Synthesis and antiviral activity of certain guanosine analogues in the thiazolo[4,5-d]pyrimidine ring system.
Several sugar-modified nucleoside derivatives of the purine analogue 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7-dione (1) were synthesized. Phosphorylation of 1 using POCl3 resulted in 5'-monophosphate 2, which was subsequently converted to 3',5'-cyclic phosphate 3, by reported methods. 5'-Sulfamoyl derivative 4 was synthesized by treatment of the 2,3-O-isopropylidene derivative of 1 with chlorosulfonamide followed by acid deprotection. Compounds 5-7, the 5'-deoxy, the tri-O-acetyl, and the 2'-deoxy derivatives of 1, respectively, were synthesized by glycosylation of 5-aminothiazolo[4,5-d]pyrimidine-2,7-dione, the aglycon of 1, with the appropriate sugar moieties, utilizing the Vorbruggen procedure. Oxidative cleavage of the C2'-C3' bond in 1 followed by reduction with sodium borohydride led to "seco" analogue 8. Nucleosides 2-8 were evaluated for antiviral activity in vivo against the Semliki Forest virus. The activity of compounds 2, 5, and 7 were similar to that of 1. Cyclic phosphate 3 was toxic at the high dose and weakly active at the lower dose. Compounds 4, 6, and 8 were inactive in this system.
Kini
G D
GD
ICN Nucleic Acid Research Institute, Costa Mesa, California 92626.
Anderson
J D
JD
Sanghvi
Y S
YS
Lewis
A F
AF
Smee
D F
DF
Revankar
G R
GR
Robins
R K
RK
Cottam
H B
HB
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis / Q000627:therapeutic use; D011684:Purine Nucleosides / Q000737:chemistry / Q000627:therapeutic use*; D012672:Semliki forest virus; D014036:Togaviridae Infections / Q000188:drug therapy*
D000998:Antiviral Agents; D011355:Prodrugs; D011684:Purine Nucleosides; D006151:Guanosine; C071272:5-amino-3-(2,3,5-tri-O-acetyl-beta-ribofuranosyl)thiazolo(4,5-d)pyrimidine-2,7-dione; C061136:isatoribine