摘要/Abstract

为了寻找高效的抗肿瘤药物，设计并合成了一系列新型的2，4-取代喹唑啉类衍生物，采用噻唑蓝（MTT）法对目标化合物在人类胃癌细胞（MGC-803）、乳腺癌细胞（MCF-7）和人正常胃黏膜上皮细胞GES-1进行抗肿瘤活性评价，结果显示部分化合物对MGC-803和MCF-7表现出中度至强效的抗肿瘤活性.喹唑啉的4位被不同芳胺取代时，2-（（（1H-苯并[d]咪唑-2-基）甲基）硫基）-N-（4-甲氧基苯基）喹唑啉-4-胺（15e）对MGC-803具有较好的抗肿瘤活性，IC₅₀值为4.60 μmol·L^-1；喹唑啉的4位被不同查尔酮取代时，（E）-1-（4-（（2-（（（1H-苯并[d]咪唑-2-基）甲基）硫基）喹唑啉-4-基）氨基）苯基）-3-（3-硝基苯基）丙-2-烯-1-酮（15k）对MGC-803具有很强的抗肿瘤活性，IC₅₀值为0.97 μmol·L^-1，明显优于化合物15e.但是化合物15e对GES-1的毒性远远大于化合物15k，化合物15k的毒性与对照药品5-氟尿嘧啶和吉非替尼相近.分子对接结果显示，化合物15k与表皮生长因子受体（EGFR）的结合模式优于15e，为研究新型的EGFR抑制剂提供了新的思路.
关键词: 喹唑啉, 苯并咪唑, 合成, 抗肿瘤活性
In order to find more efficient and economical antitumor drugs, a series of novel 2,4-substituted quinazoline derivatives containing benzimidazole were designed, synthesized and evaluated for their antitumor activities on two human tumor cell lines including human gastric cancer cells (MGC-803), human breast cancer cells (MCF-7) and the normal human gastric epithelial cell line (GES-1) by using thiazolyl blue tetrazolium bromide (MTT) assay in vitro. Among all the tested compounds, some compounds displayed moderate to potent antitumor activities against MGC-803 and MCF-7. When the 4-position of quinazoline was substituted by different aromatic amines, 2-(((1H-benzo[d]imidazol-2-yl)methyl)thio)-N-(4-methoxyphen-yl)quinazolin-4-amine (15e) had good anti-tumor activity against MGC-803 with IC₅₀ value of 4.60 μmol·L^-1. When the 4-position of quinazoline was replaced by different chalcone, (E)-1-(4-((2-(((1H-benzo[d]imidazol-2-yl)methyl)thio)quinazo-lin-4-yl)amino)phenyl)-3-(3-nitrophenyl)prop-2-en-1-one (15k) had a strong anti-tumor activity against MGC-803 with IC₅₀ value of 0.97 μmol·L^-1, which was significantly better than compound 15e. However, the toxicity of compound 15e was more serious than compound 15k whose toxicity was similar to that of the control drug 5-fluorouracil and gefitinib against GES-1. The result of docking with epidermal growth factor receptor (EGFR) suggested that the binding mode of 15k was better than that of 15e. It is believed that this work would be very useful for developing a new series of EGFR inhibitors.
Key words: quinazoline, benzimidazole, synthesis, antitumor activities


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