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 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.

Flavonoids as Epigenetic Modulators for Prostate Cancer Prevention

“…Results showed that genistein inhibited PCa cell growth through upregulation of tumor suppressor miR-34a, which directly targets HOX Transcript Antisense RNA (HOTAIR), a lncRNA that regulates key pathways in PCa invasion and metastasis [153]. A few recent studies focused on the interaction between miRNAs and lncRNAs in human cancer cells [154][155][156][157]. HOTAIR can function as a scaffold through binding and directing EZH2 and Lysine (K)-specific demethylase 1A (LSD1) to occupy the same genomic regions.…”

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

“…4,11,18 Trimethoxyflavonol ( 3 ) has been revealed to arrest cell cycle at the G 2 /M phase in murine TRAMP C2 prostate cancer cells, but have no effect on human 22Rv1 cell cycle distribution. 9 No report was available so far on PC-3 cell cycle perturbation activity of trimethoxyflavonol ( 3 ).…”

“…11,19–21 Additionally, trimethoxyflavonol ( 3 ) has been reported to induce mouse prostate carcinoma TRAMP C2 cell apoptosis in vitro as detected by annexin V staining, but not in human prostate carcinoma 22Rv1 cells. 9 No apoptosis activation of trimethoxyflavonol ( 3 ) in human androgen-insensitive PC-3 prostate cancer cell line has been reported.…”

“…1) with up to 292-fold enhanced potency as compared with the parent 3′,4′-dimethoxyflavonol ( 4 ) in human prostate cancer cell models. 11 Encouraged by these promising results, the present study aims to explore the possibility of further enhancing the anti-proliferative potency of 3′,4′,5′-trimethoxyflavonol ( 3 ) as anti-prostate cancer agents through chemical manipulations on its 3-OH group. Consequently, ten 3- O -alkyl-3′,4′,5′-trimethoxyflavonols (one known and nine new) and twelve new 3- O -dialkylaminoalkyl-3′,4′,5′-trimethoxyflavonols have been synthesized and evaluated for their ability in suppressing prostate cancer cell proliferation.…”

Nitrogen-containing derivatives of O-tetramethylquercetin: Synthesis and biological profiles in prostate cancer cell models

“…Our previous studies suggest that introduction of one substituent group, especially lengthy and/or bulky group to a phenolic hydroxyl group might be the best strategy for modification of quercetin as anti-prostate cancer agents [20]. Incorporation of an appropriate amino moiety to the 3-OH of 3',4'-dimethoxyflavonol through a three-carbon linker led to the optimal derivative 2 with up to 292-fold increase in potency [21] in three prostate cancer cell lines. Also, modification of 5-OH of 2,3-dehydrosilybin (another group of flavonoids) resulted in an optimal derivative 3 that can consistently inhibit prostate cancer cell proliferation [22].…”