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 membra ne-soluble pre-drugs of the big-active free phosphate forms. In partic ular phenyl phosphates, linked via nitrogen to methyl-esterified amino acids, were studied. All compounds were fully characterised by a rang e of methods (high-field multinuclear NMR, mass spectrometry and high performance liquid chromatography (HPLC)) and were subjected to in vit ro 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, whils t 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. (C) 1997 Elsevier Science B.V.