Fluorosubstitution and 7-alkylation as prospective modifications of biologically active 6-aryl derivatives of tricyclic acyclovir and ganciclovir analogues.
A series of fluorine containing tricyclic analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2) were synthesized and evaluated for their activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and cytostatic activity against HSV-1 thymidine kinase (TK) gene-transduced human osteosarcoma tumour cells. It was found that fluorine substitution reduced the antiviral activity, but most of the new compounds were pronounced cytostatic agents with potency and selectivity similar to those of parental ACV and GCV. Compounds 12, 13 and 16 seem to be promising as labeled substrates for (19)F NMR studies of the HSV TK-ligand interaction and/or monitoring of their metabolites in cells expressing HSV TK.
Ostrowski
Tomasz
T
Institute of Bioorganic Chemistry, Polish Academy of Sciences, ul.Noskowskiego 12/14, 61-704 Poznan, Poland.
Golankiewicz
Bozenna
B
De Clercq
Erik
E
Balzarini
Jan
J
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000478:Alkylation; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003500:Cyclization; D005461:Fluorine / Q000737:chemistry*; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000998:Antiviral Agents; D005461:Fluorine; D013937:Thymidine Kinase; D015774:Ganciclovir; D000212:Acyclovir