Synthesis and Mechanism of DNA Cross-linking of FR900482

描述(申请人提供)：拟议研究的主要目标是研究具有临床意义的抗肿瘤药物FR900482、FR66979、FK973和FK317的合成和作用机理(FK973是第一个进入临床试验的衍生物，但半合成衍生物FK317目前正在日本进行人体临床试验)。这些物质在结构和机械上与广泛使用的抗肿瘤药物丝裂霉素C(MMC)相关。1.首次完成丝裂霉素C、丝裂霉素K和丝裂霉素B的不对称全合成。2.我们计划与密歇根大学David Sherman教授的实验室合作，研究FR900482和丝裂霉素C的生物合成。特别是，我们的实验室将在这些途径上合成同位素标记的假定生物合成中间体，作为鉴定几个关键步骤的结构和机制的手段。3.与雷蒙德·里维斯教授(华盛顿州立大学)合作，我们计划继续对这些抗肿瘤药物在肿瘤转化的人类细胞上的细胞生物学的几个方面进行研究。特别是，我们建议解决以下问题：A.MMC、FR900482和FK317对IL-2表达的相对影响是什么？B.哪些癌基因和其他代谢上重要的基因被这些药物上调或下调？4.我们计划与科罗拉多州立大学的卡罗琳·卢格教授合作，研究FR900482及其类似物对核小体的交联性。5.合成一类新型的“潜伏”可触发的丝裂原、吡咯里西啶生物碱及其相关物质，作为潜在的新型抗癌药物和大分子交联剂。6.我们在全合成工作中开发的合成方法学将用于制备基于FR900482和MMC结构的丝裂原前体，这些结构可以通过替代的化学和生物化学手段触发。

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.