title: Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers.
abstract: In this study, we evaluated the abilities of a series of chalcones to inhibit the activity of the enzyme xanthine oxidase (XO) and to scavenge radicals. 20 mono- and polyhydroxylated chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and then tested for inhibitory potency against XO, a known generator of reactive oxygen species (ROS). In parallel, the ability of the synthesized chalcones to scavenge a stable radical was determined. Structure-activity relationship analysis in conjunction with molecular docking indicated that the most active XO inhibitors carried a minimum of three hydroxyl groups. Moreover, the most effective radical scavengers had two neighboring hydroxyl groups on at least one of the two phenyl rings. Since it has been proposed previously that XO inhibition and radical scavenging could be useful properties for reduction of ROS-levels in tissue, we determined the chalcones' effects to rescue neurons subjected to ROS-induced stress created by the addition of β-amyloid peptide. Best protection was provided by chalcones that combined good inhibitory potency with high radical scavenging ability in a single molecule, an observation that points to a potential therapeutic value of this compound class.
authors.affiliation: Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Hofmann
authors.affiliation: Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Webster
authors.affiliation: Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
authors.forename: Thuy
authors.initials: T
authors.lastname: Do
authors.affiliation: Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
authors.forename: Reid
authors.initials: R
authors.lastname: Kline
authors.affiliation: Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Snider
authors.affiliation: Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
authors.forename: Quintin
authors.initials: Q
authors.lastname: Hauser
authors.affiliation: Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Higginbottom
authors.affiliation: Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, USA; Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA; Department of Biochemistry, Purdue University, 175 South University Street, West Lafayette, IN 47907-2063, USA. Electronic address: paulas@purdue.edu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Paula
mesh_terms: D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006900:Hydroxylation; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047188:Chalcones; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D014969:Xanthine Oxidase
keywords: Anti-oxidants; Caffeic acid; Cell viability; Chalcones; Enzyme inhibition; Radical scavenging; Reactive oxygen species; Reperfusion injuries; Xanthine oxidase