Development of a Biocatalytic Platform for Convergent Synthesis of Chiral Amines

项目摘要 保护人类健康有赖于生物活性化合物的不断发现。 并将它们发展成有用的药物。从历史上看，合成化学使药物 化学家创造和优化新的先导化合物，并使过程化学家能够生产 治疗人群所需规模的化合物。药物发现和开发的过程 随着高效酶催化剂的发展，药物生产正在经历着戏剧性的变化 实用的合成工具。药物化学家现在正在利用酶的杂乱活性。 一步获得药物相关化合物，否则需要多步化学处理 综合。此外，过程化学家开始利用无与伦比的效率和内在的支持- 酶取代昂贵的催化剂以及有毒的试剂和溶剂的能力 许多目前的生产路线。因此，酶正迅速成为制药的重要工具。 声学合成。 不幸的是，这些变革性的发展受到相对缺乏有用的合成材料的限制。 生物催化工具箱中的反应。我们小组在扩展这个工具箱方面取得了根本性的进展 通过使用定向进化来获得新的、有用的生物催化剂，这些生物催化剂的活性可以 对于所需的底物或反应来说，已经很低或甚至检测不到。 这一建议旨在扩展和推广一种用于手性合成的强大的生物催化平台 胺。这类化合物普遍被用作涵盖所有领域的制药的基础材料 抗菌、抗真菌和抗癌药物等对人类健康的影响。在这些基础上改进的能力 化合物依赖于获得合适的构建块。我们已经鉴定出TrpB酶是一种 合成手性胺的独特生物催化剂。这种酶在一种新的反应中起着重要的调节作用。 在两种底物之间，一种是亲核的，另一种是亲电的。以前的工作几乎完全集中在 对这种酶的活性与不同的亲核底物，TrpB有适度的混杂。 相比之下，这里提出的研究旨在将酶的亲电底物范围扩大到 制造高度官能化的α-氨基酸，以及其他类别的手性胺，如氨基醇 和β-氨基酸。这项研究的结果将是一套新的生物催化剂，可以用来合成- 确定了一系列手性胺构建块的大小，用于新型药物化合物，这些化合物是广告和药物的关键。 促进人类疾病的诊断和治疗。

Project Abstract The protection of human health depends on the continued discovery of biologically active compounds and their development into useful pharmaceuticals. Historically, synthetic chemistry has enabled medicinal chemists to create and optimize novel lead compounds and has empowered process chemists to produce compounds at the scale necessary for the treatment of a population. The processes of drug discovery and drug production are undergoing a dramatic change with the development of efficient enzyme catalysts as practical tools for synthesis. Medicinal chemists are now harnessing the promiscuous activities of enzymes to access in a single step medicinally relevant compounds that otherwise require multiple-step chemical syntheses. Further, process chemists are starting to leverage the unrivalled efficiency and inherent sustain- ability of enzymes to replace the expensive catalysts and the toxic reagents and solvents that characterize many current production routes. As a result, enzymes are rapidly becoming important tools for pharmaceu- tical synthesis. These transformative developments are unfortunately limited by the relative dearth of useful synthetic reactions in the ‘biocatalytic toolbox’. Our group has made fundamental advances to expanding this toolbox by using directed evolution to obtain new, useful biocatalysts starting from enzymes whose activities may have been low or even undetectable for the desired substrate or reaction. This proposal seeks to expand and generalize a powerful biocatalytic platform for the synthesis of chiral amines. Such compounds are prevalent as building blocks for pharmaceuticals that encompass all realms of human health such as antibacterial, antifungal, and anticancer drugs. The ability to improve upon these compounds is dependent on access to suitable building blocks. We have identified the enzyme TrpB as a unique biocatalyst for the synthesis of chiral amines. This enzyme mediates a bond-forming reaction be- tween two substrates, one nucleophilic and one electrophilic. Previous work has almost exclusively focused on the activity of this enzyme with diverse nucleophilic substrates, for which TrpB has modest promiscuity. The research proposed here, by contrast, aims to expand the electrophilic substrate scope of the enzyme to make highly functionalized α-amino acids, as well as other classes of chiral amine such as amino alcohols and β-amino acids. The result of this research will be a new suite of biocatalysts that can be used to syn- thesize a wide range of chiral amine building blocks for the novel medicinal compounds essential for ad- vancing the diagnosis and treatment of human diseases.