双氢青蒿素-单硝酸异山梨酯拼合物的合成及其体外抗肿瘤活性

Synthesisof Dihydroartemisinin-Isosorbide Mononitrate Hybrid and Its Antitumor Activities in Vitro

青蒿素经硼氢化钠还原制得双氢青蒿素(2);2在4-二甲氨基吡啶(DMAP)催化下与丁二酸酐反应得到青蒿琥酯(3);以二环己基碳二亚胺为脱水剂,DMAP为催化剂,将3与一氧化氮供体单硝酸异山梨酯反应合成了双氢青蒿素-单硝酸异山梨酯拼合物(1),其结构经NMR和MS表征。采用MTT法初步考察了1对几种肿瘤细胞的增殖抑制活性,结果表明,1对CA46,Molt4和P388的IC50值分别为0.115 mg.L-1,0.098 mg.L-1和0.174 mg.L-1,显著低于青蒿素和2的相应值。实验结果提示一氧化氮供体对青蒿素衍生物的抗肿瘤活性具有增效作用。

Artemisinin was reduced by NaBH4 to give dihydroartemisinin（2）,which was then transformed into artesunate（3） by treatment with succinic anhydride using 4-dimethylaminopyridine（DMAP） as the catalyst.Dihydroartemisinin-isosorbide mononitrate hybrid（1） was obtained by coupling of 3 with the nitric oxide（NO） donor isosorbide mononitrate in the presence of dicyclohexylcarbodiimide and DMAP.The structures were characterized by NMR and MS.Antitumor activities of 1 against CA46,Molt4 and P388 cells were tested by MTT method with artemisinin and 2 as control groups.The results showed that IC50 of 1 on CA46,Molt4 and P388 cells were 0.115 mg·L-1,0.098 mg·L-1 and 0.174 mg·L-1,respectively,which are significantly lower than those of artemisinin and 2.The results showed that NO donors might enhance the anticancer activity of artemisinin derivatives.