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

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. Studies in our laboratory focus on the synthesis and investigation of molecules of structural, biological, and medicinal significance. Representative of this program are compounds (Scheme 1) such as taxol (1),1 phorbol esters (2),2 and bryostatin (3).3These fascinating molecules have been the focus of intense research activity over the past several decades and have provided the stimulus for major advances in chemistry, biology, and medicine. Taxol is now used clinically for the treatment of breast and ovarian cancers. Phorbol esters serve as molecular probes for the investigation of how cancer starts and consequently of how it might be prevented. They also serve as leads for the study of cellular signal transduction and for the development of new medicinal agents. Bryostatin is now in several phase II clinical trials as a cancer chemotherapeutic agent. In addition, it has been found to provide protection against normally lethal doses of ionizing radiation and has novel immune stimulation properties, effecting the production of interleukin and interferon. Scheme 1 : Representative Structures of Synthetic, Biological, and Medicinal Interest Taxol (1) Phorbol Esters (2) Bryostatin (3)