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. ? ?
|Bass, Phillip D; Gubler, Daniel A; Judd, Ted C et al. (2013) Mitomycinoid alkaloids: mechanism of action, biosynthesis, total syntheses, and synthetic approaches. Chem Rev 113:6816-63|
|Williams, Robert M (2011) Natural products synthesis: enabling tools to penetrate Nature's secrets of biogenesis and biomechanism. J Org Chem 76:4221-59|
|Williams, Robert M; Stille, J; Echavarren, A et al. (2011) Discussion Addendum for: 4-Methoxy-4'-nitrophenyl. Recent Advances in the Stille Biaryl Coupling Reaction and Applications in Complex Natural Products Synthesis. Organic Synth 88:197-201|
|Subramanian, Vidya; Williams, Robert M; Boger, Dale L et al. (2010) Methods to characterize the effect of DNA-modifying compounds on nucleosomal DNA. Methods Mol Biol 613:173-92|
|Chamberland, Stephen; Grüschow, Sabine; Sherman, David H et al. (2009) Synthesis of potential early-stage intermediates in the biosynthesis of FR900482 and mitomycin C. Org Lett 11:791-4|
|Gubler, Daniel A; Williams, Robert M (2009) Synthetic Studies Towards the Mitomycins: Construction of the Tetracyclic Core via a Reductive Aminocyclization Reaction. Tetrahedron Lett 50:4265-4267|
|Namiki, Hidenori; Chamberland, Stephen; Gubler, Daniel A et al. (2007) Synthetic and biosynthetic studies on FR900482 and mitomycin C: an efficient and stereoselective hydroxymethylation of an advanced benzazocane intermediate. Org Lett 9:5341-4|
|Subramanian, Vidya; Ducept, Pascal; Williams, Robert M et al. (2007) Effects of photochemically activated alkylating agents of the FR900482 family on chromatin. Chem Biol 14:553-63|
|Judd, Ted C; Williams, Robert M (2004) A concise total synthesis of (+)-FR900482 and (+)-FR66979. J Org Chem 69:2825-30|
|Williams, Robert M; Ducept, Pascal (2003) Interstrand cross-linking of DNA by FK317 and its deacetylated metabolites FR70496 and FR157471. Biochemistry 42:14696-701|
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