Catalytic Multicomponent Approach to Medicinal Aromatics

药用芳香剂的催化多组分方法

• 批准号: 8891464
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891464
• 关键词: Affect; Alkynes; Benzaldehyde; Benzene; Carbon; Couples; Coupling; Development; Diels Alder reaction; Electrons; Excision; Exhibits; Future; Health; Human Herpesvirus 4; Hydrazones; Incidence; Indoles; Investigation; Lead; Malignant Neoplasms; Metabolic; Methods; Naphthalene; Nature; Oxygen; Pathway interactions; Pattern; Pharmacologic Substance; Play; Population; Preparation; Prize; Process; Production; Property; Reaction; Reporting; Research; Role; Structure; Structure-Activity Relationship; Symptoms; System; Therapeutic; Transition Elements; Translating; analog; catalyst; design; flexibility; indole-2-carboxylic acid; lymphatic cancer; nitrene; novel; pharmacophore; process optimization; small molecule; tumor; tumor initiation

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(申请人提供)：该项目包括开发一种过渡金属催化的多组分偶联反应，用于制备与其他芳香环系统融合的高取代苯环，这是小分子化疗药物中经常遇到的一种亚结构。该方法对环境友好，由于它的双组分性质，可以提供不同的结构阵列来支持许多结构-活性关系研究。关键反应已经在一个简单的系统中得到了演示。最初的活动包括开发最佳条件，探索与催化剂和偶联伙伴有关的过程的范围和限度，以及检查与特定目标分子有关的变量，这些变量已证明与药物相关。该项目最终完成了令人难以置信的短时间全合成黄皮胺A，这是一种抑制爱泼斯坦-巴尔病毒启动肿瘤能力的化合物 纳摩尔浓度。该合成方法仅需6步反应即可得到单取代吲哚前体化合物，并具有极大的灵活性，可用于结构活性关系研究的结构相似化合物的最终生产。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，而且超过90%的美国人携带爱泼斯坦-巴尔病毒而没有症状，因此发现能够抑制肿瘤形成途径的化合物可以降低这些癌症的发病率，这些癌症对年轻人的影响不成比例。这项研究的成功意味着含有稠合芳环系统的化疗药物多样性池的显著增加，稠环系统因其代谢和环境稳定性而备受珍视，并能够作为可靠的模板融合来具体安排大量取代基团。这些结果将扩大那些容易获得的亚结构的数量，而不是目前使用的那些，对于许多苯稠合杂环来说，这些亚结构仅限于少数几个商业上可用的取代模式或来自有限范围的合成操作的化合物。