NO供体型法尼基硫代水杨酸衍生物的合成及其抗肺癌活性  

Synthesis and anti-lung cancer activity of nitric oxide-donating derivatives of farnesylthiosalicylic acid

作　　者：凌勇[1,2] 叶小磊[3] 张奕华[1] 丁晔[1] 赖宜生[1] 季晖[3] 彭司勋[1] 

机构地区：[1]中国药科大学新药研究中心,江苏南京210009 [2]南通大学医学院,江苏南通226001 [3]中国药科大学药理教研室,江苏南京210009

出　　处：《中国药物化学杂志》2010年第5期331-335,357,共6页Chinese Journal of Medicinal Chemistry

摘　　要：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。Aim To design and synthesize nitric oxide（NO） releasing derivatives of farnesylthiosalicylic acid（FTA） with more potent anti-lung cancer activity than FTA.Methods A series of novel NO-donating deri-vatives of FTA were synthesized by coupling the carboxyl group of FTA with NO-donor furoxan via different linkers.Their anti-lung cancer activity,NO-releasing ability and Ras inhibitory effect were evaluated in vitro.Results Eight novel furoxan-based NO releasing derivatives of FTA were synthesized and their structures were established by IR,MS and 1H-NMR.Most compounds displayed cytotoxicity superior to FTA.The activities of 10b,10d and 10e were equal to or even stronger than that of sorafenib.And the compounds with high cytotoxicity produced high levels of NO,and vice versa.Compound 10b had strong Ras inhibitory activity and inhibited the expression of the Ras signaling pathway-related phosphor-Akt,phosphor-ERK and phosphor-Raf.Conclusion The furoxan-FTA hybrids may hold greater anti-lung cancer activity,and are worth of further investigation.

关 键 词：一氧化氮供体 法尼基硫代水杨酸 呋咱氮氧化物 细胞毒性 RAS蛋白 

分 类 号：R914.5[医药卫生—药物化学]