姜黄素前体药物的合成及其体外抗肿瘤活性研究

目的制备姜黄素前体药物,使其在肿瘤细胞内高选择性活化,为进一步开展肿瘤靶向性化疗奠定基础。方法以姜黄素分子结构为基础,化学合成N-马来酰-L-缬氨酸酯姜黄素、N-马来酰-甘氨酸酯姜黄素,红外光谱法进行鉴定;MTT比色分析法比较两种姜黄素前体药物作用6~24 h后,人膀胱癌EJ细胞及肾小管上皮HKC细胞生长抑制的差异。结果20~40μmol.L-1的N-马来酰-L-缬氨酸酯姜黄素、N-马来酰-甘氨酸酯姜黄素作用6~24 h后,EJ细胞生长抑制率分别为6.71%~65.13%(P<0.05)、10.96%~73.01%(P<0.05),呈浓度、时间依赖性。与同浓度姜黄素比较,两种前体药物对HKC细胞生长的抑制作用均降低(P<0.01)。结论本研究成功的合成了两种姜黄素的前体药物,N-马来酰-L-缬氨酸酯姜黄素、N-马来酰-甘氨酸酯姜黄素;二者均能体外抑制人膀胱癌EJ细胞增殖,其对人肾小管上皮HKC细胞的抑制毒性作用低于姜黄素。

Preparation of curcumin prodrugs and their anti-tumor activities in vitro

Aim To prepare the prodrugs of curcumin,which could be selectively activated in tumor cells,in order to establish a basis for further development of targeted chemotherapy for cancer.Methods Based on the molecular structure of curcumin,the N-maleoyl-L-valine-curcumin(NVC) and N-maleoyl-glycine-curcumin(NGC) were chemically synthesized and identified using IR spectroscopy.After treatment with these two prodrugs for 6～24 h,the growth inhibition rates on human bladder cancer EJ cells and renal tubular epithelial(HKC) cells were detected using MTT colorimetry.Results After treatment with 20～40 μmol·L~(-1) NVC and NGC for 6～24 h,the growth inhibitory effects on EJ cells were 6.71%～65.13%%(P<0.05) and 10.96%～73.01%(P<0.05),respectively,in a dose-and time-dependent manner.When compared with the curcumin of same concentrations,the growth inhibitory effects of these two prodrugs on HKC cells were significantly decreased(P<0.01).Conclusion The two curcumin prodrugs,N-maleoyl-L-valine-curcumin and N-maleoyl-glycinecurcumin were chemically synthesized successfully and both could inhibit the growth of tumor cell in vitro.Furthermore,the two prodrugs of curcumin were less toxic in HKC cells than curcumin.