Conformation-Activity Relationships

我们的总体计划对有关天然聚酮类化合物进化的基本问题感兴趣。 产品。这些研究的重点是从两个互补的角度。第一个涉及具体的 聚酮类化合物的结构特征，它们对构象的影响，以及构象的重要性 生物活性。第二种观点集中在结构上相关的多酮类化合物和分子的共同进化。 他们的蛋白质靶标。由于聚酮类天然产物的复杂性，它们是这些研究的理想对象。 结构和多种生物活性已显示出对研究和治疗一种 治疗区域的数量。在之前的研究中，我们已经证明构象是一种 是对经典结构-活性关系的重要补充，并为 未来化疗药物的发展。作为原则的证明，构象-活性关系 对稳定微管的天然产物--埃博西酮的研究为 关于药效团以及进一步发展的新线索。在下一个授权期内， 我们的研究将调查三个基本独特的项目，1.构象-活性关系 Peloruside A，2.凋亡素与结构相关的进化关系的研究 大环内酯类、巴非霉素和康那霉素；3.前体导向生物合成的进展 复杂聚酮类似物的制备技术。针对目标的复杂天然产品 这一应用程序将通过独特而实用的合成策略进行准备。此外，在适当的情况下， 我们已经整合了许多新的合成方法的开发，以制备络合物 聚酮类天然产物共有的结构单元。

Our overall program is interested in the fundamental issues regarding the evolution of polyketide natural products. The focus of these studies are from two complementary perspectives. The first deals with specific structural features found in polyketides, their effect on conformation, and the importance of conformation on biological activity. The second perspective focuses on structurally related polyketides and the co-evolution of their protein targets. Polyketide natural products are ideal subjects for these studies due to their complex structure and diverse biological activities which have shown utility towards the study and treatment of a number of therapeutic areas. During the previous research period we have shown that conformation is an important complement to classic structure-activity relationships and provides useful information for the development of future chemotherapeutic agents. As a proof of principle, a conformation-activity relationship study of the microtubule-stabilizing natural products, the epothilones, provided important information with regards to the pharmacophore as well as new leads for further development. During the next grant period, our studies will investigate three fundamentally unique projects, 1. conformation-activity relationships of peloruside A, 2. a study of the evolutionary relationship between apoptolidin and structurally related plecomacrolides, bafilomycin and concanamycin, and 3. the development of precursor-directed biosynthetic techniques for the preparation of complex polyketide analogues. The complex natural products targeted in this application will be prepared via unique but practical synthetic strategies. Moreover, where appropriate, we have incorporated the development of a number of new synthetic methods for the preparation of complex structural units common to polyketide natural products.