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THE TOTAL SYNTHESIS OF AMBEWELLAMIDE A

安贝酰胺A的全合成

基本信息

批准号：
6706310
负责人：
STEVEN T DIVER
金额：
$ 17.66万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2006-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6706310
关键词：
alkynes antineoplastics chemical synthesis cycloalkene diene drug design /synthesis /production isomer piperazines plant extracts stereochemistry

项目摘要

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：（申请人描述）天然产物的化学合成通常是理解一个分子在细胞中与什么相互作用。此外，灵活的合成计划为合成可能无法获得的类似物提供了机会 in Nature自然. Ambewelamide A及其同系物的全合成（结构类似物）携带不同的酰基侧链是一个重要的步骤了解其有效抗癌特性的起源。安贝韦胺含有独特的环二硫二酮哌嗪核心结构，对它的合成提出了挑战。此外，其环氧官能团被认为在其抗癌特性中起着关键作用。这种分子在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和应用于安贝酰胺A的合成。对于理解自然界产品抑制癌细胞的生长，在拟议中制备的分子研究将针对癌细胞系进行评价。这是第一步识别有前景的化疗药物，并开发更详细的了解安贝韦胺与细胞靶点的相互作用。在这该方案有四个具体目标：（1）开发一种新的串联烯炔环由炔和1，5-二烯合成六元环的闭合复分解反应并扩大反应的范围;（2）采用串联复分解，天然产物安贝酰胺A的合成;（3）天然产物中的环氧化物官能团通过同类物合成结合直接测定化合物抑制癌细胞的能力，（4）开发一种新的固相合成方法，环二硫二酮哌嗪类化合物，以评价其抗肿瘤/抗癌活性特性.