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: 10649561
• 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/10649561
• 关键词: Acceleration; Alkylation; Amination; Azides; Catalysis; Chemicals; Chemistry; Collection; Complex; Creativeness; Cytochrome P450; Derivation procedure; 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; Process; Property; Reaction; Reagent; Research; Scaffolding Protein; Side; Structure; Technology; Terpenes; Transferase; Work; antimicrobial; carbene; catalyst; chemical synthesis; diazo compound; drug development; drug discovery; functional group; improved; innovation; manufacture; nitrene; novel; pharmacologic; polyketides; 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 分子构建和多样化的进展加速了药物的发现和开发。鉴于 由于C-H键在分子中普遍存在，将它们选择性地转化为官能团的方法代表了一种 这是最有吸引力的策略，可以有效地引入多样性并实现快速分子构建。 然而，尽管取得了重大进展，直接和选择性地官能化携带 多个立体中心和精细官能团仍然是一个重大挑战。创造性地使用酶， 进行新的自然C-H官能化反应可以大大加速这种过程，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羟基化衍生复杂生物活性分子的酶开始， 通过定向进化来工程化它们以进行非生物C-H官能化以提供新的C-C键，或者 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， 获得复杂分子的衍生物，其选择性和效率是当前合成方法无法达到的。 接近。这项工作还将说明进化创新机制和快速获取 新的基因编码功能。

项目成果

An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes.

• DOI: 10.1021/jacs.1c11340
• 发表时间: 2022-01-12
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Liu Z;Qin ZY;Zhu L;Athavale SV;Sengupta A;Jia ZJ;Garcia-Borràs M;Houk KN;Arnold FH
• 通讯作者: Arnold FH

Navigating the Unnatural Reaction Space: Directed Evolution of Heme Proteins for Selective Carbene and Nitrene Transfer.

• DOI: 10.1021/acs.accounts.0c00591
• 发表时间: 2021-03-02
• 期刊: Accounts of chemical research
• 影响因子: 18.3
• 作者: Yang Y;Arnold FH
• 通讯作者: Arnold FH

New-to-nature chemistry from old protein machinery: carbene and nitrene transferases.

• DOI: 10.1016/j.copbio.2020.12.005
• 发表时间: 2021-06
• 期刊: Current opinion in biotechnology
• 影响因子: 7.7
• 作者: Liu Z;Arnold FH
• 通讯作者: Arnold FH