A Synthetic Approach to Calyxins and Epicalyxins I and J

萼蛋白和表萼蛋白 I 和 J 的合成方法

基本信息

批准号：
7126978
负责人：
KEITH Thomas MEAD
金额：
$ 20.93万
依托单位：
MISSISSIPPI STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7126978
关键词：
Diels Alder reaction amides analog chemical addition human imines ions lead neoplasm /cancer sectioning

项目摘要

DESCRIPTION (provided by applicant): Three constituents of Alpinia blepharocalyx, namely calyxin I, calyxin J and epicalyxin J, are the subject of this proposal owing to their in vitro activity against human fibrosarcoma HT-1080 and murine colon 26-L5 carcinoma cells. The long-term objective of this research is to verify the absolute structures of these compounds by independent synthesis. Specifically this proposal will focus on one part of the puzzle, that being to develop a stereocontrolled approach to the fused ring system common to each compound. The research design is divided into three major sections. In section one, hetero Diels-Alder reactions between substituted dihydropyrans and N-acyl imines, leading to fused ring bicyclic acetals, will be studied. Section two focuses on Lewis acid ring cleavage reactions of these [4 + 2] cycloadducts with a variety of nucleophiles. The intended C-aryl pyranoside products will arise from nucleophilic addition of electron rich aromatic rings to oxocarbenium ions generated from these bicyclic acetals. The third section will concentrate on the application of this methodology to synthesis. Each product of ring cleavage should contain a side chain on C-2 of the tetrahydropyran ring which bears an amide moiety. A set of experiments will be designed to gradually increase the electron deficiency of this amide moiety by adding groups with increasing electron withdrawing capabilities. We hypothesize that in a Lewis acid environment, and with sufficient stabilization from neighboring groups, unimolecular dissociation of the amide functionality will lead to carbocation formation, allowing intramolecular substitution from a near-by nucleophilic center. This step is designed to provide the aforementioned three-membered fused ring system. The in vitro anti-cancer activity of these constituents makes them potential drug candidates for the treatment of human tumors. In collaboration with biologists on campus, their laboratory synthesis would eventually lead to the determination of how they kill cancer cells. Using this information, the design of analogues with superior and more selective cancer fighting properties should be possible.

描述（由申请人提供）：由于对人体纤维肉瘤HT-1080的体外活性和Murine Colon Colon 26-L5癌细胞的体外活性，因此该提案的主题是该提案的三个组成，即钙蛋白I，钙蛋白I，钙蛋白I，钙蛋白酶I，钙蛋白J和epepicalyxin J。这项研究的长期目标是通过独立合成来验证这些化合物的绝对结构。具体而言，该提案将集中在难题的一个部分上，即开发一种立体控制方法，以针对每种化合物共有的融合环系统。研究设计分为三个主要部分。在第一部分中，将研究取代的二氢吡喃和N-酰胺胺之间的杂迪尔 - alder反应，从而导致融合的环双环乙烯。第二部分侧重于这些[4 + 2]环载体与各种亲核试剂的刘易斯酸环裂解反应。预期的c-芳基丙烷剂产物将来自亲核富含电子环向这些双环乙烯产生的氧气离子的添加。第三部分将集中于将该方法的应用用于合成。环裂解的每种产物应包含具有酰胺部分的四氢吡喃环的C-2上的侧链。一组实验将设计为逐渐增加该酰胺部分的电子缺乏，并增加具有增加电子撤回功能的组。我们假设在刘易斯酸环境中，并且在相邻群体的足够稳定下，酰胺功能的单分子解离将导致碳固定形成，从而使分子内取代近乎亲核中心。此步骤旨在提供上述三元的融合环系统。这些成分的体外抗癌活性使它们成为治疗人类肿瘤的潜在候选药物。与校园的生物学家合作，其实验室合成最终将导致确定它们如何杀死癌细胞。使用这些信息，应该可以使用具有优质和更具选择性癌症特性的类似物的设计。