Synthesis, biological evaluation, and structure analysis of a series of new 1,5-anhydrohexitol nucleosides.
In view of the selective anti-HSV activity of 1,5-anhydro-2,3-dideoxy-2- (5-iodouracil-1-yl)-D-arabino-hexitol, a series of novel 1,5-anhydrohexitol nucleosides were synthesized and evaluated for their inhibitory activity against several viruses. The 5-iodouracil 3 and the 5-ethyluracil 4 derivatives are highly selective TK-dependent inhibitors of HSV-1 and HSV-2. Broad anti-herpes virus activity was noticed for 5-fluorocytosine 6 and 2,6-diaminopurine 10 analogues. From a transport study of 3, using the thymidine influx competition method, one can conclude that intracellular uptake of this compound most probably occurs by passive diffusion. X-ray analysis of compounds 3 and 9 showed that the heterocyclic base of 1,5-anhydrohexitol pyrimidine and purine is placed in the axial position and that the sugar ring adopts a slightly distorted chair conformation.
Verheggen
I
I
Laboratory of Pharmaceutical Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Van Aerschot
A
A
Van Meervelt
L
L
Rozenski
J
J
Wiebe
L
L
Snoeck
R
R
Andrei
G
G
Balzarini
J
J
Claes
P
P
De Clercq
E
E
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001692:Biological Transport; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D006564:Herpesviridae / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012328:RNA Viruses / Q000187:drug effects; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000138:chemical synthesis / Q000494:pharmacology
D000998:Antiviral Agents; D009705:Nucleosides; D013402:Sugar Alcohols