Docking, synthesis and evaluation of the antitumoral activity of 3-arylcoumarins in MCF-7 cells

Biological investigations of coumarins have revealed innumerable pathways by which they act as anticancer agents, including the hypoxia-inducible factor (HIF-1α) pathway. Hypoxia is an almost universal hallmark of HIF-1α overexpressing solid tumors in patients with breast cancer. Therefore, we proceeded to determine by molecular docking the interaction of three compounds bearing the 3-arylcoumarin scaffold with HIF-1α and ARNT, to block the formation of the functional heterodimer, and evaluate the antiproliferative activity in MCF-7 of the synthesized compounds. To perform the molecular docking, crystalline structures of the monomer HIF-1α (PDB: 4zpr), ARNT (PDB: 4zp4) and the heterodimer HIF-1α:ARNT (PDB: 4zpr), the program MOE 2019.01, and several servers, were used. This technique allowed determining protein-protein interactions and alanine mutations. Different interaction sites were identified to block the HIF-1α:ARNT, the interfaces between the DNA/bHLH domains in HIF-1α, and the bHLH and PAS-A domains in ARNT. The probability of blocking HIF-1α:ARNT, resulting from molecular docking, has been 40-60% for the three coumarins –5,7-diacetoxy-3-phenylcoumarin, 3-(3’,4’-diacetoxyphenyl)-5,7-diacetoxycoumarin, and 3-(3’-acetoxyphenyl)-5,7-diacetoxycoumarin– coinciding with the results of the antiproliferative evaluation in breast cancer cells (MCF-7), as well as with the results of luciferase activity adjusted versus control at the concentration of 256 µg/mL. The three compounds of the 3-arylcoumarin series are identified as interfering with the blockade of the heterodimer HIF-1α:ARNT and exhibiting antiproliferative activity.