Attempt to reduce cytotoxicity by synthesizing the L-enantiomer of 4′-C-ethynyl-2′-deoxypurine nucleosides as antiviral agents against HIV and HBV

Kenji Kitano, Satoru Kohgo, Kohei Yamada, Shinji Sakata, Noriyuki Ashida, Hiroyuki Hayakawa, Daisuke Nameki, Eiichi Kodama, Masao Matsuoka, Hiroaki Mitsuya, Hiroshi Ohrui

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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-β-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.

Original languageEnglish
Pages (from-to)161-167
Number of pages7
JournalAntiviral Chemistry and Chemotherapy
Volume15
Issue number3
DOIs
Publication statusPublished - 2004 May
Externally publishedYes

Keywords

  • 4′-C-ethynyl-2′-deoxy nucleosides (4′-EdNs)
  • Anti-HBV agent
  • Anti-HIV-1 agent
  • L-enantiomer
  • Lamivudine

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Virology

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