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.
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.
Rega Institute for Medical Research, K.U. Leuven, Leuven, Belgium. jan.balzarini@rega.kuleuven.be
Jan
J
Balzarini
Sofie
S
Celen
Anna
A
Karlsson
Tjibbe
T
de Groot
Alfons
A
Verbruggen
Guy
G
Bormans
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014709:Vero Cells
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001087:Arabinonucleosides; D004791:Enzyme Inhibitors; D010770:Phosphotransferases; C021892:nucleoside phosphotransferase; C010032:thymine arabinoside; D013941:Thymine; D013936:Thymidine