Synthesis of Pilot Libraries Based on Medicinal Relevant Scaffolds

基于药物相关支架的中试文库的合成

• 批准号: 7192186
• 负责人: SCOTT R GILBERTSON
• 金额: $ 34.6万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7192186
• 关键词: NIH Roadmap Initiative tag; biomedical resource; chemical reaction; chemical registry /resource; chemical structure function; chemical synthesis; cyclic ketone; drug receptors; high throughput technology; molecular site; palladium; quinones; tropanes

DESCRIPTION (provided by applicant): In this application we propose to synthesize libraries based on a variety of different structures. In general scaffolds based in structures that have promise as active compounds will be synthesized. In all but one of the cases, we will then use a variety of chemistry including palladium catalyzed coupling to derivatize these platforms. We have already developed routes to thioxanthenone dioxides and have shown that they can be easily modified with Suzuki couplings and nucleophilic substitution. A modification of the Robinson tropinone synthesis will be used to synthesize tropane scaffolds containing different functionality, as well as tropinone derivatives where pharmacophores are attached to the 3.2.1 scaffold. In conjunction with a project to synthesize compounds with activity against anthrax edema factor, we have found that cyclohexanone and cyclopentanones containing imidazole and other nitrogen heterocycles have micromolar activity. Consequently, we propose to synthesize libraries consisting of cyclic ketones that have a variety of pharmacophores attached. The reaction between Fischer carbene complexes and alkynes can produce a number of different structure types. We plan to synthesize libraries of quinones and cyclohexadienones using this chemistry. Depending on the desired library size and quantity of material desired, we will use carbene complexes attached to polymer supports as well as solution methods. While the types of scaffolds are highly varied, there are number of the same reactions and reagents that will be used in their synthesis. Palladium catalyzed coupling reactions of aryl and vinyl boronic acids and esters will be used extensively. Additionally, a number of the scaffolds will utilize ester functionality as an attachment point for different pharmacophores. A fundamental advantage of choosing libraries that are structurally different but use similar chemistry is that it is highly likely that they will have significantly different activity profiles and yet we can build them efficiently using common chemical reactions.

描述（由申请人提供）：在本申请中，我们建议根据各种不同结构合成库。 总的来说，将合成具有积极化合物的承诺的结构中的脚手架。 除一种情况外，我们将使用各种化学反应，包括钯催化耦合来衍生这些平台。 我们已经开发了通往硫酮二氧化物的途径，并表明它们可以通过铃木耦合和亲核取代很容易修饰。 鲁滨逊肌氨酸合成的修饰将用于合成含有不同功能的托型支架，以及在3.2.1支架上附着药算算术的tropinone衍生物。 结合一个与炭疽性水肿因子合成化合物的项目，我们发现含有咪唑和其他氮杂环的环己酮和环戊酮具有微摩尔活性。 因此，我们提议合成由包含各种药理的循环酮组成的文库。 Fischer Carbene复合物和炔烃之间的反应可以产生多种不同的结构类型。 我们计划使用这种化学物质合成喹酮和环己酮的文库。 根据所需的库尺寸和所需材料的数量，我们将使用附着在聚合物支架上的卡宾综合体以及溶液方法。尽管支架的类型高度多样，但在其合成中会使用相同的反应和试剂。 钯催化的芳基和乙烯基乙酸和酯的催化偶联反应将广泛使用。 此外，许多脚手架将利用酯功能作为不同药理的附着点。 选择在结构上不同但使用相似化学的文库的基本优势是，它们很有可能具有显着不同的活动曲线，但是我们可以使用常见的化学反应有效地建造它们。