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 phos phate forms. Phenyl phosphates linked via nitrogen to methyl esterified ami no acid analogues were studied, where the amino acid was an unnatural alpha -alkyl (or aryl) glycine or an alpha,alpha-dialkyl glycine. All compounds w ere characterized by a range of spectroscopic, spectrometric and analytical methods and were subjected to in vitro evaluation of their anti-human immu nodeficiency virus efficacy. It is notable that certain unnatural amino aci d derivatives could substitute for alanine with only a relatively small los s of activity and, moreover, that this activity did not fall-off with incre asing alkyl chain length for the C2-C4 mono-alkyl series. These data are fu rther probed by the application of our recently reported P-31-NMR-based car boxyl esterase assay, with informative results.