ADDUCTS OF MITOMYCIN C WITH NUCLEOTIDES

说明：丝裂霉素C是一种天然的抗肿瘤抗生素，用于 临床上的癌症化疗。该计划的广泛和长期目标 本申请是利用最近获得的、详细的 生物还原DNA烷基化的结构基础研究进展 丝裂霉素C的活性用于设计新的丝裂霉素类似物 抗肿瘤特性。这些设计的目的是制造出能够 保留丝裂霉素C的碱性还原双官能团烷基化反应机理 但作为交联剂会更有效率。新的丝裂霉素类似物将 由丝裂霉素A相对简单的化学转化合成 或C。将对它们进行DNA的还原烷基化和交联化测试。 并针对DNA序列的特异性进行修饰。此外， DNA加合物的结构将被研究。新药的细胞毒性 各种肿瘤细胞的毒剂将被确定，其相关性将 寻找它们之间的DNA交联度，用碱性测量 EMT小鼠乳腺肿瘤细胞的洗脱及其细胞毒性。 与设计工作相伴并互动，机械化 丝裂霉素C在DNA烷基化方面的研究将继续进行 在体外，交联物的CpG特异性和 某些丝裂霉素C类似物的“自我还原”活性，可由 硫醇。模型寡核苷酸底物修复的研究 含有丝裂霉素加合物的纯化哺乳动物修复酶将被 已启动。

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.