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 and cytotoxic activities on L1210 leukemia cells were studied for their mutagenicity in four strains of Salmonella typhimurium. The tested compounds are 3-methoxyindolo[3,2-c]quinoline-1,4-diones and their derivatives in which the common pyrroloquinoline nucleus is annelated either with a benzene or a cyclohexane on a pyridine ring. Almost all quinones were found to be direct-acting mutagens at different levels in all strains, mainly TA97a and TA98. Relations were established between their structure and their mutagenic activities. The mutagenicity was found to be influenced (i) by the nature of the fourth nucleus: the pyridinic compounds were the most active, the non-aromatic ones were practically inactive; (ii) by the presence of a methyl group in the 6-position that decreased the mutagenicity. Then, the mutagenic properties were compared with the topoisomerase I inhibiting property that is one of the possible mechanisms of action for these cytotoxic quinones. The results indicated a correlation between mutagenicity and enzyme inhibiting properties.
Callais
F
F
Laboratoire d'Hygiène et de Santé Publique, CNRS URA 1310, Faculté des Sciences, Paris, France.
Helissey
P
P
Min
S
S
Festy
B
B
Giorgi-Renault
S
S
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D007939:Leukemia L1210 / Q000473:pathology*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011809:Quinones / Q000494:pharmacology* / Q000633:toxicity; D012486:Salmonella typhimurium / Q000235:genetics; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
D009153:Mutagens; D011809:Quinones; D059004:Topoisomerase I Inhibitors