Phosphoramidate derivatives of stavudine as inhibitors of HIV: unnatural amino acids may substitute for alanine.
Some novel phosphoramidate derivatives of the nucleoside analogue stavudine have been prepared as membrane-soluble prodrugs of the bioactive free phosphate forms. Phenyl phosphates linked via nitrogen to methyl esterified amino acid analogues were studied, where the amino acid was an unnatural alpha-alkyl (or aryl) glycine or an alpha,alpha-dialkyl glycine. All compounds were characterized by a range of spectroscopic, spectrometric and analytical methods and were subjected to in vitro evaluation of their anti-human immunodeficiency virus efficacy. It is notable that certain unnatural amino acid derivatives could substitute for alanine with only a relatively small loss of activity and, moreover, that this activity did not fall-off with increasing alkyl chain length for the C2-C4 mono-alkyl series. These data are further probed by the application of our recently reported 31P-NMR-based carboxyl esterase assay, with informative results.
McGuigan
C
C
Welsh School of Pharmacy, Cardiff University, UK. mcguigan@cardiff.ac.uk
Bidois
L
L
Hiouni
A
A
Ballatore
C
C
De Clercq
E
E
Balzarini
J
J
D000409:Alanine; D000577:Amides / Q000737:chemistry*; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000737:chemistry; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D010756:Phosphoric Acids / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D018119:Stavudine / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D000596:Amino Acids; D019380:Anti-HIV Agents; D010756:Phosphoric Acids; D018894:Reverse Transcriptase Inhibitors; C011067:phosphoramidic acid; D018119:Stavudine; D000409:Alanine