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

Abstract

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.