The long-term goal of the proposed research is to determine the mode of action of sarcophytol-A, a very active anti-tumor promoter, and of related cembrane natural products. Compounds with anti-tumor promoting activity are important for understanding the early biochemical steps involved with carcinogenesis. This study requires that substantial quantities of tritiated material be available in order to determine: (a) whether the anti-tumor promoter chemically binds the tumor promoter; (b) whether the anti-tumor promoter can act on organs other than the skin; (c) whether it accumulates in any organs and how it is metabolized; (d) whether binding to specific anti-tumor receptors takes place. The ultimate goal of the proposed research is the isolation of the specific receptor for the cembrane anti-tumor promoters. Since the treatment of human cancers is initiated after the observation of tumors, when the disease is at an advanced stage and is difficult to control, an understanding of the mechanism of action of the anti-tumor promoters may make rational prophylaxis against cancer possible.

The strategy for the chemical synthesis of the tritiated anti- tumor promoter makes use of remote asymmetric induction. Molecular mechanics calculations have been performed to determine the minimum energy structures for the key intermediates. The initially formed stereocenters will be used to influence the stereochemistry of all subsequent steps. An enantioselective synthesis is then possible by controlling the absolute stereochemistry only of the initially formed stereocenters. This results in a shorter and more efficient synthesis.

R01CA045288

1987-07-01

1990-12-31