Development of 1‐(2‐aminophenyl)pyrrole‐based amides acting as human topoisomerase I inhibitors

Topoisomerases are ubiquitous enzymes in the human body, particularly involved in cancer development and progression. Topoisomerase I (topoI) performs DNA relaxation reactions by "controlled rotation" rather than by "strand passage." The inhibition of topoI has become a useful strategy to control cancer cell proliferation. Nowadays, different compounds have undergone clinical trials, but the search for new molecular entities is necessary and benefits from medicinal chemistry efforts. Pyrrole-based compounds emerged as promising antiproliferative agents, with particular interest in breast cancer therapy and topoI inhibition. Starting from these observations and based on the scaffold-hopping approach, we developed a small library of 1-(2-aminophenyl)pyrrole-based amides (7a-f) as new anticancer agents. Tested on a panel of cancer cell lines, 7a-f displayed the most interesting profile in MDA-MB-231 cells, where the most active compounds, 7d-f, were able to induce death by apoptosis. Direct enzymatic assays and docking simulations on the topoI active site (PDB: 1A35) revealed the inhibitory activity and potential binding site for the newly developed 1-(2-aminophenyl)pyrrole-based amides.