Design and synthesis of modified quinolones as antitumoral acridones

The bacterial topoisomerase II (DNA gyrase) and the mammalian topoisomerase II represent the cellular targets for quinolone antibacterials and a wide variety of anticancer drugs, respectively. In view of the mechanistic simil arities and sequence homologies exhibited by the two enzymes, tentative eff orts to selectively shift from an antibacterial to an antitumoral activity was made by synthesizing a series of modified tricyclic quinolones, in whic h the essential 3-carboxylic function is surrogated by phenolic OH and the classic C-6 fluorine atom is replaced by a NH2 group. The resulting 7-amino -9-acridone derivatives were assayed, for their antibacterial as well as cy totoxic activities. No antibacterial activity was found. On the other hand, many derivatives showed significant cytotoxic activity against both HL-60 and P388 leukemias and a wide panel of human and rodent solid tumor cells, derivatives 25 and 26 displaying the best overall antiproliferative activit y. Against the LoVo cell line, derivative 25 exhibited higher cytotoxic eff ects than etoposide.