The dimeric Catharanthus alkaloids vinblastine and vincristine are extremely efficacious, clinically useful anticancer agents. The isolation and purification of these compounds is a difficult process. The use of these compounds for cancer chemotherapy often causes serious side effects. The desirability of preparing and testing analogs of these compounds is apparent. Semisynthetic vinblastine and vincristine have been prepared by the coupling of naturally occurring vindoline and catharanthine. This approach has several significant limitations. Although vindoline is readily available from natural sources, catharanthine is relatively inaccessibility. In addition, the coupling procedure is not very efficient. Finally, the use of naturally obtained vindoline and catharanthine restricts the types of dimeric analogs which may be prepared. The objective is to develop efficient methods for the preparation of the dimeric Catharanthus alkaloids vinblastine and vincristine, and analogs of these compounds.
The specific aims are: (1) to develop improved procedures for the coupling of synthetic (=)-catharanthine with (+)-vindoline in order to prepare the dimeric alkaloids; (2) to prepare analogs of catharanthine; and (3) to prepare a large number of dimeric alkaloid analogs, which will be submitted for testing of biological activity.
