Synthesis of heterocycle-containing genistein analogues as anti-prostate cancer agents

Prostate cancer is the second-leading cause of cancer-related deaths in the United States. There is no effective therapy when prostate cancer becomes metastatic and refractory to conventional treatments. For this reason, the identification and exploration of new agents that reduce prostate cancer cell growth are of paramount importance. The increased risk of prostate cancer in the first generation of Asian men emigrating to the United States suggests a chemopreventive effect from traditional Asian food. Genistein, a phytoestrogen isolated from soybeans, has been identified in clinical trials as a candidate for prostate cancer prevention and treatment. However, its efficacy in clinical studies has been limited by the poor bioavailability. The hypothesis of this research project is that various heteroaromatic rings can serve as potential bioisosteres for phenyl rings in genistein and the incorporation of a basic nitrogen can improve the bioavailability of the genistein analogs. The researchers in this study have synthesized six new pyrazole genistein analogs and three known analogs without a N-containing heteroaromatic ring through a four-step reaction sequence with Suzuki-Miyaura coupling reaction as a key step. The cytotoxic and anti-proliferative effects of these analogs were evaluated against three prostate cancer cell lines (LNCaP, DU-145, and PC-3) and one aggressive cervical cancer cell line (HeLa). The synthesis, cytotoxicity, and structure-activity relationship of genistein analogs will be presented.