title: Biological properties of 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles: a new class of potent antitumour drugs.
abstract: Thirteen 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles, structurally related to the antitumour drug ellipticine, were tested for their cytotoxicity against the L1210 murine leukaemia cell line and their antitumour activity against both leukaemias and solid tumours. Most of them showed an interesting antitumour activity against L1210 leukaemia, 4-hydroxy-9-chloro-2,3, 5,11-tetramethyl-6H-pyrido[3,2-b]carbazole displaying a high antitumour activity against L1210 and P388 leukaemias, B16 melanoma and M5076 sarcoma. Despite promising cytotoxic activity, 4-ethoxy-5,11-dimethyl-6H-pyrido-[3,2-b]carbazole had no antitumour activity. The ability of four drugs to induce strand breaks in DNA was studied using the single cell gel electrophoresis assay (comet assay). Most of the molecules induced DNA breaks that were totally or partially repaired after 1 h. The effects of these compounds on the L1210 cell cycle were tested as well as their abilities to induce apoptosis in these cells. Three of them induced a G2/M blockade, without any obvious evidence of apoptosis. The other compound, 4-ethoxy-5,11-dimethyl-6H-pyrido[3,2b]carbazole, did not lead to phase-specific blockade, but was a strong inductor of apoptosis in L1210 cells.
authors.affiliation: CJF INSERM 96-03 et UPRES-EA 1772 (Groupe Regional d'Etude sur le Cancer, Université de Caen, Laboratoire de Cancérologie Expérimentale du CRLCC François Baclesse, Caen, France.
authors.forename: V
authors.initials: V
authors.lastname: Moinet-Hedin
authors.forename: T
authors.initials: T
authors.lastname: Tabka
authors.forename: L
authors.initials: L
authors.lastname: Poulain
authors.forename: T
authors.initials: T
authors.lastname: Godard
authors.forename: M
authors.initials: M
authors.lastname: Lechevrel
authors.forename: C
authors.initials: C
authors.lastname: Saturnino
authors.forename: J C
authors.initials: JC
authors.lastname: Lancelot
authors.forename: J Y
authors.initials: JY
authors.lastname: Le Talaër
authors.forename: P
authors.initials: P
authors.lastname: Gauduchon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects*; D020552:Comet Assay; D004249:DNA Damage; D015195:Drug Design; D004611:Ellipticines / Q000737:chemistry* / Q000633:toxicity*; D007939:Leukemia L1210; D007941:Leukemia P388; D008546:Melanoma, Experimental; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; C034192:ellipticine