Development of BN Heterocycles for Biomedical Research

项目摘要/摘要 在自然可以实现的范围之外产生化学空间是 合成化学和药物发现研究中的一个重要原则。BN/CC等构体(即， 用硼-氮键取代碳-碳键)已经成为一种可行的策略 增加与生物医学研究相关的化合物的化学空间。本提案描述了一种 药物化学计划旨在开发无处不在的结构基序的BN等位体 药物研究，即芳烃。研究这些BN杂环的潜在好处(也称为 包括发现氮硼化合物特有的生物活性新机制，这些机制 传统的有机分子和改进的药理特性无法达到。 虽然氮硼化合物的制备取得了良好的进展，但它们与 生物大分子实际上仍未被探索。因此，这项拟议的研究集中在建立 1，2-氮博林的独特性质(更好的水溶解性和NH氢键) 生物学背景。 具体地说，我们力求： 1)与诺华公司合作，通过直接比较 已知生物活性化合物(如CDK-2、PPAR-)的药理概况和生物活性 γ抑制剂)与其相应的BN同工酶。 2)对1，2-氨基之间的氢键相互作用有一个基本的了解 通过使用突变体T4溶菌酶作为明确定义和可调节的蛋白质模型来研究氮硼化合物和蛋白质 从中可以提取定量的结构和能量参数。 3)研究蛋白质如何适应离散配基结构的增量变化 使用同属系列的1，2-氮硼配体的构象状态，利用氮硼的 改善了水的溶解性。 拟议目标的完成将产生与BN/CC等构学有关的新的基础知识 在生物医学研究的背景下，同时推动设计和开发一种新的 药效团，未来的候选药物可以在此基础上建立起来。

Project Summary/Abstract The generation of chemical space beyond that can be achieved by Nature is one of the main goals of synthetic chemistry and an important tenet in drug discovery research. The BN/CC isosterism (i.e., replacement of a carbon-carbon bond with a boron-nitrogen bond) has emerged as a viable strategy to increase the chemical space of compounds relevant to biomedical research. This proposal describes a medicinal chemistry program geared toward developing BN isosteres of a ubiquitous structural motif in pharmaceutical research, i.e., arenes. Potential benefits of research into these BN heterocycles (also known as azaborines) include discovery of novel azaborine-specific mechanisms of biological activity that are unattainable by conventional organic molecules and improved pharmacological profiles. While good progress has been made in the preparation of azaborines, their interactions with biomacromolecules remains virtually unexplored. Thus, this proposed research is focused on establishing 1,2-azaborine's proposed distinctive features (better aqueous solubility and NH hydrogen bonding) in a biological context. Specifically, we seek to: 1) establish the therapeutic potential of azaborines in collaboration with Novartis by directly comparing the pharmacological profiles and biological activity of known biologically active compounds (e.g., CDK-2, PPAR- γ inhibitors) to their corresponding BN isosteres. 2) develop a fundamental understanding of the hydrogen bonding interaction between the NH group of 1,2- azaborines and a protein by employing mutant T4 lysozyme as a well-defined and tunable protein model from which quantitative structural and energetic parameters can be extracted. 3) investigate how proteins accommodate incremental changes in ligand structure in discrete conformational states using a congeneric series of 1,2-azaborine ligands, taking advantage of azaborine's improved aqueous solubility. Completion of the proposed aims will yield new fundamental knowledge related to BN/CC isosterism in the context of biomedical research and at the same time promote the design and development of a new pharmacophore from which future drug candidates can be built upon.