title: (Z)- and (E)-2-(1,2-dihydroxyethyl)methylenecyclopropane analogues of 2'-deoxyadenosine and 2'-deoxyguanosine. Synthesis of all stereoisomers, absolute configuration, and antiviral activity.
abstract: 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)-Methylenecyclopropylcarbinol (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 EC(50) of 6.8 and 7.5 microM and of murine cytomegalovirus (MCMV) with EC(50) of 11.3 microM. It was less active against HCMV with mutated gene UL97. It inhibited Epstein-Barr virus (EBV) with EC(50) of 8 microM. 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.
authors.affiliation: Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201-1379, USA.
authors.forename: Shaoman
authors.initials: S
authors.lastname: Zhou
authors.forename: John C
authors.initials: JC
authors.lastname: Drach
authors.forename: Mark N
authors.initials: MN
authors.lastname: Prichard
authors.forename: Jiri
authors.initials: J
authors.lastname: Zemlicka
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003521:Cyclopropanes / Q000138:chemical synthesis*; D003587:Cytomegalovirus / Q000187:drug effects; D003839:Deoxyadenosines / Q000737:chemistry* / Q000494:pharmacology; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D051379:Mice; D018146:Muromegalovirus / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D003839:Deoxyadenosines; C508672:methylenecyclopropane; D003849:Deoxyguanosine; C058118:2'-deoxyadenosine