RESUMEN
A series of 4-imidazolylflavans having a variety of substituents on the 2-phenyl ring was synthesized and investigated for their inhibitory effect against aromatase. Structure-activity relationships of these compounds were determined. An additional chlorine atom or a cyano group at the 4' position did not enhance aromatase inhibition as well as a 3'-hydroxyl group. The influence of an additional 4'-hydroxyl group depends on the substitution pattern of A ring. Among these molecules, 4'-hydroxy-4-imidazolyl-7-methoxyflavan is only 2.2-fold less active than the letrozole (as assessed by IC50 values). Letrozole is used as the first-line therapy for metastatic breast cancer.
Asunto(s)
Inhibidores de la Aromatasa , Flavonoides , Imidazoles , Aromatasa/química , Aromatasa/efectos de los fármacos , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/farmacología , Flavonoides/síntesis química , Flavonoides/farmacología , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Microsomas/efectos de los fármacos , Microsomas/enzimología , Conformación Molecular , Placenta/enzimología , Relación Estructura-ActividadRESUMEN
Aromatase is a target of pharmacological interest for the treatment of estrogen-dependent cancers. Azole derivatives such as letrozole or anastrozole have been developed for aromatase inhibition and are used for the treatment of breast tumors. In this paper, four 4-triazolylflavans were synthesized and were found to exhibit moderate to high inhibitory activity against aromatase.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores de la Aromatasa/síntesis química , Flavonas/síntesis química , Triazoles/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/farmacología , Flavonas/química , Flavonas/farmacología , Humanos , Técnicas In Vitro , Microsomas/efectos de los fármacos , Microsomas/enzimología , Placenta/ultraestructura , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
Two 4-imidazolylflavans were synthesized and their relative stereochemistry was established by 1H and 13C NMR data. These compounds were tested for their activity to inhibit aromatase. It was observed that the introduction of an imidazolyl group at carbon 4 on flavan nucleus led to potent molecules.
Asunto(s)
Inhibidores de la Aromatasa , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Flavonoides/síntesis química , Flavonoides/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Aromatasa/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Femenino , Humanos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Placenta/enzimología , Embarazo , Protones , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
PURPOSE: Aromatase inhibitors are known to prevent the conversion of androgens to estrogens and play a significant role in the treatment of estrogen dependent diseases such as breast cancer. Some flavonoids have been reported as potent aromatase inhibitors; therefore, in an effort to develop novel anti breast cancer agents, B ring substituted flavanones with a 7-methoxy group on A ring were synthesized and tested to assess their ability to inhibit aromatase activity and to determine the optimal B ring substitution pattern. METHODS: A series of flavanones was prepared by cyclisation of 2'-hydroxychalcones previously obtained by Claisen-Schmidt condensation and the aromatase inhibitory activity of these compounds was investigated using human placental microsomes and radiolabeled [1,2,6,7-(3)H]-androstenedione as substrate. RESULTS: Almost all flavanones exhibited inhibitory effect on the aromatase activity but their potency was dependent on their B ring substitution pattern. Hydroxylation at position 3' and/or 4' enhanced the anti-aromatase activity; thus, 3',4'-dihydroxy-7-methoxyflavanone was found to be twice more potent than aminoglutethimide, the first aromatase inhibitor clinically used. CONCLUSIONS: These results indicated that these flavanones could be considered as potential anti breast cancer agents through the inhibition of aromatase activity and allowed us to select some of these compounds as skeleton for the development of flavonoid structurally-related aromatase inhibitors.
Asunto(s)
Inhibidores de la Aromatasa , Flavonoides/síntesis química , Flavonoides/farmacología , Aromatasa/metabolismo , Humanos , Microsomas/efectos de los fármacos , Microsomas/enzimologíaRESUMEN
Two (E)-pyridinyl-substituted flavanone derivatives were synthesized and UV irradiation of these compounds afforded a Z-enriched mixture. These products were tested for their ability to inhibit the cytochrome P450 aromatase. It was observed that the introduction of a pyridinylmethylene group at carbon 3 on flavanone nucleus led to a significant increase of aromatase inhibitory effect. Moreover, configuration had a substantial influence on the aromatase inhibitory activity since (E)-isomers were found to be more active than (Z)-isomers.