POTENTIAL ANTI-TUMOR AGENTS .30. MUTAGENIC ACTIVITY OF SOME 9-ANILINOACRIDINES - RELATIONSHIPS BETWEEN STRUCTURE, MUTAGENIC POTENTIAL, AND ANTI-LEUKEMIC ACTIVITY

In vitro mutagenicity tests are now highly predictive for in vivo carcinogenicity. To assist development of second-generation agents of the tumor inhibitory 9-anilinoacridines, quantitative structure-mutagenicity relationships are under investigation. The carcinogenic and carcinostatic anthracyline antibiotics adriamycin and daunomycin have been included as standard agents. Employing Ames& Salmonella typhimurium tester strains TA 98, TA 100, and TA 1537, various measures of mutagenic activity have been evaluated. M50, the percentage of drug-induced mutant colonies observed at the concentration providing 50% inhibition of the growth of the bacterial strain, proves most reproduceable. Within several homologous series of 9-anilinoacridines, increasing lipophilicity provides increased toxicity to the bacterium and decreasing mutagenic activity. Effective regression equations relating both bacterial toxicity and mutagenicity with agent lipophilic-hydrophilic balance can be derived. While bacterial toxicity is determined almost entirely by lipophilic character, mutagenicity is also markedly dependent on chemical structure. It is demonstrated that in vitro mutagenicity and in vivo antitumor activity in this drug series can be readily separated by appropriate structural modification. © 1979, American Chemical Society. All rights reserved.