitotic spindle. Bioconversion by Beauveria bassiana strains, rat and human liver microsomes allowed the identification of metabolites 2, 3, and 4 oxidized in positions 3 and 5 of rhazinilam. Further experiments indicated that CYP2B6 was the main CYP responsible for the oxidation of 1 by human liver microsomes. All isolated metabolites were markedly less active than rhazinilam in vitro, which might explain its in vivo inactivity.
Décor
Anne
A
Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, France.
Bellocq
Delphine
D
Thoison
Odile
O
Lekieffre
Nicolas
N
Chiaroni
Angèle
A
Ouazzani
Jamal
J
Cresteil
Thierry
T
Guéritte
Françoise
F
Baudoin
Olivier
O
D000470:Alkaloids / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D032661:Cordyceps / Q000187:drug effects* / Q000254:growth & development; D018360:Crystallography, X-Ray; D065702:Cytochrome P-450 CYP2B6; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007212:Indolizines / Q000378:metabolism / Q000494:pharmacology; D007769:Lactams / Q000378:metabolism / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D008941:Spindle Apparatus / Q000378:metabolism; D013997:Time Factors
D000470:Alkaloids; D000970:Antineoplastic Agents; D007212:Indolizines; D007769:Lactams; C009170:rhazinilam; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating