Thalidomide analogues: Dual inhibitors of both angiogenesis and human cancer cell proliferation

The identification of agents with antiproliferative activity against endothelial cells has significant value for the treatment of many angiogenesis-dependent pathologies, such as cancer. Using ligand-based drug design strategies, we have identified two novel classes of analogues, derived from thalidomide, that demonstrate remarkable anti-angiogenic and anti-cancer properties. The two novel classes include phthalimide and quinazolinone analogues. The ability of these compounds to inhibit the growth of certain human tumors and the blood supply that feeds them is significant. More specifically, these compounds have potential to make a tremendous impact in the treatment of cancers in which poor prognosis is correlated to microvessel density.; Several generations of both the phthalimide and quinazolinone classes have been designed and synthesized using traditional medicinal chemistry techniques. Both classes show significant inhibitory activity in vitro against the proliferation of human microvascular endothelial cells (HMECs), and the quinazolinone analogues have demonstrated in vivo anti-angiogenic activity in the chicken chorioallantoic membrane (CAM) assay. Further, our phthalimide-based analogues show increased potency towards androgen positive and negative prostate cancer and leukemia while the quinazolinone class demonstrates potent activity against colon cancer. One particular quinazolinone shows anti-colon cancer activity far superior to that of 5-Fluorouracil, and it also possesses potent anti-mitotic properties. Preliminary molecular modeling experiments have identified a potential binding pocket for this analogue on beta-tubulin. We have thus demonstrated the significant therapeutic potential of these novel dual acting compounds.