The overall objective of the proposed project is to investigate the in vitro and in vivo antitumor properties of discodermolide, a marine-derived, microtubule interactive compound, and to prepare and analyze the antitumor activity of natural and synthetic derivatives, intermediates and analogs that have the potential of becoming efficacious therapeutic agents useful in the treatment of human cancer. Discodermolide's mechanism of action, which is similar to that of the chemically unrelated antitumor agent, taxol, includes the ability to block cellular proliferation at the G2/M phase of the cell cycle and to induce the premature polymerization of tubulin resulting in the formation of non-functional, microtubule """"""""bundles,"""""""" resulting in cell death. Discodermolide is active in vivo in i.p./i.p. P388 murine leukemia and in i.v./s.c. human ovarian tumor xenograft models. For the 3-year period, the principal proposes to: 1) isolate natural discodermolide analogs and prepare synthetic derivatives/intermediates and analogs of the compound, 2) utilize cytotoxicity, cell cycle, apoptosis, polymerization of purified tubulin, microtubule """"""""bundling"""""""" assays and multi-drug resistant cell lines to identify their in vitro activities and to guide our chemical and synthetic efforts, 3) evaluate the in vivo activity of compounds selected on the basis of their in vitro activity in human tumor xenograft models of lung, breast and ovarian cancers. Successful completion of the proposed research will lead to: 1) the discovery of new discodermolide analogs and compounds which will be derived from natural discodermolide or from synthetic intermediates and/or analogs which may prove more efficacious than taxol, 2) improve the efficiency of various synthetic routes by which we obtain discodermolide which will provide increased amounts of compound for anticipated pre-clinical and eventual clinical development, and 3) provide possible insight into the structure activity relationship of discodermolide and its associated binding site.
