Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors

Abstract DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC 50 value of 0.57 μM against U937 cells, which was slightly better than m -AMSA. In addition, compound 9 displayed low cytotoxicity against human normal liver cells (QSG-7701), the IC 50 of which was more than 3 times lower than m -AMSA. Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50 μM. The representative compound 9 could bind with DNA and induce U937 apoptosis through the exogenous pathway.