RATIONAL BASIS FOR THE DESIGN OF CC-1066 ANALOGS

CC-1066 类似物设计的合理基础

• 批准号: 3169229
• 负责人: LAURENCE H. HURLEY
• 金额: $ 11.75万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-07-01 至 1988-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3169229
• 关键词: Streptomyces; antineoplastic antibiotics; chemical structure function; cyclopropanes; drug design /synthesis /production; drug interactions; drug metabolism; human tissue; nucleic acid sequence; tissue /cell culture; tritium

The long range objective of this research project is to provide a rational basis for the design of new CC-1065 analogs with improved chemotherapeutic potential as antitumor agents. Collaborative studies carried out concurrently at Austin (UT) and Kalamazoo (Upjohn) have provided structural information on the CC-1065-DNA adduct as well as insight into the biochemical response to the DNA damage produced by CC-1065. Taken together these results suggest three alternative ways in which CC-1065 may exert its considerable potency as an antitumor agent. During the next project period, we propose to pin-point the molecular basis for the antitumor activity of CC-1065. Our strategy will involve correlation of biological (antitumor) and biochemical activities with structural alterations in the CC-1065-analog-DNA adducts. The three dimensional structural characterization of the CC-1065-DNA adduct and analog complexes will rely upon 1H-NMR (and possibly X-ray crystallographic analysis) studies on the defined CC-1065-oligodeoxyduplex adduct. Biochemical parameters monitored in response to CC-1065-DNA damage include DNA sequence specificity, tele-stability effects, DNA repair consequences and possibly the effects of CC-1065 on gene expression using SV40 DNA. The synthesis of CC-1065 analogs, and their biological evaluation for antitumor activity and toxicity will be conducted in a separate effort funded by The Upjohn Company. The results of this investigation will not only provide a rational basis for the design of new CC-1065 analogs with improved chemotherapeutic properties, but will provide considerable insight into the mechanisms whereby specific chemical modifications of DNA effect its structure and function.

本研究项目的长期目标是提供一个合理的 设计具有改善的化疗效果的新CC-1065类似物的基础 作为抗肿瘤剂的潜力。 开展的合作研究 同时在奥斯汀（UT）和卡拉马祖（Upjohn）提供了结构 关于CC-1065-DNA加合物的信息以及对 这是对CC-1065产生的DNA损伤的生化反应。 两者合计 这些结果表明CC-1065可以通过三种替代方式发挥其作用， 作为抗肿瘤剂的相当大的效力。 在下一个项目中 在此期间，我们建议确定抗肿瘤的分子基础， CC-1065的活性。 我们的策略将涉及生物学的相关性， （抗肿瘤）和生物化学活性， CC-1065-类似物-DNA加合物。 CC-1065-DNA加合物的三维结构表征 和类似物复合物将依赖于1H-NMR（和可能的X射线 晶体学分析）研究确定的CC-1065-寡脱氧双链体 加合物 响应CC-1065-DNA损伤监测的生化参数 包括DNA序列特异性、遥稳定性效应、DNA修复 结果和CC-1065对基因表达的可能影响， SV40 DNA CC-1065类似物的合成及其生物活性 抗肿瘤活性和毒性的评价将在 由Upjohn公司资助的独立项目。 的结果 调查不仅将为新的设计提供合理的依据， CC-1065类似物具有改善的化疗性质，但将提供 对特定化学物质 DNA的修饰影响其结构和功能。