吡唑并[1,5-a]嘧啶/喹唑啉芳胺衍生物的设计、合成与抗肿瘤活性研究

Design,synthesis and antitumor activity of a series of novel pyrazolo[1,5-a]pyrimidine/quinazoline arylamine derivatives

为寻找具有较高抗肿瘤活性的含氮稠环先导化合物,基于生物电子等排原理,本文首次设计并合成了9个未见文献报道的吡唑并[1,5-a]嘧啶/喹唑啉芳胺衍生物,其结构经核磁共振氢谱、质谱及红外光谱确证。采用CCK-8试剂盒检测法进行了体外抗肿瘤活性测试,结果表明:所合成的部分化合物对人肺癌细胞A549和非小细胞肺癌细胞H1975具有较好的抑制作用。其中,化合物14c对于肿瘤细胞A549和H1975的半数抑制浓度(IC50)分别为32.15μmol·L^(-1)和29.39μmol·L^(-1),化合物19b对肿瘤细胞A549和H1975的IC50值为54.9μmol·L^(-1)和3.107μmol·L^(-1),均优于阳性对照药物Larotrectinb(对A549和H1975细胞系的IC50值均大于200μmol·L^(-1))。对化合物14c和19b进行了ADME预测和分子对接,结果显示这两种化合物分别对EGFRwt和EGFRL858R/T790M激酶的ATP口袋具有较高的契合度,表明其具有进一步的研究价值。

To develop nitrogen-containing fused ring lead compounds with high antitumor activity,in this paper,nine pyrazolo[1,5-a]pyrimidine/quinazoline arylamine derivatives were first designed,synthesized,and reported based on the bioisosterism principle,and their structures were confirmed by 1 H NMR spectroscopy and IR spectroscopy.The in vitro antitumor activity tests were per formed using CCK-8 kit assay,and the results showed that the synthesized partial compounds exhibited good inhibitory effects on human lung cancer cell line A549 and non-small cell lung cancer cell line H1975.Among them,compound 14c exhibited half maximal inhibitory concentration(IC50)values of 32.15μmol·L^(-1)and 29.39μmol·L^(-1)for tumor cells A549 and H1975,and compound 19b exhibited IC50 values of 54.9μmol·L^(-1)and 3.107μmol·L^(-1)for tumor cells A549 and H1975,which were superior to the positive control drug larotrectinb(IC50 values greater than 200μmol·L^(-1)for both A549 and H1975 cell lines).ADME prediction and molecular docking were also performed for compounds 14c and 19b,and the results showed that these two compounds had a high fit to the ATP pocket of EGFRwt and EGFRL858R/T790M kinases,respectively,indicating their potential for further investigation.