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

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。

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

Aim To design and synthesize nitric oxide (NO) releasing derivatives of farnesylthiosalicylic acid (FTA) with more potent anti-lung cancer activity than FTA. Method A series of novel NO-donating derivatives 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.