6-位修饰的吉非替尼衍生物合成及细胞毒活性研究

Synthesis and Cytotoxic Activity of 6-Modified Gefitinib Derivatives

以2-氨基-4,5-二甲氧基苯甲酸为起始原料,经关环,选择性脱甲基,醋酸酐保护,氯代,与3-氯-4-氟苯胺取代,去保护得到关键中间体4-(3-氯-4-氟苯胺)-7-甲氧基-喹唑啉-6-醇.再经过6-位羟基成醚、成酯反应合成了共计23个吉非替尼衍生物.所有目标化合物通过IR,1H NMR,13C NMR,HRMS等结构确证.并采用四甲基偶氮唑盐(MTT)法对所得目标化合物进行了细胞毒活性测试,结果发现部分化合物具有一定的抑制活性,其中化合物7b,7c,7d,8a,8m抑制人非小细胞肺癌细胞(A549)增殖活性和化合物7c,8m抑制人肝癌细胞(Hep G-2)增殖活性与吉非替尼相当.

Twenty-three derivatives of gefitinib have been synthesized by etherification and esterification of4-（3-chloro-4-fluoroanilino）-6-hydroxy-7-methoxy quinazoline, which was prepared from 2-amino-4,5-dimethoxy-benzoic acid through the reactions of cyclization, selective demethylation, acetyl protection, chlorination, substitution with 3-chloro-4-fluoro-benzenamine and deprotection, respectively. The structures of the target compounds were characterized by IR, 1H NMR, 13 C NMR and HRMS spectra. All the title compounds were evaluated for cytotoxic activity against human non-small-cell-lung cancer cells lines（A549） and human hepatoma cell lines（Hep G2） by methyl thiazolyl tetrazolium（MTT） method. The results showed that the cytotoxic activities of compounds 7b, 7c, 7d, 8a, 8m against human non-small-cell-lung cancer cells lines and compounds 7c, 8m against human hepatoma cell lines were comparable to those of gifitinib.