RESUMEN
Design strategies that can access natural-product-like chemical space in an efficient manner may facilitate the discovery of biologically relevant compounds. We have employed a divergent intermediate strategy to construct an indole alkaloid-inspired compound collection derived from two different molecular design principles, i.e. biology-oriented synthesis and pseudo-natural products. The divergent intermediate was subjected to acid-catalyzed or newly discovered Sn-mediated conditions to selectively promote intramolecular C- or N-acylation, respectively. After further derivatization, a collection totalling 84â compounds representing four classes was obtained. Morphological profiling via the cell painting assay coupled with a subprofile analysis showed that compounds derived from different design principles have different bioactivity profiles. The subprofile analysis suggested that a pseudo-natural product class is enriched in modulators of tubulin, and subsequent assays led to the identification of compounds that suppress inâ vitro tubulin polymerization and mitotic progression.
Asunto(s)
Alcaloides , Antineoplásicos , Productos Biológicos , Oxindoles , Tubulina (Proteína) , Alcaloides Indólicos/química , Productos Biológicos/químicaRESUMEN
We developed abscinazole-E1 (Abz-E1), a specific inhibitor of abscisic acid (ABA) 8'-hydroxylase (CYP707A). This inhibitor was designed and synthesized as an enlarged analogue of uniconazole (UNI), a well-known plant growth retardant, which inhibits a gibberellin biosynthetic enzyme (ent-kaurene oxidase, CYP701A) as well as CYP707A. Our results showed that Abz-E1 functions as a potent inhibitor of CYP707A and a poor inhibitor of CYP701A both in vitro and in vivo. Abz-E1 application to plants resulted in improved desiccation tolerance and an increase in endogenous ABA.
Asunto(s)
Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Triazoles/química , Arabidopsis/enzimología , Arabidopsis/fisiología , Germinación , Oryza/enzimología , Oryza/fisiología , Proteínas de PlantasRESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Plantas/efectos de los fármacos , Plantas/enzimología , Triazoles/química , Triazoles/farmacología , Arabidopsis/enzimología , Proteínas de Arabidopsis/antagonistas & inhibidores , Proteínas de Arabidopsis/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Lactuca/efectos de los fármacos , Lactuca/crecimiento & desarrollo , Modelos Moleculares , Oryza/efectos de los fármacos , Oryza/crecimiento & desarrollo , Desarrollo de la Planta , Reguladores del Crecimiento de las Plantas/síntesis química , Reguladores del Crecimiento de las Plantas/química , Reguladores del Crecimiento de las Plantas/farmacología , Proteínas de Plantas , Plantones/efectos de los fármacos , Plantones/crecimiento & desarrollo , Triazoles/síntesis químicaRESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/química , Triazoles/química , Sistema Enzimático del Citocromo P-450/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Malus/crecimiento & desarrollo , Oryza/crecimiento & desarrollo , Proteínas de Plantas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Plantones/efectos de los fármacos , Plantones/crecimiento & desarrollo , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
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.