title: Nucleosides and nucleotides. 123. Synthesis of 1-(2-deoxy-2-isocyano-beta-D-arabinofuranosyl)cytosine and related nucleosides as potential antitumor agents.
abstract: 2'-Deoxy-2'-isocyano-1-beta-D-arabinofuranosylcytosine (8, NCDAC) has been synthesized as a potential antitumor antimetabolite from a corresponding 2'-azido-2'-deoxy-1-beta-D-arabinofuranosyluracil derivative 2a. Uracil and thymine analogues 6a and 6b of 8 were also prepared. Attempts to synthesize 2'-deoxy-2'-isocyanocytidine (14b) failed due to the insertion of the 2'-alpha isocyano group into the 3'-OH group, affording the 2',3'-oxazoline derivative 15b. Stability of the isocyano derivative 6a and 2',3'-oxazoline derivative 15a under basic and acidic conditions were examined. The isocyano group in 6a was stable in basic conditions but unstable even in weakly acidic conditions to furnish the corresponding 2'-beta formamide derivative 17. Compound 15a was easily hydrolyzed the corresponding 2'-alpha formamide derivative 16 on treatment with H2O at room temperature. The cytotoxicity of 8, 6a, and 6b was examined in mouse and human tumor cells in vitro and compared with that of ara-C. Of these nucleosides, 8 was moderately cytotoxic to these cell lines. In vivo antitumor activity of 8 against Lewis lung carcinoma cells was also investigated and 8 showed only moderate tumor volume inhibition.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Matsuda
authors.forename: A
authors.initials: A
authors.lastname: Dan
authors.forename: N
authors.initials: N
authors.lastname: Minakawa
authors.forename: S J
authors.initials: SJ
authors.lastname: Tregear
authors.forename: S
authors.initials: S
authors.lastname: Okazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D003561:Cytarabine / Q000008:administration & dosage / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D004355:Drug Stability; D006801:Humans; D017953:Isocyanates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D009062:Mouth Neoplasms / Q000188:drug therapy; D013274:Stomach Neoplasms / Q000188:drug therapy; D013941:Thymine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; D017953:Isocyanates; D003561:Cytarabine; D003841:Deoxycytidine; C085078:2'-deoxy-2'-isocyano-1-arabinofuranosylcytosine; D014498:Uracil; D013941:Thymine