Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

• Authors: Ugo Pradere, Emory University; Ethel C. Garnier-Amblard, RFS Pharma LLC; Steven J. Coats, RFS Pharma LLC; Franck Amblard, Emory University; Raymond F Schinazi, Emory University
• Journal Title: Chemical Reviews
• Volume: Volume 114, Number 18
• Publisher: American Chemical Society | 2014-09-24, Pages 9154-9218
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1021/cr5002035
• Subjects: Health Sciences, Pharmacology; Health Sciences, General
• Keywords: Science & Technology; Physical Sciences; Chemistry, Multidisciplinary; Chemistry; HEPATITIS-C VIRUS; ANTI-HIV ACTIVITY; POSSIBLE ANTIVIRAL AGENTS; PHOSPHORAMIDATE PROTIDE TECHNOLOGY; REPLICATION IN-VITRO; ACYCLOVIR DIPHOSPHATE DIMYRISTOYLGLYCEROL; PRELIMINARY BIOLOGICAL EVALUATION; ARYL PHOSPHOTRIESTER DERIVATIVES; LIPOPHILIC NUCLEOTIDE PRODRUGS; TOXIC LIPONUCLEOTIDE ANALOGS

Abstract

The article reviews the most important mono-, di-, and triphosphate and phosphonate prodrug approaches applied to nucleoside analogs from a chemical point of view, detailing the strengths and limitations of each approach. The article focuses on the various synthetic pathways discussing the chemical variation of the biolabile phosph(on)ate masking groups, the reliability of using P(III) and/or P(V) chemistry for phosphate and phosphonate prodrug synthesis, and the influence of the masking group(s) introduction conditions on the overall outcome for each method.