Development of BN Heterocycles for Biomedical Research

描述（由申请人提供）：含硼化合物最近已成为具有独特作用机制的有用生物活性物质。该提案描述了一个面向开发用于生物医学研究的含硼氮杂环（BN杂环）的合成化学计划。具体而言，我们感兴趣的是1，2-氮杂硼杂环，这是芳香族化合物与芳烃等排。芳烃的广泛用途和根本重要性与硼的独特元素和化学特征相结合，使1，2-氮杂硼杂环化合物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益处包括发现传统有机分子无法达到的新型硼特异性生物活性机制，以及减弱靶向病原体的耐药性发展。我们概述了1，2-氮杂硼杂环衍生物的制备，物理有机程序，使用相结合的合成，结构，光谱和计算方法来解决的芳香性和反应性的1，2-氮杂硼杂环，和化学生物学程序，以建立BN杂环在生物环境中的反应性和相互作用的合成程序。我们提出的研究将增强对1，2-氮杂硼杂环的结构、成键和芳香性的基本理解，并阐明经典芳香族有机分子（例如，苯和吲哚），用同构无机B-N单元取代C=C键。从拟议的工作中产生的基础科学将为新型芳烃的化学带来新的动力，同时促进新的硼衍生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学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.