Masters Thesis

Synthesis and evaluation of 7-O-Substituted flavonols for their anti-prostate cancer potential

Prostate cancer has continued to plague the globe as the second most commonly diagnosed cancer worldwide. To date, there are no effective treatments towards metastatic, advanced prostate cancer. Fisetin, a natural strawberry flavonoid, has been revealed to possess potential in treating prostate cancer according to in vitro and in vivo studies. However, fisetin is known to merely have moderate potency towards prostate cancer cells. Fisetin is characterized by four phenolic hydroxyl groups. Previous studies indicate chemical modifications on the hydroxyl groups (OH) of flavonoids can overcome, at least partially, the drawback. The goal for this thesis project was to identify and optimize a synthetic route, and, lastly, explore the potential of 7-O-substituted-3,3',4'- O-trimethylfisetins as anticancer agents. To this end, eleven analogues including one biflavonoid, have been synthesized through one-pot reactions of aldol condensation followed by Algar-Flynn-Oyamada (AFO) reactions. Their structures were characterized by the 1H NMR data, and high-resolution mass spectrometry. The anti-proliferative activities toward three human prostate cancer cell lines (PC-3, DU145, and LNCaP) have been evaluated through a WST-1 cell proliferation assay. Our results show that modification to the hydroxyl groups of the fisetin template through 7-O-aminoalkylation generally increases potency towards the prostate cancer cell lines. Literature identifies the androgen receptor as the primary drug target for advanced, castration resistant prostate cancer. Remarkably, the incorporation of certain heterocyclic amines led to analogs with both improved potency and selectivity towards the androgen receptor positive prostate cancer cell line, LNCaP.