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

Article abstract of DOI:10.1016/S0960-894X(98)00336-9

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 μM, respectively, more potently than 2'-DHAU, with IC₅₀ values of 34.5 and 27.3 μM, respectively. 2'-DHAC was effective against 9 human cell lines, with IC₅₀ values 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 of 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.