Synthesis and Mechanism of DNA Cross-linking of FR900482

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DESCRIPTION (provided by applicant): The primary objectives of the proposed research are to study the synthesis and mechanism of action of the clinically significant antitumor drugs FR900482, FR66979, FK973, and FK317 (FK973 was the first derivative to go to clinical trials however, the semi-synthetic derivative FK317 is currently in human clinical trials in Japan). These substances are structurally and mechanistically related to the widely used antitumor drug mitomycin C (MMC). Specific Aims for the forthcoming grant period include the following: 1. Completion of the first asymmetric total synthesis of mitomycin C, mitomycin K and mitomycin B. 2. We plan to study the biosynthesis of FR900482 and mitomycin C in collaboration with Prof. David Sherman's laboratory (University of Michigan). In particular, our laboratory will synthesize isotopically labeled putative biosynthetic intermediates on these pathways as a means for identifying the structure and mechanism of several key steps. 3. In collaboration with Prof. Raymond Reeves (Washington State University), we plan to continue our investigation of several aspects of the cell biology of these antitumor drugs on neoplastically transformed human cells. In particular, we propose to address the following questions: A. What are the relative effects of MMC, FR900482 and FK317 on IL-2 expression? B. What oncogenes and other metabolically important genes are up-regulated or down-regulated by these drugs? 4. In collaboration with Prof. Karolin Luger (Colorado State University) we plan to investigate the cross-linking of nucleosomes by FR900482 and congeners. 5. A new class of "latent" triggerable progenitors of mitosenes, pyrrolizidine alkaloids and substances related to the anthramycins will be synthesized and utilized as potential new anti-cancer drugs and probes for the macromolecular cross-links. 6. The synthetic methodology we have developed in the total synthesis endeavors shall be utilized to prepare mitosene progenitors based on the FR900482 and MMC structures that can be triggered by alternative chemical and biochemical means.