阿德福韦膦酸酯衍生物的肾毒性及抗HBV活性评价  

Renal cell toxicity and anti-HBV activity evaluation of adefovir phosphonates derivatives

作　　者：刘影[1] 裴健颖[1] 李靖[1] 董永喜[1] 傅晓钟[1] 查雨锋[1] 兰燕宇[1] 王永林[1] 

机构地区：[1]贵阳医学院药学院,贵州贵阳550004

出　　处：《华西药学杂志》2013年第1期45-47,共3页West China Journal of Pharmaceutical Sciences

基　　金：国家自然科学基金资助项目(批准号:20962004);贵州省社会发展攻关计划(No.QKHSYZ[2009]3081);贵州省高层次人才科研特助基金(No.TZJF-2009-36)

摘　　要：目的研究单非甾体抗炎药羧酸酯衍生物阿德福韦单硫代L-氨基酸酯的肾细胞毒性及抗HBV活性。方法采用HK-2人肾小管上皮细胞株,从细胞形态学、细胞生长和增殖活性及细胞结构损伤检测几方面评价了目标化合物的肾细胞毒性;采用HepG2.2.15细胞株,从细胞毒性与HBV-DNA抑制率方面评价了目标化合物抗HBV的作用效果。结果化合物均具有不同程度抗HBV的活性,其中,5a、5c、5e活性较强(EC50为22.73～29.72μmol.L-1);化合物5c、5d作用24、48 h后对HK-2细胞产生的形态学改变、细胞毒性(IC50>1 mmol.L-1)及不同浓度下LDH释放率均明显优于阳性对照Adefovir dipiv-oxil作用细胞24、48 h后的形态学、细胞毒性(827.18、446.99μmol.L-1)及LDH释放率。结论设计的化合物5c、5d具有抗病毒活性及较低的肾细胞毒性,有进一步研究的价值。OBJECTIVE To study renal cell toxicity and anti-HBV activity of novel mono L-amino thioacid ester,mono NSAID carboxylic ester prodrugs of PMEA.METHODS Human renal tubular epithelial cell line HK-2 was adopted to evaluate renal cell toxicity of the target compounds by detecting three investigational index including cell morphology,cell growth,proliferation,and cell structural damage;HepG2 2.2.15 cells were adopted to study anti-HBV activity of the target compounds by detecting cytotoxicity and inhibitory rate of HBV-DNA.RESULTS All synthesized compounds demonstrated anti-HBV activity with EC50 values of 22.73-50 μmol·L-1,and among them,compounds 5a,5c and 5e exhibited potent antiviral activity with high EC50 values（22.73-29.72 μmol·L-1）.The results revealed that compounds 5c and 5d had lower renal cell toxicity than adefovir dipivoxil（IC50 827.18 and 446.99 μmol·L-1） with cytotoxicity IC50 values 1 mmol·L-1 after the target compounds acting on HK-2 cell for 24 h and 48 h.The LDH leakage rate and cell morphology of target compounds 5c and 5d were significantly superior to those of adefovir dipivoxil acting on HK-2 cell for 24 h and 48 h at the same concentrations.CONCLUSION Target compounds 5c and 5d have anti-HBV activity and lower renal cell toxicity which would be worthy of further study.

关 键 词：阿德福韦 前药 HK-2细胞 肾细胞毒性 非甾体抗炎药 

分 类 号：R96[医药卫生—药理学]