2'-Nor-cGMP: a seco-cyclic nucleotide with powerful anti-DNA-viral activity.
As part of our study of antiherpetic acyclonucleosides, we synthesized a cyclic GMP analog, 9-[(2-hydroxy-1,3,2-dioxaphosphorinan-5-yl)oxymethyl]guanine P-oxide, sodium salt (2'-nor-cGMP), and discovered its potent and broad spectrum anti-DNA-viral activities. 2'-Nor-cGMP inhibits the replication of many DNA viruses, including herpes simplex virus, human cytomegalovirus, vaccinia, SV40, and adenovirus, but does not inhibit RNA viruses. In plaque reduction studies this potent antiviral agent is also approximately 10-fold more potent than 9-(1,3-dihydroxy-2-propoxymethyl)guanine (2'NDG) against varicella-zoster virus and inhibits cell transformation by bovine papilloma virus. Unlike 2'NDG, the potent activity of 2'-nor-cGMP against herpes virus is not dependent upon the action of virus-specified thymidine kinase. Intercellular metabolism of 2'-nor-cGMP produced small amounts of 2'NDG triphosphate which were insufficient to account for the antiviral activity observed, implying that this potent anti-DNA-viral agent operates by a mechanism different from that of known acyclonucleosides.
Tolman
R L
RL
Field
A K
AK
Karkas
J D
JD
Wagner
A F
AF
Germershausen
J
J
Crumpacker
C
C
Scolnick
E M
EM
D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents; D002472:Cell Transformation, Viral / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004267:DNA Viruses / Q000187:drug effects*; D005260:Female; D015774:Ganciclovir; D006147:Guanine / Q000031:analogs & derivatives*; D006558:Herpes Genitalis / Q000188:drug therapy; D014645:Herpesvirus 3, Human / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009943:Organophosphorus Compounds; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D009943:Organophosphorus Compounds; D006147:Guanine; C045511:9-((2-hydroxy-1,3,2-dioxaphosphorinan-5-yl)oxymethyl)guanine P-oxide; D013937:Thymidine Kinase; D006152:Cyclic GMP; D015774:Ganciclovir; D000212:Acyclovir