ABSTRACT
Novel 4'-substituted ß-d-2'-deoxy-2'-α-fluoro (2'd2'F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4'-substitution onto 2'd2'F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4'-substitution and not readily predictable. Combining the most potent and selective 4'-groups from N-nucleoside analogs onto a 2'd2'F C-nucleoside analog resulted in the identification of ß-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV.
Subject(s)
Adenosine/chemistry , Antiviral Agents/chemistry , DNA-Directed DNA Polymerase/chemistry , Nucleic Acid Synthesis Inhibitors/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA/chemistry , Respiratory Syncytial Viruses/enzymology , Respiratory Syncytial Viruses/physiology , Adenosine/chemical synthesis , Adenosine/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Aza Compounds/chemistry , DNA-Directed DNA Polymerase/metabolism , Drug Evaluation, Preclinical , Nucleic Acid Synthesis Inhibitors/chemical synthesis , Nucleic Acid Synthesis Inhibitors/pharmacology , RNA/metabolism , RNA, Mitochondrial , RNA-Dependent RNA Polymerase/metabolism , Respiratory Syncytial Viruses/drug effects , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Protected N-branched nucleoside phosphonates containing adenine and thymine bases were prepared as the monomers for the introduction of aza-acyclic nucleotide units into modified oligonucleotides. The phosphotriester and phosphoramidite methods were used for the incorporation of modified and natural units, respectively. The solid phase synthesis of a series of nonamers containing one central modified unit was successfully performed in both 3'â5' and 5'â3' directions. Hybridization properties of the prepared oligoribonucleotides and oligodeoxyribonucleotides were evaluated. The measurement of thermal characteristics of the complexes of modified nonamers with the complementary strand revealed a considerable destabilizing effect of the introduced units. We also examined the substrate/inhibitory properties of aza-acyclic nucleoside phosphono-diphosphate derivatives (analogues of nucleoside triphosphates) but neither inhibition of human and bacterial DNA polymerases nor polymerase-mediated incorporation of these triphosphate analogues into short DNA was observed.