Identification of novel 3-aryl-1-aminoisoquinolines-based KRASG12C inhibitors: Rational drug design and expedient construction by CH functionalization/annulation

• Published in: Bioorganic chemistry Vol. 142; p. 106954
• Main Authors: Gong, Zirong, Zhao, Yu, Xu, Buyi, Yang, Zhou, Ren, Boquan, Yang, Han, Zeng, Chengfu, Chen, Renqiang, Xu, Yan-Jun, Li, Qing
• Format: Journal Article
• Language: English
• Published: 01-01-2024
• ISSN: 1090-2120
• DOI: 10.1016/j.bioorg.2023.106954

Developing a synthetic methodology to expediently construct a specific drug scaffold with the desired biological activity remains challenging. Herein, we describe a work on rational application of a synthetic methodology in the synthesis of KRASG12C inhibitors. Novel KRASG12C inhibitors were initially designed with 1-amino-3-aryl isoquinoline scaffold using structure-based drug design strategy. A ruthenium-catalyzed direct monoCH functionalization/annulation cascade reaction of amidines and sulfoxonium ylides was then developed with high versatility of substrates and good tolerance for polar functional groups. By using this reaction, the target compounds 1-amino-3-aryl isoquinolines were facilely prepared. Further in vitro tests led to identification of two novel lead compounds with KRASG12C inhibitory activity.