title: Evaluation of the mutagenic/clastogenic potential of 3,6-di-substituted acridines targeted for anticancer chemotherapy.
abstract: The mutagenicity and clastogenicity of a series of 18 3,6-di-substituted acridines were evaluated by the Ames test on Salmonella typhimurium TA 97a and by the micronucleus assay on Chinese Hamster Ovary cells (CHO cells), as compared to their cytotoxicity against CHO cells. Experimental results overall demonstrated that simple symmetric molecules were more mutagenic than asymmetric structures. The mutagenic properties of acridines on strain TA97a mainly depended on molecular geometry and length, and on the nature of the substituted groups. The clastogenicity of acridines mainly depended on molecular length and electrophilicity in mammalian cells. Structure-activity relationships indicated that cytotoxicity could be decoupled from genotoxicity by introducing several chemical groups that induced asymmetry or bulkiness in the acridine compounds. They led to the synthesis of the promising 3-acetamido-6-(4-fluorobenzamido)acridine, which displayed a strong cytotoxic activity and was not mutagenic.
authors.affiliation: Laboratoire de Biogénotoxicologie et Mutagenèse Environnementale (EA 1784, FR 3098 - ECCOREV), Université Aix-Marseille, Faculté de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Di Giorgio
authors.forename: Yohann
authors.initials: Y
authors.lastname: Benchabane
authors.forename: Gérard
authors.initials: G
authors.lastname: Boyer
authors.forename: Philippe
authors.initials: P
authors.lastname: Piccerelle
authors.forename: Michel
authors.initials: M
authors.lastname: De Méo
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D016208:Databases, Factual; D015162:Micronucleus Tests; D015394:Molecular Structure; D012486:Salmonella typhimurium / Q000187:drug effects*
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents