Synthesis, Cytotoxic Activity and Docking Study of Two Indole-Chalcone Derivatives

Background and Chalcones are promising lead for anticancer drug design and discovery. Chalcones with different mechanisms including tubulin polymerization inhibition induce apoptosis in cancer cells. The aim of current work was synthesis of two indole-chalcone derivatives and investigation of their cytotoxic activity against cancer and normal cell lines, as well as molecular docking study with the proposed target tubulin.
In this study, the indole-chalcone derivatives (3a and 3b) were prepared by the reaction of 4-methoxybenzaldehyde with 3-acetylindole or N-methyl-3-acetyl-indole in the presence of LiOH as catalyst. The pure compounds obtained were characterized by 1H NMR, IR, and Mass spectroscopy. The cytotoxic activity of synthesized compounds was tested using MTT assay toward four cancer cell lines (A549, MCF7, HepG2 and SKOV3) and a normal cell line (NIH3T3) in comparison with etoposide. Molecular docking was performed by using AutoDock 4.2 software to evaluate potential mechanism and interactions of chalcone compounds with the tubulin (1SA0) binding site.
The 1H NMR spectra of compounds showed two doublets related to the vinylic protons with coupling constant value of 15.6 Hz, demonstrating trans configuration of the compounds. Cytotoxicity assay showed that these compounds had a significant effect against viability of cancer cells. The compound 3b with IC50 value of 8.1 μg/ml against HepG2 had the most potent cytotoxic effect. Furthermore, this compound had no significant cytotoxic effect against normal cell line. Docking analysis showed that compound 3b is bound to the colchicine binding site of tubulin via hydrogen and hydrophobic interactions.
The indole-derived chalcones had a significant selective cytotoxic effect against cancer cells. The N-methyl-indole analog 3b showed better profile of activity against tested cell lines. This analog can be considered as a lead compound for further optimization and development of potent anticancer agents.