STRUCTURE OF ANTICANCER AGENTS BY X-RAY DIFFRACTION

X 射线衍射分析抗癌剂的结构

• 批准号: 3164731
• 负责人: DICK VAN DER HELM
• 金额: $ 14.28万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-09-01 至 1993-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3164731
• 关键词: X ray crystallography; antineoplastics; chemical structure; chemical structure function; chemical synthesis; crystallization; enzyme inhibitors; estrogen analog; heterocyclic compounds; nuclear magnetic resonance spectroscopy; protein kinase C; saltwater environment; terpenes

The project involves the structure determination by single crystal X-ray diffraction of both natural and synthetic anticancer agents. In each group of compounds specific plans are described for the interpretation of the results and for the correlation of the observations with the activity of the compounds. In a continuing project the structures of new natural products isolated from marine organisms will be determined. This will involve all pure compounds with very high activity (O.O1 mug/ml) as well as those new compounds which are based on a novel chemical skeleton. In general also the absolute configuration of the compounds will be determined. The most active compounds have M.W. above 1000 and can be peptides, alkaloids, macrolides or polyethers and sometimes have a combination of these characteristics. Additionally a special effort will be made to understand all conformational characteristics of didemnin for which we recently determined the structure. This will be done by structure determination of others in the same family, various crystal forms and by molecular dynamics simulations. The structures of a series of heteroarotinoids will be determined. These synthetic analogs will explore different chemical features of the compounds. The selection will be made on the basis of their activity with respect to the inhibition of ODC production. It is hypothesized that the compounds are inhibitors for protein kinase C. The crystal structures of all compounds more active than retinoic acid and structurally related less active compounds will be determined. The conformations of the compounds will be explored with molecular mechanics. The structures of a set of compounds with pure antiestrogenic activity will be determined. These compounds are cyclopropyl analogs of diphenyl and triphenyl ethylene derivatives and based on the newly synthesized diphenyl gen dichloro cyclopropane (Analog II) which has been shown to have only antiestrogenic activity. The structures present in the literature and our own results will be used to understand their molecular function in binding the estrogen receptor or more generally those structural features of the molecules which result in pure antagonist action.

该项目涉及单晶的结构测定 天然和合成抗癌药的X射线衍射。 在每组化合物中，描述了特定计划 结果的解释和有关 与化合物活性的观测。 在一个持续的项目中，新天然产品的结构 将从海洋生物中分离出来。 这会 涉及所有具有很高活性的纯化合物（O.O1杯/mL） 以及基于新颖化学物质的新化合物 骨骼。 通常，也绝对的配置 将确定化合物。 最活跃的化合物具有M.W. 超过1000，可以是肽，生物碱，大环内酯类或聚乙烯 有时有这些特征的组合。 此外，将要做出特别的努力来了解所有人 我们最近为dodemnin的构象特征 确定结构。 这将通过结构完成 在同一家庭中确定他人，各种晶体形式 并通过分子动力学模拟。 将确定一系列异质素的结构。 这些合成类似物将探索不同的化学特征 化合物。 选择将根据他们的 关于抑制ODC产生的活性。 这是 假设这些化合物是蛋白激酶的抑制剂 C.所有化合物的晶体结构比 视黄酸和结构相关的较低活性化合物将 可以确定。 将探索化合物的构象 与分子力学。 一组具有纯抗雌激素的化合物的结构 将确定活动。 这些化合物是环丙基 二苯基和三苯基乙烯衍生物的类似物和基于基于的类似物 在新合成的二苯基二氯丙烷（类似物）上 ii）已显示仅具有抗雌激素活性。 这 文献中存在的结构，我们自己的结果将是 用于理解其结合雌激素时的分子功能 受体或更一般的结构特征 产生纯拮抗作用的分子。