含苯并咪唑的2,4-取代喹唑啉衍生物的合成及抗肿瘤活性评价（英文）

Synthesis and Antitumor Evaluation of 2,4-Substituted Quinazoline Derivatives Containing Benzimidazole

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4.60μmol·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0.97μmol·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.

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-（（（1 H-benzo[d]imidazol-2-yl）methyl）thio）-N-（4-methoxyphenyl）quinazolin-4-amine（15 e） 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-（（（1 H-benzo[d]imidazol-2-yl）methyl）thio）quinazolin-4-yl）amino）phenyl）-3-（3-nitrophenyl）prop-2-en-1-one（15 k） had a strong anti-tumor activity against MGC-803 with IC50 value of 0.97 μmol·L-1, which was significantly better than compound 15 e. However, the toxicity of compound 15 e was more serious than compound 15 k 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 15 k was better than that of 15 e. It is believed that this work would be very useful for developing a new series of EGFR inhibitors.