Molecular Libraries from Imidazole-4,5-Dicarboxylic Acid

4,5-咪唑二甲酸分子库

• 批准号: 7287795
• 负责人: Paul W. Baures
• 金额: $ 15.86万
• 依托单位: UNIVERSITY OF TULSA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2009-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7287795
• 关键词: Alkylation; Amides; Amines; Amino Acids; Aniline; Biochemical; Biological; Biological Assay; Biotin; Bistris; Carboxylic Acids; Cell physiology; Cells; Class; Clinical; Cytoskeletal Proteins; Detection; Development; Diamide; Dicarboxylic Acids; Disease; Enzymes; Esters; Fluorescent Probes; Hydrogen; Imidazole; Ion Channel; Label; Lead; Libraries; Membrane Proteins; Methodology; Molecular Bank; Molecular Conformation; Nucleic Acids; Pathway interactions; Peptides; Phosphotransferases; Process; Proteins; Research Personnel; Screening procedure; Side; Signal Transduction; Site; Structure; Structure-Activity Relationship; Therapeutic; United States National Institutes of Health; Ursidae Family; Work; analog; base; biomedical resource; design; dimer; functional group; improved; inhibitor/antagonist; interest; kinase inhibitor; member; protein protein interaction; receptor; repository; scaffold; size; small molecule; small molecule libraries; success; tool

DESCRIPTION (provided by applicant): Molecular libraries derived from an imidazole-4,5-dicarboxylic acid (I45DA) scaffold are proposed. Multiple classes of compounds are targeted, including monomeric and oligomeric I45DA derivatives. The nearly 1200 monomeric I45DA derivatives have structural and conformational features necessary to interact with receptors, kinases, ion channels, enzymes, and cytoskeletal proteins. Two partially overlapping subsets of these compounds have either a free amine or carboxylic acid that can be used for derivatization with probes. All of the compounds can be modified through the imidazole ring. Symmetrical oligomeric I45DA derivatives bearing anilines can interfere with the same protein targets as above, as well as with unique targets like receptor dimers. A class of linear I45DA oligomers prepared with amino acid substituents and approximating 500 members is designed to discover inhibitors of protein-protein interactions. These compounds can be derivatized with probes at either free amine or carboxylic acid functionalities. Thus, our specific aims are summarized as follows: 1) to deliver 719 monomeric I45DA derivatives that include diamides, ester-amide, and diester combinations, 2) to deliver analogs of the first specific aim modified by imidazole ring alkylation, functional group derivitization around a bioactive lead, and by removing protecting groups to yield 322 compounds amenable to probe derivitization, and 3) to deliver approximately 500 oligomeric I45DA derivatives, the majority of which bear amino acid side chains for inhibiting protein-protein interactions. We will prepare the I45DA libraries in small, parallel syntheses. All compounds will be characterized for identity by hydrogen NMR and LC-MS analysis with detection at 214 nm. Small molecule tools for studying the cell and cellular processes promise to improve our understanding of disease development and progression. The I45DA derivatives are easy to prepare and the compounds, as well as the synthetic methodology to make them, will be made public. This will provide a valuable set of resources for biomedical researchers and to those interested in developing new clinical therapeutics based on the structure-activity relationships of these compounds.

描述（由申请人提供）：提出了源自咪唑-4,5-二羧酸（I45DA）支架的分子库。多类化合物是目标化合物，包括单体和低聚 I45DA 衍生物。近 1200 种单体 I45DA 衍生物具有与受体、激酶、离子通道、酶和细胞骨架蛋白相互作用所需的结构和构象特征。这些化合物的两个部分重叠的子集具有可用于探针衍生化的游离胺或羧酸。所有化合物都可以通过咪唑环进行修饰。带有苯胺的对称寡聚 I45DA 衍生物可以干扰与上述相同的蛋白质靶标，以及受体二聚体等独特靶标。一类由氨基酸取代基制备的线性 I45DA 寡聚物约有 500 个成员，旨在发现蛋白质-蛋白质相互作用的抑制剂。这些化合物可以用探针在游离胺或羧酸官能团处衍生化。因此，我们的具体目标总结如下：1）提供 719 种单体 I45DA 衍生物，包括二酰胺、酯-酰胺和二酯组合，2）提供通过咪唑环烷基化、生物活性先导周围的官能团衍生化修饰的第一个具体目标的类似物，并通过去除保护基团产生 322 种适合探测的化合物 衍生化，3) 递送大约 500 种寡聚 I45DA 衍生物，其中大部分带有氨基酸侧链，用于抑制蛋白质-蛋白质相互作用。我们将以小型并行合成的方式制备 I45DA 文库。所有化合物将通过氢核磁共振和 LC-MS 分析进行鉴定，并在 214 nm 处进行检测。 用于研究细胞和细胞过程的小分子工具有望提高我们对疾病发生和进展的理解。 I45DA 衍生物很容易制备，并且该化合物及其合成方法将被公开。这将为生物医学研究人员和那些有兴趣根据这些化合物的结构-活性关系开发新的临床疗法的人提供一组宝贵的资源。