Symmetrically substituted carbazole derivatives exert antiproliferative effects through catalytic inhibition of topoisomerase II and apoptosis induction

Abstract

Abstract Human DNA topoisomerases are vital enzymes for DNA replication, transcription, chromatin condensation, and maintenance of their structure. Due to this fact inhibition of topoisomerase II is a common approach used in cancer treatment. Carbazole scaffold has a wide range of biological activities and appears as a core in many active compounds. It also plays important role in anticancer research. The present study shows the in vitro biological evaluation of three symmetric carbazole derivatives, substituted with furan or thiophene, as potential antitumor agents. Compounds efficiently inhibited the proliferation of all tested cancer cell lines mostly at nanomolar concentrations. They were further characterized for their effect on cell cycle progression, mitochondria disruption, DNA damage induction, and type of cellular death. Moreover, analysis of their mode of action indicates, that investigated carbazole derivatives inhibit topoisomerase II. Among them, compound 36a exhibited the strongest catalytic inhibitory activity against topoisomerase IIα and could be a potential lead compound for developing novel promising anticancer compounds.