Jf. Nave et al., SYNTHESIS, ANTIVIRAL ACTIVITY AND ENZYMATIC PHOSPHORYLATION OF 9-PHOSPHONOPENTENYL DERIVATIVES OF GUANINE, Antiviral research, 27(3), 1995, pp. 301-316
(E)-9-(5-Phosphonopent-4-enyl)guanine and -[3-(hydroxymethyl)-5-phosph
onopent-4-enyl]guanine which bear a vinyl phosphonate moiety as a mimi
c of the phosphate group were synthesized. Their activities against hu
man immunodeficiency virus type-1 (HIV-1), herpes simplex virus type-1
(HSV-1) and human cytomegalovirus (HCMV) were evaluated in vitro in p
arallel 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 ph
osphonate analogues were inactive. The selectivity index, calculated a
s the ratio of the toxicity for the host cells (50% reduction in cell
viability or in [methyl-H-3]thymidine incorporation) to the 50% inhibi
tory concentration for HIV-1 replication, was the highest for [3-(hydr
oxymethyl)-5-phosphonopent-4-enyl]guanine. The acyclonucleotide analog
ues were also studied as substrates of guanylate kinase, an enzyme bel
ieved to play a critical role in the conversion of acyclic phosphate a
nd phosphonate derivatives of guanine to their antivirally active diph
osphate derivatives. (E)-9-(5-Phosphonopent-4-enyl)guanine and -[3-(hy
droxymethyl)-5-phosphonopent-4-enyl]guanine were good substrates of gu
anylate kinase.