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

• Published in: Journal of medicinal chemistry Vol. 26; no. 12; pp. 1691 - 1696
• Main Authors: Lin, Tai Shun, Gao, You Song, Mancini, William R
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.12.1983
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Carbohydrates. Nucleosides and nucleotides; Chemistry; Deoxycytidine - analogs & derivatives; Deoxycytidine - chemical synthesis; Deoxycytidine - therapeutic use; Deoxycytidine Kinase - antagonists & inhibitors; Deoxyuridine - analogs & derivatives; Deoxyuridine - chemical synthesis; Deoxyuridine - therapeutic use; Exact sciences and technology; Leukemia L1210 - drug therapy; Mice; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Sarcoma 180 - drug therapy; Thymidine Kinase - antagonists & inhibitors; Antineoplastic agent; L1210 Leukemia; Aminonucleoside; Deoxyribonucleoside; Sarcoma 180; Pyrimidine nucleoside; Biological activity
• DOI: 10.1021/jm00366a006
• ISSN: 0022-2623

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.