Design, synthesis, and anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives.
We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates.
Mehellou
Youcef
Y
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, UK.
McGuigan
Christopher
C
Brancale
Andrea
A
Balzarini
Jan
J
D000577:Amides / Q000737:chemistry*; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000737:chemistry*; D015195:Drug Design; D015497:HIV-1 / Q000378:metabolism; D015498:HIV-2 / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry; D009705:Nucleosides / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D010756:Phosphoric Acids / Q000737:chemistry*; D010766:Phosphorylation; D013938:Thymidine Monophosphate / Q000737:chemistry
D000577:Amides; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D009705:Nucleosides; D010710:Phosphates; D010756:Phosphoric Acids; D013938:Thymidine Monophosphate; C058925:2',3'-didehydro-2',3'-dideoxyuridine; C059513:2',3'-dideoxyuridine; C011067:phosphoramidic acid; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase