Synthesis, antiviral activity and enzymatic phosphorylation of 9-phosphonopentenyl derivatives of guanine.
(E)-9-(5-Phosphonopent-4-enyl)guanine and (E)-9-[3-(hydroxymethyl)-5- phosphonopent-4-enyl]guanine which bear a vinyl phosphonate moiety as a mimic of the phosphate group were synthesized. Their activities against human immunodeficiency virus type-1 (HIV-1), herpes simplex virus type-1 (HSV-1) and human cytomegalovirus (HCMV) were evaluated in vitro in parallel with those of 9-(5-phosphonopentyl)guanine and 9-(5,5-difluoro-5- phosphonopentyl)guanine. Both vinyl phosphonates exhibited anti-HIV-1 and anti-HCMV activities, whereas the methyl- and difluoromethyl phosphonate analogues were inactive. The selectivity index, calculated as the ratio of the toxicity for the host cells (50% reduction in cell viability or in [methyl-3H]thymidine incorporation) to the 50% inhibitory concentration for HIV-1 replication, was the highest for (E)-9-[3-(hydroxymethyl)-5-phosphonopent-4-enyl]guanine. The acyclonucleotide analogues were also studied as substrates of guanylate kinase, an enzyme believed to play a critical role in the conversion of acyclic phosphate and phosphonate derivatives of guanine to their antivirally active diphosphate derivatives. (E)-9-(5-Phosphonopent-4- enyl)guanine and (E)-9-[3-(hydroxymethyl)-5-phosphonopent-4-enyl]guanine were good substrates of guanylate kinase, being phosphorylated with efficiencies of 14 and 36% of that determined for GMP, respectively. These results contrast with the poor efficiency found for 9-(5-phosphonopentyl)guanine (0.3%) and the lack of phosphorylation of 9-(5,5-difluoro-5-phosphonopentyl)guanine by guanylate kinase (Navé et al. (1992) Arch. Biochem. Biophys. 295, 253-257). The role of the vinyl phosphonate group in the expression of the anti-HIV-1 activity of the phosphonopentenyl derivatives of guanine is discussed.
Navé
J F
JF
Marion Merrell Dow Research Institute, Strasbourg, France.
Taylor
D
D
Tyms
S
S
Kenny
M
M
Eggenspiller
A
A
Eschbach
A
A
Dulworth
J
J
Brennan
T
T
Piriou
F
F
Halazy
S
S
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000187:drug effects; D004357:Drug Synergism; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051528:Guanylate Kinases; D015497:HIV-1 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D010766:Phosphorylation; D012254:Ribavirin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014709:Vero Cells
C097410:9-(3-(hydroxymethyl)-5-phosphonopent-4-enyl)guanine; C097409:9-(5-phosphonopent-4-enyl)guanine; D000998:Antiviral Agents; D012254:Ribavirin; D006147:Guanine; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases