6-取代亚甲肼基-2,4-双吗啉嘧啶及三嗪类衍生物的合成与抗肿瘤活性研究

Synthesis and antitumor activity of novel 6-substituted methylenehydrazinyl-2,4-bismorpholino-pyrimidine and 1,3,5-triazine derivatives

目的设计合成一系列6-取代亚甲肼基嘧啶及三嗪衍生物,并对其体外抗肿瘤活性进行初步评价。方法以2,4,6-三氯嘧啶或三聚氯氰、苯胺、苯并咪唑、吡咯为起始原料,经多步反应合成目标化合物;采用MTT法,以BMCL-200908069-1为阳性对照药,以H460、A549和H226为测试细胞株,对目标化合物进行抗肿瘤活性评价。结果合成了20个未见文献报道的6-取代亚甲肼基-2,4-双吗啉嘧啶及三嗪类化合物,其结构经MS、1H-NMR谱确证。结论体外活性实验显示:该系列化合物具有较强的抗肿瘤活性,其中,化合物6a活性最佳,其对H460、A549和H226抑制作用的IC50值分别为3.4、0.75、0.86μmol.L-1,其活性为阳性对照药的2.8～16.8倍。

A series of 6-substituted methylenehydrazinyl-2,4-bismorpholino-pyrimidine and 1,3,5-triazine derivatives were synthesized and their chemical structures were confirmed by I H-NMR and MS spectra. As the raw materials, 2,4,6-trichloropyrimidine or cyanuric chloride, aniline, benzimidazole, and pyrrole were used to obtain the title compounds by multi-step reactions including substitution, cyclization, N-alkylation, and Vilsmeier reaction. All the synthesized compounds were evaluated for their antitumor activities against three cancer cell lines（ H460 ,A549 and H226） by the MTT method and BMCL-200908069-1 as the positive control. Most of the prepared compounds exhibited moderate cytotoxic activities and high selectivity against H460 cancer cell line and A549 compared with the positive control compound. The pharmacological data in- dicated that the introduction of substituted aryl methylene group was favorable for increasing the antitumor activity. The most promising compound 6a showed a strong antitumor activity against H460, A549 and H226 cell lines with ICs0 values of 3.4 μmol.L -i ,0.75 μmol.L-1 and 0.86 μmol.L -1 ,which were 2.8 to 16.8 times more active than the positive control（9.52 μmol L-1 ,29.24 μmol.L-1 ,36.21 μmol-L-1） ,respec- tively. Further studies are currently underway and will be reported in the future.