Synthesis and biological activity of tricyclic analogues of 9-[[cis-1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine.

Abstract The base moiety of the potent antiherpetic agent 9-{[ cis -1′,2′-bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine 3 was transformed into that of the tricyclic 3,9-dihydro-9-oxo-6- R -5 H -imidazo[1,2- a ]purine system. The tricyclic analogues 5a – d were evaluated for their activity against herpes viruses as well as for cytostatic activity against HSV-1 thymidine kinase (TK) gene-transduced human osteosarcoma tumor cells. Marked activity was found against VZV. The 6-phenyl-substituted fluorescent analogues 5c and d were comparable to that of parent 3 in activity against the VZV strain YS and were 3-fold less active against the VZV strain OKA. The compounds 5a – d also showed marked activity against HSV-1 (KOS) and HSV-2 (G)—against the former generally approximately comparable to that of acyclovir 1a and one order of magnitude lower than 3 ; against the latter comparable to that of 1a and approximately 6- to 30-fold lower than that of 3 . The most pronounced cytostatic activity (5-fold lower than that of 3 ) was exhibited by compounds 5c and d . Tricyclic analogues with pseudosugar moieties are intrinsically bio-active.