苯胺基嘧啶/偶氮鎓二醇盐杂合物的设计、合成及其抗非小细胞肺癌活性

Design, synthesis and anti-NSCLC activity of hybrids of anilinopyrimidines and diazeniumdiolates

摘要: 为寻找活性强的抗非小细胞肺癌(NSCLC)药物，设计、合成了15个结构新颖的苯胺基嘧啶/偶氮鎓二醇盐杂合物 9a ~ 9e 、 10a ~ 10e 、 11a ~ 11e ，采用MTT法考察其对表皮生长因子受体(EGFR)L858R/T790M突变的人肺腺癌细胞H1975的增殖抑制活性。结果表明，化合物 9a ~ 9 e 显著抑制H1975细胞的增殖，优于对照药吉非替尼(gefitinib)。其中，化合物 9b 活性最强(IC₅₀=0.65 μmol/L)。分子对接提示，化合物 9b 可能通过氢键和静电作用力等与EGFR T790M活性部分结合，值得进一步研究。

Abstract: To search for potent drugs against non-small-cell lung cancer(NSCLC), a series of hybrids( 9a - 9e , 10a - 10e and 11a - 11e) from anilinopyrimidines and diazeniumdiolates were designed and synthesized. The MTT assay was employed to evaluate their antiproliferative activity against H1975 cells harboring epithelial growth factor receptor(EGFR)L858R/T790M mutation. The results showed that compounds 9a - 9e displayed remarkable inhibitory activity on H1975 cells. Among these compounds, the most potent was compound 9b (IC₅₀=0. 65 μmol/L), which was superior to the positive control gefitinib. Additionally, molecular docking study indicated that 9b could bind with EGFR T790M by forming hydrogen bond, electrostatic interactions, et al, suggesting that compound 9b may be a potential anti-NSCLC agent for further investigation.