5,8-Dimethyl-9H-carbazole Derivatives Blocking hTopo I Activity and Actin Dynamics

Over the years, carbazoles have been largely studied for their numerous biological properties, including antibacterial, antimalarial, antioxidant, antidiabetic, neuroprotective, anticancer, and many more. Some of them have gained great interest for their anticancer activity in breast cancer due to their capability in inhibiting essential DNA-dependent enzymes, namely topoisomerases I and II. With this in mind, we studied the anticancer activity of a series of carbazole derivatives against two breast cancer cell lines, namely the triple negative MDA-MB-231 and MCF-7 cells. Compounds 3 and 4 were found to be the most active towards the MDA-MB-231 cell line without interfering with the normal counterpart. Using docking simulations, we assessed the ability of these carbazole derivatives to bind human topoisomerases I and II and actin. In vitro specific assays confirmed that the lead compounds selectively inhibited the human topoisomerase I and interfered with the normal organization of the actin system, triggering apoptosis as a final effect. Thus, compounds 3 and 4 are strong candidates for further drug development in multi-targeted therapy for the treatment of triple negative breast cancer, for which safe therapeutic regimens are not yet available.

Automated summary

Carbazoles have been extensively studied for their various biological properties, including their potential as antibacterial, antimalarial, antioxidant, antidiabetic, neuroprotective, and anticancer agents. This study focused on the anticancer activity of a series of carbazole derivatives against breast cancer cell lines. Compounds 3 and 4 showed the highest activity against the triple negative MDA-MB-231 cell line without affecting normal cells. Further investigations revealed that these compounds selectively inhibited human topoisomerase I and disrupted the actin system, leading to apoptosis. Therefore, compounds 3 and 4 hold promise for the development of multi-targeted therapy for triple negative breast cancer.