Synthesis and characterization of CAPE derivatives as xanthine oxidase inhibitors with radical scavenging properties

• Published in: Bioorganic chemistry 2019-05, Vol.86, p.686-695
• Main Authors: Choi, Wonbeen, Villegas, Valente, Istre, Hannah, Heppler, Ben, Gonzalez, Niki, Brusman, Nicole, Snider, Lindsey, Hogle, Emily, Tucker, Janelle, Oñate, Alma, Oñate, Sandra, Ma, Lili, Paula, Stefan
• Format: Article
• Language: English
• Subjects: Animals; Biphenyl Compounds - antagonists & inhibitors; Caffeic acid derivatives; Caffeic Acids - chemical synthesis; Caffeic Acids - chemistry; Caffeic Acids - pharmacology; Cattle; Dose-Response Relationship, Drug; Dual properties; Enzyme inhibition; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Free Radical Scavengers - chemical synthesis; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacology; Knoevenagel condensation; Ligand docking; Models, Molecular; Molecular Structure; Phenylethyl Alcohol - analogs & derivatives; Phenylethyl Alcohol - chemical synthesis; Phenylethyl Alcohol - chemistry; Phenylethyl Alcohol - pharmacology; Picrates - antagonists & inhibitors; Radical scavenging; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.02.049

[Display omitted] •Established efficient synthetic route to hydroxylated CAPE derivatives.•Measured inhibitory potencies of synthesized compounds against xanthine oxidase.•Determined radical scavenging capabilities of newly synthesized compounds.•Evaluated compounds’ potential use as agents against reperfusion injuries. Inhibitors of the enzyme xanthine oxidase (XO) with radical scavenging properties hold promise as novel agents against reperfusion injuries after ischemic events. By suppressing the formation of damaging reactive oxygen species (ROS) by XO or scavenging ROS from other sources, these compounds may prevent a buildup of ROS in the aftermath of a heart attack or stroke. To combine these two properties in a single molecule, we synthesized and characterized the non-purine XO inhibitor caffeic acid phenethylester (CAPE) and 19 derivatives using a convenient microwave-assisted Knoevenagel condensation protocol. Varying systematically the number and positions of the hydroxyl groups at the two phenyl rings, we derived structure-activity relationships based on experimentally determined XO inhibition data. Molecular docking suggested that critical enzyme/inhibitor interactions involved π-π interactions between the phenolic inhibitor ring and Tyr914, hydrogen bonds between inhibitor hydroxyl groups and Glu802, and hydrophobic interactions between the CAPE phenyl ring and non-polar residues located at the entrance of the binding site. To effectively scavenge the stable radical DPPH, two hydroxyl groups in 1,2- or 1,4-position at the phenyl ring were required. Among all compounds tested, E-phenyl 3-(3,4-dihydroxyphenyl)acrylate, a CAPE analog without the ethyl tether, showed the most promising properties.