The goal of this proposal is to rationally design novel cancer chemotherapeutic agents based on the pharmacophore of bryostatin 1. This will be accomplished using a three part system of molecular modeling, chemical synthesis, and biological assays. Programming the pharmacophore of bryostatin 1 into a modeling program will allow use of that program to find a best fit between the pharmacophore model and the proposed drug candidates. Simplified analogues or novel structures that keep the key functionally of the actual drugs intact will be designed and chemically synthesized. Upon synthesis of these compounds, the biological assays that have been used previously for the bryostatins will be used to test the effectiveness of the new drugs. The system can be fine tuned because the synthetic route is simple and flexible, allowing for small conformational changes in the pharmacophore. Those compounds that are efficiently synthesized and contain biological activity equivalent to or greater than bryostatin 1 will be excellent candidates to be tested for cancer therapy.
