title: Synthesis and in vitro antitumor activity of novel ring D analogues of the marine pyridoacridine ascididemin: structure-activity relationship.
abstract: Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significantly improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC(50) value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone.
authors.affiliation: Centre de Phytopharmacie, UMR-CNRS 5054, Université de Perpignan, 52 Avenue de Villeneuve, 66860 Perpignan Cedex, France. delfourn@univ-perp.fr
authors.forename: Evelyne
authors.initials: E
authors.lastname: Delfourne
authors.forename: Francis
authors.initials: F
authors.lastname: Darro
authors.forename: Philippe
authors.initials: P
authors.lastname: Portefaix
authors.forename: Chantal
authors.initials: C
authors.lastname: Galaup
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bayssade
authors.forename: Anne
authors.initials: A
authors.lastname: Bouteillé
authors.forename: Laurent
authors.initials: L
authors.lastname: Le Corre
authors.forename: Jean
authors.initials: J
authors.lastname: Bastide
authors.forename: Françoise
authors.initials: F
authors.lastname: Collignon
authors.forename: Brigitte
authors.initials: B
authors.lastname: Lesur
authors.forename: Armand
authors.initials: A
authors.lastname: Frydman
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010618:Phenanthrolines; D011804:Quinolines; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000166:Acridines; D000470:Alkaloids; D000970:Antineoplastic Agents; D010618:Phenanthrolines; D011804:Quinolines; C412046:ascididemin