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.

Several monocarbamate compounds derived from felbamate were synthesized and 11 target compounds (1, 4, and 6–14) were initially evaluated in mice MES and PTZ models in our laboratory. Carbamate compounds with varying substituents on the oxygen (1–4) gave anticonvulsant activity with a wide range of ED50 in MES test from <20 mg/kg (2) to >300 mg/kg (4) and compounds with different groups on the nitrogen (5–14) also were quite active in the range of 15 mg/kg (14) to 170.5 mg/kg (6). This suggested that the spatial limitation in the MES model seemed flexible especially on the nitrogen end. All tested compounds showed some activity against mice scPTZ test, but none had the ED50 value <50 mg/kg. Ten selected compounds (1 and 6–14) for subsequent pharmacological evaluation in NIH all gave positive mice MES activity except 8 and 9, which were unexpectedly active in rats after further evaluations. Among the compounds, 1, 8, and 9 advanced to the quantitative study and 1 and 9 provided the highest PI values, 15 and 21, respectively, in the rat oral MES test.