Synthesis and anti-HIV-1 evaluation of phosphonates which mimic the 5'-monophosphate of 4'-branched 2',3'-didehydro-2',3'-dideoxy nucleosides.
Synthesis of the 4'-ethynyl and 4'-cyano phosphonates 8-11, which mimic the 5'-monophosphate of 4'-branched 2',3'-didehydro-2',3'-dideoxy nucleosides, was investigated by employing the 3',4'-unsaturated nucleosides (13 and 28) as the starting material. The synthesis was initiated by the electrophilic addition of NIS/(EtO)(2)P(O)CH(2)OH to these unsaturated nucleosides. After introduction of the 2',3'-double bond, the 4'-hydroxylmethyl group of the resulting adducts was transformed into the ethynyl or cyano group. While the 4'-cyano phosphonates 9 and 11 were not sufficiently stable to be isolated, the 4'-ethynyl counterparts (8 and 10) were obtained as their mono-ammonium salts. The adenine derivative 8 showed almost comparable anti-HIV-1 activity to that of d4T.
Kubota
Yutaka
Y
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. y-kubota@pharm.showa-u.ac.jp
Ishizaki
Nobuhide
N
Haraguchi
Kazuhiro
K
Hamasaki
Takayuki
T
Baba
Masanori
M
Tanaka
Hiromichi
H
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018119:Stavudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D063065:Organophosphonates; D018119:Stavudine