TANDEM ENEDIYNE RADICAL CYCLIZATION SYNTHETIC STUDIES

串联烯炔自由基环化合成研究

• 批准号: 2187556
• 负责人: JANET W GRISSOM
• 金额: $ 10.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2187556
• 关键词: DNA damage; carbene; carbopolycyclic compound; chemical synthesis; cyclization

This proposal addresses the development of a new radical tricyclization protocol which allows the simultaneous construction of three carbon- carbon bonds and three rings in one synthetic step leading to the synthesis of biologically active products. The mechanism for this transformation involves the conversion of enediynes into reactive biradical intermediates which can trap pendent acceptors in radical cyclization reactions. These biradicals are also known to possess DNA cleaving and anticancer activity and the present studies describe the discovery of a new class of potential DNA cleaving agents. Although these studies are significant to the understanding of the chemical behavior of these unique reactive species and to the development of efficient methods for the synthesis of multicyclic systems, the preliminary results and proposed studies are of importance to the health sciences field. The potential for efficient construction of complex ring systems should permit the synthesis of biologically important natural products such as anticancer, antibiotic, antiinflammatory and anti-AIDS agents in a minimum number of steps. The described methodology should also be applicable to various structural analogues of biologically active natural products. In addition, assays will be done to study the DNA cleaving activity of these compounds. these studies may yield useful data for enhancing the activity of these DNA cleaving agents and providing broader applications of enediynes as antitumor agents. Finally, the pursuit of the synthetic challenges described herein will serve to train organic chemists whose talents will be needed in the future as researchers in the pharmaceutical industry.

该建议涉及新的激进三环化的发展 协议允许同时构建三个碳 - 一个合成步骤中的碳键和三个环，导致 生物活性产物的合成。 这个机制 转换涉及将endiynes转化为反应性 Biradical中间体可以将受体捕获在根本上 环化反应。 这些Biradicals也有DNA 分裂和抗癌活性，目前的研究描述了 发现一类新的潜在DNA切割剂。 尽管这些研究对于理解 这些独特的反应物种的化学行为以及开发 用于合成多机状系统的有效方法 初步结果和拟议的研究对健康至关重要 科学领域。 有效构建复杂环的潜力 系统应允许合成生物学上重要的自然 抗癌，抗生素，抗炎和抗AID等产品 代理以最小数量的步骤。 所述的方法应该 也适用于生物活性的各种结构类似物 天然产品。 此外，将进行测定以研究DNA 这些化合物的分裂活性。 这些研究可能会产生有用 增强这些DNA切割剂的活性的数据和 提供Enediynes作为抗肿瘤剂的更广泛应用。 最后，对本文所述的合成挑战的追求将 训练有机化学家，他们的才华需要 作为制药行业的研究人员的未来。