We report the synthesis and anticancer activity of a series of AZT phosphoramidate 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 stereochemical preference for the L-amino acid stereochemistry was also observed in MCF-7 cells. There was no consistent enhancement of cytotoxicity of the methyl amides over the corresponding methyl esters. AZT and the two AZT aromatic amino acid methyl ester phosphoramidates 8a and 9a were found to be more cytotoxic toward MCF-7 cells than to CEM cells (human T-cell lymphoblastic leukemia). The selective cytotoxicity toward MCF-7 cells may be associated with greater intracellular levels of phosphoramidate monoester and/or phosphorylated AZT.
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). -Investigation of in vitro anticancer activity of two series of title compounds in comparison to AZT itself shows that phosphoramidates (Ia) and (Ib) are more selectively cytotoxic towards human breast cancer cell line MCF-7 than towards T-leukemia cell line CEM. Further studies of their in vivo activity are underway. -(IYER, VIDHYA V.; GRIESGRABER, GEORGE W.; RADMER, MATTHEW R.; MCINTEE, EDWARD J.; WAGNER, CARSTON R.; J.
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