Synthesis of sorafenib analogues incorporating a 1,2,3-triazole ring and cytotoxicity towards hepatocellular carcinoma cell lines.
Bioorg Chem
; 112: 104831, 2021 07.
Article
em En
| MEDLINE
| ID: mdl-33831675
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 significant 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) towards Huh7 which is much superior to that of Sorafenib (SI = 6.73). The molecular docking studies revealed that the analogue 2m bound B-RAF near the binding position of Sorafenib, while it interacted VEGFR2 efficiently at the same binding position of Sorafenib. However, 2m exhibited moderate inhibitory activity toward B-RAF, implying that its anti-Huh7 effect might not strictly relate to inhibition of B-RAF. Wound healing and BrdU cell proliferation assays 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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Triazóis
/
Sorafenibe
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Tailândia