Modified uridine nucleosides and DNA: New concepts in antiviral and antineoplastic therapy

Nucleoside 2{dollar}spprime{dollar}-deoxyuridine analogs with C-5 position appended carbonyl groups are capable of forming reversible covalent crosslinks with nucleophiles. Use of these analogs as antineoplastics and antivirals is explored in two areas of research: nucleoside analog drug development and oligonucleotide antisense control of gene expression. The synthesis of these analogs is described using a new, active palladium catalyst that achieves improved yields in carbon-carbon bond forming reactions over conventional methods. One of these analogs, 5-formyl-2{dollar}spprime{dollar}-deoxyuridine, has been tested as an antineoplastic against human erythroleukemia (K562) and mouse melanoma (B161F1) cell lines. Additionally, 5-formyl-2{dollar}spprime{dollar}-deoxyuridine has been incorporated into an EcoR I 8-mer sequence d(GGAAT{dollar}sp*{dollar}TCC), where T{dollar}sp*{dollar} denotes the position of substitution. Melting studies on the sequence show a dramatic increase in duplex T{dollar}sb{lcub}rm m{rcub}{dollar} compared to the native sequence.