The first goal of this proposal is the design and synthesis of novel antimalarial drugs. It has recently been reported that manzamine A is a highly potent antimalarial agent, making the synthesis and biological evaluation of manzamine-related structures an important goal in medicine. The synthesis of simple manzamine analogs and the biological evaluation of these structures in collaboration with Dr. David Skanchey at the Walter Reed Army Institute of Research (WRAIR) is described. The methodology that was developed in the Winkler laboratory for the first total synthesis of manzamine A will be used in the construction of these novel antimalarial drug candidates. The second goal of this proposal is the completion of the first total synthesis of ingenol, a naturally occurring diterpene that is a potent activator of the ubiquitous cell signaling system protein kinase C (PKC). Given the biological responses induced by activators of PKC, the development of inhibitors of this enzyme may lead to therapeutic agents useful in the treatment of chronic inflammatory and proliferative diseases. To date, ingenol has not yet yielded to total synthesis, despite the efforts of laboratories around the world. The intramolecular dioxenone reaction developed in the Winkler laboratory provides a unique approach to the control of the critical inside-outside stereochemical relationship in the construction of ingenol. The combination of literature precedent from the Winkler laboratory with the unpublished results described in the Progress Report should lead to the completion of the first total synthesis of ingenol during the proposed project period.
