ADDUCTS OF MITOMYCIN C WITH NUCLEOTIDES

描述：丝裂霉素C是一种天然的抗肿瘤抗生素，用于 临床癌症化疗。 《行动纲领》的广泛和长期目标 本申请将利用最近获得的、详细的 关于生物还原性DNA烷基化的结构基础的信息 丝裂霉素C的活性，用于设计具有改进的 抗肿瘤特性。 这些设计旨在制造药物， 保留丝裂霉素C的基本还原性双官能烷基化机理 但作为交联剂将更有效。 新的丝裂霉素类似物将 通过丝裂霉素A的相对简单的化学转化来合成 或C.他们将被测试的还原烷基化和交联的DNA 以及修饰的DNA序列特异性。 此外该 将研究DNA加合物的结构。 新的细胞毒性 将确定药物对多种肿瘤细胞的作用， 通过碱性磷酸酶测定， EMT小鼠乳腺肿瘤细胞中的洗脱及其细胞毒性。 与设计工作同时进行并相互作用的，机械的 丝裂霉素C在DNA烷基化方面的研究将继续进行 在体外，基于交联的CpG特异性和 某些丝裂霉素C类似物的“自还原”活性，可由 硫醇 模型寡核苷酸底物的修复研究 含有丝裂霉素加合物的纯化的哺乳动物修复酶， 启动。

DESCRIPTION: Mitomycin C is a natural antitumor antibiotic used in clinically 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 cytotoxicity. 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.