Development and optimization of the phyllanthusmin class of arylnaphthalene lignan natural products

A series of arylnaphthalene lignans, referred to collectively as the phyllanthusmins, was isolated from Phyllanthus poilanei by the Kinghorn lab as a part of a collaborative program project grant directed at the identification of novel anticancer agents (P01 CA125066). These compounds bear a strong structural resemblance to etoposide, a semi-synthetic DNA topoisomerase II (topo II) poison. Although the phyllanthusmins have been shown not to inhibit topo II activity, many of these compounds have demonstrated potent in vitro antiproliferative activity against HT-29 and other cancer cells. In an effort to understand the structure-activity requirements and to remedy the limited aqueous solubility of this class of molecules for in vivo studies, a series of structural analogues has been synthesized and screened for biological activity, ultimately leading to compounds with improved properties. This iterative process of optimization in collaboration with other members of this program grant will be highlighted.