       Document 0148
 DOCN  M9640148
 TI    Synthesis, antiviral activity and enzymatic phosphorylation of
       9-phosphonopentenyl derivatives of guanine.
 DT    9604
 AU    Nave JF; Taylor D; Tyms S; Kenny M; Eggenspiller A; Eschbach A; Dulworth
       J; Brennan T; Piriou F; Halazy S; Marion Merrell Dow Research Institute,
       Strasbourg, France.
 SO    Antiviral Res. 1995 Jun;27(3):301-16. Unique Identifier : AIDSLINE
       MED/96145338
 AB    (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 (Nave 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.
 DE    Animal  Antiviral Agents/CHEMICAL SYNTHESIS/METABOLISM/*PHARMACOLOGY
       Cell Line  Cercopithecus aethiops  Cytomegalovirus/DRUG EFFECTS  Drug
       Synergism  Guanine/*ANALOGS & DERIVATIVES/CHEMICAL SYNTHESIS/METABOLISM/
       PHARMACOLOGY  Herpesvirus 1, Human/DRUG EFFECTS  Human  HIV-1/DRUG
       EFFECTS  Leukocytes, Mononuclear/CYTOLOGY  Nucleoside-Phosphate
       Kinase/METABOLISM  Phosphorylation  Ribavirin/PHARMACOLOGY
       Structure-Activity Relationship  Vero Cells  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

