COMBINATORIAL SYNTHESIS OF QUINACRINE ANALOGS

奎纳克林类似物的组合合成

• 批准号: 7447338
• 负责人: Rodney Kiplin Guy
• 金额: $ 35.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7447338
• 关键词: Acridines; Chemicals; Combinatorial Synthesis; Development; Distal; Evaluation; Health; Libraries; Methods; Modeling; Molecular; Pharmaceutical Preparations; PrPSc Proteins; Prion Diseases; Quantitative Structure-Activity Relationship; Quinacrine; Research Design; Site; Structure-Activity Relationship; System; Therapeutic; Toxic effect; Variant; analog; chemical synthesis; combinatorial; combinatorial chemistry; design; inhibitor/antagonist; member; novel

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.

该提案的广泛、长期目标是开发平行合成奎纳克林类似物的新方法，并彻底探索吖啶类化合物阻止 PrP sc 形成的能力的结构-活性关系。该提案的具体目标是：1）利用大约2000个奎纳克林吖啶类似物的库，探索吖啶三环杂芳核的A环和C环的结构活性关系，同时允许两个环之间的协同作用； 2) 使用大约2000个类似物的文库，探索连接到奎纳克林远端基本中心的两个侧基的结构活性关系，同时允许两个位点之间的协同作用； 3) 开发新的化学方法来合成吖啶环系统的替代类型侧链； 4）探索结构活动关系 使用大约2000个类似物的文库，分析吖啶核心和奎纳克林远端碱性基团官能团之间的连接体，同时允许核心杂环中的一些变化和远端碱性基团的取代； 5) 使用包含药物所有三个子部分中约 2000 个类似物变体的完全组合库来完善奎纳克林的结构活性关系。该图书馆的成员将成为所有先前研究中获得的信息的目标。在该项目的五年过程中，我们将建立一个包含 10,000 种新型吖啶的库，用于评估潜在的治疗方法。该项目与健康的相关性在于，具有更高功效和更低毒性的奎纳克林形式可能在治疗朊病毒疾病方面非常有用。该研究设计是利用分子设计和组合化学来开发PrP so抑制剂。所使用的方法有化学合成、平行合成和定量结构活性关系建模。