A new class of flavonol-based anti-prostate cancer agents: Design, synthesis, and evaluation in cell models

Abstract

Flavonoids are a large class of polyphenolic compounds ubiquitously distributed in dietary plants with an array of biological activities. Flavonols are a major sub-class of flavonoids featuring a hydroxyl group at C-3. Certain natural flavonols, such as quercetin and fisetin, have been shown by in vitro cell-based and in vivo animal experiments to be potential anti-prostate cancer agents. However, the Achilles' heel of flavonols as drug candidates is their moderate potency and poor pharmacokinetic profiles. This study aims to explore the substitution effect of 3-OH in flavonols on the in vitro anti-proliferative potency against both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Our first lead flavonol (3',4'-dimethoxyflavonol), eight 3-O-alkyl-3',4'-dimethoxyflavonols, and six 3-O-aminoalkyl-3',4'-dimethoxyflavonols have been synthesized through aldol condensation and the Algar-Flynn-Oyamada (AFO) reaction. The WST-1 cell proliferation assay indicates (i) that all synthesized 3-O-alkyl-3',4'-dimethoxyflavonols and 3-O-aminoalkyl-3',4'-dimethoxyflavonols are more potent than the parent 3',4'-dimethoxyflavonol and the natural flavonol quercetin in suppressing prostate cancer cell proliferation; and (ii) that incorporation of a dibutylamino group to the 3-OH group through a three- to five-carbon linker leads to the optimal derivatives with up to 292-fold enhanced potency as compared with the parent flavonol. Flow cytometry analysis showed that the most potent derivative 22 can activate PC-3 cell cycle arrest at the G2/M phase and induce PC-3 cell apoptosis. No inhibitory ability of 22 up to 50μM concentration was observed against PWR-1E normal human epithelial prostate cells, suggesting its in vitro safety profile. The results indicate that chemical modulation at 3-OH is a vital strategy to optimize flavonols as anti-prostate cancer agents.

Keywords: 3′,4′-Dimethoxyflavonol; Cell proliferation; Flavonol; Prostate cancer; Quercetin.

Figure 1. Structures of some naturally occurring flavonols

Figure 3

Evolution of viable, apoptotic, and necrotic PC-3 cells populations in response to derivative 22 at 1-100 μM concentrations.

Figure 4

Cell cycle analysis of PC-3 cells. PC-3 cancer cells were untreated or treated with 22 at 10 μM. Cells were harvested after 20 and 24 hours, fixed, stained, and analyzed for DNA content.

Scheme 1. Synthesis of 3′,4′-dimethoxyflavonol

Scheme 2. Synthesis of 3-O-alkyl-3′,4′-dimethoxyflavonols

Scheme 3. Synthesis of 3-O-aminoalkyl-3′,4′-O-dimethoxyflavonols