Ongoing research: fluorous asymmetric synthesis and new antibacterial agents

正在进行的研究：氟不对称合成和新型抗菌剂

• 批准号: 155310-2006
• 负责人: Hultin, Philip
• 金额: $ 3.21万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2008
• 资助国家: 加拿大
• 起止时间: 2008-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=391741
• 关键词: Ongoing; research; fluorous; asymmetric; synthesis

Our ongoing research program is focused on pharmaceutical chemistry.  We are working on two projects in this general area: 1) Methods for pharmaceutical discovery synthesis - Fluorous Supported Asymmetric Synthesis.  Biologically active molecules are generally complex, often as a result of their detailed 3-dimensional geometries.  When seeking to make new drug compounds, control over this 3-dimensional aspect of structure ("stereochemistry") is important.  Drug discovery programs in pharmaceutical companies are increasingly employing automated high throughput methods, where dozens or hundreds of related molecules are synthesized in parallel.  The problem is that many of the methods available for synthesizing molecules with control over stereochemistry are not amenable to this automated environment.  We have devised tools to address this problem and this proposal describes our plans for developing and demonstrating these tools further. 2) New approaches to antibiotics - Carbohydrate-based Anti-Tuberculosis Compounds.  TB has re-emerged as a global health threat, and the complacency that followed the first successful anti-TB drugs in the post-WWII years has only recently been replaced by awareness that the bacterium has been developing multi-drug resistance and our standard treatments may not continue to be effective much longer.  There is a need for fundamentally new approaches to anti-TB drugs.  We have targeted the biosynthesis of a portion of the cell wall in Mycobacterium tuberculosis.  Previous work revealed three modestly active inhibitors of this biosynthetic pathway in laboratory tests, but much more needs to be learned if these leads are to be developed into really effective drug candidates suitable for testing in animals, let alone humans.  This proposal describes the next step in this process of exploration.

我们正在进行的研究项目的重点是药物化学。我们在这一领域有两个项目：1)药物发现合成方法-氟支持不对称合成。生物活性分子通常是复杂的，通常是由于它们详细的三维几何形状。当寻求制造新的药物化合物时，控制这种三维结构（“立体化学”）是很重要的。制药公司的药物发现项目越来越多地采用自动化的高通量方法，其中数十或数百个相关分子并行合成。问题是，许多可用于控制立体化学合成分子的方法不适合这种自动化环境。我们已经设计了一些工具来解决这个问题，本提案描述了我们进一步开发和演示这些工具的计划。2)抗生素的新途径——碳水化合物抗结核化合物。结核病已重新成为一种全球健康威胁，二战后抗结核药物首次取得成功之后的自满情绪，直到最近才被认识到这种细菌正在产生多种药物耐药性以及我们的标准治疗可能不会继续有效太久的认识所取代。需要从根本上采用新的方法来生产抗结核药物。我们的目标是结核分枝杆菌细胞壁的一部分的生物合成。先前的工作在实验室测试中揭示了三种适度活性的生物合成途径抑制剂，但如果要将这些线索开发成真正有效的候选药物，更不用说在人类身上进行测试，还需要了解更多。这个建议描述了这个探索过程的下一步。