STRATEGIES FOR THE SYNTHESIS OF ANTITUMOR COMPOUNDS

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DESCRIPTION: (Principal Investigator's) This proposal is directed towards the development of new approaches to the construction of naturally occurring substances with important biological activity. One of the major goals of this research program continues to be the development of photochemical methodology in organic synthesis. The vinylogous amide photocycloaddition-retro-Mannich fragmentation-Mannich closure sequence leads to a highly efficient approach to the synthesis of the manzamine alkaloids, which have important antitumor properties. One of the major goals of the proposed renewal period is to complete the synthesis of manzamine using the photochemical methodology developed in our laboratory. The intramolecular dioxenone photocycloaddition reaction provides a unique approach for the assembly of the ingenane diterpenes, with the establishment of the critical "inside-outside" stereochemical relationship that is necessary for biological activity. This methodology has been successfully applied to the synthesis of the first ingenane analogs that are high affinity ligands for protein kinase C, an important cell signalling system. Given the biological responses induced by activators of protein kinase C, the development of inhibitors of this enzyme may lead to therapeutic agents useful in the treatment of chronic inflammatory and proliferative diseases. The total synthesis of ingenol and the synthesis and study of novel analogs is the second major goal for the proposed renewal period.