Catalytic Multicomponent Approach to Medicinal Aromatics

描述（由申请人提供）：该项目涉及过渡金属催化的多组分偶联反应的开发，用于制备与其他芳环系统稠合的高度取代的苯环，这是小分子化疗中经常遇到的子结构。该方法是环境友好的，并且由于其双组分性质，可以提供多种结构，以支持许多结构-活性关系研究。该关键反应已在一个简单的体系中得到证实。初始活动包括开发最佳条件，探索催化剂和偶联伙伴方面的工艺范围和限制，以及检查与已证明具有药物相关性的特定靶分子相关的变量。该项目的高潮是一个令人难以置信的短的总合成黄皮胺A，一种化合物，抑制肿瘤起始能力的爱泼斯坦巴尔病毒在 纳摩尔浓度。该合成仅涉及6个步骤，从一个容易获得的单取代吲哚前体化合物，并具有巨大的灵活性，最终生产的结构相似的化合物的结构活性关系的调查。由于爱泼斯坦-巴尔病毒在美国常见的几种淋巴癌中起致病作用，并且由于超过90%的美国人口携带爱泼斯坦-巴尔病毒而没有症状，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病率，这些癌症不成比例地影响年轻人。这项研究的成功执行转化为含有稠合芳环系统的化疗药物的多样性池的急剧增加，这些系统因其代谢和环境稳定性而受到重视，并且能够作为专门排列许多取代基的可靠模板。这些结果将扩大容易获得的子结构的数量超出目前采用的那些，这对于许多苯稠合杂环来说限于一些取代的市售模式或衍生自其有限范围的合成操作的化合物。

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.