Background: Matrix metalloproteinases are known as extracellular matrix degrading enzymes and have
important role on tumor progression.
Objective: This study reports the effects of 1,3,5-trisubstituted indole derivatives on cytotoxicity, apoptosis and MMP-
2/MMP-9 mRNA expression of MCF-7 human breast carcinoma cells.
Method: The cytotoxic effects of the compounds on MCF-7 cells were performed by MTT test, and cell proliferation
was determined via BrdU incorporation. The apoptotic effects were observed by cell death detection elisa. The effects
of the compounds on MMP-2/-9 enzyme activity and mRNA expression were also performed.
Results: The compounds inhibited the proliferation of MCF-7 breast carcinoma cells significantly in a dose dependent
manner. All compounds were able to induce DNA fragmentation, especially compound 1. The IC50 values of
compound 2 and 4 for MMP-2 were 0.42 μM and 1.88 μM, respectively. MMP-2 mRNA expression results were
correlated with the inhibition of enzyme activity, such compound 4 inhibited MMP-2 mRNA expression at all treated
concentrations. Docking simulation has also been performed to analyze the binding mode of compounds and the results
showed that compound 2, the most active compound, formed a hydrogen bond with Glu202 for binding to the MMP-2
active site. In addition, the hydrophobic parts of compound 2 are in contact with nonpolar surface areas of MMP-2,
such as His201, His211, Tyr223 and Tyr193.
Conclusion: According to the molecular docking results along with the biological assay data, it is suggested that
compound 2 might be used for further design and development of MMP-2 inhibitors.