Synthesis and bioactivity of mixed phosphonate derivatives of adefovir with hepatic targeting property
10.11665/j.issn.1000 -5048.20180106
- VernacularTitle:肝靶向阿德福韦混膦酯衍生物的合成及生物活性
- Author:
Wenzheng ZHANG
1
,
2
,
3
;
Yang YANG
;
Ya CHEN
;
Tao XIAO
;
Xiaozhong FU
;
Yongxi DONG
Author Information
1. 贵州医科大学 药学院 贵阳550004
2. 贵州医科大学 贵州省药物制剂重点实验室 贵阳550004
3. 贵州医科大学 国家苗药工程技术研究中心 贵阳550004
- Keywords:
adefovir;
derivatives;
enterohepatic circulation;
tissue distribution;
hepatotrophic property;
synthesis
- From:
Journal of China Pharmaceutical University
2018;49(1):39-47
- CountryChina
- Language:Chinese
-
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 circula-tion 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(EC500.92μmol/L,SI 512.63)was further investi-gated 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.
