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

• Published in: European journal of medicinal chemistry 2018-09, Vol.157, p.978-993
• Main Authors: Li, Xiang, Zhang, Changde, Guo, Shanchun, Rajaram, Pravien, Lee, Maizie, Chen, Guanglin, Fong, Ryan, Gonzalez, Aaron, Zhang, Qiang, Zheng, Shilong, Wang, Guangdi, Chen, Qiao-Hong
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Cell apoptosis; Cell Proliferation - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavonol; Flavonols - chemical synthesis; Flavonols - chemistry; Flavonols - pharmacokinetics; Flavonols - pharmacology; Humans; Male; Molecular Structure; Pharmacokinetic study; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.08.047

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. [Display omitted] •63 3-O-substituted flavonols were evaluated in prostate epithelial cell models.•An appropriate amino group to 3-OH of flavonols did improve the potency.•The optimal carbon linkers and terminal amino groups were identified.•One promising compound exhibit improved potency and bioavailability.