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Synthesis and Evaluation of Prodrugs of α-Carboxy Nucleoside Phosphonates. | LitMetric

Synthesis and Evaluation of Prodrugs of α-Carboxy Nucleoside Phosphonates.

J Org Chem

School of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork T12 K8AF, Ireland.

Published: November 2022

AI Article Synopsis

Article Abstract

A range of lipophilic prodrugs of α-carboxy nucleoside phosphonates, potent inhibitors of HIV-1 reverse transcriptase without requiring prior phosphorylation, were synthesized to evaluate their in vivo potency against HIV in cell culture. A series of prodrug derivatives bearing a free carboxylic acid where the phosphonate was masked with bispivaloyloxymethyl, diisopropyloxycarbonyloxymethyl, bisamidate, aryloxyphosphoramidate, hexadecyloxypropyl, CycloSal, and acycloxybenzyl moieties were synthesized, adapting existing methodologies for phosphonate protection to accommodate the adjacent carboxylic acid moiety. The prodrugs were assayed for anti-HIV activity in CEM cell cultures─the bispivaloyloxymethyl free acid monophosphonate prodrug exhibited some activity (inhibitory concentration-50 (IC) 59 ± 17 μM), while the other prodrugs were inactive at 100 μM. A racemic bispivaloyloxymethyl methyl ester monophosphonate prodrug was also prepared to assess the suitability of the methyl ester as a carboxylic acid prodrug. This compound exhibited no activity against HIV in cellular assays.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9639015PMC
http://dx.doi.org/10.1021/acs.joc.2c02135DOI Listing

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