The Synthesis and Antiviral Properties of Acyclic Nucleoside Analogues with a Phosphonomethoxy Fragment in the Side Chain

Abstract

Acyclic nucleoside analogues bearing phosphonomethoxy residues in the side chain (ANP) attract much attention due to a very beneficial combination of biological properties. Intensive work of organic chemists during the last two decades resulted in a large panel of new compounds that were evaluated as potential antiviral drugs. Herein, we present an overview of major chemical structures within the group of acyclic nucleoside analogues containing phosphonomethoxy side fragments and describe main aspects of their synthesis and antiviral potential. We also describe progress in "prodrug" approaches applied to this chemical group to improve pharmacokinetic profiles of the potential candidates. Chemical modifications in the molecule of parental ANP aimed at blocking of phosphonate charges resulted in a set of promising derivatives, two of which have been recently approved for treatment of hepatits B (Hepsera) and HIV (Viread). The preparation, antiviral properties and some aspects of metabolic transformations and pharmacokinetics of ANP prodrugs are discussed.

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…After De Clercq, Holy, Rosenberg and their colleagues reported strong antiviral activity of acyclic nucleoside phosphonates such as 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and ( S ) - 9-(3-hydroxy-2-phosphonyl-methoxypropyl) adenine (( S ) - HPMPA [48] (Reviewed in [49]), the activity of these compounds stimulated great interest in development of prodrug forms to enhance the membrane permeability of these drugs. An early focus was pivaloyloxymethyl (POM) modified phosphonates, a prodrug format that first had been advanced for use with phosphate monoesters [50,51].…”