Synthesis and enantioselectivity of the antiviral effects of (R,Z)-,(S,Z)-methylenecyclopropane analogues of purine nucleosides and phosphoralaninateprodrugs: influence of heterocyclic base, type of virus and host cells

A series of R and S enantiomers of 2-aminopurine methylenecyclopropane anal ogues of nucleosides was synthesized. Two diastereoisomeric lipophilic phos phate prodrugs derived from R and S enantiomers of 2,6-diaminopurine analog ue were also prepared. Enantioselectivity (diastereoselectivity in case of prodrugs) of in vitro antiviral effects was investigated with human and mur ine cytomegalovirus (HCMV and MCMV, respectively), herpes simplex virus typ es 1 and 2 (HSV-1 and HSV-2, respectively), human immunodeficiency virus ty pe 1 (HIV-1), hepatitis B virus (HBV), Epstein-Barr virus (EBV) and varicel la tester virus (VZV). Strong differences in enantioselectivity were found between the R and S enantiomers of adenine analogue and enantiomeric 2-amin opurine analogues. Thus, the enantiomers of adenine analogue were equipoten t against HCMV but not MCMV, where the S enantiomer is strongly preferred. The same S preference was found throughout the 2-aminopurine series for bot h HCMV and MCMV. In contrast, R-synadenol in HIV-1 assays was the best agen t, whereas the S enantiomers of moderately effective 2-amino-6-cyclo-propyl amino and 2-amino-6-methoxypurine analogues were preferred. Little enantiom eric preference was found for R and S enantiomers of synadenol and the corr esponding enantiomers of 2,6-diaminopurine analogue against HBV. A mixed pa ttern of enantioselectivity was observed for EBV depending on the type of h ost cells and assay. Against VZV, the R and S enantiomers of adenine analog ue were equipotent or almost equipotent, but throughout the series of 2-ami nopurine analogues a distinct preference for the S enantiomers was found. T he stereoselectivity pattern of both diastereoisomeric prodrugs mostly foll owed enantioselectivity of the parent analogues. The varying enantioselecti vities in the series of purine methylenecyclopropane analogues are probably a consequence of differences in the mechanisms of action in different viru s/host cell systems.