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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.

SUBMITTER: Li X

PROVIDER: S-EPMC6245954 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Li Xiang X Zhang Changde C Guo Shanchun S Rajaram Pravien P Lee Maizie M Chen Guanglin G Fong Ryan R Gonzalez Aaron A Zhang Qiang Q Zheng Shilong S Wang Guangdi G Chen Qiao-Hong QH

European journal of medicinal chemistry 20180822

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 ...[more]

PMID: 30165345

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Project description:Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nucleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thiophene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide portion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cytotoxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In addition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents.

Dataset Information

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

Publications

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

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