Multicomponent Coupling--Steroids /Etoposide Derivatices

多组分偶联--类固醇/依托泊苷衍生物

• 批准号: 6469251
• 负责人: JAMES W HERNDON
• 金额: $ 6.87万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6469251
• 关键词: alkenes; carbonyl group; chemical conjugate; chemical reaction; chemical synthesis; drug design /synthesis /production; etoposide; steroid analog

The major objective of this proposal is to explore a series of novel synthetic reactions which culminate in new synthetic routes to pharmaceutically-important aromatic and heteroaromatic compounds, including synthetic steroids, etoposide anti-cancer drugs, and 2-arylfuran natural products. The reaction under investigation involves the coupling of highly conjugated acetylene derivatives with Fischer carbene complexes, and is divided into two sections: coupling of carbene complexes with enzyme-carbonyl compounds, and coupling complexes with conjugated enediynes. The major focus involves exploration of the coupling of Fischer carbene complexes with enyne-carbonyl compounds, which provides the biologically-important furan ring system in a single step. Extension of the reaction to aromatic systems will lead to the unstable isobenzofuran ring system, which can undergo high-yielding a predictable reactions with electron-deficient alkenes. Exploitation of this reaction for the single step synthesis of the steroid ring system provides a remarkable versatile method to prepare a diverse array of steroid derivatives for biological testing. A similar reaction process can provide rapid synthetic routs to the structural analogs of the anti-cancer drug etoposide. The other area to be investigated is the coupling of conjugated enediynes with Fischer carbene complexes. This reaction process affords aromatic diradical intermediates, and a major effort will be made to understand and control the reaction pathways of the free radical intermediates. A major feature of these reaction processes is the selective introduction of functional groups into unfunctionalized alkyl chains. Use of this reaction for the synthesis of 2-arylfuran natural products will also be investigated. The field of synthetic organic chemistry has had a profound impact on human health. Investigation of the synthesis of pharmaceutically- important molecules can provide analogs, which are useful for maximizing the desired pharmacological effects and for a better understanding of the mode of action.

本研究的主要目的是探索一系列新颖的合成反应，最终获得具有重要药用价值的芳香族和杂芳香族化合物的新合成路线，包括合成类固醇、依托泊苷抗癌药物和2-芳基呋喃天然产物。所研究的反应包括高共轭乙炔衍生物与Fischer卡宾络合物的偶联，并分为两个部分：卡宾络合物与酶-羰基化合物的偶联，以及与共轭烯二炔的偶联络合物。主要的焦点涉及探索的耦合与烯炔羰基化合物，它提供了生物重要的呋喃环系统在一个单一的步骤Fischer卡宾配合物。 将反应扩展到芳族体系将导致不稳定的异苯并呋喃环体系，其可以与缺电子烯烃进行高产率的可预测反应。利用该反应一步合成甾体环体系提供了一种制备用于生物测试的各种甾体衍生物的显着的通用方法。类似的反应过程可以为抗癌药物依托泊苷的结构类似物提供快速合成路线。另一个要研究的领域是共轭烯二炔与Fischer卡宾配合物的偶联。该反应过程提供了芳香族双自由基中间体，并且将做出主要努力来理解和控制自由基中间体的反应途径。这些反应过程的一个主要特征是将官能团选择性地引入未官能化的烷基链中。利用该反应合成2-芳基呋喃天然产物也将进行研究。合成有机化学领域对人类健康产生了深远的影响。对药学上重要的分子的合成的研究可以提供类似物，其可用于最大化所需的药理学作用和更好地理解作用模式。