Amino-Substituted 2-[2-(Dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. Synthesis, Antitumor Activity, and Quantitative Structure-Activity Relationship

Sets of 2-[2-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones with amino and actylamino groups at each of the eight positions on the anthracene nucleus were synthesized from appropriately substituted anthracenes. Their evaluation in in vitro antitumor and cardiotoxicity assays revealed a very strong dependence of potency on the position of substitution. Certain compounds, including the 4-, 5-, 7-, and 9-amino derivatives, showed significantly higher potency than the unsubstituted parent compound, azonafide. Among them, 7-aminoazonafide had low cardiotoxicity relative to cytotoxicity. In general, the acetylamino analogues were less potent than the amino derivatives against tumor cells and neonatal rat heart myocytes; however, 5-(acetylamino)azonafide was highly cardiotoxic. 9-Aminoazonafide was more efficacious than azonafide or amonafide against P388 leukemia in mice. Statistically significant correlations were made between the ability of amino analogues to increase the transition melt temperature (delta Tm) of DNA and their potency against solid tumors, leukemia cells, or cardiac myocytes.