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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）：良姜眼睑萼的三种成分，即花萼蛋白 I、花萼蛋白 J 和外萼蛋白 J，由于其对人纤维肉瘤 HT-1080 和鼠结肠 26-L5 癌细胞的体外活性，因此成为本提案的主题。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。具体来说，该提案将重点关注难题的一部分，即开发一种立体控制方法来研究每种化合物共有的稠合环系统。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-酰基亚胺之间产生稠环双环缩醛的杂狄尔斯-阿尔德反应。第二节重点介绍这些[4 + 2]环加合物与各种亲核试剂的路易斯酸环裂解反应。预期的C-芳基吡喃糖苷产物将通过富电子芳环与由这些双环缩醛产生的氧碳鎓离子的亲核加成产生。第三部分将集中讨论该方法在合成中的应用。每个环裂解产物应在四氢吡喃环的C-2上含有带有酰胺部分的侧链。将设计一组实验，通过添加具有增加吸电子能力的基团来逐渐增加该酰胺部分的电子缺陷。我们假设在路易斯酸环境中，并且在邻近基团足够稳定的情况下，酰胺官能团的单分子解离将导致碳正离子形成，从而允许从附近的亲核中心进行分子内取代。该步骤旨在提供前述三元稠合环体系。这些成分的体外抗癌活性使其成为治疗人类肿瘤的潜在候选药物。通过与校园生物学家的合作，他们的实验室合成最终将确定它们如何杀死癌细胞。利用这些信息，应该可以设计出具有优越且更具选择性的抗癌特性的类似物。