THE TOTAL SYNTHESIS OF AMBEWELLAMIDE A

安贝酰胺A的全合成

• 批准号: 6633992
• 负责人: STEVEN T DIVER
• 金额: $ 17.63万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633992
• 关键词: alkynes; antineoplastics; chemical synthesis; diene; drug design /synthesis /production; isomer; piperazines; plant extracts; stereochemistry

DESCRIPTION: (Applicant's Description) Chemical synthesis of natural products with promising biological properties is often the first step to understanding what a molecule interacts with in the Cell. Moreover, flexible synthetic plans provide an opportunity for the synthesis of analogs that may not be available in Nature. The proposed total synthesis of ambewelamide A and its congeners (structural analogs) that bear different acyl sidechains is an important step toward understanding the origin of its potent anticancer properties. Ambewelamide contains a unique epidithiadiketopiperazine core structure that presents a challenge for its synthesis. In addition, its epoxide functionality is thought to play a critical role in its anticancer properties. This molecule is available in very limited quantities from Nature. A new chemical method for the synthesis of part of the natural product will be developed and employed in the synthesis of ambewelamide A. Crucial to understanding how the natural product inhibits cancer cell growth, the molecules prepared in the proposed investigation will be evaluated against cancer cell lines. This is a first step to identifying promising chemotherapeutics and developing a more detailed understanding of the interaction of ambewelamide with cellular targets. In this proposal there are four specific aims: (1) To develop a new tandem enyne-ring closing metathesis to synthesize six membered rings from alkynes and 1,5 dienes and to develop the reaction's scope; (2) to employ tandem metathesis to synthesize the natural product ambewelamide A; (3) to test the importance of the epoxide functionality in the natural product through congener synthesis coupled with direct assay of the compounds ability to inhibit cancer cell growth; (4) to develop a new solid phase synthesis approach to making simple epidithiadiketopiperazines in order to evaluate their antitumor/anticancer properties.

描述：（申请人的描述）天然产物的化学合成 具有有前途的生物学特性通常是理解的第一步 分子在细胞中与什么相互作用。此外，灵活的综合计划 为合成可能无法获得的类似物提供机会 在大自然中。 ambewelamide A 及其同系物的全合成方案 具有不同酰基侧链的（结构类似物）是重要的一步 了解其有效抗癌特性的起源。 Ambewelamide 含有独特的epidithiadiketopiperazine 核心结构， 对其合成提出了挑战。此外，其环氧化物官能团 被认为在其抗癌特性中发挥着关键作用。这个分子 自然界中的数量非常有限。一种新的化学方法 部分天然产物的合成将被开发并用于 ambewelamide A 的合成对于理解天然产物的合成至关重要 产品抑制癌细胞生长，建议中制备的分子 调查将针对癌细胞系进行评估。这是第一步 以确定有前途的化疗药物并开发更详细的 了解 ambewelamide 与细胞靶标的相互作用。在这个 提案有四个具体目标：（1）开发新的串联烯炔环 由炔烃和 1,5 二烯进行闭合复分解合成六元环 并发展反应的范围； (2) 采用串联复分解法 合成天然产物ambewelamide A； (3) 检验重要性 通过同系物合成获得天然产物中的环氧化物官能团 结合直接测定化合物抑制癌细胞的能力 生长; (4)开发新的固相合成方法，使制备简单 附硫二酮哌嗪类药物以评估其抗肿瘤/抗癌作用 特性。