The novel dipeptide CC-1065 is a potent antitumor antibiotic which has been shown to be more cytotoxic than maytansine, adriamycin, and actinomycin D against a variety of murine and human cancer cells. Unfortunately, it also shows a lethal delayed hepatotoxicity at therapeutic antineoplastic doses in rodents. Recent work at the Upjohn Company has shown, however, that a highly modified analog of CC-1065 can be quite active while having a much reduced hepatotoxicity. We propose to continue our current studies aimed at completing the synthesis of CC-1065 as well as systematically synthesizing a number of structural analogs of CC-1065. Our versatile photochemical approach will provide a variety of B and C type units, and will provide a new route to the dienone A unit and its analogs. In addition, an in-depth study of appropriate coupling and blocking procedures will be made in order to assemble the tricyclic units. Final objectives in addition to CC-1065 itself include a variety of deoxy analogs, as well as analogs containing sulfur or oxygen in place of the indole nitrogens.
