CONFORMATION ACTIVITY RELATIONSHIPS

小分子天然产物是蛋白质和细胞功能研究中有价值的配体集合。在分子水平上对受体-配体相互作用的详细了解将有助于设计和制备新的化疗药物。具体来说，一些复杂的天然产物的构象和生物活性之间的关系正在被研究。结合高场核磁共振（NMR）和基于计算机的分子建模分析的合成能力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、分子模型和构象改变类似物的生物活性数据将为这些配体与各自的生物受体结合时的构象提供重要信息。这一方法要取得成功，必须满足两个重要标准；1)选择的靶标必须包含可以在不显著损失结合亲和力的情况下进行结构修饰的区域；2)用于控制构象的结构单元必须最小限度地改变分子的立体结构和电子结构。艾替隆A和B代表了寻找改良化疗药物的重要新线索。合成、生物和分析技术正被用于探索埃泊霉素类的构象及其与它们有趣的生物活性的关系。已经开发出一条实用的合成埃泊霉素A的路线。提出了一种新的合成埃泊霉素B的途径。正在制备两种母体化合物的类似物，其中包含策略性放置的构象控制元件。生物活性研究和构象分析应提供与微管结合时的构象。在分子水平上对埃波霉素作用方式的进一步了解将有助于制备下一代微管稳定抗有丝分裂药物。

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.