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.