6-三氮唑-4-氨基喹唑啉类新型抗肿瘤药物的合成及活性研究

Synthesis and activity of 6-triazolyl-4-aminoquinazoline new anti-tumor drugs

目的:找到活性更好的的新结构抗肿瘤药物。方法:以氨基苯甲酸为原料,经碘代、合环、氯代、亲核反应、Sonogashira偶联并脱掉三甲基硅基,与叠氮化合物反应6步反应得三氮唑中间体,最后Suzuki偶联得到18个目标化合物,其结构均经1H-NMR和LC-MS确证。用MTT法评价了其对EGFR高表达的乳腺癌细胞株SKBR3和非小细胞肺癌细胞株A549的抑制活性。结果与结论:大多数化合物对A549细胞株的抑制能力均比拉帕替尼强,其中化合物7对SKBR3和A549细胞株均表现出强于对照药拉帕替尼的细胞活性,IC50分别是4.7,0.025 mol·L-1,小鼠体内代谢优异,并且对A549细胞有一定的治疗作用,有可能弥补拉帕替尼在非小细胞肺癌治疗方面的不足。

Objective：To explore the antitumor drugs with a new structure and better activity.Methods：2-Aminobenzoic acid was used as raw material;then the triazole intermediates was synthesized by iodine generation reaction,cyclization,chlorination,nucleophilic reaction,Sonogashira coupling,deprotection and combined with azides;finally,18 target compounds were generated via Suzuki coupling.Their structures were confirmed by1H-NMR and LC-MS.The in vitro anti-proliferative activity in SKBR3 and A549 cells was assessed by MTT detection assay.Results and Conclusion：The inhibiting activities of most compounds were stronger than lapatinib in A549 cells.The inhibitory activity of compound 7 was higher than the marketed drug lapatinib in both cell lines;its pharmakinetic properties were excellent in mice;it was effective in A549 cells.The compound may compensate the inadequacy of lapatinib in the treatment of non-small cell lung cancer.