Characterization of the Activation Pathway of Phosphoramidate Triester Prodrugs of Stavudine and Zidovudine
The phosphoramidate triester prodrugs of anti-human HIV 2â²,3â²-dideoxynucleoside analogs (ddN) represent a convenient approach to bypass the first phosphorylation to ddN 5â²-monophosphate (ddNMP), resulting in an improved formation of ddN 5â²-triphosphate and, hence, higher antiviral efficacy....
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Veröffentlicht in: | Molecular pharmacology 1999-10, Vol.56 (4), p.693-704 |
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Zusammenfassung: | The phosphoramidate triester prodrugs of anti-human HIV 2â²,3â²-dideoxynucleoside analogs (ddN) represent a convenient approach
to bypass the first phosphorylation to ddN 5â²-monophosphate (ddNMP), resulting in an improved formation of ddN 5â²-triphosphate
and, hence, higher antiviral efficacy. Although phosphoramidate derivatization markedly increases the anti-HIV activity of
2â²,3â²-didehydro-2â²,3â²-dideoxythymidine (d4T) in both wild-type and thymidine kinase-deficient CEM cells, the concept is far
less successful for the 3â²-azido-2â²,3â²-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.
Although l -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. |
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ISSN: | 0026-895X 1521-0111 |