氟代索拉非尼的合成及其抗肿瘤活性研究

Synthesis and antitumor activities of fluorinated Sorafenib

以N-甲基-4-氯-2-吡啶甲酰胺为原料,经过4步共合成4个化合物(S-1,S-2,R-1和R-2),其中2个为新的化合物(S-1和R-2)。经过1H NMR,13C NMR,HR-MS等方法对其结构表征。最后通过CTG法,测试4种化合物对四种人肝癌细胞(PLC/PRF/5,Hep3B,HepG2,BEL-7402)的抑制活性。结果表明:S-1,S-2,R-1和R-2均表现较明显的对4种细胞的抑制活性,且呈现出浓度依赖关系。IC50值从1304nM到11228nM。其中化合物R-1(瑞格非尼)对PLC/PRF/5和HepG2细胞,S-1对Hep3B细胞的抑制活性,R-2对HepG2的细胞活性均较高于原药索拉非尼。

Four compounds(S-1,S-2,R-1 and R-2)including two novel compounds(S-1 and R-2)were synthesized via a four-step procedure starting from N-methyl-4-chloropyridine-2-carboxamide.Their structures were confirmed by 1H NMR,13C NMR and HR-MS.Their antitumor activities against various human hepatoma carcinoma cell lines(PLC/PRF/5,Hep3B,HepG2 and BEL-7402)in vivo were evaluated by CTG arrays.The antitumor screening assay showed that compound S-1,S-2,R-1 and R-2 exhibited obvious antitumor activities with IC50 range from 1304nM to 11228nM in concentration-dependent manner.Compound R-1(Regorafenib)(against tumor cell line PLC/PRF/5 and HepG2),compound S-1(against tumor cell line Hep3B),compound R-2(against tumor cell line HepG2)exhibited slightly better antitumor activity than Sorafenib.