Development of BN Heterocycles for Biomedical Research

用于生物医学研究的氮化硼杂环化合物的开发

• 批准号: 9173274
• 负责人: Shih-Yuan Liu
• 金额: $ 23.05万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173274
• 关键词: Address; Biological; Biological Assay; Biological Availability; Biomedical Research; Boron; Carbon; Case Study; Chemicals; Chemistry; Collaborations; Data; Development; Drug Kinetics; Engineering; Exhibits; Future; Generations; Goals; Heterocyclic Compounds; Human; Hydrogen Bonding; In Vitro; Institutes; Investigation; Knowledge; Lead; Ligands; Measurement; Medical; Modeling; Molecular Conformation; Muramidase; Nature; Nitrogen; Oral; PPAR gamma; Pharmaceutical Chemistry; Pharmacologic Substance; Preparation; Protein Conformation; Proteins; Research; Resolution; Roentgen Rays; Series; Solubility; Structure; Synthesis Chemistry; Therapeutic; Thermodynamics; Time; Work; abstracting; analog; aqueous; base; biological systems; biomacromolecule; design; drug candidate; drug development; drug discovery; improved; in vivo; inhibitor/antagonist; mutant; novel; pharmacophore; programs; screening; small molecule; tool

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.

项目概要/摘要 产生超出自然所能实现的化学空间是人类的主要目标之一 合成化学和药物发现研究的重要原则。 BN/CC 等排（即 用硼-氮键取代碳-碳键）已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。该提案描述了一个 药物化学项目旨在开发普遍存在的结构基序的 BN 等排体 药物研究，即芳烃。研究这些 BN 杂环（也称为 作为氮硼烷）包括发现新的氮硼烷特异性生物活性机制 这是传统有机分子和改进的药理学特性无法实现的。 虽然氮杂硼烷的制备已取得良好进展，但它们与 生物大分子实际上仍未被探索。因此，本提议的研究重点是建立 1,2-氮硼烷的独特特征（更好的水溶性和 NH 氢键） 生物学背景。 具体来说，我们力求： 1) 通过直接比较氮杂硼烷与诺华合作确定其治疗潜力 已知生物活性化合物（例如 CDK-2、PPAR- γ抑制剂）与其相应的BN等排体。 2) 对 1,2- NH 基团之间的氢键相互作用有基本的了解 使用突变型 T4 溶菌酶作为明确且可调节的蛋白质模型来研究氮杂硼烷和蛋白质 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体结构的增量变化 使用同属系列 1,2-azaborine 配体，利用 azaborine 的构象状态 改善水溶性。 完成所提出的目标将产生与 BN/CC 电子等排相关的新基础知识 生物医学研究的背景，同时促进新的设计和开发 药效基团，未来的候选药物可以以此为基础。