CONFORMATION ACTIVITY RELATIONSHIPS

小分子天然产物是用于研究蛋白质和细胞功能的一系列有价值的配体。在分子水平上对受体-配体相互作用的详细了解将有助于设计和制备新的化疗药物。具体地说，正在研究一些复杂的天然产物的构象和生物活性之间的关系。合成能力与高场核磁共振(NMR)和基于计算机的分子模拟分析相结合，将提供对这些重要化合物的溶液构象性质的详细了解。此外，核磁共振、分子模拟和构象改变类似物的生物活性数据将提供有关这些配体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的标准：1)必须选择包含可以进行结构修饰而不会显著丧失结合亲和力的区域的靶；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结构。Epothilone A和B在寻找改进的化疗药物方面是一个重要的新线索。合成、生物和分析技术正被用来探索埃博西酮类化合物的构象及其与其有趣的生物活性的关系。已开发出一条合成环氧乙烷酮A的实用路线。提出了一条合成环氧乙硫酮B的新路线。这两种母体化合物的类似物正在制备中，其中包含具有战略意义的构象控制元件。生物活性研究和构象分析应提供结合在微管上的埃维酮的构象。这种在分子水平上对埃博西隆作用模式的进一步了解将使下一代稳定微管的抗有丝分裂药物的制备成为可能。

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.