3--amino-2--3--dideoxyuridine and Leukemia-L1210

The (chloroethyl)nitrosourea analogues of 2'-deoxyuridine and 2'-deoxy-5-fluorouridine, 3'-[3-(2-chloroethyl)-3-nitrosoureido]-2',3'-dideoxyuridine (3'-CdUNU, 7) and 3'-[3-(2-chloroethyl)-3-nitrosoureido]-2,3'-dideoxy-5-fluorouridine (3'-CFdUNU, 8), have been synthesized by treatment of the corresponding 3'-amino nucleosides with chloroethyl isocyanate, followed by nitrosation of the resulting ureas. Nucleoside nitrosoureas 7 and 8 exhibited marked anticancer activity against L1210 leukemia in tumor-bearing mice. At an optimum dosage level of 40 mg/kg, 7 and 8 produced 90% and 60% "cures" (greater than 60-day survivors), respectively. The structure-activity relationships are discussed.

Topics: Alkylation; Animals; Antineoplastic Agents; Deoxyuridine; Dideoxynucleosides; Female; Floxuridine; Leukemia L1210; Mice; Nitrosourea Compounds; Structure-Activity Relationship

Several new 3'-azido and 3'-amino nucleosides (8, 9, 12, and 13) have been synthesized and their biological activities evaluated. Among them, 3'-amino-2',3'-dideoxycytidine (13) was found to exhibit potent cytotoxic activity against both L1210 and S-180 cells in vitro with an ID50 of 0.7 and 4.0 microM, respectively. Furthermore, 13 has also shown antitumor activity against L1210 tumor bearing mice with a T/C X 100 value of 283.

Topics: Animals; Antineoplastic Agents; Body Weight; DNA Replication; Leukemia L1210; Mice; Pyrimidine Nucleosides

Various new 5-substituted 3'-azido- and 3'-amino derivatives of 2'-deoxyuridine and 2'-deoxycytidine have been 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 found to be the most active against murine L1210 and sarcoma 180 neoplastic cells in vitro, with an ED50 of 15 and 1 microM, 0.7 and 4 microM, and 10 and 1 microM, 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. Our preliminary findings indicate that compound 7c (6 X 200 mg/kg) was as active as the positive control, 5-fluorouracil (6 X 20 mg/kg), yielding a T/C X 100 of 146 and 129, respectively. However, 3 was found to be inactive in this experiment.

Topics: Animals; Antineoplastic Agents; Deoxycytidine; Deoxycytidine Kinase; Deoxyuridine; Leukemia L1210; Mice; Sarcoma 180; Thymidine Kinase