DIACRIDINES, BIFUNCTIONAL INTERCALATORS - CHEMISTRY AND ANTI-TUMOR ACTIVITY

The synthesis and the 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 has been noted; whereas the 3-amino monoacridines cannot form stable di-hydrochloride salts, the corresponding diacridines can form stable trihydrochloride salts. The biological activity of the diacridines encompasses a broad spectrum of action. Their antitumor activity (% ILS) and their toxicity have been correlated with their biological actions. The % ILS, as measured by inhibition of growth of P-388 ascites cells in BDF/1 mice, shows no significant correlation with their ability to inhibit the growth of P-388 cells in culture (I50). The toxicity of the diacridines does not correlate 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 that has been 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. Furthermore, the results suggest that effective antitumor drugs are those that affect the host-tumor interaction and that the toxicity of the drugs may not be essential to their antitumor properties. © 1978, American Chemical Society. All rights reserved.