6-芳氧基取代喹唑啉衍生物的设计、合成及体外抗肿瘤活性评价

Design, synthesis, and in vitro antitumor activity evaluation of 6-aryloxyl substituted quinazoline derivatives

目的 基于波奇替尼的结构,设计合成6-芳氧基取代喹唑啉衍生物,以研究其抑制EGFR活性。方法 以4-[(3,4-二氯-2-氟苯基)氨基]-7-甲氧基喹唑啉-6-醇为起始原料,经取代和还原反应得到关键中间体3a~3e,中间体3a~3e经酰化反应合成目标化合物4a~4t。通过MTT法评价目标化合物的体外抗肿瘤活性。结果与结论合成了20个未见文献报道的6-芳氧基取代喹唑啉化合物,其结构均经H-NMR和HR-MS谱确证。其中化合物4k活性最佳,对N87和H1975细胞系显示出较好的抗肿瘤活性,IC值分别为6.3 nmol·L^(-1)和7.5 nmol·L^(-1),具有进一步研究价值。

Based on the structure of poziotinib, novel 6-aryloxyl substituted quinazoline derivatives were synthesized and their structures were confirmed by ~1H-NMR and HR-MS.The in vitro antitumor activity was evaluated by MTT method using human gastric cancer N87(HER),non-small cell lung cancer H1975(EGFR),and A549(EGFR) cell lines.Particularly, compound 4 k exhibited potent antitumor activity with ICvalues of 6.3 nmol·L^(-1)and 7.5 nmol·L^(-1)against N87 and H1975 cell lines, respectively.The results demonstrated that the modification of C-6 in quinazoline had certain research value, which can provide leading compound for the development of new quinazoline anticancer drugs in the future.