MUTAGENICITY OF SYNTHETIC ACRIDINONES AND THIOACRIDINES IN DIRECT AMES' SALMONELLA MUTAGENICITY ASSAY

Newly synthesized antitrypanosomal and antiplasmid acridinones, thio-substituted acndines and thioacridinones were tested for a direct genotoxic effect on TA97a and TAI00 tester strains by Ames' Salmonella mutagenicity assay. Of acridinones, only 9-(hydrazinothiazolo[5,4-a])acridinone I showed strong mutagenic activity on TA97a strain. However, mutagenic activity was manifested invariably by all three acridinones on TA100 strain. Of thioacridines, 2,7-dimethoxy-9-thioacridinone 4, 2,7-dimethoxy-9-(3'aminopropyl) 5 and 2,7-dihydroxy-9-acetamidothioacridine 6 were explicitly mutagenic on TA97a, but on TAI00 they were just weakly mutagenic. Introduction Acndine compounds are known to have a broad spectrum of biologic activities such as antibacterial (1, 2, 3), antiparasitic (4, 5, 6, 7), mutagenic (8) and antitumor ones (9, 10, 11, 12). The effects of acridines on bacteria were studied for their antibacterial and antiplasmid actions. Their activities on bacteria seem to depend on the substitution on the tricyclic skeleton (1). Acridinones have been proved to be trypanocidal by being capable of intercalation into the DNA of the Trypanosoma cruzi (4, 6). The trypanocidal activity was also shown against the Trypanosoma brucei strains with very low concentration of substituted acndines with simultaneous brief irradiation (7) and without irradiation (13). The antitumor activity of acndine derivatives attributes to their ability of intercalation to DNA, stabilizing the DNA-topoisomerase II intermediate complex. This cleavable complex appears to be toxic to cancerous cells (9). The DNA-topoisomerase II inhibiting acridines are primarily chromosomal mutagens in mammalian cells, although they are frameshift mutagens in bacterial and bacteriophage systems (8). Mutagenicity of various acridine compounds have been studied by Ames' Salmonella mutagenicity assay. Acridines are planar polycyclic aromatic molecules which bind noncovalently and reversibly to DNA by intercalation. Simple acridines are frameshift mutagens. However, benzacridines are rather base-pair substitution mutagens by interacting covalently with DNA following microsomal activation (14). Acndine mustards such as the ICR compounds, acting as carriers to target alkylating agents to DNA, are frameshift as well as base-pair substitution mutants. Nitroacridines may act as either simple acridines or alkylating agents, depending on the position of the nitro group (8).