Catalytic Multicomponent Approach to Medicinal Aromatics

药用芳香剂的催化多组分方法

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9265873
• 关键词: Affect; Alkynes; Benzaldehyde; Benzene; Carbon; Couples; Coupling; Development; Diels Alder reaction; Electrons; Excision; Exhibits; Future; 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; Transition Elements; Translating; analog; catalyst; design; flexibility; indole-2-carboxylic acid; lymphatic cancer; nanomolar; nitrene; novel; pharmacophore; process optimization; public health relevance; small molecule; small molecule therapeutics; 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.

项目描述（由申请人提供）：该项目涉及开发过渡金属催化的多组分偶联反应，用于制备高取代苯环与其他芳香环体系融合，这是小分子化疗药物中经常遇到的亚结构。该方法是环保的，由于其双组分性质，可以提供多种结构，以支持许多结构-活性关系的研究。在一个简单的体系中证明了关键反应。初始活动包括开发最佳条件，探索有关催化剂和偶联伙伴的过程的范围和限制，以及检查与已证明具有药学相关性的特定目标分子相关的变量。该项目以令人难以置信的短时间内完全合成氯胺酮A达到高潮，氯胺酮A是一种抑制爱泼斯坦·巴尔病毒肿瘤启动能力的化合物

项目成果

Synthesis of highly substituted benzene ring systems through three-component coupling of enyne imines, Fischer carbene complexes, and electron-deficient alkynes.

• DOI: 10.1016/j.tetlet.2017.02.070
• 发表时间: 2017-04-05
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Dhakal B;Gamage LSR;Zhang Y;Herndon JW
• 通讯作者: Herndon JW