取代非环核苷混膦酸酯类衍生物的合成及生物活性  

Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates

作　　者：欧瑜[1] 傅晓钟[2] 查雨锋[2] 张顺[2] 苏航[2] 董永喜[2] 

机构地区：[1]贵阳市妇幼保健院药剂科,贵阳550001 [2]贵阳医学院药学院,民族药与中药开发应用教育部工程研究中心,贵阳550004

出　　处：《中国药科大学学报》2014年第6期649-656,共8页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81460523);贵州省优秀青年科技人才培养对象专项基金资助项目(No.2013-45);贵州省社会发展攻关计划项目资助(No.2013-3031)~~

摘　　要：为寻找抗乙肝病毒(HBV)取代非环核苷混膦酸酯有效的结构优化策略。以阿德福韦单L-氨基酸酯和单非甾体药物羧酸酯为先导化合物,结合核苷类似物阿巴卡韦与阿拉莫韦的结构特征,采用亚结构拼合原理设计并合成了6-取代嘌呤非环核苷膦酸单L-氨基酸酯、单非甾体药物羧酸酯前药(9a^9l),其结构经1H NMR,ESI-MS,ESI-HRMS确证。采用HepG2 2.2.15细胞株、HK-2细胞株进行了目标化合物抗HBV活性以及肾细胞毒性评价。结果表明,化合物9a具有较强的抗病毒活性与作用选择性(EC500.48μmol/L,SI 763.72),具有较低的肾细胞毒性以及较高的化学与酶学稳定性,值得进一步深入研究。In order to find structural optimization strategy for substituted mixed phosphonates of acyclonucleoside phosphonates,mono L-amino acid ester,mono NSAID carboxylic ester prodrugs of adefovir was used as lead compound. Based on the structural features of abacavir and alamifovir,sub-structure combination method was used to introduce substituted phenylthio or amino fragments at 6-position of purine ring. Therefore,purine ring substituted acyclonucleside phosphonate mixed phosphonate ester derivatives（ 9a-9l） were designed and synthesized, and their structures were confirmed by 1 H NMR,ESI-MS,and ESI-HRMS. Hep G2.2.2.15 and HK-2 cell line were used for in vitro anti-HBV activity and renal cell toxicity evaluation models,respectively. Several compounds exhibited anti-HBV activity,of which compound 9a displayed the most potent antiviral activity with higher selectivity index（ EC50 0.48 μmol / L,SI 763.72）, lower renal cell toxicity, and higher chemical and enzymatic stability,making it a potential anti-HBV candidate for further investigation.

关 键 词：非环核苷膦酸 阿巴卡韦 阿拉莫韦 非甾体抗炎药 合成 抗病毒活性 

分 类 号：R914.5[医药卫生—药物化学] R965[医药卫生—药学]