Abstract: The current FDA-approved first-line treatment for castration-resistant prostate cancer can barely prolong maximum 2-3 years of survival for a prostate cancer patient. Even worse, the reason that approximately 30,000 men die each year of castration-resistant prostate cancer in the USA is because they becomes refractory by the inevitable progression of resistance to first-line treatment with docetaxel. It is thus an urgent need to search for an effective treatment for this medical unmet disease. Silybin, extracted from milk thistle (Silybum marianium), is a naturally occurring hybrid molecule of flavonoid and lignan. It has a long history used as treatment for mushroom poisoning and as dietary supplements, suggesting its positive and non-toxic profile. This has been supported by its phase I clinical trial data in advanced prostate cancer patients. The in vitro and in vivo investigations have demonstrated its therapeutic potential for prostate cancer. The in vivo anti-tumor efficacy of silybin has been evidenced in a DU-145 human prostate cancer cell xenograft model in athymic mice and a 3,2’-dimethy-4-aminobiphenyl-induced prostate cancer model in rats. The effectiveness of silybin as a potential anticancer clinical therapeutic is however discounted by its low potency and bioavailability. Hence, structure modifications of silybin to synthesize new chemical entities with enhanced potency and bioavailability are highly desired and are the core focus of our research project. A group of new silybin derivatives have been designed and synthesized for the evaluation of their anti-proliferative activities towards prostate cancer cells. In the WST-1 assay, eight out of the ten derivatives exhibited better inhibitory activity than parental silybin towards the proliferation of human androgen-independent PC-3 prostate cancer cells at 1 µM and 10 µM concentrations. The most promising three derivatives are 10-time more potent than silybin based on the comparison of their IC50 values. The effects of the properties and attaching points of various substituents on the proliferation of prostate cancer cells were explored. The design, synthesis, anti-proliferative activity, and structure-activity relationships of these silybin derivatives will be presented. Keywords: silybin, prostate cancer, anti-proliferative activity

Silybin derivatives as antiprostate cancer agents: Synthesis and antiproliferative activity

249th National Meeting (2015)

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