(Z)- and (E)-2-(1,2-Dihydroxyethyl)methylenecyclopropane Analogues of 2′-Deoxyadenosine and 2′-Deoxyguanosine. Synthesis of All Stereoisomers, Absolute Configuration, and Antiviral Activity

Chiral Z- and E-stereoisomers of (1,2-dihydroxyethyl)methylenecyclopropane analogues of 2'-deoxyadenosine and 2'-deoxyguanosine were. synthesized, and their antiviral activity was investigated. (S)-Methylenecyclo-propylcarbinol (16) was converted in seven steps to reagents 26 and 27, which were used for alkylation-elimination of adenine and 2-amino-6-chloropurine to get ultimately analogues 12a, 12b, 13a, 13b, 14a, 14b, 15a, and 15b. The enantiomeric series ent-12a, ent-12b, ent-13a, ent-13b, ent-14a, ent-14b, ent-15a, and ent-15b was obtained by similar procedures starting from (R)-methylenecyclopropylcarbinol (ent-16). The Z-isomer ent-12b was an inhibitor of two strains of human cytomegalovirus (HCMV) with EC50 of 6.8 and 7.5 mu M and of murine cytomegalovirus (MCMV) with EC50 of 11.3 mu M. It was less active against HCMV with mutated gene UL97. It inhibited Epstein-Barr virus (EBV) with EC50 of 8 mu M. The E-isomers ent-15a, ent-13a, and 15b were less effective. All adenine analogues with the exception of the Z-isomers ent-12a and ent-14a were moderate substrates for adenosine deaminase.