Evaluation of the mutagenic/clastogenic potential of 3,6-di-substituted acridines targeted for anticancer chemotherapy

• Published in: Food and chemical toxicology 2011-11, Vol.49 (11), p.2773-2779
• Main Authors: Di Giorgio, Carole, Benchabane, Yohann, Boyer, Gérard, Piccerelle, Philippe, De Méo, Michel
• Format: Article
• Language: English
• Subjects: Acridines; Acridines - chemistry; Acridines - pharmacology; Ames test; Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Asymmetry; Biological and medical sciences; Chemical mutagenesis; Chemotherapy; Chinese hamsters; CHO Cells; Cricetinae; Cytotoxicity; Databases, Factual; drug therapy; Drug toxicity and drugs side effects treatment; Foods; Genotoxicity; Hamsters; Medical sciences; Micronucleus assay; Micronucleus Tests; Miscellaneous (drug allergy, mutagens, teratogens...); Molecular Structure; Mutagenicity; Pharmacology. Drug treatments; Salmonella; Salmonella Typhimurium; Salmonella typhimurium - drug effects; Strain; structure-activity relationships; Synthesis; Toxicology
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2011.07.046

► The mutagenicity of 3,6-di-substituted acridines was evaluated by the Ames test (TA97a). ► Their clastogenicity was assessed by the micronucleus assay as compared to their cytotoxicity. ► Simple symmetric molecules were more genotoxic than asymmetric structures. ► Cytotoxicity was decoupled from genotoxicity by introducing asymmetric and bulky chemical groups. ► 3-acetamido-6-(4-fluorobenzamido)acridine was the most promising anticancer compound. 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.