Synthesis and biological activity of various 3'-azido and 3'-amino analogs of 5-substituted pyrimidine deoxyribonucleosides

Abstract

Various new 5-substituted 3''-azido- and 3''-amino derivatives of 2''-deoxyuridine and 2''-deoxycytidine were synthesized and biologically evaluated. Among these compounds, 3''-amino-2'',3''-dideoxy-5-fluorouridine (3), 3''-amino-2'',3''-dideoxycytidine (7a), and 3''-amino-2'',3''-dideoxy-5-fluorocytidine (7c) were the most active against murine L1210 [leukemia] and sarcoma 180 neoplastic cells in vitro, with an ED50 of 15 and 1 .mu.M, 0.7 and 4 .mu.M, and 10 and 1 .mu.M, respectively. The 3''-azido derivatives, 2 and 6c, were less active in comparison with their 3''-amino counterparts. In addition, the 5-fluoro-3''-amino nucleosides, 3 and 7c, were tested against L1210 leukemia bearing CDF1 mice. Preliminary findings indicate that compound 7c (6 .times. 200 mg/kg) was as active as the positive control, 5-fluorouracil (6 .times. 20 mg/kg), yielding a T/C .times. 100 of 146 and 129, respectively. However, 3 was found to be inactive in this experiment.