title: Synthesis of enantiomerically pure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation.
abstract: Based upon the fact that L-nucleosides have been generally known to be less cytotoxic than D-counterparts, L-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. D-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, D-thymine nucleoside, D-2 and L-thymine nucleoside, L-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas D-2 exhibited high cytotoxicity in MT-4 cell lines, L-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that L-2 may be a good candidate for an anti-AIDS drug. L-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2',3'-dideoxy structure. Potent antiviral effects of D-2 and L-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports L-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity.
authors.affiliation: Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea.
authors.forename: Ah-Young
authors.initials: AY
authors.lastname: Park
authors.forename: Won Hee
authors.initials: WH
authors.lastname: Kim
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Kang
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Chong-Kyo
authors.initials: CK
authors.lastname: Lee
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D002460:Cell Line; D004267:DNA Viruses / Q000187:drug effects; D004811:Epichlorohydrin / Q000737:chemistry; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D012328:RNA Viruses / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D001643:Bridged Bicyclo Compounds; D009705:Nucleosides; D004811:Epichlorohydrin