Synthesis, solution conformation and anti-HIV activity of novel 3'-substituted-2',3'-dideoxy-5-hydroxymethyluridines and their 4,5-substituted analogues.
To decrease the toxicity of potent anti-HIV nucleosides 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxy-3'-fluorothymidine (3'-FddThd, FLT), their new analogues, 3'-azido-2',3'-dideoxy-5-hydroxymethyluridine (3'-Az5HmddUrd) and 2',3'-dideoxy-3'-fluoro-5-hydroxymethyluridine (3'-F5HmddUrd), were synthesized. The reaction of 3'-azido-2',3'-dideoxyuridine (3'-AzddUrd) and 2',3'-dideoxy-3'-fluorouridine (3'-FddUrd) with formaldehyde, under strongly alkaline conditions and at elevated temperature, proceeded after 4 days to completion to afford the corresponding 5-hydroxymethyl derivatives 3'-Az5HmddUrd and 3'-F5HmddUrd in good yield. These compounds were also prepared by oxidation of AZT and FLT with the use of K2S2O8. 1H NMR analyses were subjected to the series of 3', 4 and 5-substituted pyrimidine 2'-deoxy- and 2',3'-dideoxynucleosides involving 3'-Az5HmddUrd and 3'-F5HmddUrd. Analysis of the sugar furanose ring puckering demonstrated that all 3'-fluorine derivatives exhibited strong domination of the S conformation (approximately 100%) while 3'-substitution by electron-donating groups, such as NH2, increased population of the N conformation. Experimentally observed substituent effect on the furanose ring puckering equilibrium was reconstructed in the 100 ps molecular dynamic trajectories obtained for AZT, FLT, dThd, 2',3'-ddThd and 3'-amino-2',3'-ddThd. It may be concluded that anti-HIV activity is linked to a direct interaction of the 3'-substituent with reverse transcriptase (RT) binding site. Anti-HIV activities of 3'-Az5HmddUrd and 3'-F5HmddUrd are lower than activity of AZT and FLT; however, 3'-Az5HmddUrd and 3'-F5HmddUrd are less toxic than AZT and FLT.
Poznanski
Jaroslaw
J
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Bretner
Maria
M
Kulikowski
Tadeusz
T
Balzarini
Jan
J
Van Aerschot
Arthur
A
De Clercq
Erik
E
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006678:HIV / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D018894:Reverse Transcriptase Inhibitors; D003857:Deoxyuridine