Diacridines, bifunctional intercalators. Chemistry and antitumor activity

Abstract

The synthesis and characterization of a number of diacridines, connected through the 9-amino position of the acridine rings by alkyl chains of varying lengths and with various substituents on the acridine ring, are described. An interesting chemical property was noted; whereas the 3-amino monoacridines cannot form stable dihydrochloride salts, the corresponding diacridines form stable trihydrochloride salts. The biological activity of the diacridines encompasses a broad spectrum of action. Their antitumor activity (% ILS) and their toxicity were correlated with their biological actions. The % ILS, as measured by inhibition of growth of [mouse neoplastic] P-388 ascites cells in BDF/1 mice, shows no significant correlation with the inhibition of DNA or of RNA synthesis, the uptake of the diacridines by P-388 cells or with % ILS. The only significant correlation found to date between the antitumor effectiveness of the diacridines and their effects on intact cells occurs between % ILS and cell agglutination. These results emphasize that caution should be used in attributing the antitumor activity of a single compound or of a small number of congeners of a given chemical structure to a particular site of biological inhibition. Effective antitumor drugs are apparently those that affect the host-tumor interaction. The toxicity of the drugs may not be essential to their antitumor properties.