Abstract
A series of phosphonate ester prodrugs of adefovir incorporating l-amino (thio)acid and non-steroidal anti-inflammatory drug (NSAID) moieties were synthesized and their anti-HBV activity and renal cell toxicity were evaluated in HepG2 2.2.15 and HK-2 cells respectively. Bioactivity evaluation results revealed that this kind of adefovir prodrug have lower renal cell toxicity than adefovir dipivoxil. Compounds 8a and 8b, incorporating the NSAID ketoprofen and the l-amino acid (Val or Ile) structural fragments, exhibited more potent anti-HBV activity than adefovir dipivoxil with IC(50) = 0.51 and 0.73 μM, SI = 1697.64 and 881.92 respectively. In vitro stability studies showed that the synthesized prodrugs have higher chemical and plasma stability than the positive control adefovir dipivoxil.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemical synthesis
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Adenine / chemistry
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Adenine / pharmacology
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Adenine / toxicity
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Anti-Inflammatory Agents, Non-Steroidal / toxicity
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Antiviral Agents / chemical synthesis
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Antiviral Agents / toxicity
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Cell Line
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Cell Survival / drug effects
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Hep G2 Cells
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Hepatitis B / drug therapy
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Hepatitis B virus / drug effects*
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Hepatocytes / drug effects
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Humans
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Organophosphonates / chemical synthesis
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Organophosphonates / chemistry
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Organophosphonates / pharmacology*
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Organophosphonates / toxicity
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Prodrugs / chemical synthesis
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Prodrugs / chemistry
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Prodrugs / pharmacology*
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Prodrugs / toxicity
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antiviral Agents
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Organophosphonates
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Prodrugs
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adefovir
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Adenine