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Molecular Pharmacology

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Research ArticleArticle

Characterization of the Activation Pathway of Phosphoramidate Triester Prodrugs of Stavudine and Zidovudine

Didier Saboulard, Lieve Naesens, Dominique Cahard, Antonio Salgado, Ranjith Pathirana, Sonsoles Velazquez, Christopher McGuigan, Erik De Clercq and Jan Balzarini
Molecular Pharmacology October 1999, 56 (4) 693-704;
Didier Saboulard
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Lieve Naesens
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Dominique Cahard
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Antonio Salgado
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Ranjith Pathirana
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Sonsoles Velazquez
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Christopher McGuigan
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Erik De Clercq
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Jan Balzarini
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Abstract

The phosphoramidate triester prodrugs of anti-human HIV 2′,3′-dideoxynucleoside analogs (ddN) represent a convenient approach to bypass the first phosphorylation to ddN 5′-monophosphate (ddNMP), resulting in an improved formation of ddN 5′-triphosphate and, hence, higher antiviral efficacy. Although phosphoramidate derivatization markedly increases the anti-HIV activity of 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) in both wild-type and thymidine kinase-deficient CEM cells, the concept is far less successful for the 3′-azido-2′,3′-dideoxythymidine (AZT) triesters. We now investigated the metabolism of triester prodrugs of d4T and AZT using pure enzymes or different biological media. The efficiency of the first activation step, mediated by carboxylesterases, consists of the formation of the amino acyl ddNMP metabolite. The efficiency of this step was shown to be dependent on the amino acid, alkyl ester, and ddN moiety. Triesters that showed no conversion to the amino acyl ddNMP accumulated as the phenyl-containing intermediate and had poor, if any, anti-HIV activity. In contrast to the relative stability of the triesters in human serum, carboxylesterase-mediated cleavage of the prodrugs was found to be remarkably high in mouse serum. The subsequent conversion of the amino acyl ddNMP metabolite to ddNMP or ddN was highest in rat liver cytosolic enzyme preparations. Althoughl-alaninyl-d4TMP was efficiently converted to d4TMP, the main metabolite formed from l-alaninyl-AZTMP was the free nucleoside (AZT), thus explaining why d4T prodrugs, but not AZT prodrugs, retain anti-HIV activity in HIV-infected thymidine kinase-deficient cell cultures. The rat liver phosphoramidase responsible for the formation of ddNMP was shown to be distinct from creatine kinase, alkaline phosphatase, and phosphodiesterase.

Footnotes

  • Send reprint requests to: Dr. Lieve Naesens, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. E-mail: lieve.naesens{at}rega.kuleuven.ac.be

  • This work was supported by Biomedical Research Programme of the European Commission, Belgian Geconcerteerde Onderzoeksacties (Project 95/5), and Fondation Singer-Polignac, Paris, France.

  • Abbreviations:
    ddN
    2′,3′-dideoxynucleoside analog
    ddNMP
    2′,3′-dideoxynucleoside 5′-monophosphate
    ddNTP
    2′,3′-dideoxynucleoside 5′-triphosphate
    d4T
    2′,3′-didehydro-2′,3′-dideoxythymidine
    PMSF
    phenylmethylsulfonyl fluoride
    AZT
    3′-azido-2′,3′-dideoxythymidine
    CC50
    50% cytotoxic concentration
    HIV
    human immunodeficiency virus
    IM
    intermediate metabolite
    AAM
    amino acyl metabolite
    • Received April 14, 1999.
    • Accepted July 14, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (4)
Molecular Pharmacology
Vol. 56, Issue 4
1 Oct 1999
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Research ArticleArticle

Characterization of the Activation Pathway of Phosphoramidate Triester Prodrugs of Stavudine and Zidovudine

Didier Saboulard, Lieve Naesens, Dominique Cahard, Antonio Salgado, Ranjith Pathirana, Sonsoles Velazquez, Christopher McGuigan, Erik De Clercq and Jan Balzarini
Molecular Pharmacology October 1, 1999, 56 (4) 693-704;

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Research ArticleArticle

Characterization of the Activation Pathway of Phosphoramidate Triester Prodrugs of Stavudine and Zidovudine

Didier Saboulard, Lieve Naesens, Dominique Cahard, Antonio Salgado, Ranjith Pathirana, Sonsoles Velazquez, Christopher McGuigan, Erik De Clercq and Jan Balzarini
Molecular Pharmacology October 1, 1999, 56 (4) 693-704;
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