title: Attempt to reduce cytotoxicity by synthesizing the L-enantiomer of 4'-C-ethynyl-2'-deoxypurine nucleosides as antiviral agents against HIV and HBV.
abstract: We investigated the potential of 4'-C-substituted nucleosides for the treatment of HIV-1 and HBV. Of the nucleosides we prepared, several 4'-C-ethynyl-2'-deoxypurine nucleosides showed the most potent anti-HIV activity. However, two candidates, 4'-C-ethynyl-2'-deoxyguanosine and 9-(2-deoxy-4-C-ethynyl-beta-D-ribo-pentofuranosyl)-2,6-diaminopurine, were very toxic during in vivo study. On the other hand, lamivudine (3TC) is known to show remarkable activity against HIV and HBV with lower cytotoxicity. Therefore, we attempted to synthesize the L-enantiomer of 4'-C-ethynyl-2'-deoxypurine nucleosides in 20-21 steps. These methods consisted of preparing 4-C-ethynyl-L-sugar, starting from D-arabinose and then condensing the L-sugar derivative with 2,6-diaminopurine. 4'-C-Ethynyl-2'-deoxyguanosine was also prepared by enzymatic deamination from the 2,6-diaminopurine derivative. The compounds' antiviral activity against HIV and HBV was then evaluated. Unfortunately, they demonstrated no activity and no cytotoxicity.
authors.affiliation: Biochemical Division, Yamasa Corporation, Choshi, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitano
authors.forename: Satoru
authors.initials: S
authors.lastname: Kohgo
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamada
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakata
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ashida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nameki
authors.forename: Eiichi
authors.initials: E
authors.lastname: Kodama
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohrui
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006509:Hepatitis B / Q000188:drug therapy*; D006515:Hepatitis B virus; D006801:Humans; D016133:Polymerase Chain Reaction; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors