Synthesis of Sorafenib Analogues Incorporating a 1,2,3-Triazole Ring and Cytotoxicity towards Hepatocellular Carcinoma Cell Lines

Abstract A series of 1,2,3-triazole-containing Sorafenib analogues, in which the aryl urea moiety of Sorafenib (1) was replaced with a 1,2,3-triazole ring linking a substituted phenoxy fragment, were prepared successfully via Huisgen 1,3-dipolar cycloaddition and nucleophilic aromatic substitution. The studies of cytotoxicity towards human hepatocellular carcinoma (HCC) cell lines, HepG2 and Huh7, indicated that p-tert-butylphenoxy analogue 2m showed significantly inhibitory activity against Huh7 with IC50 = 5.67 ± 0.57 µM. More importantly, 2m showed low cytotoxicity against human embryonal lung fibroblast cell line, MRC-5, with IC50 >100 µM, suggesting its highly selective cytotoxic activity (SI >17.6) toward Huh7 cell line which is much superior to that of Sorafenib (SI = 6.73). The molecular docking studies revealed that the analogue 2m bound B-RAF and VEGFR-2 efficiently near the binding position of Sorafenib. Wound healing and BrdU cell proliferation assay confirmed anti-cell migration and anti-cell proliferative activities towards Huh7. With its inhibitory efficiency and high safety profile, 2m has been identified as a promising candidate for the treatment of HCC.