肝靶向阿德福韦混膦酯衍生物的合成及生物活性

张文政; 杨洋; 陈雅; 肖涛; 傅晓钟; 董永喜

doi:10.11665/j.issn.1000-5048.20180106

肝靶向阿德福韦混膦酯衍生物的合成及生物活性

张文政^1,2,3,
杨洋^1,2,3,
陈雅^1,3,4,
肖涛^1,2,3,
傅晓钟^1,4,
董永喜^1,4

1.
贵州医科大学药学院
2.
贵州省药物制剂重点实验室
3.
国家苗药工程技术研究中心
4.
民族药与中药开发应用教育部工程研究中心

基金项目: 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(No.2013-45)；贵州省社会发展攻关计划项目(No.2013-3031)

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- 刊出日期: 2018-02-24

Synthesis and bioactivity of mixed phosphonate derivatives of adefovir with hepatic targeting property

ZHANG Wenzheng^1,2,3,
YANG Yang^1,2,3,
CHEN Ya^1,3,4,
XIAO Tao^1,2,3,
FU Xiaozhong^1,4,
DONG Yongxi^1,4

摘要

摘要: 为获得具有肝靶向性的阿德福韦酯衍生物，以阿德福韦双L-氨基酸酯为先导化合物，利用胆汁酸的肠肝循环特性，采用骈合原理设计合成了10个阿德福韦单L-(硫代)氨基酸酯，单胆酸酯衍生物( 6a~6j )，其结构经过¹H NMR，¹³C NMR，ESI-MS，ESI-HRMS确证。采用HepG 2.2.15细胞株研究化合物的抗HBV活性，挑选其中抗病毒活性好且选择性指数较高的化合物 6c (EC₅₀ 0.92 μmol/L，SI 512.63)进行小鼠体内组织分布研究。结果表明，从给药15 min到12 h的各个时间点上，化合物 6c 在肝中的含量均比其他脏器中高，在肾中含量均比其他脏器低，且肝中含量在各时间点上均高于阳性对照阿德福韦，肾中含量均低于阳性对照。以上结果提示化合物 6c 具有较高的抗病毒活性，且具有良好的肝靶向性并降低了在肾中的蓄积，具有进一步研究的价值。
- 阿德福韦 /
- 衍生物 /
- 肠肝循环 /
- 组织分布 /
- 肝靶向性 /
- 合成
Abstract: In order to search for new adefovir analogues as anti-HBV agents with enhanced antiviral activity and hepatotrophic property, adefovir bis L-amino acid ester was used as lead compound to produce ten adefovir mono L-(thio)amino acid ester, mono bile acid ester derivatives( 6a-6j ). The design based on bile acid prodrug strategy, which can improve drug oral bioavaliability and liver-targeted enrichment by using enterohepatic circulation of bile acid. Sub-structure combination method was adopted to introduce L-(thio)amino acid ester and bile acid ester fragments on the phosphonate functionality of adefovir. The structures of target compounds were confirmed by ¹H NMR, ¹³C NMR, ESI-MS and ESI-HRMS. HepG 2. 2. 15 cell were used for in vitro anti-HBV activity assessment. Compound 6c with high antiviral activity(EC₅₀ 0. 92μmol/L, SI 512. 63)was further investigated for its tissue distribution in mice. The results showed that content of compound 6c in liver was higher than that of adefovir dipivoxil, and in contrast its content in kidney was lower than that in positive control at all time points(0. 25-12 h). Compound 6c exhibits higher antiviral activity, selective index and higher liver distribution, making it a potential anti HBV agent for further investigation.
- adefovir /
- derivatives /
- enterohepatic circulation /
- tissue distribution /
- hepatotrophic property /
- synthesis

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参考文献(17)

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肝靶向阿德福韦混膦酯衍生物的合成及生物活性

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Synthesis and bioactivity of mixed phosphonate derivatives of adefovir with hepatic targeting property

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出版历程

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