Green Contributions to the Chemistry of Perezone and Oxidation of the Double Bond of the Side Chain: A Theoretical Study and Cytotoxic Evaluation in MDA-MB231 Cells

Abstract

Perezone, a sesquiterpene quinone, was the first natural product isolated in crystalline form on the American continent in 1852. It is commonly found in the roots of herbs from the Acourtia species (formerly Perezia). This molecule, along with its synthetic isomer isoperezone, exhibits antineoplastic effects, among others. In this study, an enzymatic reaction (green chemistry) was employed to oxidize the C12−C13 double bond of perezone and isoperezone. This method proved to be more effective than traditional toxic chemical oxidants. As result, epoxides were obtained, followed by acetonides, diols, and esters. All compounds were successfully synthesized and characterized using standard spectroscopic techniques. In breast cancer cell tests, the isoperezone acetonide showed the highest cytotoxicity, with an IC50 of 8.44 μM. Additionally, a computational study was performed at the DFT (B3LYP) level of theory, indicating that the geometrical and energy differences between 6-R and 6-S stereoisomers are 0.5 kcal/mol, and the spectroscopic and electronic properties aligned with the experimental data. Finally, molecular docking revealed binding energies of −8.14 kcal/mol for 6-R and −8.04 kcal/mol for 6-S, with a hydrogen bond of 2.9 Å involving the His121 residue. A chemoinformatic prediction was also conducted to compare cytotoxicity results.