Li Shun, Shi Yonglin, Tang Juan, Yan Meixin, Huang Shunyao, Dou Tingying, Wang Shenxiang, Jin Xinchao, Su Zhishan, Jiang Weidong, Xu Jiaqi, Zheng Xueli, Li Ruixiang, Chen Hua, Xue Weichao, Fu Haiyan
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, Sichuan, PR China.
College of New Energy Materials and Chemistry, Leshan Normal University, Leshan, Sichuan, PR China.
Nat Commun. 2025 Aug 2;16(1):7112. doi: 10.1038/s41467-025-62547-7.
Scaffold hopping is a key strategy in drug discovery. While one-to-one scaffold hopping strategies are thriving and evolving, one-to-multiple strategies remain challenging to design. We present here a distinct scaffold hopping strategy for the skeletal editing of pyrimidines into a wide range of heteroarenes through the addition of nucleophiles, ring-opening, fragmentation, and ring-closing (ANROFRC) processes. This method features the in situ generation of a vinamidinium salt intermediate, which serves as a unique N-C-C-C four-atom (A4) synthon that reacts with A1 and A2 synthons. Mechanistic studies reveal that C4-aryl substituents play a crucial role in stabilizing the vinamidinium salt intermediate. This work provides a powerful tool for the systematic construction and modification of nitrogen heterocycles, thereby expanding conventional molecular editing techniques.
骨架跃迁是药物发现中的关键策略。虽然一对一的骨架跃迁策略蓬勃发展且不断演变，但一对多的策略在设计上仍具有挑战性。我们在此提出一种独特的骨架跃迁策略，通过亲核试剂的添加、开环、碎片化和闭环（ANROFRC）过程，将嘧啶进行骨架编辑转化为多种杂芳烃。该方法的特点是原位生成脒鎓盐中间体，它作为一种独特的N-C-C-C四原子（A4）合成子与A1和A2合成子反应。机理研究表明，C4-芳基取代基在稳定脒鎓盐中间体方面起着关键作用。这项工作为氮杂环的系统构建和修饰提供了一个强大的工具，从而扩展了传统的分子编辑技术。
