PLANT STEROL BIOSYNTHESIS - NOVEL POTENT AND SELECTIVE INHIBITORS OF CYTOCHROME P450-DEPENDENT OBTUSIFOLIOL 14-ALPHA-METHYL DEMETHYLASE

The R-(-) isomer of methyl 1-(2,2-dimethylindan-1-yl) imidazole-5-carboxylate (CGA 214372; 2) strongly inhibited P450-dependent obtusifoliol 14α-demethylase (P450OBT.14DM) (I50 = 8 × 10-9M, I50 Km = 5 × 10-5) in a maize (Zea mays) microsomal preparation. Kinetic studies indicated uncompetitive inhibition with respect to obtusifoliol. The corresponding S-(+) isomer was a 20-fold weaker inhibitor for P450OBT.14DM. The molecular features of a variety of analogues of 2 were related to their potency as inhibitors of P450OBT.14DM in vitro, allowing delineation of the key structural requirements governing inhibition of the demethylase. CGA 214372 proved to have a high degree of selectivity for P450OBT.14DM. This allowed easy distinction of this activity from other P450-dependent activities present in the maize microsomal preparation and gave strong evidence that P450OBT.14DM is a herbicidal target. Microsomal maize P450OBT.14DM and yeast P450LAN.14DM, the only known examples of P450-dependent enzymes carrying out an identical metabolic function in different eukaryotes, showed distinct inhibition patterns with CGA 214372 and ketoconazole, a substituted imidazole antimycotic. © 1992.