The synthesis and biological evaluation of novel deuterated and non-deuterated aminobenzenesulfonamide derivatives as EGFR inhibitor.

Twenty novel pyrimidine derivatives of deuterated and non-deuterated aminobenzenesulfonamide molecules were designed and synthesized, and their potential application as epidermal growth factor receptor (EGFR) inhibitors for non-small cell lung cancer (NSCLC) was evaluated. The anti-tumor cell proliferation assay demonstrated that most of the synthesized compounds had good inhibitory activity against H1975-EGFR L858R/T790M and PC9-EGFR Del19 tumor cells, with IC₅₀ values in the nanomolar range. Among them, the IC₅₀ values of the lead compound 12b against H1975 and PC9 cells were 12 nM and 16 nM respectively. In rat liver microsomal stability assays, the half-life of deuterated compound 12b was significantly longer than that of its non-deuterated analog 12l. Mechanistic studies revealed that 12b inhibits tumor cell proliferation, induces cell apoptosis, and suppresses tumor cell migration by binding to EGFR and inhibiting its phosphorylation as well as downstream signaling pathways. In H1975 xenograft nude mouse models, 12b achieved a tumor growth inhibition (TGI) rate of 94% at an oral dose of 10 mg/kg. Collectively, these results suggest that 12b holds promising research potential as a highly effective anti-cancer agent for NSCLC.