Structure-activity relationship and pharmacokinetic studies of 3-O-substitutedflavonols as anti-prostate cancer agents

Abstract Thirty-eight 3- O -substituted-3′,4′-dimethoxyflavonols and twenty-five 3- O -substituted-3′,4′,7-trimethoxyflavonols have been synthesized for systematic investigation on the structure-activity relationships of 3- O -substituted-3′,4′-dimethoxyflavonols in three human prostate cancer cell models. Our findings indicate that incorporation of an appropriate amino group to 3-OH of 3′,4′-dimethoxyflavonol and 3′,4′,7-trimethoxyflavonol through a 3- to 5-carbon linker can substantially improve the in vitro antiproliferative potency in three human prostate cancer cell models, but not in two non-neoplastic human epithelial cell models (MCF 10A and PWR-1E). 1-Methylpiperazine, pyrrolidine, and dibutylamine are optimal terminal amine groups that, in combination with a 3- to 5-carbon linker, are notably beneficial to the anti-proliferative potency of 3- O -substituted-3′,4′-dimethoxyflavonols. It is worth noting that 3- O -(4-methylpiperazin-1-yl)propyl-3′,4′,7-trimethoxyflavonol ( 76 ) induces PC-3 cell death in a completely different way from 3- O -pyrrolidinopentyl-3′,4′,7-trimethoxyflavonol ( 81 ) even though they belong to 3- O -substituted-3′,4′,7-trimethoxyflavonols and exhibit similar potency in inhibiting PC-3 cell proliferation, suggesting that the mechanism of action for each specific 3- O -substitutedflavonol varies with different amino moiety. 3- O -( N , N -Dibutylamino)propyl-3′,4′-dimethoxyflavonol ( 42 ) emerged as the most promising derivative due to its substantially improved potency in cell models, superior bioavailability in rats, and good selectivity of inhibiting prostate cancer cell proliferation over non-neoplastic human epithelial cell proliferation.