New antitumor agents containing the anthracene nucleus.

A series of 21 new compounds related to bisantrene was synthesized and tested in vitro by using clonogenic assays against a variety of human tumor cell lines, fresh human tumors, and P-388 leukemia. Those most closely related to bisantrene were less active than it was, but a subset of compounds with saturated side chains containing two basic nitrogens showed good activity. Two compounds of this subset, N,N'-bis[2-(dimethylamino)ethyl]-9,10-anthracenebis(methylamine)(6 ), and N,N'-bis(1-ethyl-3-piperidinyl)-9,10-anthracenebis(methylamine)(19 ), were very active in vitro against human tumor cell lines, but not active against fresh human tumors or P-388 leukemia cells. They had only marginal activity in mouse tumor models. Thus, the fresh human tumors and P-388 leukemia cells in vitro were better predictors than the established cell lines for the activity of these anthracene compounds in vivo against mouse tumors. These compounds appear to be distinct from bisantrene in aspects of mode of action. For example, 6 did not cause inhibition of macromolecular synthesis and promotion of DNA single strand breakage at cytotoxic drug concentrations. Toxicological studies showed that its rapid administration caused acute neurotoxicity resulting in apnea. It also produced skin ulcers on id administration, but they were less severe than those caused by bisantrene.