Synthesis Strategies for Bioactive Natural Products

生物活性天然产物的合成策略

• 批准号: 6868848
• 负责人: THOMAS R. HOYE
• 金额: $ 24.46万
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868848
• 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）：这是开发新的建议 适用于化学合成的策略，概念和方法 生物活性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 相关化合物。访问自然的（通常更简单）类似物 产品本身将产生。这些将进行评估，以尝试 确定包括最小药效团的结构元素。 AIM I.利用我们的大量“内部”专业知识 Xestospongin C（XEC，I），有效的膜可渗透抑制剂 细胞内肌醇三磷酸（IP3）诱导的Ca ++释放。发展 XEC的变体（包括Xestospongin 0）作为潜在的有价值的探针 钙释放的研究。 目标II。研究新型无环β-囊肿的反应性和稳定性 卡比诺酰胺功能以及大环化的新方法 （环氧/酸环开口和串联大环/环收缩 酰化氧）在合成Zampanolide（II）期间。 目标三。发展我们新发现的接力环的力量 在其应用于卵母素的合成中，元理解（RRCM）策略 A/Haterumalide Na（III），一种独立发现的剂 完全不同的生物具有显着的抗真菌和 抗增生性质。 目标IV。利用强大的动力学乳酸化 关键中间体的对称化，并展示 rrcm在合成最近孤立的结构新颖的过程中 大环内酯类，Peloruside A（IV）。