Identification of novel 3-aryl-1-aminoisoquinolines-based KRASG12C inhibitors: Rational drug design and expedient construction by C-H functionalization/annulation
Bioorganic Chemistry(2024)
Abstract
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 mono-C-H 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.
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Key words
KRAS G12C inhibitors,1-aminoisoquinolines,C -H functionalization,Annulation,Synthetic methodology
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