Catalytic Multicomponent Approach to Medicinal Aromatics

药用芳香剂的催化多组分方法

基本信息

批准号：
9265873
负责人：
JAMES W HERNDON
金额：
$ 10.95万
依托单位：
NEW MEXICO STATE UNIVERSITY LAS CRUCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2019-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The project involves the development of a transition metal catalyzed multicomponent coupling reaction for the preparation of highly substituted benzene rings fused to other aromatic ring systems, which is a substructure frequently encountered in small molecule chemotherapeutics. The method is environmentally friendly and due to its two-component nature can provide a diverse array of structures to support many structure-activity relationship studies. The key reaction has been demonstrated in a simple system. Initial activities involve the development of the optimal conditions and exploring the scope and limit of the process with respect to catalyst and coupling partners, and the examination of variables related to specific target molecules that have demonstrated pharmaceutical relevance. The project culminates with an incredible short total synthesis of clausamine A, a compound that inhibits the tumor initiation capability of the Epstein Barr virus at nanomolar concentrations. The synthesis involves only 6 steps from a readily available monosubstituted indole precursor compound and has tremendous flexibility for the eventual production of structurally similar compounds for the investigation of structure activity relationships. Since the Epstein-Barr virus is a plays a causative role in several lymphatic cancers common in the USA, and since greater than 90% of the USA population carries the Epstein Barr virus without symptoms, discovery of compounds that can inhibit the tumor formation pathway can reduce the incidence of these cancers which disproportionately affect younger people. Successful execution of this research translates to a dramatic increase in the diversity pool for chemotherapeutics that contain fused aromatic ring systems, which are prized for their metabolic and environmental stability, and the ability to serve as a reliable template fo specifically arranging numerous substituent groups. These results will expand the number of readily-available substructures beyond those currently employed, which for many benzene-fused heterocycles is limited to a few substitution commercially available patterns or compounds derived from their limited range of synthetic manipulations.

描述（由申请人提供）：该项目涉及开发过渡金属催化的多组分耦合反应，以制备融合到其他芳族环系统的高度取代的苯环，这是在小分子化学治疗中经常遇到的子结构。该方法是环保的，由于其两个组成的性质可以提供各种结构，以支持许多结构活性关系研究。在一个简单的系统中已证明了关键反应。最初的活动涉及最佳条件的发展，并探索相对于催化剂和耦合伙伴的过程范围和限制，以及检查与特定靶标分子相关的变量，这些变量证明了药物相关性。该项目最终以令人难以置信的简短总合成锁骨A（一种抑制爱泼斯坦Barr病毒的肿瘤起始能力）的化合物纳摩尔浓度。该合成仅涉及从易于获得的单叠生成的吲哚前体化合物的6个步骤，并且对于最终生产结构相似的化合物，用于研究结构活动关系，具有极大的灵活性。由于爱泼斯坦 - 巴尔病毒在美国常见的几种淋巴癌中起着致命作用，而且由于超过90％的美国人群带有没有症状的爱泼斯坦Barr病毒，因此发现可以抑制肿瘤形成途径的化合物可以降低这些癌症的发生率，从而减少这些癌症的发生率，从而影响年轻的年轻人。这项研究的成功执行表明，包含融合的芳环系统的化学治疗库的多样性库急剧增加，这些芳族环系统因其代谢和环境稳定性而备受赞誉，并且具有作为可靠的模板fo专门布置的众多定产组的能力。这些结果将扩大易于使用的子结构的数量，而不是当前使用的子结构，对于许多苯融合的杂环而言，这些子结构仅限于少数替代的市售模式或从其有限的合成操作范围而得出的化合物。