title: Imidazonaphthyridine systems (part 2): Functionalization of the phenyl ring linked to the pyridine pharmacophore and its replacement by a pyridinone ring produces intriguing differences in cytocidal activity.
abstract: We recently discovered that five- and pseudo-five-fused-ring derivatives in an imidazonaphthyridine series were promising hit compounds for the development of new DNA-intercalators. In this study, novel (dihydro)imidazo[1,6] and [1,7]naphthyridi(no)nes were prepared including pseudo-pentacycles. All the compounds synthesized were screened against four tumor cell lines. Compounds 3(b-d) showed significant in vitro cytotoxicity, and DNA intercalation properties were demonstrated at 25 μM. Imidazonaphthyridinones exhibited no DNA binding affinity despite significant growth inhibition activity. Interestingly, when a pyridinone pharmacophore was linked to the imidazo[1,2-a]pyridine scaffold, the geometric orientation of the link had a strong impact on the growth inhibition activity. From these results we conclude that the moderate cytotoxicity observed for these compounds is independent of their DNA-binding and topoisomerase inhibition activities.
authors.affiliation: U990 INSERM, rue Montalembert, BP 184, 63000 Clermont-Ferrand, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Masurier
authors.forename: Eric
authors.initials: E
authors.lastname: Debiton
authors.forename: Alicia
authors.initials: A
authors.lastname: Jacquemet
authors.forename: Antoine
authors.initials: A
authors.lastname: Bussière
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chezal
authors.forename: Anthony
authors.initials: A
authors.lastname: Ollivier
authors.forename: Daté
authors.initials: D
authors.lastname: Tétégan
authors.forename: Mounir
authors.initials: M
authors.lastname: Andaloussi
authors.forename: Marie-Joseph
authors.initials: MJ
authors.lastname: Galmier
authors.forename: Jacques
authors.initials: J
authors.lastname: Lacroix
authors.forename: Damien
authors.initials: D
authors.lastname: Canitrot
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Teulade
authors.forename: René C
authors.initials: RC
authors.lastname: Gaudreault
authors.forename: Olivier
authors.initials: O
authors.lastname: Chavignon
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moreau
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010957:Plasmids / Q000235:genetics; D011725:Pyridines / Q000737:chemistry*; D011728:Pyridones / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009287:Naphthyridines; D011725:Pyridines; D011728:Pyridones; D004247:DNA; C023666:pyridine