Synthesis Strategies for Bioactive Natural Products

生物活性天然产物的合成策略

• 批准号: 6706299
• 负责人: THOMAS R. HOYE
• 金额: $ 24.48万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6706299
• 关键词: analog; antifungal agents; antineoplastics; biological products; biotechnology; calcium flux; chemical kinetics; chemical structure function; chemical synthesis; enzyme inhibitors; molecular dynamics; oxazoles; pharmacology; reagent /indicator; stereoisomer; technology /technique development; thermodynamics

DESCRIPTION (provided by applicant): This is a proposal to develop new strategies, concepts, and methods applicable to the chemical synthesis of biologically active natural products and their structural analogs. These discoveries will be applicable to the synthesis of other pharmaceutically relevant compounds as well. Access to (often simpler) analogs of the natural products themselves will result. These will be evaluated in an attempt to identify the structural elements comprising the minimum pharmacophore. Aim I. Capitalize on our substantial body of "in house" expertise with xestospongin C (XeC, I), a potent, membrane permeable inhibitor of intracellular inositol triphosphate (IP3) induced Ca++ release. Develop variants of XeC (including xestospongin 0) as potentially valuable probes for study of calcium release. Aim II. Study the reactivity and stability of the novel acyclic Beta-acyloxy carbinolamide functionality as well as new methods for macrocyclization (epoxide/acid ring opening and a tandem macrocyclization/ring contraction of acylated oximes) during the synthesis of zampanolide (II). Aim III. Develop the power of our newly discovered relay ring-closing metathesis (RRCM) strategy in its application to a synthesis of oocydin A/haterumalide NA (III), an independently discovered agent isolated from two quite different organisms, which possesses remarkable antifungal and antiproliferative properties. Aim IV. Take advantage of a powerful kinetic lactonization in the desymmetrization of a key intermediate and demonstrate additional features of RRCM in the course of synthesizing the recently isolated, structurally novel macrolide, peloruside A (IV).

描述（由申请人提供）：这是一份开发新产品的提案 适用于化学合成的策略、概念和方法 具有生物活性的天然产物及其结构类似物。这些 发现将适用于其他药物的合成 以及相关化合物。获得（通常更简单）自然的类似物 产品本身就会产生。这些将被评估以试图 确定构成最小药效团的结构元件。 目标 I. 利用我们大量的“内部”专业知识 xestospongin C (XeC, I)，一种有效的膜渗透性抑制剂 细胞内三磷酸肌醇 (IP3) 诱导 Ca++ 释放。发展 XeC 的变体（包括 xestospongin 0）作为潜在有价值的探针 钙释放的研究。 目标二。研究新型无环β-酰氧基的反应活性和稳定性 甲醇酰胺功能以及大环化的新方法 （环氧化物/酸环打开和串联大环化/环收缩 酰化肟）在 Zampanolide (II) 的合成过程中。 目标三。开发我们新发现的继电器闭环的力量 复分解（RRCM）策略在卵胞素合成中的应用 A/haterumalide NA (III)，一种独立发现的药物，从两种药物中分离出来 完全不同的生物体，具有显着的抗真菌和 抗增殖特性。 目标四。利用强大的动力学内酯化作用 关键中间体的去对称化并展示其附加特征 RRCM 正在合成最近分离的、结构新颖的 大环内酯、peloruside A (IV)。