The chemistry-medicine continuum: Synthetic, computer, spectroscopic and biological studies on new chemotherapeutic leads

Abstract

This lecture provides an overview of investigations directed towards understanding the molecular mechanism of protein kinase C (PKC) activation and function. Central to this effort are studies on the total synthesis of phorbol, the first asymmetric synthesis of phorbol, and the first synthesis of resiniferatoxin, all involving highly effective applications of [5+2] oxidopyrylium-alkene cycloadditions. The synthesis and affinities of the phorbol ester binding domain of PKC are also presented. In addition, a pharmacophore model for agonist binding to PKC is presented in connection with the design of novel PKC activators. Finally, the computer modeling, NMR structure, synthesis, and biological activity of the first fully synthetic bryostatin analogs are described.