2-芳基取代苯/吡啶并咪唑衍生物的合成及生物活性研究

Synthesis and biological activity of 2-aryl substituted benzene/pyridoimidazole derivatives

目的设计、合成系列2-芳基取代苯/吡啶并咪唑衍生物,进行化合物体外抗肿瘤细胞增殖活性测试,选择活性较好的化合物进行表皮生长因子受体(EGFR)、血管内皮细胞生长因子受体(KDR)和肝细胞生长因子受体(c-Met)激酶抑制活性测试。方法以6,7-双(2-甲氧基乙氧基)喹唑啉-4(3H)-酮为起始原料,经过氯代、偶联、缩合、环合反应制备目标化合物5a~5m。选择人肺癌细胞A549和人胃癌细胞SNU-5进行体外抗肿瘤增殖活性筛选,对活性较优的化合物进行体外激酶(EGFR、KDR和c-Met)抑制活性测试。结果与结论共合成13个未见文献报道的新化合物,结构经MS、^(1)H-NMR谱确证。体外抗肿瘤细胞活性研究结果表明,化合物5a和5f在测试浓度下显示出优于对照药物厄洛替尼的抗增殖活性;在测试浓度下化合物对A549抗增殖活性与阳性对照药厄洛替尼相比未见提高,在1μmol·L^(-1)浓度时化合物5a活性稍弱于阳性对照药,且苯并咪唑类衍生物活性略优于吡啶并咪唑类衍生物。选择化合物5a进行体外激酶抑制活性测试,结果显示其对EGFR、KDR及c-Met三种激酶抑制活性较弱,提示化合物5a有进一步结构改造的空间,推测喹唑啉环6,7位不同取代基可能对活性产生影响。本研究初步明确了2-芳基取代苯/吡啶并咪唑衍生物主要修饰位点,为后续深入研究构效关系提供指导。

According to literature reports,a series of new compounds were designed and synthesized by introducing a 2-aryl substituted benzene/pyridoimidazole fragment into the quinazoline core.Using 6,7-bis(2-methoxyethoxy)quinazolin-4(3 H)-one as the starting material,the target compounds were prepared through chlorination,coupling,condensation,and ring closure reactions.Threeteen new target compounds(5 a-5 m)were synthesized,and their structures were confirmed by MS and ^(1)H-NMR spectra.Compounds5 a and 5 f show ed better anti-proliferative activity to SNU-5 cells than erlotinib at the test concentration.Further tests show ed that the inhibitory activity of compound 5 a on EGFR,KDR and c-Met kinases was weak.It is speculated that the different substituents at 6,7 positions of quinazoline ring may affect the activity,which needs further investigation.