Diacridines, bifunctional intercalators. Chemistry and antitumor 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 dihydrochloride 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 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.
D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000371:Agglutination; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D000166:Acridines; D000970:Antineoplastic Agents; D012334:RNA, Neoplasm