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DEVELOPING ISONITRILE CHEMISTRY FOR MEDICINAL APPLICATIONS

开发异腈化学的医药应用

基本信息

批准号：
8231026
负责人：
Bruce Beaver
金额：
$ 46.32万
依托单位：
DUQUESNE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-15 至 2016-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Bioactive isonitrile-containing metabolites are among the best small-molecule leads for addressing the 300-500 million infections and 1-3 million deaths caused annually by malaria. Unfortunately few isonitrile-based synthetic methods exist that maintain the isonitrile functionality which is preventing direct, rapid access to bioactive isonitrile-containing carbocycles. This proposal aims to develop new connectivity methods, access isonitriles having new structural diversity, reveal fundamental reactivity patterns in alkylations and conjugate additions, and establish the essential principles for performing transition metal catalysis with isonitriles. As such the proposal fits into the mandate of NIAID for advances leading to rapid synthesis of disease treatments, particularly malaria. This proposal launches a new initiative to address the dearth of isonitrile-based synthetic methods. Three complementary developments will be explored to develop new methods (a) for alkylating isonitriles through deprotonations with mixed metal bases, (b) a new exchange process in which an activated isonitrile is converted into a metalated isonitrile, an alkeneisonitrile, or an alkyneisonitrile, and (c) for developing transition metal catalysts capable of promoting reactions without irreversibly binding the isonitrile functionality. Preliminary results demonstrate the viability of two different, but complementary, alkylation strategies to access bioactive isonitriles. The long term goal is to develop these methods into robust syntheses of isonitriles using NMR analyses and alkylation selectivities to probe the nature of the reactive intermediates. Another strategy addresses the long-standing challenge of developing transition metal catalysts capable of processing the carbon architecture without irreversibly binding to the isonitrile group. The approach is to develop catalysts for non-polar reactions, such as the Diels-Alder cycloaddition, and then apply the understanding to more challenging conjugate addition reactions. If successful, this will allow researchers to rapidly access isonitriles with diverse substitution patterns. In summary, if successful the proposal will provide a new strategy for rapidly assembling substituted isonitriles ideally suited to diverse biomedical applications. Developing a robust route to these extremely valuable building blocks should facilitate their use in pharmaceutical synthesis and provide fundamental insight for developing additional isonitrile-based methods. PUBLIC HEALTH RELEVANCE: Isonitriles are functionalities primed for conversion to peptide mimics, bioactive heterocycles, and binding to radioactive metals used in tumor imaging. The proposal describes the synthesis of diverse isonitriles to address their limited availability and simultaneously advance fundamental bond forming reactions with this functionality.

描述（由申请人提供）：含生物活性异腈代谢物是解决每年由疟疾引起的3 -5亿感染和1-3百万死亡的最佳小分子引线之一。不幸的是，很少有基于异腈的合成方法能够保持异腈的功能，这阻碍了直接、快速地获得具有生物活性的含异腈的碳环。本课题旨在开发新的连接方法，获得具有新的结构多样性的异腈化合物，揭示烷基化反应和共轭加成反应的基本模式，建立用异腈化合物进行过渡金属催化的基本原理。因此，该提案符合NIAID的任务，即取得进展，从而快速合成疾病治疗方法，特别是疟疾。该提案发起了一项新的倡议，以解决基于异腈的合成方法的缺乏。将探索三个互补的发展，以开发新的方法(a)通过混合金属碱的脱质子使异腈烷基化，(b)一种新的交换过程，其中活化的异腈转化为金属化异腈、烯基异腈或炔基异腈，以及(c)开发能够促进反应的过渡金属催化剂，而不会不可逆地结合异腈的功能。初步结果证明了两种不同但互补的烷基化策略获得生物活性异腈的可行性。长期目标是利用核磁共振分析和烷基化选择性来探索反应中间体的性质，将这些方法发展成强大的异腈合成。另一种策略解决了长期存在的挑战，即开发能够处理碳结构而不与异腈基不可逆结合的过渡金属催化剂。该方法是开发非极性反应的催化剂，如Diels-Alder环加成反应，然后将其应用于更具挑战性的共轭加成反应。如果成功，这将使研究人员能够快速获得具有不同取代模式的异腈。总之，如果成功，该提案将提供一种快速组装取代异腈的新策略，非常适合各种生物医学应用。开发这些极有价值的构建块的可靠途径应有助于它们在药物合成中的应用，并为开发其他基于异腈的方法提供基本见解。