Synthesis and evaluation of sulfonylethyl-containing phosphotriesters of 3′-azido-3′-deoxythymidine as anticancer prodrugs.

A series of bis(sulfonylethyl) and mono(sulfonylethyl) phenyl phosphotriesters of zidovudine (3′-azido-3′-deoxythymidine, AZT) were synthesized as potential anticancer prodrugs that liberate AZT monophosphate via nonenzymatic β -elimination mechanism. Stability studies demonstrated that all the synthesized prodrugs spontaneously liberate AZT monophosphate with half-lives in the range of 0.07–278.8 h under model physiological conditions in 0.1 M phosphate buffer at pH 7.4 and 37 °C. Analogous to aldophosphamide, the elimination rates were accelerated in the presence of reconstituted human plasma under the same conditions. Among the compounds, 3 , 4 , 8 , and 10 were comparable or superior to AZT against five established human cancerous cell lines in vitro. Moreover, the selected compounds were equally sensitive to both the wild-type osteosarcoma 143B and the thymidine kinase-deficient 143B/TK − cell lines. The findings are consistent with that these compounds deliver AZT monophosphate intracellularly. [ABSTRACT FROM AUTHOR]