Synthesis and anti-human immunodeficiency virus type 1 (HIV-1) activity of 3-substituted derivatives of 3'-azido-3'-deoxythymidine (AZT), and inhibition of HIV-1 reverse transcriptase by their 5'-triphosphates.
Various 3-substituted 3'-azido-3'-deoxythymidine analogs (2a-i) were prepared by the reaction of 3'-azido-3'-deoxythymidine (1), AZT with N,N-dimethylformamide dialkylacetal or alkyl bromide in the presence of base and their activities against human-immunodeficiency virus type-1 (HIV-1) were evaluated. The corresponding 5'-triphosphate analogs (9) were also synthesized in order to examine inhibition of HIV-1 reverse transcriptase activity. Beyond expectation, some N3-derivatives of AZT were found to reserve the anti-HIV-1 activity to some extent. Among the compounds (2a-i) obtained, 3-allyl-AZT (2e) was the most active against HIV-1 replication in MT-4 cells in vitro with an EC50 value of 0.9 microM. 3-Allyl-AZT 5'-triphosphate (9e), however, exhibited no inhibition of HIV-1 reverse transcriptase activity.
Kitade
Y
Y
Department of Medicinal Chemistry, Gifu Pharmaceutical University, Japan.
Suzuki
A
A
Hirota
K
K
Maki
Y
Y
Nakane
H
H
Ono
K
K
Baba
M
M
Shigeta
S
S
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D010710:Phosphates / Q000138:chemical synthesis / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D015215:Zidovudine / Q000031:analogs & derivatives*
D000998:Antiviral Agents; D010710:Phosphates; D018894:Reverse Transcriptase Inhibitors; D014764:Viral Proteins; D015215:Zidovudine