Design, efficient synthesis, and anti-HIV activity of 4'-C-cyano- and 4'-C-ethynyl-2'-deoxy purine nucleosides.
Some 4'-C-ethynyl-2'-deoxy purine nucleosides showed the most potent anti-HIV activity among the series of 4'-C-substituted 2'-deoxynucleosides whose 4'-C-substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C-4' position they have, the more acceptable biological activity they show. Thus, 4'-C-cyano-2'-deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4'-C-cyano-2'-deoxy purine nucleosides (4'-CNdNs) and 4'-C-ethynyl-2'-deoxy purine nucleosides (4'-EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2'-deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C-4' position of the sugar moiety from 2'-deoxyadenosine and 2,6-diaminopurine 2'-deoxyriboside. Unfortunately, 4'-C-cyano derivatives showed lower activity against HIV-1, and two 4'-C-ethynyl derivatives suggested high toxicity in vivo.
Kohgo
Satoru
S
Biochemicals Division, Yamasa Corporation, Chiba, Japan.
Yamada
Kohei
K
Kitano
Kenji
K
Iwai
Yuko
Y
Sakata
Shinji
S
Ashida
Noriyuki
N
Hayakawa
Hiroyuki
H
Nameki
Daisuke
D
Kodama
Eiichi
E
Matsuoka
Masao
M
Mitsuya
Hiroaki
H
Ohrui
Hiroshi
H
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D015195:Drug Design; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D011684:Purine Nucleosides