NUCLEOSIDES AND NUCLEOTIDES - 176 - 2'-DEOXY-2'-HYDROXYLAMINOCYLIDINE- A NEW ANTITUMOR NUCLEOSIDE THAT INHIBITS DNA-SYNTHESIS ALTHOUGH IT HAS A RIBONUCLEOSIDE STRUCTURE

The design and synthesis of potential antitumor antimetabolites 2'-deo xy-2'-hydroxylaminouridine (2'-DHAU) and -cytidine (2'-DHAC) are descr ibed. We found that 2'-DHAC in neutral solution generated 2'-aminoxy r adicals at room temperature. 2'-DHAC inhibited the growth of L1210 and KB cells, with IC50 values of 1.58 and 1.99 mu M, respectively, more potently than 2'-DHAU, with IC50 values of 34.5 and 27.3 mu M, respect ively. 2'-DHAC was effective against 9 human cell lines, with IC50 val ues 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 kinas e was essential for its cytotoxicity, as suggested by a competition ex periment using several common nucleosides. Inhibition of DNA synthesis was the predominant mechanism of action of 2'-DHAC, although it has a ribo-configuration. (C) 1998 Elsevier Science Ltd. All rights reserve d.