知识与财富的链接
采用具有喹唑啉为母核的抗肿瘤药物作为先导化合物,利用生物电子等排原理,设计并合成一系列4-(N-芳基)胺基-6-长链烷氧基取代蝶啶类化合物7a~7l,并利用MTT法测试其对A549、KG1a和HGC-27肿瘤细胞的增殖抑制作用。以3-氨基吡嗪-2-羧酸甲酯为起始底物,通过6步反应合成12种目标化合物(7a~7l)并确证其结构(1H NMR、13C NMR、MS)。生物活性试验表明,蝶啶4位为2-氯-5-硝基苯胺基取代时,其活性均高于其他苯胺基取代的产物。化合物7b对A549的活性(IC50=11.55 μmol/L)与阳性对照物吉非替尼(IC50=5.95 μmol/L)十分接近;化合物7k对3组细胞的IC50均十分接近对照物吉非替尼。由于筛选出的化合物均有2-氯-5-硝基苯胺基片段,可以此结构为基础进行深入研究。
A series of 4-(N-aryl)amino-6-alkoxyl pteridine derivatives was designed and synthesized via the bioisostere principle using anti-cancer drugs with quinazoline cores as lead compounds. The proliferative inhibitory activities of the synthesized compounds against tumor cells A549, KG1a and HGC-27 were also performed by MTT assay. Using methyl 3-aminopyrazine-2-carboxylate as the starting material, 12 target compounds(7a-7l)were synthesized through six-step reaction, and characterized by 1H NMR, 13C NMR and MS. It was showed that antitumor activity of pteridines with 2-chloro-5-nitro-anilino substituted in position 4 was more potent than that of others. The activity of compound 7b on A549 cells(IC50=11. 55 μmol/L)was closely approximate to that of positive control gefitinib(IC50=5. 95 μmol/L). IC50 values of compound 7k on three cell lines were all close to those of gefitinib. A 2-chloro-5-nitro-anilino fragment was contained in preferred compounds which might be modified for further investigation.
