摘要
目的设计并合成结构新颖的N-甲基-4-苯氧基吡啶-2-甲酰胺衍生物,并对其抗肿瘤活性进行初步评价。方法通过分析索拉菲尼与B-Raf激酶的共结晶模型,在保留其药效团的基础上,设计了16个目标化合物,以吡啶甲酸为原料,经氯代、酯化、取代、还原、氨解及与取代的氨基甲酸苯酯反应制得9个目标化合物;经氯代、氨解、取代及与取代的氨基甲酸苯酯反应得到7个目标化合物;以索拉菲尼为阳性对照,采用MTT法,评价目标化合物对人肺癌细胞株H460、人结肠癌细胞株HT-29和人胃癌细胞株MKN-45增殖的抑制活性。结果与结论部分目标化合物显示出较好的抗肿瘤活性,活性优于或与索拉菲尼相当,其中化合物9b和12f的活性突出。初步构效关系研究表明,末端苯环上取代基的电性效应和取代位置对化合物的活性具有显著影响。
Based on the leading compound structure of sorafenib, new N-methyl-4-phenoxypicolinamide derivatives bearing a biuret moiety were designed. Starting from picolinic acid, 16 target compounds were synthesized through six steps or four steps including chlorination, esterification, substitution, aminolysis and so on. Their in vitro antitumor activities were evaluated against three cancer cell lines, namely H460, HT-29 and MKN-45 ,using standard MTT assay. Some compounds exhibited good antitumor activity, similar to or even higher than that of sorafenib. Compound 9b showed the best potency against H460, HT-29 and MKN-45 cells with IC50 values of 1.1,2. 3 and 13.1 μmol.L^-1 respectively. And compound 12f showed the best potency against H460, HT-29 and MKN-45 cells with IC50 values of 2.3,1.7 and 4. 7 μmol. L ^- 1 respectively. Preliminary structure-activity relationships revealed that the electron property, nature and substituted position of substituents on terminal phenyl ring were all related to antitumor potency.
出处
《中国药物化学杂志》
CAS
CSCD
2014年第5期345-350,共6页
Chinese Journal of Medicinal Chemistry
基金
国家基础科学人才培养基金项目(J1103606)
