Your browser doesn't support javascript.
loading
Synthesis of sorafenib analogues incorporating a 1,2,3-triazole ring and cytotoxicity towards hepatocellular carcinoma cell lines.
Palakhachane, Sarinya; Ketkaew, Yuwaporn; Chuaypen, Natthaya; Sirirak, Jitnapa; Boonsombat, Jutatip; Ruchirawat, Somsak; Tangkijvanich, Pisit; Suksamrarn, Apichart; Limpachayaporn, Panupun.
Afiliação
  • Palakhachane S; Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom 73000, Thailand.
  • Ketkaew Y; Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
  • Chuaypen N; Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
  • Sirirak J; Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom 73000, Thailand.
  • Boonsombat J; Chulabhorn Research Institute, Bangkok 10210, Thailand.
  • Ruchirawat S; Chulabhorn Research Institute, Bangkok 10210, Thailand; Chulabhorn Graduate Institute, Chemical Biology Program, Chulabhorn Royal Academy, Kamphaeng Phet 6 Road, Bangkok 10210, Thailand.
  • Tangkijvanich P; Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
  • Suksamrarn A; Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok 10240, Thailand.
  • Limpachayaporn P; Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom 73000, Thailand. Electronic address: limpachayaporn_p@silpakorn.edu.
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.
Assuntos
Palavras-chave

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

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