Abstract

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.

摘要

索拉非尼被推荐为肝细胞癌患者的主要治疗药物。为了发现一种避免索拉非尼治疗中出现的低反应率和毒副作用的新化合物，我们设计并合成了索拉非尼和 2,4,5-trimethylpyridin-3-ols 的新型杂化化合物。化合物6被选为抑制四种 Raf 激酶中每一种的 24 种杂交体中最好的。6在 HepG2、Hep3B 和 Huh7 细胞系中的抗增殖活性略低于索拉非尼。然而，在 H6c7 和 CCD841 正常上皮细胞系中，6的细胞毒性远低于索拉非尼。此外，与索拉非尼类似，化合物6抑制Hep3B细胞球体形成能力植入 Huh7 细胞的小鸡绒毛膜尿囊膜的异种移植肿瘤模型中的体外和肿瘤生长。化合物6可能是一种有前景的靶向肝细胞癌的候选物，对正常细胞的毒副作用小。