Synthesis, in vitro anti-breast cancer activity, and intracellular decomposition of amino acid methyl ester and alkyl amide phosphoramidate monoesters of 3 '-azido-3 '-deoxythymidine (AZT)

We report the synthesis and anticancer activity of a series of AZT phosphor amidate monoesters containing amino acid methyl ester (3a-11a) and N-alkyl amide (3b-11b, 9c-9f) moieties. The aromatic amino acid methyl esters were found to be more cytotoxic than the aliphatic analogues toward MCF-7 cells (human pleural effusion breast adenocarcinoma cell line). A marked stereoch emical preference for the L-amino acid stereochemistry was also observed in MCF-7 cells. There was no consistent enhancement of cytotoxicity of the me thyl amides over the corresponding methyl esters. AZT and the two AZT aroma tic amino acid methyl ester phosphoramidates 8a and 9a were found to be mor e cytotoxic toward MCF-7 cells than to CEM cells (human T-cell lymphoblasti c leukemia). The selective cytotoxicity toward MCF-7 cells may be associate d with greater intracellular levels of phosphoramidate monoester and/or pho sphorylated AZT.