DiversityExpanding the Synthetic Utility of a Flavin-dependent Monooxygenases

项目摘要 天然产品是药物灵感的重要来源。世界卫生组织估计 世界上约80%的人口依赖于由天然产品制成的传统药物。的 制药行业有大约50%的药物基于或衍生自天然产物。可惜 这些分子的合成通常非常复杂，需要安装多个功能性的 具有非常特殊的三维结构的群体，对他们的生物活性至关重要。 酚类化合物的氧化脱芳构化反应是合成配合物的有力手段 分子，因为它引入立体化学并产生引发进一步反应的产物。比如说， 该反应是异色酚酮II和叶黄素A生物合成的关键步骤， HIV表面的糖蛋白gp 120与T细胞表面的CD 4之间的相互作用 是艾滋病病毒入侵机制的核心假设抑制这种蛋白质-蛋白质相互作用会破坏 人类免疫缺陷病毒（HIV）进入细胞。只有有限数量的对映选择性 已经报道了氧化脱芳构化的方法，限制了这种转化在工业中的应用。 合成化学为了实现高度的立体选择性，化学计量量的手性金属 除了冗长的反应时间、低温和苛刻的条件之外，还需要络合物。 生物催化反应体现了理想化学转化的许多特征，包括 无可挑剔的选择性，高催化效率，温和的反应条件和环境友好的使用 试剂这些优点产生了对新的生物催化剂的需求，这些生物催化剂扩大了生物催化剂的产品组合。 合成化学家可以利用的复杂生成反应。然而，经常存在的权衡 生物催化剂的底物范围与其选择性之间的矛盾限制了酶在合成中的应用。 在这个提议中，我们探索了一组FAD-单加氧酶，TropB，AfoD，AzaH和SorbC， 互补底物的范围和高水平的网站和立体选择性在一系列的结构 不同的基质。 本研究计划旨在开发一套具有互补选择性的催化剂， 为合成生物活性分子提供了一条有价值的手性中间体的有效途径。这 研究将集中于FAF-单加氧酶、TropB、AfoD、AzaH和SorbC。我将（1）确定 （2）转置该信息以通过以下方式扩展TropB的底物范围： 利用蛋白质工程对残基进行修饰（3）通过以下方式进一步增强生物催化剂的反应性： 利用C8-FAD类似物。此类工具将提供获得有价值的手性中间体的有效途径， 生物活性分子的合成。

Project Summary Natural products are an essential source of inspiration for medicines. The World Health Organization estimates that ~80% of the world's population relies on traditional medicines made from natural products (ref). The Pharmaceutical industry has ~50% of all drugs based on or derived from natural products. Unfortunately, the synthesis of these molecules is often prohibitively complex, requiring the installation of multiple functional groups with very specific 3D architecture critical to their biological activity. Oxidative dearomatization of phenolic compounds is a powerful transformation for the synthesis of complex molecules, as it introduces stereochemistry and generates products primed for further reaction. For example, this reaction is the key step in the biosynthesis of isochromophilone II and luteusin A, inhibitors of the interaction between gp120, a glycoprotein found on the surface of HIV, and CD4, on the surface of T-cells central to the HIV invasion mechanism. Inhibition of this protein-protein interaction is hypothesized to disrupt the entry of the human immunodeficiency virus (HIV) into cells. Only a limited number of enantioselective methods have been reported for oxidative dearomatization, limiting the application of this transformation in synthetic chemistry. To achieve high degrees of stereoselectivity, stoichiometric amounts of the chiral metal complexes are required in addition to lengthy reaction times, cryogenic temperatures, and harsh conditions. Biocatalytic reactions embody many features of ideal chemical transformations, including the potential for impeccable selectivity, high catalytic efficiency, mild reaction conditions and the use of environmentally benign reagents. These advantages have created a demand for new biocatalysts that expand the portfolio of complexity-generating reactions available to synthetic chemists. However, the tradeoff that often exists between the substrate scope of a biocatalyst and its selectivity limits the application of enzymes in synthesis. On this proposal, we explore a panel of FAD-monooxygenases, TropB, AfoD, AzaH, and SorbC containing complementary substrates scopes and high levels of site- and stereoselectivity across a range of structurally diverse substrates. This research proposal aims to aim to develop a suite of catalysts with complementary selectivities in order to provide an efficient route to valuable chiral intermediates for the synthesis of bioactive molecules. This research will focus on FAF-monooxygenases, TropB, AfoD, AzaH, and SorbC. Were I will (1) Determine the binding of the panel of enzymes (2) Transpose this information to expand the substrate scope of TropB by modification of residues utilizing protein engineering (3) Further enhance the reactivity of the biocatalyst by utilizing C8-FAD analogs. Such tools will provide an efficient route to valuable chiral intermediates for the synthesis of bioactive molecules.