通过催化C‒H化合成用于PROTAC应用的异构功能分子的后期合成
Daniele Antermite1, Stig D Friis1, Johan R Johansson1
1Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
蛋白质溶解向金马体 (PROTACs) 的合成通过一种新的催化C-H化简化. 这种方法有效地创建复杂的PROTAC和用于药物发现和化学生物学的合物.
科学领域:
- 药用化学 医学化学
- 有机合成 有机合成
- 化学生物学 化学生物学
背景情况:
- 蛋白质溶解向金马 (PROTACs) 是药物发现的有希望的异质双功能分子.
- PROTAC的合成和结构-活动关系的阐明带来了重大挑战.
- 模块化和可靠的合成策略对于 PROTAC 开发至关重要.
研究的目的:
- 开发一种强大的催化后期C-H化策略,用于PROTAC合成.
- 为了使链接器能够在复杂的生物活性分子上有效和选择性地安装链接器.
- 为了证明用于治疗和化学生物学应用的PROTAC合物的合成.
主要方法:
- 催化后期C-H化使用二佐试剂.
- 复杂的生物活性分子的后期功能化.
- 在单个步骤中合成CRBN和生物联体.
主要成果:
- 在具有高选择性和功能组耐受性的多种复杂分子上成功进行C-H化.
- 连接器的高效安装与直角的功能柄,以进一步阐述.
- 证明了CRBN和生物PROTAC合物的单步合成.
结论:
- 开发的C-H化策略为PROTAC合成提供了一个模块化和可靠的方法.
- 这种方法提供了有效和可持续的访问先进的治疗和化学生物学工具.
- 催化胺化显著简化了复杂的异构功能分子的产生.
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