RATIONAL BASIS FOR THE DESIGN OF CC-1066 ANALOGS

这项研究项目的长期目标是提供一个合理的 改进化疗的新型CC-1065类似物的设计依据 作为抗肿瘤药物的潜力。开展合作研究 同时在奥斯汀(德克萨斯大学)和卡拉马祖(厄普约翰)提供了结构 关于CC-1065-DNA加合物的信息以及对 CC-1065对DNA损伤的生化反应加在一起 这些结果表明，CC-1065可能通过三种替代方式发挥其作用 作为一种抗肿瘤药物，具有相当大的效力。在下一个项目中 期间，我们建议锁定抗肿瘤的分子基础。 CC-1065的活性。我们的战略将涉及生物相关 (抗肿瘤)和具有结构变化的生化活性 CC-1065-模拟DNA加合物。 CC-1065-DNA加合物的三维结构表征 而模拟化合物将依赖于1H-核磁共振(可能还有X射线) 结晶学分析)已定义的CC-1065-寡脱氧双链的研究 相加。CC-1065-DNA损伤后的生化指标监测 包括DNA序列特异性、远距离稳定效应、DNA修复 CC-1065的后果和可能对基因表达的影响 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估将在 由Upjohn公司资助的单独努力。这样做的结果 调查不仅将为新建筑的设计提供合理的依据 CC-1065类似物具有更好的化疗性能，但将提供 对特定化学物质的作用机制有相当深入的了解 DNA的修饰会影响其结构和功能。

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.