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采用基于片段的药物发现方法,对前期研究的膦酸酯化合物进行优化,寻找抗肿瘤先导化合物。设计合成了15个含氨基酸片段的膦酸酯衍生物,经IR、~1H NMR、~(13)C NMR及元素分析确认结构。采用溴化噻唑蓝四氮唑(MTT)法进行了初步体外抗肿瘤细胞增殖活性研究。结果表明:目标化合物呈现不同的抗肿瘤活性,其中化合物4e、4n对A-549有明显增殖抑制作用,IC_(50)分别为8.7±0.8、8.2±1.0μmol·L~(-1);化合物4c对SGC-7901的IC50为9.8±0.9μmol·L~(-1);化合物4l、4n对肿瘤细胞EC-109的增长具有显著抑制作用,IC50分别为9.5±0.6、9.4±0.5μmol·L~(-1)。
The fragment-based drug discovery method was used to optimize the phosphonate compounds studied in the previous study to find anti-tumor lead compounds. Fifteen phosphonate derivatives with amino acid residues were designed and synthesized. Their structures were confirmed by IR, ~ 1H NMR, ~ (13) C NMR and elemental analysis. A preliminary in vitro anti-tumor cell proliferative activity assay was carried out by MTT method. The results showed that the target compounds exhibited different antitumor activities. Compounds 4e and 4n showed a significant inhibitory effect on the proliferation of A-549 with IC 50 of 8.7 ± 0.8 and 8.2 ± 1.0μmol·L -1, respectively. Compounds The IC50 of 4c to SGC-7901 was 9.8 ± 0.9μmol·L -1. Compounds 4l and 4n had significant inhibitory effects on the growth of EC-109 cells with IC50 of 9.5 ± 0.6 and 9.4 ± 0.5μmol·L ~ (-1).