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.
Subject(s)
Acridines/pharmacology , Antineoplastic Agents/pharmacology , Salmonella typhimurium/drug effects , Acridines/chemistry , Animals , Antineoplastic Agents/chemistry , CHO Cells , Cricetinae , Databases, Factual , Micronucleus Tests , Molecular StructureABSTRACT
The cytotoxicity and photo-enhanced cytotoxicity of a series of 18 3,6-di-substituted acridines were evaluated on both tumour CHO cells and human normal keratinocytes, and compared to their corresponding clastogenicity as assessed by the micronucleus assay. Compounds 2f tert-butyl N-[(6-tert-butoxycarbonylamino)acridin-3-yl]carbamate and 2d N-[6-(pivalamino)acridin-3-yl]pivalamide displayed a specific cytotoxicity on CHO cells. These results suggested that the two derivatives could be considered as interesting candidates for anticancer chemotherapy and hypothesized that the presence of 1,1-dimethylethyl substituents was responsible for a strong nonclastogenic cytotoxicity. Compounds 2b and 2c, on the contrary, displayed a strong clastogenicity. They indicated that the presence of nonbranched aliphatic chains on positions 3 and 6 of the acridine rings tended to induce a significant clastogenic effect. Finally, they established that most of the acridine compounds could be photo-activated by UVA-visible rays and focussed on the significant role of light irradiation on their biological properties.
Subject(s)
Acridines/pharmacology , Acridines/radiation effects , Keratinocytes/drug effects , Light , Proflavine/chemistry , Acridines/chemistry , Acylation , Animals , CHO Cells , Cell Proliferation/drug effects , Cricetinae , Cricetulus , Drug Evaluation, Preclinical , Humans , Micronucleus Tests , Molecular Structure , Photochemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Electrospray ionization (ESI) tandem mass spectrometry (MS/MS) has been used to differentiate two positional isomers of acridine derivatives, N-acridin-4-ylbenzylamide and N-acridin-2-ylbenzylamide. The study revealed that the isomeric ion structures produced by these heterocycles could be distinguished upon collision-induced dissociations (CID). In particular, the loss of a water molecule was shown to be a regiospecific reaction of the protonated N-acridin-4-ylbenzylamide, in which the location of the benzylamide substituent with respect to the acridinic nitrogen greatly assists proton migration by allowing the creation of intramolecular hydrogen bonds. To a lesser extent, the two isomers could also be distinguished by the difference in the abundance of the benzoyl cation in the MS/MS spectra of the [M+H]+ ions, as this ion is produced with a much higher rate from N-acridin-4-ylbenzylamide. Calculations based on quantum-mechanical models have been performed to evaluate the stability of the ion structures and to support mechanisms proposed for these two dissociation reactions.
