COMBINATORIAL SYNTHESIS OF QUINACRINE ANALOGS

这项提议的广泛、长期的目标是开发新的方法来平行合成喹啉类似物，并彻底探索相对于它们阻止PrP sc形成的能力的吖啶类化合物的构效关系。这项建议的具体目的是：1)利用约2000个吖啶类似物的文库，探索吖啶的三环杂环核心的A和C环的构效关系，同时允许两环之间的协同作用；2)利用约2000个类似物的文库，探索连接到喹啉的远端碱性中心的两个侧基的结构活性关系，同时允许两个位置之间的协同作用；3)开发新的化学方法来合成吖啶环系的替代类型的侧链；4)探索结构活性关系 使用大约2000个类似物的文库，在允许核心杂环中的一些变异和远端碱性基团的取代的同时，利用药物的所有三个亚部分中的大约2000个类似物的完全组合文库来精炼奎纳克林的构效关系。这个图书馆的成员将成为先前所有研究中获得的信息的目标。在这个项目的五年过程中，我们将建立一个包含10,000种新型吖啶类药物的库，用于评估其潜在的治疗方法。该项目与健康有关的是，具有更高疗效和更低毒性的奎纳克林形式可能在治疗普恩病毒疾病方面非常有用。研究设计是利用分子设计和组合化学来开发PrP-SO抑制剂。拟采用的方法有化学合成法、平行合成法和定量构效关系模型法。

The broad, long-term objectives of this proposal are the development of novel methods for the parallel synthesis of quinacrine analogs and a thorough exploration of the structure-activity relationships of the acridines with respect to their ability to block the formation of PrP sc. The Specific Aims of this proposal are: 1) to explore the structure activity relationships of the A and C rings of the tricyclic heteroaromatic core of acridine, while allowing for synergy between the two rings, using a library of approximately 2000 acridine analogs to quinacrine; 2) to explore the structure activity relationships of the two pendant groups attached to the distal basic center of quinacrine, while allowing for synergy between the two sites, using a library of approximately 2000 analogs; 3) to develop new chemical approaches to the synthesis of alternate types of sidechains to the acridine ring system; 4) to explore the structure activity relationships of the linker between the acridine core and distal basic group functionalities of quinacrine, while allowing for some variation in the core heterocycle and the substitution of the distal basic group, using a library of approximately 2000 analogs; 5) to refine the structure activity relationships of quinacrine using a fully combinatorial library of approximately 2000 analogs variant in all three sub-portions of the drug. The members of this library will be targeted by information gained in all of the prior studies. Over the five year course of this project, we will build a library of 10,000 novel acridines for evaluation as potential therapeutics. The health relatedness of this project is that forms of quinacrine with increased efficacy and reduced toxicity might be quite useful in the treatment of prion diseases. The research design is the use of molecular design and combinatorial chemistry to develop PrP so inhibitors. The methods to be used are chemical synthesis, parallel synthesis, and quantitative structure activity relationship modeling.