THE TOTAL SYNTHESIS OF AMBEWELLAMIDE A

描述：(申请人描述)天然产物的化学合成 具有良好的生物学特性通常是了解 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 在自然界。安培威胺A及其同系物的全合成建议 (结构类似物)带有不同的酰基侧链是重要的一步 有助于了解其强大的抗癌特性的来源。 安贝韦胺含有独特的己二硫酮哌嗪核心结构， 对其合成提出了挑战。此外，它的环氧化物功能 被认为在其抗癌特性中起着关键作用。这种分子 可从大自然获得的数量非常有限。一种新的化学方法 部分天然产物的合成将被开发并用于 安培韦胺的合成A.对于理解天然的 产品抑制癌细胞生长，该分子在建议中制备 研究将针对癌细胞株进行评估。这是第一步 到确定有前景的化疗药物并开发更详细的 了解安培韦胺与细胞靶标的相互作用。在这 建议有四个具体目标：(1)开发一种新的串列烯炔环 以炔烃和1，5-二烯为原料闭合复分解合成六元环 和扩大反应的范围；(2)采用串联复分解来 合成天然产物安培韦拉明A；(3)测试 同系物合成天然产物中的环氧官能团 结合直接测定化合物抑制癌细胞的能力 生长；(4)开发一种新的固相合成方法，使简单 表二硫代二酮基哌嗪类化合物的抗肿瘤/抗癌研究 属性。

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.