This proposal describes the continuation of a research program involving the synthesis and mode of action studies of structurally complex natural products that have demonstrated unique antitumor activity. Three major projects are described. The first project involves synthetic and biological studies on apoptolidin a macrolide antitumor agent that induces transformed cells to undergo programmed cell death. We plan to continue development of a concise synthesis of apoptolidin and structural analogs designed to probe the cellular target of apoptolidin, an interaction presumed responsible for the unique onset of cell death. A second project is directed toward the synthesis of the structurally complex natural product hibarimicin B, a specific inhibitor of tyrosine kinase and oncogenic cell transformation. A third project is directed towards the development of a general method for the rapid assembly of 2-deoxy oligosaccharides, a frequent structural feature of natural antitumor antibiotics. Overall, this program is expected to have a significant impact on the areas of chemistry, biology and medicine.
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