Novel Direct Approaches Toward Bioactive Heterocycles

描述（由申请人提供）：计划开发新型快速有效的方法来合成具有生物学意义的杂环化合物。拟议项目包括四个主要部分。第一部分致力于调查和发展的新的环异构化方法对单环和稠合呋喃，吡咯，噻吩，和级联迁移/环化方法的发展路线高度取代的杂环。第二部分是针对调查的范围最近发现的transannulation反应作为一个非常有吸引力的模块化的方法，各种不同的杂芳族支架。第三部分涵盖了过渡金属和刘易斯酸催化的C-H官能化的芳香族和杂环结构单元采用最近提出的Si-系链基序。第四部分旨在开发新的合成方法，用于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和非天然杂环分子。所提出的研究的合成目标包括现有技术不易获得的各种二氮杂取代的中氮茚，潜在的选择性V族sPLA 2抑制剂;片螺素D及其类似物;新型片螺素-喜树碱杂合五环支架，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QR 2和芳香酶抑制剂。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药物。该提议的方法学部分对用于构建和官能化不同稠合杂环的通用和有效方法具有更广泛的影响，因为在开发时，它将极大地拓宽可用于药物化学家和生物学家的生物学重要分子的库，并且肯定会影响药物发现研究和相关的健康科学。 公共卫生相关性：所提出的工作的合成部分将集中于合成不容易通过现有技术获得的二氮杂取代的中氮茚，潜在的选择性V族sPLA 2抑制剂;片螺素D及其类似物;新型片螺素-campthothecin杂合五环支架，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QR 2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。该提议的方法学部分对用于构建和官能化不同稠合杂环的通用和有效方法具有更广泛的影响，因为在开发时，它将极大地拓宽可用于药物化学家和生物学家的生物学重要分子的库，并且肯定会影响药物发现研究和相关的健康科学。

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.