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.

该提案的主要目的是探索一系列新型的合成反应，这些反应在新的合成途径中达到了最重要的芳族和异性芳香族化合物，包括合成类固醇，依托泊苷抗癌药物，以及2-芳烃天然产物。所研究的反应涉及高度结合的乙炔衍生物与菲舍尔碳烯络合物的偶联，并分为两个部分：与酶 - carbonyl化合物的碳烯配合物偶联，并将复合物与偶联的eneDiynes偶联。主要重点是探索Fischer Carbene络合物与Enyne-Carbonyl化合物的耦合，该化合物在一个步骤中提供了最重要的Furan环系统。 对芳族系统的反应的扩展将导致不稳定的异苯并呋喃环系统，这可以与电子缺陷型烷烃进行高收益的可预测反应。对类固醇环系统的单步合成的这种反应的开发提供了一种出色的多功能方法，可以准备多种类固醇衍生物进行生物学测试。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的合成溃败。要研究的另一个区域是将结合的Enediynes与Fischer Carbene Complexs结合在一起。该反应过程提供了芳香自由基中间体，并将付出重大的努力来理解和控制自由基中间体的反应途径。这些反应过程的主要特征是将官能团的选择性引入不官能化的烷基链中。还将研究该反应的合成2-芳烃天然产物。合成有机化学领域对人类健康产生了深远的影响。研究药物合成的重要分子可以提供类似物，这对于最大程度地提高了所需的药理作用和更好地理解作用方式。