Theoretical Study of Radical Inactivation, LOX Inhibition, and Iron Chelation: The Role of Ferulic Acid in Skin Protection against UVA Induced Oxidative Stress

Ana Amić; Jasmina M Dimitrić Marković; Zoran Marković; Dejan Milenković; Žiko Milanović; Marko Antonijević; Denisa Mastiľák Cagardová; Jaime Rodríguez-Guerra Pedregal

doi:10.3390/antiox10081303

Theoretical Study of Radical Inactivation, LOX Inhibition, and Iron Chelation: The Role of Ferulic Acid in Skin Protection against UVA Induced Oxidative Stress

Antioxidants (Basel). 2021 Aug 18;10(8):1303. doi: 10.3390/antiox10081303.

Authors

Ana Amić¹, Jasmina M Dimitrić Marković², Zoran Marković³, Dejan Milenković³, Žiko Milanović^{3

4}, Marko Antonijević³, Denisa Mastiľák Cagardová⁵, Jaime Rodríguez-Guerra Pedregal⁶

Affiliations

¹ Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Ulica cara Hadrijana 8A, 31000 Osijek, Croatia.
² Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
³ Department of Science, Institute for Information Technologies, University of Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, Serbia.
⁴ Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia.
⁵ Institute of Physical Chemistry and Chemical Physics, Department of Chemical Physics, Slovak University of Technology in Bratislava, Radlinského 9, SK-812 37 Bratislava, Slovakia.
⁶ In Silico Toxicology, Institute of Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

Abstract

Ferulic acid (FA) is used in skin formulations for protection against the damaging actions of the reactive oxygen species (ROS) produced by UVA radiation. Possible underlying protective mechanisms are not fully elucidated. By considering the kinetics of proton-coupled electron transfer (PCET) and radical-radical coupling (RRC) mechanisms, it appears that direct scavenging could be operative, providing that a high local concentration of FA is present at the place of ^•OH generation. The resulting FA phenoxyl radical, after the scavenging of a second ^•OH and keto-enol tautomerization of the intermediate, produces 5-hydroxyferulic acid (5OHFA). Inhibition of the lipoxygenase (LOX) enzyme, one of the enzymes that catalyse free radical production, by FA and 5OHFA were analysed. Results of molecular docking calculations indicate favourable binding interactions of FA and 5OHFA with the LOX active site. The exergonicity of chelation reactions of the catalytic Fe²⁺ ion with FA and 5OHFA indicate the potency of these chelators to prevent the formation of ^•OH radicals via Fenton-like reactions. The inhibition of the prooxidant LOX enzyme could be more relevant mechanism of skin protection against UVA induced oxidative stress than iron chelation and assumed direct scavenging of ROS.

Keywords: 5-hydroxyferulic acid; PCET; density functional theory (DFT) and molecular docking; ferulic acid; iron chelation; lipoxygenase; minimum energy crossing point (MECP); radical scavenging; radical-radical coupling; water assisted tautomerization.