摘要/Abstract

以2-吡啶甲酸和取代苯胺为原料，设计合成了17个新型二苯氨基硫脲类索拉菲尼衍生物.目标化合物均经过NMR和HRMS进行结构表征.采用人结肠癌细胞HCT116、人乳腺癌细胞MDA-MB-231、人前列腺癌细胞PC-3和小鼠黑色素瘤细胞B16BL6对目标化合物的体外抗肿瘤活性进行了研究.结果表明1-（4-氯-3-三氟甲基苯基）-3-{4-[2-（异丙氨甲酰基）吡啶-4-氨基]苯基}硫脲（9g）对四种细胞株的抑制活性均优于阳性药物索拉菲尼，1-（3-三氟甲基-4-氯苯基）-3-{4-[2-（甲基氨甲酰基）吡啶-4-氨基]苯基}硫脲（9b）和1-（3-三氟甲基-4-氟苯基）-3-{4-[2-（异丙氨甲酰基）吡啶-4-氨基]苯基}硫脲（9j）对MDA-MB-231细胞株、PC-3细胞株和B16BL6细胞株具有优于索拉菲尼的抑制活性，同时探讨了新化合物9j与B-Raf受体的三维晶体结构（5HI2）活性位点的结合模式，为今后新型索拉菲尼衍生物的设计合成提供了有用参考.
关键词: B-Raf, 分子对接, 抗肿瘤活性, 二苯氨基硫脲, 索拉菲尼衍生物
17 novel sorafenib derivatives possessing diphenylamine and thiourea structures were designed and synthesized using 2-picolinic acid and substituted anilines as raw materials. The structures of the target compounds were all characterized by NMR and HRMS. In addition, the in vitro antiproliferation activity of the target compounds was studied in human colon cancer cell HCT116, human breast cancer cell line MDA-MB-231, human prostate cancer cell line PC-3 and mouse melanoma cell line B16BL6. The results showed that 1-(4-chloro-3-trifluoromethylphenyl)-3-(4-(2-(isopropylcarbamoyl)pyridine-4-amino)phenyl)thiourea (9g) had better inhibitory activity against four cell lines than the positive drug sorafenib, and 1-(3-trifluoromethyl-4-chlorophenyl)-3-{4-[2-(methylcarbamoyl)pyridine-4-amino]phenyl}thiourea (9b) and 1-(3-trifluoro-methyl-4-fluorophenyl)-3-{4-[2-(isopropylcarbamoyl)pyridine-4-amino]phenyl}thiourea (9j) had better inhibitory activity against MDA-MB-231, PC-3 and B16BL6 cell lines. The molecular docking of the active small molecule 9j was further studied, and its binding mode with the active site of the 3-D crystal structure (5HI2) of B-Raf receptor was discussed, which provided a useful reference for the design and synthesis of novel sorafenib derivatives in the future.
Key words: B-Raf, molecular docking, an-titumor activity, diphenylamine and thiourea, sorafenib derivatives


PDF全文下载地址:

点我下载PDF