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

用于生物活性分子构建和多样化的非生物酶 C–H 功能化

• 批准号: 10386710
• 负责人: FRANCES H ARNOLD
• 金额: $ 2.48万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386710
• 关键词: Alkylation; Amination; Award; Azides; Catalysis; Chemicals; Chemistry; Collection; Complex; Cytochrome P450; Development; Directed Molecular Evolution; Engineering; Enzymes; Evolution; Family; Goals; Heme; Heme Iron; Hydrogen Bonding; Hydroxylation; Iron; Laboratories; Metals; Methods; Molecular; Nature; Nitrogen; Parents; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Process; Property; Reaction; Reagent; Research; Scaffolding Protein; Side; Structure; Technology; Terpenes; Transferase; Variant; Work; antimicrobial; base; c new; carbene; catalyst; chemical synthesis; diazo compound; drug development; drug discovery; functional group; improved; innovation; nitrene; novel; scaffold; small molecule; tool

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.

项目摘要（父母奖R01GM138740：生物活性的物质酶促C – H功能化 分子构造和多样化） 分子建设和多元化的进步加速了药物发现和开发。鉴于 C – H键在分子中的普遍性，选择性转化为官能团的方法代表其中之一 有效地引入多样性并实现快速分子结构的最有吸引力的策略。尽管 然而，显着进步直接和有选择地使具有多个的复合物分子官能化 立体中心和精致的功能组仍然是一个重大挑战。创造酶的创造性使用 新的C – H功能化反应可以极大地加速此类过程，同时提供 可持续和更具选择性的替代方法，用于当前使用的化学计量方法或高贵的金属催化剂。 我们建议从通过C – H羟基化衍生复合生物活性分子的酶开始 通过指示进化来对他们进行工程，以执行实践C – H的易算法，以提供新的C – C债券或 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，该平台将提供快速 通过当前合成的选择性和效率无法获得的选择性和效率，访问复杂分子的衍生物 方法。这项工作还将说明进化创新机制和新颖的快速获取 遗传编码的功能。