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Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir.

ABSTRACT: We report the synthesis and biological evaluation of Ala-(Val-)l-Ser-CO(2)R prodrugs of 1, where a dipeptide promoiety is conjugated to the P(OH)(2) group of cidofovir (1) via esterification by the Ser side chain hydroxyl group and an ethyl group (4 and 5) or alone (6 and 7). In a murine model, oral administration of 4 or 5 did not significantly increase total cidofovir species in the plasma compared to 1 or 2, but 7 resulted in a 15-fold increase in a rat model and had an in vitro EC(50) value against human cytomegalovirus comparable to 1. Neither 6 nor 7 exhibited toxicity up to 100 ?M in KB or HFF cells.

SUBMITTER: Peterson LW

PROVIDER: S-EPMC3115518 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir.

Peterson Larryn W LW Kim Jae-Seung JS Kijek Paul P Mitchell Stefanie S Hilfinger John J Breitenbach Julie J Borysko Kathy K Drach John C JC Kashemirov Boris A BA McKenna Charles E CE

Bioorganic & medicinal chemistry letters 20110503 13

We report the synthesis and biological evaluation of Ala-(Val-)l-Ser-CO(2)R prodrugs of 1, where a dipeptide promoiety is conjugated to the P(OH)(2) group of cidofovir (1) via esterification by the Ser side chain hydroxyl group and an ethyl group (4 and 5) or alone (6 and 7). In a murine model, oral administration of 4 or 5 did not significantly increase total cidofovir species in the plasma compared to 1 or 2, but 7 resulted in a 15-fold increase in a rat model and had an in vitro EC(50) value ...[more]

PMID: 21641218

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Synthesis and broad spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides.

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| S-EPMC7111275 | biostudies-literature

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