Mitomycin C is a natural antitumor antibiotic used in clinical cancer chemotherapy. The broad, long-term objective of the present application is to utilize the recently obtained, detailed information on the structural basis of the bioreductive DNA-alkylating activity of mitomycin C for designing new mitomycin analogs with improved antitumor properties. The designs aim at constructing drugs which will retain the basic reductive bifunctional alkylation mechanism of mitomycin C but will be more efficient as cross-linkers. The new mitomycin analogs will be synthesized by relatively simple chemical transformations of mitomycins A or C. They will be tested for reductive alkylation and cross-linking of DNA and for DNA sequence specificity of the modifications. In addition, the structures of the DNA adducts will be investigated. Cytotoxicity of the new agents to a variety of tumor cells will be determined and a correlation will be sought between their DNA cross-linking activity, measured by alkaline elution in EMT mouse mammary tumor cells, and their cytoxicity. Concomitant and interactive with the design efforts, mechanistic investigations of mitomycin C will continue with respect to DNA alkylation in vitro, basis of the CpG specificity of the cross-link and the """"""""self-reducing"""""""" activity of certain mitomycin C analogs, inducible by thiols. An investigation of repair of model oligonucleotide substrates containing mitomycin adducts by a purified mammalian repair enzyme will be initiated.
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