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.

项目总结/摘要 化学空间的产生超出了自然界所能实现的范围，这是化学的主要目标之一。 合成化学和药物发现研究的重要原则。BN/CC电子等排性（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。该提案描述了一个 药物化学计划，旨在开发一个普遍存在的结构基序的BN电子等排体， 药物研究，即，芳烃。对这些BN杂环的研究的潜在益处（也称为 作为氮杂硼杂环化合物）包括发现新的氮杂硼杂环化合物特异性的生物活性机制， 这是常规有机分子和改进的药理学特性所无法达到的。 虽然在制备氮杂硼杂环已取得了良好的进展，但它们与 生物大分子实际上仍然未被探索。因此，这项研究的重点是建立 1，2-氮杂硼杂环己二烯的提出的独特特征（更好的水溶性和NH氢键）在一个 生物背景。 具体而言，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的药理学特性和生物活性（例如，CDK-2、PPAR- γ抑制剂）与其相应的BN电子等排体。 2)发展的氢键之间的相互作用的基本理解1，2- 通过使用突变T4溶菌酶作为明确定义和可调的蛋白质模型， 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配体结构的增量变化， 构象状态，使用同源系列的1，2-氮杂硼杂配体，利用氮杂硼杂的 改进的水溶性。 完成所提出的目标将产生新的基础知识，有关BN/CC电子等排体在 生物医学研究的背景下，同时促进设计和开发新的 药效团，未来的候选药物可以建立在此基础上。