Synthesis of Pilot Libraries Based on Medicinal Relevant Scaffolds

描述（由申请人提供）：在这个申请中，我们建议基于各种不同的结构来合成库。一般来说，基于有希望成为活性化合物的结构的支架将被合成。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。我们已经开发了合成二硫代蒽酮的途径，并表明它们可以很容易地通过铃木偶联和亲核取代进行修饰。罗宾逊托品酮合成的一种修饰将用于合成具有不同功能的托品酮支架，以及将药效团附着在3.2.1支架上的托品酮衍生物。结合一个合成抗炭疽水肿因子活性化合物的项目，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，我们建议合成含有多种药物载体的环酮文库。费雪卡宾配合物与炔之间的反应可以产生许多不同的结构类型。我们计划用这种化学方法合成醌类和环己二烯酮类化合物库。根据所需文库的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碳配合物以及溶液方法。虽然支架的类型多种多样，但在它们的合成过程中会使用许多相同的反应和试剂。钯催化芳基硼酸和乙烯基硼酸酯的偶联反应将得到广泛应用。此外，许多支架将利用酯功能作为不同药物载体的附着点。选择结构不同但使用相似化学物质的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.