The purpose of this projects is to synthesize and characterize new analogs at the antineoplastic dimeric indole alkaloids of the vincristine- vinblastine type. The synthetic targets are nor and homo analogs in which methylene groups are inserted or deleted at the C-6' and C-17' position of the normal vinblastine structure. These compounds will be synthesized from a small group of iboga alkaloid intermediates prepared by synthetic methods developed in the principal investigator's laboratory. The effect of these structural changes and related substituent effects on the mechanism and efficiency of coupling will be investigated. New conditions for coupling of the iboga structures with the alkaloid vindoline will be explored with particular emphasis being placed on homolytic and electron- transfer- induced fragmentation to produce reactive intermediates for coupling. The steroelectivity of a group of open C-ring structures related to the iboga derivative cleavamine will be examined. Synthetic routes which can be adapted to utilize intermediates with a preference for either alpha or beta approach of nucleophiles will be explored. All products of coupling reactions will be characterized and identified by spectroscopic methods. The compounds will be assessed for ability to act as tubulin assembly inhibitors. Since activity as a tubulin assembly inhibitor is frequently predictive of anti-tumor activity, compounds which show such activity will be submitted to the drug development program of the National Cancer Institute for screening.
