Zidovudine prodrugs

D. Saboulard, L. Naesens, D. Cahard, A. Salgado, R. Pathirana, S. Velazquez, C. McGui-gan, E. De Clercq, J. Balzarini, Characterization of the Activation Pathway of Phosphoramidate Triester Prodrugs of Stavudine and Zidovudine , Mol. Pharmacol. 1999, 56, 693-704. 

In the past, various serendipitous discoveries have capitalized on the differential expression of enzymes by host and viral infected cells. For example, the prodrug Acyclovir, used widely for the treatment of herpes simplex and herpes zoster infections, is selectively activated through phosphorylation by viral thymidine kinase to acyclovir monophosphate which is then converted to the triphosphate, which inhibits DNA polymerase, by host cellular enzymes. Similarly several 2, 3 -dideoxynucleoside analogs such as Zidovudine (azidothymidine, AZT) and 2, 3 -didehydro-3 -deoxythymidine (D4T) have potent antiviral activity against human immunodeficiency vims (HIV). These compounds are selectively phosphoiylated intracellularly to the 5 -triphosphate derivatives which inhibit the viral reverse transcriptase. 

Figure 19.28 Zidovudine or AZT (82) and reiated nucieoside anaiogs. An eariy nucieoside anaiog antivirai drug, acyciovir 83, and the endogenous nucieoside deoxythymidine 84, from which 82 was designed are aiso shown. Tenofovir disoproxii, 85, is an oraiiy bioavaiiabie prodrug of tenofovir, 86, which was aiso designed from 83. (With permission from Proudfoot.)...

Saboulard D, Naesens L, Cahard D, Salgado A, Pathirana R, Velazquez S, McGuigan C, De Clercq E, Balzarini J (1999) Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. Mol Pharmacol 56 693-704... 

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