title: Synthesis, antitumor activity, and antiviral activity of 3-substituted 3-deazacytidines and 3-substituted 3-deazauridines.
abstract: Novel 3-substituted analogues of 4-amino-1-beta-D-ribofuranosyl-2(1H)-pyridinone (3-deazacytidine, 3) and 4-hydroxy-1-beta-D-ribofuranosyl-2(1H)-pyridinone (3-deazauridine, 4) have been synthesized and tested for antitumor and antiviral activity. Thus the 3-chloro (9a), 3-bromo (9b), and 3-nitro (9c) analogues of 3 and the 3-chloro (9d), 3-bromo (9e), and 3-nitro (9f) analogues of 4 were prepared by standard glycosylating procedures. Novel requisite heterocycles 4-amino-3-chloro-2(1H)-pyridinone (7a) and 4-amino-3-bromo-2(1H)-pyridinone (7b) were prepared by halogenating 4-amino-2(1H)-pyridinone (5). Requisite heterocycles 4-amino-3-nitro-2(1H)-pyridinone (7c), 3-chloro-4-hydroxy-2(1H)-pyridinone (7d), 3-bromo-4-hydroxy-2(1H)-pyridinone (7e), and 4-hydroxy-3-nitro-2(1H)-pyridinone (7f) were synthesized by known procedures from 4-hydroxy-2(1H)-pyridinone (6). Structure proof of target nucleosides was provided by independent synthesis, 1H NMR, and UV. Compounds 9a-f were devoid of activity against intraperitoneally implanted L1210 leukemia in mice. Compound 9f displayed significant activity against rhinovirus type 34 grown in WISH cells. 4-Amino-3-fluoro-1-beta-D-ribofuranosyl-2(1H)-pyridinone (1) displayed good activity against intraperitoneally implanted P388 leukemia in mice, but it was devoid of activity against M5076 sarcoma, amelanotic (LOX) melanoma xenograft, and subrenal capsule human mammary carcinoma MX-1 xenograft in mice. Compound 1 also displayed significant activity against rhinovirus type 34.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: D J
authors.initials: DJ
authors.lastname: McNamara
authors.forename: P D
authors.initials: PD
authors.lastname: Cook
authors.forename: L B
authors.initials: LB
authors.lastname: Allen
authors.forename: M J
authors.initials: MJ
authors.lastname: Kehoe
authors.forename: C S
authors.initials: CS
authors.lastname: Holland
authors.forename: A G
authors.initials: AG
authors.lastname: Teepe
mesh_terms: D015092:3-Deazauridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D000998:Antiviral Agents / Q000138:chemical synthesis*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D012229:Rhinovirus / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship; D013370:Subrenal Capsule Assay; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D014529:Uridine / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D007202:Indicators and Reagents; D015092:3-Deazauridine; C000852:3-deazacytidine; D003562:Cytidine; D014529:Uridine