New 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]
isoquinoline-1,3- diones with substituents at the 4, 8, 9, 10, and 11 positions were synthesized. Diazonium
salts prepared from aminoazonafides were key intermediates for many of the analogues. Six of the new compounds were more potent than
azonafide in a panel of
tumor cells including human
melanoma and ovarian
carcinoma and murine L1210
leukemias. Three of these compounds, the 10-OCH3, 10-OC2H5, and 10-F analogues, had better ratios of
cardiotoxicity to
tumor-cell toxicity than
azonafide. Eight compounds were not cross-resistant with MDR
L1210 leukemia, and the 10-CN analogue was more potent against solid
tumor cells than
leukemia cells. The 9-OH, 10-CN, and 10-F analogues had high potency against both sensitive and resistant cell lines of MFX 7
breast carcinoma and WiDr colon
carcinoma and sensitivity A599 lung
carcinoma. Advantages of the 10-Cl, 10-NH2, and 10-CN analogues over
azonafide were apparent in
P388 leukemia in mice, and the 10-CN analogue was more effective than
doxorubicin in this assay. Quantitative structure-activity relationship studies revealed statistically significant correlations between
DNA binding strength of 8- and 10-substituted azonafides, as measured by deltaTm, and toxicity to
tumor cells. There also were correlations between substituent size, as measured by MR, and cytotoxicity for 9- and 10-substituted azonafides and between MR and deltaTm for 4- and 11-substituted azonafides. Lipophilicity of substituents (pi) correlated with cytotoxicity for 9-, 10-, and 11-substituted azonafides. These results lend support to a model in which
DNA binding strength influences cytotoxic potency, and lipophilicity increases
DNA binding whereas large substituents decrease it.