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: 10029605
• 负责人: FRANCES H ARNOLD
• 金额: $ 32.24万
• 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/10029605
• 关键词: Alkylation; Amination; 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; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Process; Property; Reaction; Reagent; Research; Scaffolding Protein; Side; Structure; Technology; Terpenes; Transferase; 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 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 functionalization 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