title: Structure-activity relationships of (S,Z)-2-aminopurine methylenecyclopropane analogues of nucleosides. Variation of purine-6 substituents and activity against herpesviruses and hepatitis B virus.
abstract: A series of 13 new (S,Z)-2-aminopurine methylenecyclopropane analogues was synthesized, and their antiviral activity was investigated. The nucleophilic displacement of chlorine of 2-amino-6-chloropurine derivative 5 with allyl-, propargyl-, cyclopropylmethyl-, isopropyl-, benzyl-, cyclohexyl-, and 2-hydroxyethylamine gave N(6)-alkyl compounds 2a, 2b, 2c, 2d, 2e,2f, and 2g. A similar reaction of 5 with allyl, cyclopropylmethyl, propyl, or pentyl alcohol catalyzed by K(2)CO(3) afforded O(6)-alkyl analogues 3a, 3c, 3h and 3i. Propane- and pentanethiol furnished S(6)-alkyl compounds 4h and 4i. The N(6)-alkyl derivatives 2a, 2b, O(6) analogues 3a, 3c, 3h, 3i, and S(6) compounds 4h, 4i which were highly effective in all CMV assays and exhibited the lowest cytotoxicity in proliferating HFF cells appear to be good candidates for in vivo assays. Activity of new analogues against HSV-1 or HSV-2 was restricted to BSC-1 and Vero cultures. Compounds 2c, 2b, 3a and 3h were effective against EBV in one of two assays (Daudi or H-1). Analogues 3a and 4i were the most active anti-VZV agents whereas compounds 3h, 3i, and 4h inhibited the replication of HBV in a micromolar concentration range.
authors.affiliation: Department of Chemistry, Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201-1379, USA.
authors.forename: Xinchao
authors.initials: X
authors.lastname: Chen
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: John C
authors.initials: JC
authors.lastname: Drach
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gullen
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: Jiri
authors.initials: J
authors.lastname: Zemlicka
mesh_terms: D000632:Aminopyrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006515:Hepatitis B virus / Q000187:drug effects*; D006564:Herpesviridae / Q000187:drug effects*; D006801:Humans; D051379:Mice; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D011684:Purine Nucleosides; D000632:Aminopyrine