Molecular Libraries from Imidazole-4,5-Dicarboxylic Acid

4,5-咪唑二甲酸分子库

• 批准号: 7484158
• 负责人: Paul W. Baures
• 金额: $ 15.65万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484158
• 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）：提出了衍生自咪唑-4，5-二羧酸（I45 DA）支架的分子文库。靶向多种类型的化合物，包括单体和低聚I45 DA衍生物。近1200种单体I45 DA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必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与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。带有苯胺的对称低聚I45 DA衍生物可以干扰与上述相同的蛋白质靶标，以及独特的靶标如受体二聚体。一类线性I45 DA低聚物制备的氨基酸取代基和约500个成员的目的是发现蛋白质-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，我们的具体目标概述如下：1）递送719种单体I45 DA衍生物，其包括二酰胺、酯-酰胺和二酯组合，2）递送通过咪唑环烷基化、围绕生物活性先导物的官能团衍生化以及通过去除保护基而修饰的第一特定目的的类似物，以产生322种适合于探针衍生化的化合物，和3）递送大约500种寡聚I45 DA衍生物，其中大部分带有抑制蛋白质-蛋白质相互作用的氨基酸侧链。我们将以小型并行合成的方式准备I45 DA库。通过氢NMR和LC-MS分析（在214 nm处检测）对所有化合物进行鉴别。 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展和进展的理解。I45 DA衍生物很容易制备，这些化合物以及合成方法将被公开。这将为生物医学研究人员和那些有兴趣基于这些化合物的结构-活性关系开发新的临床治疗方法的人提供一组有价值的资源。