Novel Furan Cycloaddictions for Preparation of Medicinally Important Compounds

用于制备重要药用化合物的新型呋喃环化

• 批准号: 7426619
• 负责人: JAMES W HERNDON
• 金额: $ 21.21万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426619
• 关键词: Aldehydes; Alder plant; Alkaloids; Alkenes; Alkynes; Amides; Antineoplastic Agents; Apomorphine; Aporphines; Area; Biological Factors; Chemicals; Chromium; Complex; Coupling; Cyclization; Development; Diels Alder reaction; Dopamine Receptor; Electrons; Esters; Event; Furans; Goals; Hydrazones; Hypertension; Malignant Neoplasms; Marines; Methodology; Methods; Microtubule Polymerization; Microtubules; Parkinson Disease; Pattern; Phase; Population; Preparation; Procedures; Process; Protocols documentation; Pyrroles; Quality of life; Reaction; Relative (related person); Route; Scheme; Screening procedure; System; Testing; Variant; Work; analog; base; carbene; cycloaddition; design; diazene; eleutherobin; enantiomer; furan; hypertension treatment; nervous system disorder; nitrene; novel; preference; size; stereochemistry; tanshinone; undecane

DESCRIPTION (provided by applicant): The work in this proposal involves the development of new furan and pyrrole-based cycloaddition reactions that result in the formation of complex ring systems from simple and readily available components. The cycloaddition mode depends upon the synthetic route and the substitution pattern for the furan/pyrrole core. The [8+2]-cycloaddition mode occurs when alkynes couple with dienylfurans. This reaction assembles the core ring system (furan-bridged ten-membered ring) of the marine-derived experimental anti-cancer agent eleutherobin. The full synthetic potential of this reaction will be developed, including delineation of the scope, limit, and stereochemistry of the [8+2]-cycloaddition followed by a study of the reactivity profile for densely functionalized [8+2]-cycloadducts. These chemical processes will be employed in the design of new anti-cancer agents that structurally resemble eleutherobin. The ability of these compounds to promote microtubule polymerization will be tested, and active candidates will be further tested as anti-cancer agents. The coupling of chromium carbene complexes with ortho-alkynylbenzoyl derivatives leads to activated furan/pyrrole rings, which undergo efficient cycloaddition with a variety of alkenes and alkynes. A variant of this process will be developed where highly unsaturated chromium carbene complexes afford phenanthroid ring systems in a formal [5+5]-cycloaddition reaction. These reactions are the cornerstone for versatile and efficient synthetic approaches to tanshinones, useful for the treatment of hypertension, and to apomorphine, a dopamine receptor useful for the treatment of Parkinson's disease. Work in this proposal provides structurally complex and medicinally important compounds from simple and readily available components. The reaction process can conveniently provide compounds (or more importantly structural analogs) that have shown potent anti-cancer activity, anti-hypertension activity, and activity against neurologic disorders such as Parkinson's disease. These are all very common ailments that negatively impact the quality of life a large portion of the U.S. population.

描述（由申请人提供）：本提案中的工作涉及开发基于新的Furan和基于吡咯的环加成反应，从而从简单且易于可用的组件形成复杂的环系统。环加成模式取决于呋喃/吡咯芯的合成路线和替代模式。 [8+2] - 环载模式发生时，会出现与二烯氟氟苯甲基的伴侣时。该反应组装了海洋来源的实验性抗癌剂eleteutomelobin的核心环系统（弗兰桥的十元环）。将开发该反应的全合成潜力，包括[8+2] - 环载条的范围，极限和立体化学的描述，然后研究对密度官能化[8+2] cycloaducts的反应性曲线。这些化学过程将用于与结构类似于元育蛋白的新抗癌剂的设计。将测试这些化合物促进微管聚合的能力，并将积极的候选物作为抗癌剂进行进一步测试。铬碳烯络合物与正烷基苯苯甲酰衍生物的偶联导致激活的呋喃/吡咯环，通过各种烷烃和炔烃进行有效的环加成。该过程的一种变体将开发出高度不饱和的碳纤维络合物在形式[5+5] - 环载反应中提供妥刺环系统。这些反应是对坦希酮的多功能和有效合成方法的基石，可用于治疗高血压，以及对帕金森氏病治疗治疗的多巴胺受体的阿哌汀。 该提案中的工作提供了结构上复杂且具有医学上重要的化合物，可提供简单且随时可用的组件。反应过程可以方便地提供表现出有效的抗癌活性，抗高血压活性以及针对神经系统疾病（如帕金森氏病）的活性的化合物（或更重要的结构类似物）。这些都是非常普遍的疾病，会对生活质量产生负面影响。