3-O-Substituted-3′,4′,5′-trimethoxyflavonols: Synthesis and cell-based evaluation as anti-prostate cancer agents

Abstract

Twenty-two 3-O-substituted-3′,4′,5′-trimethoxyflavonols have been designed and synthesized for their anti-proliferative activity towards three human prostate cancer cell lines. Our results indicate that most of them are significantly more potent than the parent 3′,4′,5′-trimethoxyflavonol in inhibiting the cell proliferation in PC-3 and LNCaP prostate cancer cell models. 3-O-Substituted-3′,4′,5′-trimethoxyflavonols have generally higher potency towards PC-3 and LNCaP cell lines than the DU145 cell line. Incorporation of an ethyl group to 3-OH of 3′,4′,5′-trimethoxyflavonol leads to 3-O-ethyl-3′,4′,5′-trimethoxyflavonol as the optimal derivative with up to 36-fold enhanced potency as compared with the corresponding lead compound 3′,4′,5′-trimethoxyflavonol, but with reversed PC-3 cell apoptotic response. Introduction of a dipentylaminopropyl group to 3-OH increases not only the antiproliferative potency but also the ability in activating PC-3 cell apoptosis. Our findings imply that modification on 3-OH of trimethoxyflavonol can further enhance its in vitro anti-proliferative potency and PC-3 cell apoptosis induction.

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

“…Our earlier WST-1 cell proliferation assay in three prostate cancer cell models suggests that the antiproliferative potency of 3′,4′-dimethoxyflavonol ( 4 ) and 3′,4′,5′-trimethoxyflavonol ( 3 ) could be appreciably enhanced through chemical modifications on its 3-OH group [19–20]. 3′,4′Dimethoxyflavonol ( 4 ) and 3′,4′,5′-trimethoxyflavonol ( 3 ) were chosen as our first two lead flavonols because they contain two or three methoxyl groups instead of phenolic hydroxyl groups on ring B.…”