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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 G 2 /M phase and induce PC-3 cell apoptosis. No inhibitory ability of 22 up to 50 μM 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. [ABSTRACT FROM AUTHOR]

[Display omitted] • An amide mimic of desTHPdactylolide was synthesized via a 26-step transformation. • Antiproliferative activity was evaluated against five prostate cancer cell lines. • The lactam moiety can serve as a bioisostere for the lactone in desTHPdactylodide. (−)-Zampanolide is a unique microtubule stabilizing agent (MSA) with covalent-binding mechanism and low nanomolar anitproliferative potency towards multi-drug resistant cancer cells. MSAs have a special connection with prostate cancer by inhibiting androgen receptor nuclear translocation. Zampanolide and the structurally related dactylolide have thus been sought after by us as lead compounds for development of anti-prostate cancer agents. DesTHPdactylolide is a simplified mimic of dactylolide and has previously been synthesized by us in both configurations, with the (17 R) configuration being more potent in suppressing prostate cancer cell proliferation. The current study aims to synthesize an amide mimic of (17 R) desTHPdactylolide that was anticipated to be metabolically more stable than (17 R) desTHPdactylolide. To this end, the amide mimic has been successfully synthesized through a 26-step transformation from 2-butyn-1-ol. Our WST-1 cell proliferation assay in five human prostate cancer cell models indicated that the lactam moiety can serve as a bioisostere for the lactone in desTHPdactylolide. [ABSTRACT FROM AUTHOR]