ChemInform Abstract: 2-(2′-(Dimethylamino)ethyl)-1,2-dihydro-3H-dibenz(de,h)isoquinoline-1, 3-diones with Substituents at Positions 4, 8, 9, 10, and 11. Synthesis, Antitumor Activity, and Quantitative Structure-Activity Relationships.

Abstract

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 ana...