Synthesis and anti-hepatocellular carcinoma activity of aminopyridinol-sorafenib hybrids

• Egile Nagusiak: Bhuwan Prasad Awasthi (Egilea), Prakash Chaudhary (Egilea), Diwakar Guragain (Egilea), Jun-Goo Jee (Egilea), Jung-Ae Kim (Egilea), Byeong-Seon Jeong (Egilea)
• Formatua: Liburua
• Argitaratua: Taylor & Francis Group, 2021-01-01T00:00:00Z.
• Gaiak: article
• Sarrera elektronikoa: Connect to this object online.
• Notes: 1475-6366; 1475-6374; 10.1080/14756366.2021.1953997
• Keywords: molecular hybridisation; raf kinase; hepatocellular carcinoma; tumour spheroid formation; antitumour activity; Therapeutics. Pharmacology; RM1-950
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1884-1897 (2021)

Sorafenib is recommended as the primary therapeutic drug for patients with hepatocellular carcinoma. To discover a new compound that avoids low response rates and toxic side effects that occur in sorafenib therapy, we designed and synthesized new hybrid compounds of sorafenib and 2,4,5-trimethylpyridin-3-ols. Compound 6 was selected as the best of 24 hybrids that inhibit each of the four Raf kinases. The anti-proliferative activity of 6 in HepG2, Hep3B, and Huh7 cell lines was slightly lower than that of sorafenib. However, in H6c7 and CCD841 normal epithelial cell lines, the cytotoxicity of 6 was much lower than that of sorafenib. In addition, similar to sorafenib, compound 6 inhibited spheroid forming ability of Hep3B cells in vitro and tumour growth in a xenograft tumour model of the chick chorioallantoic membrane implanted with Huh7 cells. Compound 6 may be a promising candidate targeting hepatocellular carcinoma with low toxic side effects on normal cells.