New Methods for the Synthesis and Study of Bioactive Nitrogen-Containing Molecules

生物活性含氮分子的合成与研究新方法

基本信息

批准号：
9239649
负责人：
Qiu Wang
金额：
$ 24.29万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-05 至 2020-12-31
项目状态：
已结题

项目摘要

TITLE New Methods for the Synthesis and Study of Bioactive Nitrogen-Containing Molecules PROJECT SUMMARY/ABSTRACT The ubiquitous presence of nitrogen atom in small-molecule probes and drugs highlights the significance of nitrogen-containing molecules in biomedical research and drug discovery. Rapid and efficient synthesis of structurally diverse nitrogen-containing skeletons is of the utmost importance, as is the ability to understand their biology, pharmacology and potential as chemical probes and drug candidates. Thus, developing new methods for the synthesis and study of novel nitrogen-containing molecules is significant and necessary to advance our understanding of human disease and the discovery of new therapies. The broad availability of drugs is directly dependent on the existence of cost-efficient methods that can reliably build such novel molecular structures and uncover their biological activity and therapeutic promise. The long-term goal of our research is to establish a chemical platform for designing and developing novel small-molecule probes and tools to advance the understanding and treatment of human disease. The objective of this proposal is to develop new methods that offer rapid and efficient access to valuable nitrogen-containing building blocks for the synthesis and study of relevant biologically active molecules and pharmaceuticals. Toward this, the proposed strategy innovatively exploits the unique and diverse reactivity of heteroatom-nitrogen bonds–– readily available yet traditionally underutilized nitrogen precursors––to design powerful C–N bond formation reactions that are new and different but complementary to existing methods, through the following three specific aims: aim 1) Direct arene C–H amination and amidation via H–Zn exchange and electrophilic amino trapping; aim 2) selective difunctionalization of alkenes by electrophilic amino activation; and aim 3) new methods for constructing diverse azaheterocycles with facile installation of imaging tags. Successful implementation of these studies will greatly facilitate the synthesis and study of a wide range of nitrogen- containing molecules that are difficult or impossible to access with current technologies. With the importance of nitrogen-containing molecules in biomedical research, new methods developed in this application and the products generated from these transformations will have broad impact on developing novel chemical probes and lead compounds for the understanding and treatment of disease.

标题生物活性含氮分子的合成与研究新方法项目概要/摘要小分子探针和药物中普遍存在的氮原子凸显了氮原子的重要性生物医学研究和药物发现中的含氮分子的快速高效合成。结构多样化的含氮骨架至关重要，理解的能力也是如此它们的生物学、药理学以及作为化学探针和候选药物的潜力。新型含氮分子的合成和研究方法对于促进我们对人类疾病的理解和新疗法的发现。药物直接依赖于是否存在能够可靠地构建此类新型药物的具有成本效益的方法分子结构并揭示其生物活性和治疗前景是我们的长期目标。研究目的是建立一个化学平台来设计和开发新型小分子探针和该提案的目的是促进对人类疾病的理解和治疗。开发新方法，快速有效地获取有价值的含氮结构单元相关生物活性分子和药物的合成和研究。所提出的策略创新地利用了杂原子-氮键独特且多样的反应性–– 容易获得但传统上未充分利用的氮前体——设计强大的 C-N 键形成通过以下三种反应，新的、不同的、但与现有方法互补的反应具体目标：目标 1) 通过 H-Zn 交换和亲电子氨基直接芳烃 C-H 胺化和酰胺化捕获；目标 2) 通过亲电氨基活化选择性双官能化；目标 3) 新通过轻松安装成像标签来构建多种氮杂环的方法。这些研究的实施将极大地促进各种氮的合成和研究含有用现有技术很难或不可能获得的分子。含氮分子在生物医学研究中的应用及其开发的新方法这些转化产生的产物将对开发新型化学探针产生广泛影响以及用于了解和治疗疾病的先导化合物。