Novel Direct Approaches Toward Bioactive Heterocycles

描述(由申请人提供)：计划开发新的、快速和有效的方法来合成具有生物意义的杂环化合物。拟议的项目包括四个主要部分。第一部分致力于研究和开发单环和稠合呋喃、吡咯和噻吩环异构化的新方法，以及在获得高取代杂环的路线上的级联迁移/环化方法的发展。第二部分针对最近发现的跨环反应的范围进行了调查，该反应是一种非常有吸引力的模块化方法，用于各种不同的杂芳烃支架。第三部分介绍了过渡金属和Lewis酸催化的芳香族和杂环构筑基团的C-H官能化，采用了最近提出的Si-Tether基序。第四部分的目的是开发新的合成方法，利用我们实验室开发的方法快速构建具有生物重要性的天然和非天然杂环分子。拟议研究的合成目标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族sPLA2抑制剂；薄层菌素D及其类似物；新型薄层菌素-Campthothecin杂化的五环支架，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。针对选定靶点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药物。这一提议的方法学部分对构建和功能化不同的稠合杂环具有更广泛的影响，因为在开发时，它将极大地扩大药物化学家和生物学家可用的生物重要分子文库，并肯定会影响药物发现研究和相关的健康导向科学。 与公共卫生相关：拟议工作的合成部分将集中于合成现有技术不易获得的多种取代的吲哚氮类化合物，潜在的选择性V族sPLA2抑制剂；薄层菌素D及其类似物；新型薄层菌素-Campthothecin杂化五环支架，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。这项工作是必不可少的，因为它可能导致发现有效的抗炎和抗癌药物。这一提议的方法学部分对构建和功能化不同的稠合杂环具有更广泛的影响，因为在开发时，它将极大地扩大药物化学家和生物学家可用的生物重要分子文库，并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.