Abiological Enzymatic C–H Functionalization for Bioactive Molecule Construction and Diversification

项目摘要(家长奖R01GM138740：生物活性的非生物酶C-H功能化 分子结构和多样化) 分子结构和多样化的进步加速了药物的发现和开发。给定 分子中普遍存在的C-H键，选择性地将它们转化为官能团的方法代表以下方法之一 最吸引人的策略是有效地引入多样性并实现快速的分子构建。尽管 然而，重要的进展是，直接和选择性地使含有多个 立体中心和微妙的官能团仍然是一个重大挑战。创造性地使用酶进行表演 新的C-H官能化反应可以极大地加速这一过程，同时提供 目前使用的化学计量方法或贵金属催化剂的可持续和更具选择性的替代品。 我们建议从通过C-H羟基化和C-H羟基化衍生复杂生物活性分子的酶开始 通过定向进化来设计它们，以执行非生物C-H官能化，以提供新的C-C键或 C-N键。我们设想，这些努力将建立一个多功能的生物催化平台，将提供快速 获得复杂分子的衍生物，其选择性和效率是目前合成方法所无法达到的 接近了。这项工作还将说明进化创新机制和小说的快速获得 基因编码的功能。

Project Abstract (parent award R01GM138740: Abiological Enzymatic C–H Functionalization for Bioactive Molecule Construction and Diversification) Advances in molecule construction and diversification expedite drug discovery and development. Given the ubiquity of C–H bonds in molecules, methods to selectively convert them into functional groups represent one of the most attractive strategies to introduce diversity efficiently and enable rapid molecular construction. Despite significant advances, however, directly and selectively functionalizing complex molecules bearing multiple stereocenters and delicate functional groups remains a major challenge. Creative use of enzymes to perform new-to-nature C–H functionalization reactions can greatly accelerate such processes, while providing sustainable and more selective alternatives to currently used stoichiometric methods or noble metal catalysts. We propose to start from enzymes that derivatize complex bioactive molecules via C–H hydroxylation and engineer them by directed evolution to perform abiological C–H unctionalization to furnish new C–C bonds or C–N bonds. We envision that these efforts will establish a versatile biocatalytic platform that will provide rapid access to derivatives of complex molecules with selectivity and efficiency unattainable by current synthetic approaches. This work will also illustrate evolutionary innovation mechanisms and the rapid acquisition of novel genetically encoded functions.