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: 7287791
• 负责人: SCOTT R GILBERTSON
• 金额: $ 32.64万
• 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/7287791
• 关键词: 3-tropinone; Adenylate Cyclase; Alkynes; Boronic Acids; Chemistry; Complex; Coupling; Cyclohexanones; Databases; Esters; Imidazole; Individual; Libraries; Methods; Modification; Nitrogen; Numbers; Palladium; Phase; Polymers; Positioning Attribute; Quinones; Reaction; Reagent; Route; Site; Solid; Solutions; Structure; Tropanes; United States National Institutes of Health; analog; anthrax edema factor; base; benzoquinone; boronic acid; carbene; chemical reaction; cyclic ketone; cyclohexadienone; cyclohexanone; cyclopentanone; desire; functional group; high throughput screening; member; novel; nucleophilic substitution; pharmacophore; repository; scaffold; size; small molecule

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，我们提出合成基于多种不同结构的文库。 一般来说，将合成基于有希望作为活性化合物的结构的支架。 在所有情况下，除了一种情况外，我们将使用各种化学方法，包括钯催化偶联来衍生这些平台。 我们已经开发了硫杂蒽酮二氧化物的路线，并表明它们可以很容易地用铃木偶联和亲核取代进行修饰。 罗宾逊托品酮合成的改进将用于合成含有不同官能度的托品烷支架，以及药效团连接到3.2.1支架的托品酮衍生物。 结合一个合成具有抗炭疽水肿因子活性的化合物的项目，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，我们建议合成具有各种连接的药效团的环状酮组成的库。 Fischer卡宾配合物与炔的反应可以产生许多不同的结构类型。 我们计划使用这种化学方法合成醌和环己二烯酮的库。 根据所需的库大小和所需材料的量，我们将使用连接到聚合物载体的卡宾络合物以及溶液方法。虽然支架的类型多种多样，但在其合成中将使用许多相同的反应和试剂。 钯催化的芳基和乙烯基硼酸酯的偶联反应将得到广泛的应用。 此外，许多支架将利用酯官能团作为不同药效团的连接点。 选择结构不同但使用相似化学的文库的一个基本优势是，它们极有可能具有显著不同的活性谱，但我们可以使用常见的化学反应有效地构建它们。