Synthesis and biological evaluation of 4-imidazolylflavans as nonsteroidal aromatase inhibitors

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.