Inhibition of human Topoisomerase II by new N,N,N‐trimethylethanammonium iodide alkylcarbazole derivatives

Chemotherapy is used for treatment of all stages of breast cancer, including the metastatic disease and tends to be tailored for each person situation. However, chemotherapeutic agents are the leading cause of serious drug-related adverse effects and, often, resistance occurs. In this paper, we designed and synthesized a new series of N-alkylcarbazole derived by Ellipticine, an alcaloid with carbazole structure initially used in the treatment of metastatic breast cancer and then dismissed because of poor solubility in water and dramatic side effects. After the evaluation of the binding modes of our class of newly synthesized compounds with human Topoisomerase II (hTopo II) we performed hTopo II decatenation assay, obtaining that compound 4f is a good inhibitor. Moreover, 4f and 4g showed a good anti-proliferative activity on breast cancer cells, causing apoptosis by activation of the caspases pathway. Interesting is the activity of these two compounds on triple negative MDA-MB-231 cells, which tend to be highly metastatic and aggressive, strictly connected with the observed inhibition of hTopo II.