title: Selectivity improvement of an azole inhibitor of CYP707A by replacing the monosubstituted azole with a disubstituted azole.
abstract: The plant growth-retardant uniconazole (UNI), a triazole inhibitor of gibberellin biosynthetic enzyme (CYP701A), inhibits multiple P450 enzymes including ABA 8'-hydroxylase (CYP707A), a key enzyme in ABA catabolism. Azole P450 inhibitors bind to a P450 active site by both coordinating to the heme-iron atom via sp2 nitrogen and interacting with surrounding protein residues through a lipophilic region. We hypothesized that poor selectivity of UNI may result from adopting a distinct conformation and orientation for different active sites. Based on this hypothesis, we designed and synthesized novel UNI analogs with a disubstituted azole ring (DSI). These analogs were expected to have higher selectivity than UNI because the added functional group may interact with the active site to restrict orientation of the molecule in the active site. DSI-505ME and DSI-505MZ, which have an imidazolyl group with a methyl 5-acrylate, strongly inhibited recombinant CYP707A3, with no growth-retardant effect.
authors.affiliation: Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan. aytodor@agr.shizuoka.ac.jp
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Todoroki
authors.forename: Kumi
authors.initials: K
authors.lastname: Naiki
authors.forename: Hikaru
authors.initials: H
authors.lastname: Aoyama
authors.forename: Minaho
authors.initials: M
authors.lastname: Shirakura
authors.forename: Kotomi
authors.initials: K
authors.lastname: Ueno
authors.forename: Masaharu
authors.initials: M
authors.lastname: Mizutani
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Hirai
mesh_terms: D017360:Arabidopsis / Q000201:enzymology; D029681:Arabidopsis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018545:Lactuca / Q000187:drug effects / Q000254:growth & development; D008958:Models, Molecular; D012275:Oryza / Q000187:drug effects / Q000254:growth & development; D063245:Plant Development; D010937:Plant Growth Regulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010940:Plant Proteins; D010944:Plants / Q000187:drug effects* / Q000201:enzymology*; D036226:Seedlings / Q000187:drug effects / Q000254:growth & development; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D029681:Arabidopsis Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010937:Plant Growth Regulators; D010940:Plant Proteins; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System; C107203:abscisic acid 8'-hydroxylase; C092705:uniconazole