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

ZHANG Wenzheng; YANG Yang; CHEN Ya; XIAO Tao; FU Xiaozhong; DONG Yongxi

doi:10.11665/j.issn.1000-5048.20180106

Journal of China Pharmaceutical University > 2018 > 49(1): 39-47. > DOI: 10.11665/j.issn.1000-5048.20180106

ZHANG Wenzheng, YANG Yang, CHEN Ya, XIAO Tao, FU Xiaozhong, DONG Yongxi. Synthesis and bioactivity of mixed phosphonate derivatives of adefovir with hepatic targeting property[J]. Journal of China Pharmaceutical University, 2018, 49(1): 39-47. DOI: 10.11665/j.issn.1000-5048.20180106

Citation:

PDF (1047 KB)

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

More Information

Graphical Abstract

Abstract

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

FullText(HTML)

References (17)

References

[1]	Tanji N,Tanji K,Kambham N,et al.Adefovir nephrotoxicity:Possible role of mitochondrial DNA depletion[J].Hum Pathol,2001,32(7):734-740.
[2]	Trauner M,Boyer JL.Bile salt transporters:molecular characte-rization,function,and regulation[J].Physiol Rev,2003,83(2):633-671.
[3]	Enhsen A,Kramer W,Wess G.Bile acids in drug discovery[J].Drug Discov Today,1998,3(9):409-418.
[4]	Kullak-Ublick GA,Glasa J,Böker C,et al.Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas[J].Gastroenterology,1997,113(4):1295-1305.
[5]	Fiorucci S,Antonelli E,Brancaleone V,et al.NCX-1000,a nitric oxide-releasing derivative of ursodeoxycholic acid,ameliorates portal hypertension and lowers norepinephrine-induced intrahepatic resistance in the isolated and perfused rat liver[J].J Hepatol,2003,39(6):932-939.
[6]	Balakrishnan A,Polli JE.Apical sodium dependent bile acid transporter(ASBT,SLC10A2):a potential prodrug target[J].Mol Pharm,2006,3(3):223-230.
[7]	Meier PJ,Stieger B.Bile salt transporters[J].Annu Rev Physiol,2002,64:635-661
[8]	Schaap FG,Trauner M,Jansen PLM.Bile acid receptors as targets for drug development[J].Nat Rev Gastro Hepat,2014,11(1):55-67.
[9]	Fu X,Jiang S,Li C,et al.Design and synthesis of novel bis(L-amino acid)ester prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine(PMEA)with improved anti-HBV activity[J].Bioorg Med Chem Lett,2007,17(2):465-470.
[10]	Fu XZ,Jiang SH,Yang YS,et al.Design,synthesis and anti-HBV activity of L-amino acid ester prodrugs of acyclic nucleoside phosphonates[J].Acta Pharm Sin(药学学报),2008,43(5):495-503.
[11]	Su H,Chen Y,Fu XZ,et al.Synthesis,antiviral activity and primary hepatocyte uptake evaluation of adefovir L-amino acid and bile acid ester derivatives[J].Chin J Pharm(中国医药工业杂志),2016,(03):264-268.
[12]	Pei JY,Liu Y,Fu XZ,et al.Design and synthesis of phosphonates derivatives of adefovir with reduced nephrotoxicity[J].West China J Pharm Sci(华西药学杂志),2012,27(05):478-482.
[13]	Honkoop P, de Man RA, Zondervan PE, et al. Histological improvement in patients with chronic hepatitis B virus infection treated with lamivudine[J].Liver Int,2010,17(2):103-106.
[14]	Chen Y,Li J,Zhang WZ,et al.Establishment and identification of HEK293 cell lines with stable and high expression of NTCP[J].Chin Pharmacol Bull(中国药理学通报),2016,32(12):1767-1772.
[15]	Xu ZR,Jiang Y,Zhang XQ,et al.Study on pharmacokinetics and tissue distribution of adefovir dipivoxil in rats[J].Chin J Mod Appl Pharm(中国现代应用药学),2005,22(7):617-620.
[16]	Gu XH,Qiu ZW,Xu H,et al.Study on the distribution and liver targeting of OA-PLGA-TPGS-NPs in mice[J].J China Pharm(中国药房),2012,23(33):3086-3088.
[17]	Juling S,Bachler G,Von GN,et al. In vivo distribution of nanosilver in the rat:The role of ions and de novo-formed secondary particles[J].Food Chem Toxicol,2016,97:327-335.

Cited By

Get Citation

PDF

XML

Article views (787) PDF downloads (1093)

Turn off MathJax

Article Contents

Abstract

References

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

Abstract

References

Catalog

Export File

Citation

Format

Content