Novel Direct Approaches Toward Bioactive Heterocycles

开发新的快速有效的生物合成方法 重要的杂环化合物正在计划中。拟议的项目包括四个主要部分。这个 第一部分致力于环异构化新方法的研究和开发。 单环和稠合呋喃、吡咯和噻吩类化合物对叶栅发展的影响 高取代杂环的迁移/环化方法。第二部分是 旨在调查最近发现的经导管反应的范围，作为一种高度 吸引人的模块化方法，以各种不同的杂芳烃支架。第三部分包括 过渡金属催化的两亲杂环构筑基团的亲核或功能化 亲电交叉偶联反应。第四部分是针对新型合成材料的开发。 快速构建天然和非天然杂环分子的方法 使用我们实验室开发的方法进行生物重要性研究。建议的综合目标 研究包括现有技术不易获得的各种不同取代的吲哚氮类化合物， 潜在的选择性V组sPLA2抑制剂；层粘连蛋白D及其类似物，以及新的层粘连蛋白-Campthothecin 杂化五环支架，潜在的拓扑异构酶I抑制剂。 针对选定目标的拟议工作的合成部分是必不可少的，因为它可能导致发现 有效的抗炎和抗癌剂。这项建议的方法论部分是针对一般 而构建和功能化各种稠合杂环的有效方法也更加广泛 对发展的影响，它将极大地扩大具有生物学重要性的图书馆的武器库 可供药物化学家和生物学家使用的分子，肯定会影响药物发现 研究和相关的健康导向科学。

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-catalyzed functionalization of amphiphilic heterocyclic building blocks through nucleophilic or electrophilic cross-coupling reactions. 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, and novel lamellarin-campthothecin hybrid pentacyclic scaffolds, potential topoisomerase I 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.