Molecular Libraries from Imidazole-4,5-Dicarboxylic Acid

4,5-咪唑二甲酸分子库

• 批准号: 7192304
• 负责人: Paul W. Baures
• 金额: $ 26.34万
• 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/7192304
• 关键词: NIH Roadmap Initiative tag; biomedical resource; chemical reaction; chemical registry /resource; chemical synthesis; combinatorial chemistry; conformation; dicarboxylate; high throughput technology; imidazole; liquid chromatography mass spectrometry; nuclear magnetic resonance spectroscopy; physical separation

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)：从咪唑-4，5-二元酸(I45DA)支架衍生的分子文库被提出。多类化合物为靶标，包括单体和低聚I45DA衍生物。近1200个单体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必需的结构和构象特征。这些化合物的两个部分重叠的亚群具有游离胺或羧酸，可用于探针的衍生化。所有化合物都可以通过咪唑环进行修饰。含有苯胺的对称寡聚体I45DA衍生物可以干扰与上述相同的蛋白质靶点，也可以干扰受体二聚体等独特的靶点。一类含有约500个氨基酸取代基的线形~(45)DA低聚物被设计用来寻找蛋白质-蛋白质相互作用的抑制剂。这些化合物可以用游离胺或羧酸官能团的探针进行衍生化。因此，我们的具体目标总结如下：1)提供719个单体I45DA衍生物，包括二胺、酯-酰胺和双酯组合；2)提供第一个特定目标的类似物，通过咪唑环烷基化、生物活性铅周围的官能团衍生化以及通过去除保护基团来产生322个可进行探针衍生化的化合物；以及3)提供约500个低聚I45DA衍生物，其中大部分带有用于抑制蛋白质-蛋白质相互作用的氨基酸侧链。我们将以小型、并行的合成方式准备I45DA文库。所有化合物将通过氢核磁共振和LC-MS分析进行表征，检测波长为214 nm。 用于研究细胞和细胞过程的小分子工具有望改善我们对疾病发展和进展的理解。I45DA的衍生物很容易制备，这些化合物以及制造它们的合成方法将被公开。这将为生物医学研究人员和那些对基于这些化合物的构效关系开发新的临床疗法感兴趣的人提供一套宝贵的资源。