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目的设计并合成NO供体型法尼基硫代水杨酸(FTA)衍生物,以期获得抗肺癌活性比FTA更强的化合物。方法将NO供体呋咱氮氧化物通过连接基团与FTA的羧基连接制得NO供体型FTA衍生物。测试目标物体外对肺癌细胞增殖的抑制作用和NO的释放情况,同时测定活性化合物对Ras蛋白的抑制活性。结果合成了8个结构新颖的NO供体型FTA衍生物,其结构经IR、MS和1H-NMR谱确证。大部分目标物对肺癌细胞增殖的抑制活性明显高于FTA,其中,化合物10b、10d和10e比阳性对照药索拉菲尼(sorafenib)稍强或者与其相当。NO释放研究表明,细胞毒性较强的化合物释放NO的量相对较多,而活性较弱的化合物释放量较少。化合物10b对Ras下游信号通路phosphor-Akt、phosphor-ERK和phosphor-Raf抗体的表达有很好的抑制作用。结论法尼基硫代水杨酸与呋咱氮氧化物的杂合物具有较强的抗肺癌活性,值得深入研究。
OBJECTIVE To design and synthesize NO-donor farnesylthio-salicylic acid (FTA) derivatives in order to obtain more potent anti-lung cancer compounds than FTA. Methods The NO donor FTA derivatives were prepared by attaching the NO donor furazan oxalate to the carboxyl group of FTA through a linker. The inhibitory effect of the target substance on the proliferation of lung cancer cells and the release of NO were measured in vitro, and the inhibitory activity of the active compound on the Ras protein was also determined. Results Eight novel NO-donor FTA derivatives were synthesized and their structures were confirmed by IR, MS and 1H-NMR spectra. The inhibitory activity of most of the targets on the proliferation of lung cancer cells was significantly higher than that of FTA. Among them, the compounds 10b, 10d and 10e were slightly stronger than or comparable to the positive control sorafenib. NO release studies have shown that compounds with higher cytotoxicity release relatively more NO and less active compounds release less. Compound 10b has a good inhibitory effect on the expression of phosphor-Akt, phosphor-ERK and phosphor-Raf downstream Ras signaling pathway. Conclusions The hybrids of farnesyl thiosalicylate and furazan nitrogen oxides have strong anti-lung cancer activity and deserve further study.