Antiviral activity of 5-methylthiomethyl-2′deoxyuridine and other 5-substituted 2′-deoxyuridines

Abstract

Of a series of eight 5-substituted 2'-deoxyuridine (dUrd) derivatives, which were evaluated for their antiviral and antimetabolic activities in primary rabbit kidney or human skin fibroblast cell cultures, five dUrd derivatives, 5-dimethylaminomethyl-dUrd, 5-chloroacetamidomethyl-dUrd, 5-iodoacetamidomethyl-dUrd, 5-pyrrolidinylmethyl-dUrd and 5- N-methylpiperazinylmethyl-dUrd, showed little, if any, activity. The three others, 5-formyl-dUrd, 5-azidomethyl-dUrd and 5-methylthiom-ethyl-dUrd, were found to inhibit the replication of various HSV (herpes simplex virus) strains (whether type 1 or 2) at a concentration of approximately 1–10 μg/ml. The antiviral activity of 5-formyl-dUrd may be accounted for by an inhibition of thymidylate synthetase. The inhibitory effect of 5-formyl-dUrd on HSV multiplication was readily reversed by adddition of 2'-deoxythymidine (dThd), and, in analogy with other established thymidylate synthetase inhibitors, 5-formyl-dUrd blocked the incorporation of [2- 14C]dUrd into cellular DNA to a markedly greater extent than the incorporation of [methyl- 3H]dThd. Unlike 5-formyl-dUrd, 5-azidomethyl-dUrd and 5-methylthiomethyl-dUrd did not preferentially inhibit the incorporation of [2- 14C]dUrd. Antiviral indexes, defined as the id 50 for [2- 14C]dUrd incorporation divided by the id 50 for HSV (type 1, strain KOS) replication, were 0.25, 43 and > 100 for 5-formyl-dUrd, 5-azidomethyl-dUrd and 5-methylthiomethyl-dUrd, respectively. The latter two compounds may therefore be considered as rather selective anti-herpes agents.