title: Syntheses and antiproliferative activities of 7-azarebeccamycin analogues bearing one 7-azaindole moiety.
abstract: Rebeccamycin analogues containing one azaindole unit, with and without a methyl group on the imide nitrogen and with the sugar moiety coupled either to the indole nitrogen or to the azaindole nitrogen were synthesized. To increase the solubility and induce stronger interactions with the target macromolecules, a bromo or nitro substitutent was introduced on the indole unit. The DNA binding and topoisomerase I inhibition properties were investigated together with the antiproliferative activities toward nine tumor cell lines. In addition, the effect of the compounds on the cell cycle of L1210 leukemia cells was examined. The nonaza analogues were found to be cytotoxic against all cell lines of the panel whereas the aza-analogues showed a selective action toward certain cell lines. They strongly inhibited the proliferation of SK-N-MC neuroblastoma, A431 epidermoid carcinoma and NCI-H69 small cell lung carcinoma cells, but showed little or no cytotoxic effect against IGROV ovary carcinoma, HT29 colon carcinoma, and A549 non small cell lung carcinoma cells. Whatever their cytotoxicity profile, all compounds induce similar cell cycle effects, with a marked G2+M block observed with L1210 leukemia cells. The data suggest that the molecular mechanism of action of the aza-analogue derivatives is different from that of rebeccamycin.
authors.affiliation: Université Blaise Pascal, Synthèse et Etude de Systèmes à Intérêt Biologique, UMR 6504, 63177 Aubière, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Marminon
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Valérie
authors.initials: V
authors.lastname: Pérez
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Alexandra
authors.initials: A
authors.lastname: Joubert
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: John
authors.initials: J
authors.lastname: Hickman
authors.forename: Michelle
authors.initials: M
authors.lastname: Prudhomme
mesh_terms: D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles; D002453:Cell Cycle / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001372:Aza Compounds; D002227:Carbazoles; D007211:Indoles; D059004:Topoisomerase I Inhibitors; D004247:DNA; C053339:rebeccamycin; D004264:DNA Topoisomerases, Type I