Conformation-Activity Relationships

构象-活性关系

• 批准号: 7091812
• 负责人: Richard E. Taylor
• 金额: $ 28.8万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091812
• 关键词: analog; chemical structure; chemical substitution; chemical synthesis; combinatorial chemistry; computational biology; conformation; epothilon; esterification; heterocyclic polycyclic compound; lactones; macrolide antibiotics; method development; microtubules; nuclear magnetic resonance spectroscopy; polyketide synthase; polymerization; stereochemistry

DESCRIPTION (provided by applicant): Our overall program is interested in the fundamental issues regarding the evolution of polyketide natural products. The focus of these studies is 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.

描述（由申请人提供）：我们的整体计划是关于聚酮化合物天然产物的演变的基本问题感兴趣。这些研究的重点是从两个互补的角度。第一个涉及到聚酮化合物中发现的特定结构特征，它们对构象的影响，以及构象对生物活性的重要性。第二个视角关注结构相关的聚酮化合物及其蛋白质靶点的共同进化。聚酮化合物天然产物由于其复杂的结构和多样的生物活性而成为这些研究的理想对象，这些生物活性已显示出对许多治疗领域的研究和治疗的效用。在之前的研究期间，我们已经表明构象是经典结构-活性关系的重要补充，并为未来化疗药物的开发提供了有用的信息。作为原理的证明，微管稳定天然产物埃坡霉素的构象-活性关系研究提供了关于药效团的重要信息以及进一步开发的新线索。在下一个赠款期间，我们的研究将调查三个基本独特的项目，1。peloruside A的构象-活性关系，2.一项研究的进化关系之间的martolidin和结构相关的plecomacrolides，巴弗洛霉素和concanamycin，和3。以生物合成技术为导向之合成复杂聚酮化合物。本申请中针对的复杂天然产物将通过独特但实用的合成策略制备。此外，在适当的情况下，我们已经纳入了一些新的合成方法的开发，用于制备聚酮化合物天然产物常见的复杂结构单元。