Development of BN Heterocycles for Biomedical Research

描述（由申请人提供）：含硼化合物是最近出现的有用的生物活性物质，具有独特的作用机制。本提案描述了一个合成化学项目，旨在开发用于生物医学研究的含硼氮杂环（BN杂环）。具体来说，我们对1,2-氮杂环很感兴趣，这是一种与芳烃等构的芳香化合物。芳烃的广泛用途和基本重要性，结合硼独特的元素和化学特性，使1,2-氮杂核糖成为生物医学研究的有吸引力的目标。硼基药物研究的潜在好处包括发现新的硼特异性生物活性机制，这是传统有机分子无法实现的，并减轻了目标病原体的耐药性。我们概述了一个制备1,2-氮杂环衍生物的合成程序，一个物理有机程序，使用合成，结构，光谱和计算相结合的方法来解决1,2-氮杂环的芳香性和反应性，以及一个化学生物学程序来建立BN杂环在生物环境中的反应性和相互作用。我们提出的研究将增强对1,2-氮杂环的结构、成键和芳香性的基本理解，并阐明经典芳香有机分子（如苯和吲哚）在用同构无机B-N单元取代C=C键后性质的变化。所提出的工作所产生的基础科学将为新型芳香化合物的化学研究带来新的动力，同时促进新的硼源生物活性化合物的设计和开发，这些化合物具有改进的药理特征和化学生物学的新机制工具。

DESCRIPTION (provided by applicant): Boron-containing compounds have recently emerged as useful biologically active substances with unique mechanisms of action. This proposal describes a program in synthetic chemistry geared toward developing boron-nitrogen-containing heterocycles (BN heterocycles) for use in biomedical research. Specifically, we are interested in 1,2-azaborine heterocycles, which are aromatic compounds isosteric with arenes. The broad utility and fundamental importance of arenes combined with the unique elemental and chemical features of boron make 1,2-azaborines attractive targets for biomedical investigations. Potential benefits of research into boron-based drugs include discovery of novel boron-specific mechanisms of biological activity that are unattainable by conventional organic molecules and attenuated development of drug resistance by targeted pathogens. We outline a synthetic program for the preparation of 1,2-azaborine derivatives, a physical organic program that uses a combined synthetic, structural, spectroscopic, and computational approach to address the aromaticity and reactivity of 1,2-azaborines, and a chemical biology program to establish the reactivity and interactions of BN heterocycles in a biological environment. Our proposed studies will enhance the fundamental understanding of the structure, bonding, and aromaticity the 1,2-azaborine heterocycle and illuminate the changes in the properties of classic aromatic organic molecules (e.g., benzene and indole) upon the replacement of a C=C bond with the isostructural inorganic B-N unit. The basic science resulting from the proposed work will bring new impetus to the chemistry of novel aromatics while at the same time promote the design and development of new boron-derived biologically active compounds with improved pharmacological profiles and new mechanistic tools for chemical biology.