Attempt to reduce cytotoxicity by synthesizing the L-enantiomer of 4'-C-ethynyl-2'-deoxypurine nucleosides as antiviral agents against HIV and HBV.
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.
Kitano
Kenji
K
Biochemical Division, Yamasa Corporation, Choshi, Japan.
Kohgo
Satoru
S
Yamada
Kohei
K
Sakata
Shinji
S
Ashida
Noriyuki
N
Hayakawa
Hiroyuki
H
Nameki
Daisuke
D
Kodama
Eiichi
E
Matsuoka
Masao
M
Mitsuya
Hiroaki
H
Ohrui
Hiroshi
H
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
D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors