title: Saperconazole: a selective inhibitor of the cytochrome P-450-dependent ergosterol synthesis in Candida albicans, Aspergillus fumigatus and Trichophyton mentagrophytes.
abstract: The N-1-substituted triazole antifungal, saperconazole, is a potent inhibitor of ergosterol synthesis in Candida albicans, Aspergillus fumigatus and Trichophyton mentagrophytes. Fifty % inhibition is already achieved at nanomolar concentrations. The saperconazole-induced inhibition of ergosterol synthesis coincides with an accumulation of 14-methylated sterols, such as 24-methylenedihydrolanosterol, lanosterol, obtusifoliol, 14 alpha-methylfecosterol, 14 alpha-methylergosta-8,24(28)-dien-3 beta-6 alpha-diol and 14 alpha-methylergosta-5,7,22,24(28)-tetraenol. This indicates that saperconazole interferes with the cytochrome P-450 (P-450)-dependent 14 alpha-demethylation of lanosterol and/or 24-methylenedihydrolanosterol. Saperconazole forms stable drug-P-450-complexes by binding via its free triazole nitrogen to the heme iron and via its N-1 substituent to the apoprotein moiety. The triazole derivative is a highly selective inhibitor of the 14 alpha-demethylase in fungal cells. It is a poor inhibitor of the 14 alpha-demethylation of lanosterol in rat and human liver cells. Saperconazole is, at concentrations as high as 10 microM, devoid of effects on the P-450-dependent cholesterol side-chain cleavage and 11 beta-hydroxylase, 17,20-lyase,21-hydroxylase and aromatase. Saperconazole does not interfere with the 2 alpha, 6 alpha-, 6 beta- and 7 alpha-hydroxylations of testosterone in microsomes from male rat liver. At high concentrations (greater than 5 microM) an inhibition of the 16 beta-hydroxylations is seen.
authors.affiliation: Janssen Research Foundation, Beerse, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Vanden Bossche
authors.forename: P
authors.initials: P
authors.lastname: Marichal
authors.forename: G
authors.initials: G
authors.lastname: Willemsens
authors.forename: D
authors.initials: D
authors.lastname: Bellens
authors.forename: J
authors.initials: J
authors.lastname: Gorrens
authors.forename: I
authors.initials: I
authors.lastname: Roels
authors.forename: M C
authors.initials: MC
authors.lastname: Coene
authors.forename: L
authors.initials: L
authors.lastname: Le Jeune
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D001393:Azoles / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D002417:Cattle; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004875:Ergosterol / Q000037:antagonists & inhibitors; D011817:Rabbits; D013552:Swine; D014249:Trichophyton / Q000187:drug effects*
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D003577:Cytochrome P-450 Enzyme System; C060571:saperconazole; D004875:Ergosterol