Development of BN Heterocycles for Biomedical Research

描述(申请人提供)：含硼化合物最近作为有用的生物活性物质出现，具有独特的作用机制。这项建议描述了一项合成化学计划，旨在开发用于生物医学研究的含硼氮杂环(BN杂环)。具体地说，我们对1，2-氮硼杂环感兴趣，这是一种与芳烃等构型的芳香化合物。芳烃的广泛用途和基本重要性与硼独特的元素和化学性质相结合，使1，2-氮硼化合物成为生物医学研究的诱人目标。研究基于硼的药物的潜在好处包括发现传统有机分子无法获得的新的特定于硼的生物活性机制，以及减缓靶向病原体的耐药性的发展。我们概述了制备1，2-氮硼杂环衍生物的合成程序，使用合成、结构、光谱和计算相结合的方法来研究1，2-氮硼杂环化合物的芳香性和反应性的物理有机程序，以及建立生物环境中BN杂环的反应性和相互作用的化学生物学程序。我们的研究将加深对1，2-氮杂环的结构、成键和芳香性的基本了解，并阐明用等结构的无机B-N单元取代C=C键后经典的芳香有机分子(如苯和吲哚)的性质变化。这项工作所产生的基础科学将为新型芳香族化合物的化学带来新的动力，同时也将促进新的含硼生物活性化合物的设计和开发，这些化合物具有更好的药理特性和新的化学生物学机械工具。

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.