In vitro oxidative metabolism study of (−)-rhazinilam

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 5; pp. 1558 - 1564
• Main Authors: Décor, Anne, Bellocq, Delphine, Thoison, Odile, Lekieffre, Nicolas, Chiaroni, Angèle, Ouazzani, Jamal, Cresteil, Thierry, Guéritte, Françoise, Baudoin, Olivier
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2006; Elsevier Science; Elsevier
• Subjects: Alkaloids - metabolism; Alkaloids - pharmacology; Animals; Antineoplastic agents; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Aryl Hydrocarbon Hydroxylases - metabolism; Beauveria bassiana; Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Biotransformation; Chemical Sciences; Cordyceps - drug effects; Cordyceps - growth & development; Crystallography, X-Ray; CYP; Cytochrome P-450 CYP2B6; Fundamental and applied biological sciences. Psychology; Gas Chromatography-Mass Spectrometry; General aspects; Humans; Indolizines - metabolism; Indolizines - pharmacology; Lactams - metabolism; Lactams - pharmacology; Medical sciences; Metabolism; Methods. Procedures. Technologies; Microsomes, Liver - enzymology; Organic chemistry; Oxidation-Reduction; Oxidoreductases, N-Demethylating - metabolism; Pharmacology. Drug treatments; Rats; Rhazinilam; Spindle Apparatus - metabolism; Time Factors; Tubulin; Rhazinilam; Tubulin; CYP; Metabolism; Antineoplastic agent; Chemical analysis; Rat; Angular nitrogen heterocycle; Metabolite; Liver; Lactam; HPLC chromatography; Cytotoxicity; Microsome; Fungi; Beauveria bassiana; Alkaloid; Biotransformation; Aromatic compound; Oxidation; Fungi Imperfecti; Antimitotic; Tumor cell; Thallophyta; Human; Rodentia; Antitubulin; Epidermis; Tetracyclic compound; In vitro; Biological activity; Vertebrata; Mammalia; Cell line; Animal; KB cell line; Enzymatic reaction
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.10.015

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.