RESUMO
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.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Plantas/efeitos dos fármacos , Plantas/enzimologia , Triazóis/química , Triazóis/farmacologia , Arabidopsis/enzimologia , Proteínas de Arabidopsis/antagonistas & inibidores , Proteínas de Arabidopsis/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lactuca/efeitos dos fármacos , Lactuca/crescimento & desenvolvimento , Modelos Moleculares , Oryza/efeitos dos fármacos , Oryza/crescimento & desenvolvimento , Desenvolvimento Vegetal , Reguladores de Crescimento de Plantas/síntese química , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/farmacologia , Proteínas de Plantas , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Triazóis/síntese químicaRESUMO
We enlarged the uniconazole (UNI) molecule to find a specific inhibitor of abscisic acid (ABA) 8'-hydroxylase, and synthesized various UNI derivatives that were substituted with hydrophilic and hydrophobic groups at the 4-chlorine of the phenyl group of UNI using click chemistry. Considering its potency in ABA 8'-hydroxylase inhibition, its small effect on seedling growth, and its ease of application, UT4, the UNI derivative containing the C4 alkyltriazole, was the best candidate for a highly selective inhibitor of ABA 8'-hydroxylase.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/química , Triazóis/química , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Malus/crescimento & desenvolvimento , Oryza/crescimento & desenvolvimento , Proteínas de Plantas , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
To develop a specific inhibitor of abscisic acid (ABA) 8'-hydroxylase, a key enzyme in the catabolism of ABA, a plant hormone involved in stress tolerance, seed dormancy, and other various physiological events, we designed and synthesized conformationally restricted analogues of uniconazole (UNI), a well-known plant growth retardant, which inhibits a biosynthetic enzyme (ent-kaurene oxidase) of gibberellin as well as ABA 8'-hydroxylase. Although most of these analogues were less effective than UNI in inhibition of ABA 8'-hydroxylase and rice seedling growth, we found that a lactol-bridged analogue with an imidazole is a potent inhibitor of ABA 8'-hydroxylase but not of plant growth. This compound, abscinazole-F1, induced drought tolerance in apple seedlings upon spray treatment with a 10 microM solution.
