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

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.