STRUCTURE-MUTAGENICITY RELATIONSHIPS IN SERIES OF 11H-INDOLO[3,2-C]QUINOLINE-1,4-DIONES, TETRAHYDRO-11H-INDOLO[3,2-C]QUINOLINE-1,4-DIONES AND 11H-PYRIDO[3',4' 4,5]PYRROLO[3,2-C]QUINOLINE-1,4-DIONES WITH LEUKEMIA CYTOTOXIC PROPERTIES - RELATIONS WITH TOPOISOMERASE-I INHIBITING PROPERTIES/

Six heterocyclic quinones with topoisomerase I inhibiting properties a nd cytotoxic activities on L1210 leukemia cells were studied for their mutagenicity in four strains of Salmonella typhimurium. The tested co mpounds are 3-methoxyindolo[3,2-c]quinoline-1,4-diones and their deriv atives in which the common pyrroloquinoline nucleus is annelated eithe r with a benzene or a cyclohexane on a pyridine ring. Almost all quino nes were found to be direct-acting mutagens at different levels in all strains, mainly TA97a and TA98. Relations were established between th eir structure and their mutagenic activities. The mutagenicity was fou nd to be influenced (i) by the nature of the fourth nucleus: the pyrid inic compounds were the most active, the non-aromatic ones were practi cally inactive; (ii) by the presence of a methyl group in the 6-positi on that decreased the mutagenicity. Then, the mutagenic properties wer e compared with the topoisomerase I inhibiting property that is one of the possible mechanisms of action for these cytotoxic quinones. The r esults indicated a correlation between mutagenicity and enzyme inhibit ing properties.