title: 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.affiliation: Laboratory of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ogawa
authors.forename: S
authors.initials: S
authors.lastname: Shuto
authors.forename: O
authors.initials: O
authors.lastname: Inanami
authors.forename: M
authors.initials: M
authors.lastname: Kuwabara
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.forename: A
authors.initials: A
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D006898:Hydroxylamines / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D014407:Tumor Cells, Cultured
chemical_list: C116287:2'-deoxy-2'-(hydroxylamino)cytidine; C116858:2'-deoxy-2'-hydroxylaminouridine; D000964:Antimetabolites, Antineoplastic; D006898:Hydroxylamines; D003841:Deoxycytidine; D003857:Deoxyuridine