Nucleosides and nucleotides. 180. Synthesis and antitumor activity of nucleosides that have a hydroxylamino group instead of a hydroxyl group at the 2'- or 3'-position of the sugar moiety.

Abstract

The design and synthesis of potential antitumor antimetabolites 2'-deoxy-2'-(hydroxylamino)uridine (15), -cytidine (19, 2'-DHAC), and -adenosine (35), their regioisomers, 3'-deoxy-3'-(hydroxylamino)uridine (40) and -cytidine (45, 3'-DHAC), and their 2'-deoxy analogues, 2', 3'-dideoxy-3'-(hydroxylamino)uridine (49) and -cytidine (52, 3'-dDHAC), are described. We measured the pKa values of the hydroxylamino group in 15 and 40 using 13C NMR spectroscopy as a function of pH to be 2.9 and 3.4, respectively. We also found that these nucleosides gradually decomposed in neutral solution but not in acidic solution. This decomposition may be related to the generation of aminoxy radicals at the sugar moiety. The in vitro cytotoxicity of these nucleosides was evaluated using L1210 and KB cells. 2'-DHAC (19) inhibited the growth of L1210 and KB cells, with IC50 values of 1.58 and 1.99 microM, respectively. 3'-DHAC (45) and 3'-dDHAC (52) were also cytotoxic against L1210 cells, with IC50 values of 4.03 and 1.84 microM, respectively, but not against KB cells. The cytotoxicity of 2'-DHAC (19) and 3'-DHAC (45) against L1210 cells in vitro was reversed by the addition of cytidine, while that of 3'-dDHAC (52) was reversed by 2'-deoxycytidine. 2'-DHAC (19) and 3'-dDHAC (52) mainly inhibited DNA synthesis in L1210 cells, while 3'-DHAC (45) inhibited RNA synthesis. We also evaluated the antitumor activities of 2'-DHAC (19) and 3'-DHAC (45) against murine Meth-A fibrosarcoma cells in vivo. 2'-DHAC (19) was more active than 3'-DHAC (45) when administered intravenously on days 1-10 consecutively at 10 mg/kg/day. 2'-DHAC (19) inhibited tumor growth at a rate of 66.9%.

• Authors: A Ogawa, M Tanaka, T Sasaki, A Matsuda
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 41 Issue 25 Pg. 5094-107 (Dec 03 1998) ISSN: 0022-2623 [Print] United States
• PMID: 9836625 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2'-deoxy-2'-(hydroxylamino)cytidine
• 3'-deoxy-3'-(hydroxylamino)cytidine
• Antimetabolites, Antineoplastic
• DNA, Neoplasm
• RNA, Neoplasm
• Deoxycytidine
• Cytidine

Topics

• Animals
• Antimetabolites, Antineoplastic (chemical synthesis, chemistry, pharmacology)
• Cytidine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• DNA, Neoplasm (antagonists & inhibitors)
• Deoxycytidine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Female
• Fibrosarcoma (drug therapy, pathology)
• Humans
• Inhibitory Concentration 50
• Leukemia P388 (drug therapy, pathology)
• Neoplasm Transplantation
• RNA, Neoplasm (antagonists & inhibitors)
• Structure-Activity Relationship
• Tumor Cells, Cultured