CONFORMATION ACTIVITY RELATIONSHIPS

构象活动关系

• 批准号: 6362748
• 负责人: Richard E. Taylor
• 金额: $ 16.76万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362748
• 关键词: antineoplastics; chemical structure function; chemical synthesis; conformation; cytotoxicity; drug design /synthesis /production; microtubules; nuclear magnetic resonance spectroscopy; receptor; solutions

Small molecule natural products represent a valuable collection of ligands for use in the study of protein and cellular function. A detailed understanding of receptor-ligand interactions at the molecular level will allow for the design and preparation of new chemotherapeutic agents. Specifically, the relationship between conformation and biological activity of a number of complex natural products is being investigated. The power of synthesis in combination with high field nuclear magnetic resonance (NMR) and computer-based molecular modeling analysis will provide a detailed understanding of the solution conformational properties of these important compounds. In addition, NMR, molecular modeling, and biological activity data of conformationally-altered analogues will provide important information about the conformation of these ligands while bound to their respective biological receptor. Two important criteria must be met for success with this approach; 1) targets must be selected which contain regions where structural modifications can be made without significant loss of binding affinity and 2) the structural units used to control conformation must minimally alter the sterics and electronics of the molecule. Epothilone A and B represent an important new lead in the search for improved chemotherapeutic agents. Synthetic, biological, and analytic techniques are being used to explore the conformation of the epothilone class and its relationship to their interesting biological activity. A practical synthetic route to epothilone A has already been developed. A novel route to epothilone B is proposed. Analogues of both parent compounds are being prepared which contain strategically placed conformational control elements. Biological activity studies as well as conformational analysis should provide the conformation of epothilone while bound to microtubules. This increased understanding of epothilone's mode of action at the molecular level will allow for the preparation of the next generation of microtubule-stabilizing anti-mitotic agents.

小分子天然产物代表了用于蛋白质和细胞功能研究的有价值的配体集合。在分子水平上对受体-配体相互作用的详细理解将允许设计和制备新的化疗药物。 具体而言，一些复杂的天然产物的构象和生物活性之间的关系正在调查。 高场核磁共振（NMR）和基于计算机的分子建模分析相结合的合成能力将提供这些重要化合物的溶液构象特性的详细了解。 此外，构象改变的类似物的NMR、分子建模和生物活性数据将提供关于这些配体在与其各自的生物受体结合时的构象的重要信息。 这种方法的成功必须满足两个重要标准; 1）必须选择含有可以进行结构修饰而不显著损失结合亲和力的区域的靶标，以及2）用于控制构象的结构单元必须最小限度地改变分子的空间和电子学。 埃坡霉素A和B代表了一个重要的新的领导在寻找改进的化疗药物。 合成，生物和分析技术正在被用来探索埃坡霉素类的构象及其与其有趣的生物活性的关系。 埃坡霉素A的一条实用的合成路线已经被开发出来。 提出了一条合成埃坡霉素B的新路线。 正在制备两种母体化合物的类似物，其含有策略性放置的构象控制元件。 生物活性研究以及构象分析应提供埃坡霉素的构象，而结合到微管。 在分子水平上对埃坡霉素作用模式的理解的增加将允许制备下一代微管稳定抗有丝分裂剂。