Synthesis of Pilot Libraries Based on Medicinal Relevant Scaffolds

描述(由申请人提供)：在本申请中，我们建议基于各种不同的结构来合成库。一般来说，基于有希望作为活性化合物的结构的支架将被合成。在除一种情况外的所有情况下，我们将使用各种化学方法，包括钯催化的偶联来衍生这些平台。我们已经开发了合成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合和亲核取代进行修饰。对Robinson托皮酮合成的改进将用于合成含有不同功能的托烷支架，以及托品酮衍生物，其中药效团连接到3.2.1支架上。结合一项合成具有抗炭疽肿胀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，我们建议合成由环酮组成的文库，这些环酮连接着各种药效团。Fischer卡宾络合物和炔烃之间的反应可以产生许多不同的结构类型。我们计划利用这种化学方法合成苯二酮和环己二烯酮的文库。根据所需的文库大小和所需材料的数量，我们将使用附着在聚合物载体上的卡宾络合物以及溶液方法。虽然支架的类型有很大的不同，但在它们的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与酯的偶联反应将得到广泛的应用。此外，一些支架将利用酯功能作为不同药效团的连接点。选择结构不同但使用相似化学成分的文库的一个基本优势是，它们很可能具有显着不同的活性图谱，但我们可以使用常见的化学反应高效地构建它们。

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.