The Effect of a Methyl or 2-fluoroethyl Substituent at the N-3 Position of Thymidine, 3′-fluoro-3′-deoxythymi-dine and 1-β-D-arabinosylthymine on Their Antiviral and Cytostatic Activity in Cell Culture

Abstract

Thymidine (Thd), 1-β-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 nucleo-side analogues coincides with a significantly lower affinity of the modified Thd analogues for the cellular and viral (activating) nucleoside kinases.