STRUCTURE-ACTIVITY-RELATIONSHIPS FOR ACRIDINE-SUBSTITUTED ANALOGS OF THE MIXED TOPOISOMERASE I II INHIBITOR N-[2-(DIMETHYLAMINO)ETHYL]ACRIDINE-4-CARBOXAMIDE/

The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl] acri dine-4-carboxamide (DACA) is currently in clinical trial as an antican cer drug. A series of acridine-substituted analogues were prepared, us ing a new synthetic route to substituted acridine-4-carboxylic acids ( conversion of substituted diphenylamine diacid monoesters to the corre sponding aldehydes and mild acid-catalyzed ring closure to form the ac ridines directly). The analogues were evaluated in a panel of cell lin es which included wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of the human Jurkat leukemia line. The latter mutant lines are resist ant to topoisomerase II targeted agents due to lower levels of the enz yme. Structure-activity studies suggest that the electronic properties of the substituents do not markedly affect cytotoxicity, but steric b ulk is important, with larger groups leading to loss of activity. The compounds fell broadly into two categories. The majority had cytotoxic ities similar to (or lower than) that of DACA itself and were equitoxi c in all the Jurkat lines, suggesting a relatively greater effect on t opoisomerase I compared with topoisomerase II. Most of the 5-substitut ed derivatives and the 7-Ph compound were more cytotoxic than DACA, bu t were less effective against JL(A) and JL(D) cell lines than in the w ild-type JL(C), suggesting a mode of cytotoxicity largely mediated by effects on topoisomerase II. Both DACA and selected acridine-substitut ed analogues were active in the relatively refractory subcutaneous col on 38 tumor model in vivo.