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.

项目摘要/摘要 自然可以实现的化学空间的产生是主要目标之一 合成化学和药物发现研究中的重要宗旨。 BN/CC同义（即 用硼氮键代替碳碳键已成为可行的策略 增加与生物医学研究相关的化合物的化学空间。该提议描述了 药物化学计划旨在开发无处不在的结构基序的BN等质量 药物研究，即领域。研究这些BN杂环的潜在好处（也已知 作为Azaborines）包括发现新型的无偶氮生物活性机理 传统有机分子无法实现的并改善了药物特征。 虽然在准备阿扎代理方面取得了良好的进步，但它们与 生物大分子几乎是意外的。这项拟议的研究重点是建立 1,2-亚恰当提出的独特特征（更好的水溶性和NH氢键） 生物环境。 具体来说，我们寻求： 1）通过直接比较 已知生物活性化合物的药理谱和生物学活性（例如CDK-2，PPAR- γ抑制剂）与它们相应的BN等速器。 2）对1,2-的NH组之间的氢键相互作用有基本的了解 阿扎代理和蛋白质通过使用突变体T4溶菌酶作为明确且可调的蛋白质模型 可以从中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 利用Azaborine的1,2-亚恰当配体的同类系列的构象状态 提高了水溶性。 拟议目标的完成将产生与BN/CC同义有关的新的基本知识 生物医学研究的背景，同时促进了新的设计和开发 可以建立未来候选药物的药理。