Novel Direct Approaches Toward Bioactive Heterocycles

描述（由申请人提供）：计划开发新的快速有效的方法来合成具有生物学意义的杂环化合物。拟议项目由四个主要部分组成。第一部分致力于研究和开发单环和稠合呋喃、吡咯和噻吩的新型环异构化方法，以及开发高度取代杂环的级联迁移/环化方法。第二部分旨在研究最近发现的转环反应的范围，作为各种不同的杂芳族支架的一种极具吸引力的模块化方法。第三部分介绍了采用最近提出的 Si-tether 基序的过渡金属和路易斯酸催化的芳香族和杂环结构单元的 C-H 官能化。第四部分旨在开发新的合成方法，使用我们实验室开发的方法快速构建具有生物学重要性的天然存在和非天然杂环分子。拟议研究的合成靶点包括现有技术不易获得的各种不同取代的中氮茚、潜在的选择性 V 族 sPLA2 抑制剂；板层素D及其类似物；新型片层素-喜树碱混合五环支架、潜在的拓扑异构酶 I 抑制剂，以及四环和五环杂环骨架、潜在的 QR2 和芳香酶抑制剂。针对选定目标的拟议工作的合成部分至关重要，因为它可能导致发现有效的抗炎和抗癌药物。该提案的方法部分针对构建和功能化多种稠合杂环的通用且有效的方法具有更广泛的影响，因为一旦开发，它将极大地扩大药物化学家和生物学家可用的生物学重要分子库的库，并且肯定会影响药物发现研究和相关的健康导向科学。 公共卫生相关性：拟议工作的合成部分将集中于现有技术不易获得的多种取代的中氮茚的合成，潜在的选择性 V 族 sPLA2 抑制剂；板层素D及其类似物；新型片层素-喜树碱混合五环支架、潜在的拓扑异构酶 I 抑制剂，以及四环和五环杂环骨架、潜在的 QR2 和芳香酶抑制剂。这项工作至关重要，因为它可能导致发现有效的抗炎和抗癌药物。该提案的方法部分针对构建和功能化多种稠合杂环的通用且有效的方法具有更广泛的影响，因为一旦开发，它将极大地扩大药物化学家和生物学家可用的生物学重要分子库的库，并且肯定会影响药物发现研究和相关的健康导向科学。

DESCRIPTION (provided by applicant): The development of novel expeditious and efficient methodologies toward the synthesis of biologically significant heterocyclic compounds is planned. The proposed project consists of four major sections. The first section is devoted to the investigation and development of novel cycloisomerization approaches toward monocyclic and fused furans, pyrroles, and thiophenes, and to the development of cascade migration/cyclization methodologies en route to highly substituted heterocycles. The second section is directed toward investigation of the scope of the recently discovered transannulation reaction as a highly attractive modular approach to a variety of diverse heteroaromatic scaffolds. The third section covers transition metal- and Lewis acid-catalyzed C-H functionalization of aromatic and heterocyclic building blocks employing a recently proposed Si-tether motif. The fourth section is aimed at development of new synthetic approaches for the rapid construction of naturally occurring and unnatural heterocyclic molecules of biological importance using methodologies developed in our laboratories. Synthetic targets for the proposed research include various diversely substituted indolizines not easily available by existing techniques, potential selective group V sPLA2 inhibitors; lamellarin D and its analogs; novel lamellarin-campthothecin hybrid pentacyclic scaffolds, potential topoisomerase I inhibitors, and tetra- and pentacyclic heterocyclic skeletons, potential QR2 and aromatase inhibitors. The synthetic part of the proposed work toward selected targets is essential as it may lead to discovery of potent anti-inflammatory and anticancer agents. The methodological part of this proposal toward general and efficient methods for construction and functionalization of diverse fused heterocycles has even broader impact, as upon development, it would dramatically broaden the arsenal of libraries of biologically important molecules available for medicinal chemists and biologists, and will most certainly impact drug discovery research and related health-oriented sciences. PUBLIC HEALTH RELEVANCE: The synthetic part of the proposed work will be focused on the synthesis of diversely substituted indolizines not easily available by existing techniques, potential selective group V sPLA2 inhibitors; lamellarin D and its analogs; novel lamellarin-campthothecin hybrid pentacyclic scaffolds, potential topoisomerase I inhibitors, and tetra- and pentacyclic heterocyclic skeletons, potential QR2 and aromatase inhibitors. This work is essential as it may lead to discovery of potent anti-inflammatory and anticancer agents. The methodological part of this proposal toward general and efficient methods for construction and functionalization of diverse fused heterocycles has even broader impact, as upon development, it would dramatically broaden the arsenal of libraries of biologically important molecules available for medicinal chemists and biologists, and will most certainly impact drug discovery research and related health-oriented sciences.