ADDUCTS OF MITOMYCIN C WITH NUCLEOTIDES

丝裂霉素 C 与核苷酸的加合物

• 批准号: 2700339
• 负责人: MARIA TOMASZ
• 金额: $ 21.67万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-07-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2700339
• 关键词: DNA repair; adduct; alkylation; analog; antineoplastic antibiotics; cell line; chemical structure; crosslink; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; mitomycin C; neoplasm /cancer pharmacology; nucleic acid sequence; nucleotides; synthetic nucleotide

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.

描述：丝裂霉素C是一种天然的抗肿瘤抗生素 临床上癌症化疗。 广泛的长期目标 目前的应用是利用最近获得的详细信息 基于生物学DNA-烷基的结构基础的信息 丝裂霉素C的活性，用于设计新的丝裂霉素类似物的改进 抗肿瘤特性。 设计旨在建造将 保留丝裂霉素C的基本还原性双功能烷基化机制 但是作为交联的效率将更加有效。 新的丝裂霉素类似物将 通过相对简单的丝裂霉素A的化学转化合成 或C.它们将进行测试以进行还原性烷基化和DNA的交联 以及用于修饰的DNA序列特异性。 另外， 将研究DNA加合物的结构。 新的细胞毒性 将确定各种肿瘤细胞的药物，并将 通过碱性测量的DNA交联活性之间寻求 EMT小鼠乳腺肿瘤细胞的洗脱及其细胞毒性。 与设计工作，机械性的伴随和互动 丝裂霉素C的研究将在DNA烷基化方面继续 在体外，交联的CpG特异性基础和 某些丝裂霉素C类似物的“自我还原”活性，可诱导 硫醇。 模型寡核苷酸底物修复的研究 通过纯化的哺乳动物修复酶含有丝裂霉素加合物将是 发起。