十八烷氧乙基替诺福韦酯的合成及抗病毒活性研究  

Synthesis and antiviral activity of octadecyloxyethyl-tenofovir

作　　者：孟帅[1] 蔡步林[1] 陶佩珍[1] 彭宗根[1] 章天[1] 易红[1] 李玉环[1] 李卓荣[1] 

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所,北京100050

出　　处：《中国抗生素杂志》2011年第3期201-204,共4页Chinese Journal of Antibiotics

基　　金：国家科技重大专项重大新药创制(2009ZX09103-135)

摘　　要：目的研究十八烷氧乙基替诺福韦酯的合成及其抗病毒活性。方法以替诺福韦为原料,与脂性侧链2-十八烷氧基-1-乙醇反应得到目标化合物。通过细胞培养法对其体外抗HIV、HBV活性进行测定;通过血清药理学研究,测定小鼠血清的抗HIV-1作用。结果合成得到了目标化合物十八烷氧乙基替诺福韦酯,其结构经过核磁共振谱和质谱的确证;对其进行的体外和小鼠血清抗病毒活性研究结果显示,体外抗HIV-1的半数有效浓度(EC50)为0.165nmol/L,对HBV病毒的抑制活性EC50为0.17μmol/L;灌胃给药ODE-TFV后的小鼠血清对HIV-1显示出强和持久的抑制作用。结论在替诺福韦分子中磷酸基的一个羟基上引入脂溶性长链十八烷氧乙基,体外呈现出较强的抗病毒活性,并且生物利用度得到进一步改善。Objective The synthesis and antiviral activity of octadecyloxyethyl-tenofovir（ODE-TFV）were studied. Methods The target compound was obtained from tenofovir reacted with 2-（octadecyloxy）ethanol. Using cell culture methods, the anti-HIV and anti-HBV activities were evaluated in vitro respectively. The activities against HIV-I of mice serum after oral administration were also evaluated based on the inhibition of p24 antigen. Results The target compound ODE-TFV was synthesized and its structure was confirmed by NMR and MS. The results of antiviral activity showed that the compound possesed better anti-HIV activity and anti-HBV activity with EC50 values 0.165nmol/L and 0.17umol/L. Anti-HIV activity of mice serum showed strong and lasting after oral administration. Compared to the control compound tenofovir disoproxil fumarate（TFV DF）, the antiviral potencies are improved after that the phosphonate group was monoalkoxyalkyl modified and it could be absorbed after oral administration. Conclusion Introducing monoalkoxyalkyl group to the phosphonate group of tenofovir, ODE-TFV was obtained maintaining the antiviral activity and better bioavailability.

关 键 词：十八烷氧乙基 替诺福韦酯 合成 抗病毒 

分 类 号：R978.7[医药卫生—药品]