The effect of a methyl or 2-fluoroethyl substituent at the N-3 position of thymidine, 3'-fluoro-3'-deoxythymidine and 1-beta-D-arabinosylthymine on their antiviral and cytostatic activity in cell culture

Abstract

Thymidine (Thd), 1-beta-D-arabinosylthymine (ara-T) and 3'-fluoro-3'-deoxythymidine (FLT) have been substituted at N-3 by a methyl or a 2-fluoroethyl group. FLT and ara-T are markedly inhibitory against human immunodeficiency virus type 1 (HIV-1) and HIV-2, and herpes simplex virus type 1 (HSV-1) and HSV-2, respectively. Modification at N-3 of these compounds markedly decreases both the antiviral and cytostatic activity of the parent compounds FLT and ara-T except for N-3-(methyl)-Thd that proved highly cytostatic for murine leukaemia L1210 cells. The decreased biological activity of the N-3-substituted pyrimidine nucleoside analogues coincides with a significantly lower affinity of the modified Thd analogues for the cellular and viral (activating) nucleoside kinases.