Tetrasubstituted Pyrrole Derivative Mimetics of Protein–Protein Interaction Hot-Spot Residues: A Promising Class of Anticancer Agents Targeting Melanoma Cells

A new series of tetrasubstituted pyrrole derivatives (TSPs) was synthesized based on a previ-ously developed hypothesis on their ability to mimic hydrophobic protein motifs. The new TSPs resulted endowed with a significant toxicity against human epithelial melanoma A375 cells showing IC50 values ranging from 10 to 27 μM, consistent with the IC50 value of the reference compound nutlin-3a (IC50 = 15 μM). In particular, compound 10a (IC50 = 10 μM) resulted both the most soluble and active among the previous and present TSPs. The biological investigation evi-denced that the anticancer activity is related to the activation of apoptotic cell death pathways, supporting our rational design based on the ability of TSPs to interfere with PPI involved in the cell cycle regulation of cancer cells and in particular, in the p53 pathway. A reinvestigation of the TSP pharmacophore by using DFT calculations showed that the three aromatic substituents on the pyrrole core are able to mimic the hydrophobic side chains of the hot spot residues of paral-lel and anti-parallel coiled coil structures suggesting a possible molecular mechanism of action. Structure–activity relationship (SAR) analysis included solubility studies allowing us to ration-alize the role of the different substituents on the pyrrole core.