Nucleosides and nucleotides. 176. 2'-Deoxy-2'-hydroxylaminocytidine: a new antitumor nucleoside that inhibits DNA synthesis although it has a ribonucleoside structure.

Abstract

The design and synthesis of potential antitumor antimetabolites 2'-deoxy-2'-hydroxylaminouridine (2'-DHAU) and -cytidine (2'-DHAC) are described. We found that 2'-DHAC in neutral solution generated 2'-aminoxy radicals at room temperature. 2'-DHAC inhibited the growth of L1210 and KB cells, with IC50 values of 1.58 and 1.99 microM, respectively, more potently than 2'-DHAU, with IC50 values of 34.5 and 27.3 microM, respectively. 2'-DHAC was effective against 9 human cell lines, with IC50 values of in the micromolar range. The in vivo antitumor activity of 2'-DHAC was also examined using the mouse leukemia P388 model, which gave a T/C value 167%. Phosphorylation of 2'-DHAC by uridine/cytidine kinase was essential for its cytotoxicity, as suggested by a competition experiment using several common nucleosides. Inhibition of DNA synthesis was the predominant mechanism of action of 2'-DHAC, although it has a ribo-configuration.

• Authors: A Ogawa, S Shuto, O Inanami, M Kuwabara, M Tanaka, T Sasaki, A Matsuda
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 8 Issue 14 Pg. 1913-8 (Jul 21 1998) ISSN: 0960-894X [Print] England
• PMID: 9873458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2'-deoxy-2'-(hydroxylamino)cytidine
• 2'-deoxy-2'-hydroxylaminouridine
• Antimetabolites, Antineoplastic
• Hydroxylamines
• Deoxycytidine
• Deoxyuridine

Topics

• Animals
• Antimetabolites, Antineoplastic (chemistry, pharmacology)
• DNA Replication (drug effects)
• Deoxycytidine (analogs & derivatives, chemistry, pharmacology)
• Deoxyuridine (analogs & derivatives, chemistry, pharmacology)
• Electron Spin Resonance Spectroscopy
• Humans
• Hydroxylamines (chemistry, pharmacology)
• Mice
• Phosphorylation
• Tumor Cells, Cultured