Metal ion complexes of antivirally active nucleotide analogues. Conclusions regarding their biological action

Abstract

Acyclic nucleoside phosphonates (ANPs), i.e., analogues of (2′-deoxy)nucleoside 5′-monophosphates, have been studied during the past 15 years for their potential as antiviral drugs. One of these compounds, 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; Adefovir) was recently approved in the form of its bis(pivaloyloxymethyl)ester (Adefovir dipivoxil) for use in hepatitis B therapy, a disease evoked by a DNA virus. Diphosphorylated PMEA²⁻, i.e., PMEApp⁴⁻, is initially recognized by nucleic acid polymerases as an excellent substrate, but after insertion in the growing nucleic acid chain, this is terminated due to the lack of a 3′-hydroxy group. Based on the metal ion-binding properties of PMEApp⁴⁻ it can be explained why the ether oxygen in the aliphatic chain, R–CH₂–O–CH₂–PO₃pp⁴⁻, is compulsory for a useful biological activity. Consequently, this critical review presents an overview on the coordination chemistry of various ANPs and correlates this to their biological properties.