SYNTHESIS, ANTIVIRAL ACTIVITY AND ENZYMATIC PHOSPHORYLATION OF 9-PHOSPHONOPENTENYL DERIVATIVES OF GUANINE

(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.