title: Nucleosides and nucleotides. 141. Chemical stability of a new antitumor nucleoside, 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine in alkaline medium: formation of 2'-C-cyano-2'-deoxy-1-beta-D-ribo-pentofuranosylcytosine and its antitumor activity.
abstract: We have designed 2'-C-cyano-2'-deoxy-1-beta-D-arabino- pentofuranosylcytosine (CNDAC) as a potential mechanism-based DNA-strand-breaking nucleoside, which showed potent tumor cell growth inhibitory activity against various human tumor cell lines in vitro and in vivo. When measuring the pKa of the 2' alpha-proton of CNDAC, we found that CNDAC epimerized to 2'-C-cyano-2'-deoxy-1-beta-D-ribo-pentofuranosylcytosine (CNDC) with concomitant degradation of both CNDAC and CNDC to cytosine and 1,4-anhydro-2-C-cyano-2-deoxy-D-erythro-pent-1- enitol. Kinetic analysis of these reactions showed that abstraction of the acidic 2'-proton of CNDAC and CNDC initiated the reactions, which quickly reached an equilibrium. In the equilibrium, a concentration ratio of CNDAC and CNDC was about 3:5. Concomitant degradation of these nucleosides was found to be rather slow. Deuterium incorporation experiments with CNDAC in a D2O buffer suggested the mechanism of the beta-elimination reactions is an E1cB type. These epimerization and degradation reactions were found even in neutral conditions (pH 7.5) and also occurred in RPMI 1640 cell culture medium. The discovery of which nucleoside possesses the predominate tumor cell growth inhibitory activity was important. While both nucleosides showed potent tumor cell growth inhibitory activity against three human tumor cell lines (colon carcinoma WiDr, small cell lung carcinoma SBC-5, and stomach carcinoma MKN-74 cells) in 48 h of incubation, in 20 min of incubation, CNDAC was 11-50 times more effective than CNDC. In vivo antileukemic activity of these nucleosides against a mouse P388 model, CNDAC was obviously superior to CNDC.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Azuma
authors.forename: K
authors.initials: K
authors.lastname: Hanaoka
authors.forename: A
authors.initials: A
authors.lastname: Kurihara
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Miyauchi
authors.forename: N
authors.initials: N
authors.lastname: Kamo
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: D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007941:Leukemia P388 / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013057:Spectrum Analysis; D014407:Tumor Cells, Cultured
chemical_list: C095359:2'-C-cyano-2'-deoxy-1-ribopentofuranosylcytosine; D000970:Antineoplastic Agents; D012263:Ribonucleosides; D003561:Cytarabine; C070279:2'-cyano-2'-deoxyarabinofuranosylcytosine