Ovarian cancer is the most fatal of all female reproductive cancers with a 5-year survival rate below 50%. Over 90% of diagnosed ovarian cancers are categorized as epithelial white germ cell cancer. Epithelial ovarian cancer commonly causes tumors, including both high grade serous carcinomas (HGSC) or low-grade serous carcinomas (LGSC), that can grow unknowingly on the ovarian tissue for many years. First-line defenses include surgical debulking, platinum-based chemotherapy, and natural product-based chemotherapies (paclitaxel and camptothecin). Unfortunately, all first line chemotherapies are prone to resistance and disease recurrence, necessitating the continued development of new therapies with novel mechanisms of action against ovarian cancer. With this in mind, current efforts in our lab have focused on the development of the lead compound, PHY-34. This compound was developed during the course of studies on the natural product phyllanthusmin D, an arylnaphthalene lignan lactone isolated from the Vietnamese plant Phyllanthus poilanei. PHY-34 has demonstrated potent sub nanomolar in vitro activity in HGSC cancer cell lines as well as in vivo activity in a xenograft model. The primary target of PHY-34 has been demonstrated to be v-ATPase. Structure-activity relationship studies and in silico modeling have subsequently been utilized to explore compound potency and selectivity against v-ATPase and optimize the drug properties of potential analogues for in vivo administration. In particular, a combination of computational methods and synthetic approaches have been utilized to vary the size and electronic nature of the D-ring of PHY-34, leading to a new generation of analogues that probe the potential pharmacophore and improve predicted drug properties.

Methods of D-ring synthesis for optimization of the phyllanthusmin class of natural products against ovarian cancer

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