Phosphoramidate derivatives of d4T as inhibitors of HIV: the effect of amino acid variation.
Phosphoramidate derivatives of the nucleoside analogue, 2',3'-dideoxy-2',3'-didehydro thymidine (d4T) have been prepared as potential membrane-soluble pro-drugs of the big-active free phosphate forms. In particular phenyl phosphates, linked via nitrogen to methyl-esterified amino acids, were studied. All compounds were fully characterised by a range of methods (high-field multinuclear NMR, mass spectrometry and high performance liquid chromatography (HPLC)) and were subjected to in vitro evaluation of their anti-HIV efficacy. The nature of the amino acid appeared to be extremely important for the eventual antiviral action. Of the amino acids studied, L-alanine was the most efficacious, whilst L-proline and glycine were particularly poor. However, an unnatural amino acid moiety, dimethylglycine, could substitute for alanine with little or no loss of activity.
McGuigan
C
C
Welsh School of Pharmacy, University of Wales Cardiff, UK.
Tsang
H W
HW
Cahard
D
D
Turner
K
K
Velazquez
S
S
Salgado
A
A
Bidois
L
L
Naesens
L
L
De Clercq
E
E
Balzarini
J
J
D000577:Amides / Q000494:pharmacology; D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D006678:HIV / Q000187:drug effects* / Q000254:growth & development; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development; D015498:HIV-2 / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D051379:Mice; D010755:Organophosphates / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000494:pharmacology; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000378:metabolism
D000577:Amides; D000596:Amino Acids; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010756:Phosphoric Acids; C011067:phosphoramidic acid; D018119:Stavudine; D013937:Thymidine Kinase