Antioxidant properties and free radical-scavenging reactivity of a family of hydroxynaphthalenones and dihydroxyanthracenones Jorge Rodrı ´guez, a,b Claudio Olea-Azar, a, * Cristina Cavieres, b Ester Norambuena, b Toma ´s Delgado-Castro, c Jorge Soto-Delgado c and Ramiro Araya-Maturana c a Departamento de Quı ´ mica Inorga ´ nica y Analı ´tica, Facultad de Ciencias Quı ´ micas y Farmace ´uticas, Universidad de Chile, Chile b Departamento de Quı ´ mica, Facultad de Ciencias Ba ´ sicas, Universidad Metropolitana de Ciencias de la Educacio ´ n, Chile c Departamento de Quı ´ mica Orga ´ nica y Fisicoquı ´ mica, Facultad de Ciencias Quı ´ micas y Farmace ´uticas, Universidad de Chile, Chile Received 24 April 2007; revised 17 July 2007; accepted 18 July 2007 Available online 7 August 2007 Abstract—This study was undertaken to investigate the free radical-scavenging and antioxidant activities of various structurally related hydroquinones including hydroxynaphthalenones and dihydroxyanthracenones. Electron spin resonance spectroscopy and spin trapping techniques were used to evaluate the ability of hydroquinones to scavenge hydroxyl, diphenylpicrylhydrazyl, and galvinoxyl radicals. In addition, the oxygen radical absorbing capacity assay using fluorescein (ORAC-FL) was used to obtain the relative antioxidant capacity of these radicals. The rate constants of the first H atom abstraction by 2,2-diphenyl-2-pic- rylhydrazyl (k 2 ), were obtained under pseudo-first-order conditions. The free radical-scavenging activities and k 2 values discriminate well between hydroxynaphthalenones and dihydroxyanthracenones, showing that the latter have better antioxidant properties. The aforementioned experimental data agree with quantum-chemical results demonstrating the relevance of intramolecular H bonding to radical-scavenging activities. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction Reactions of free radicals and reactive oxygen species (ROS) with biological molecules in vivo play an impor- tant physiological role in many diseases such as can- cer, 1,2 gastric ulcers, 3,4 Alzheimer’s disease, arthritis, and ischemia–reperfusion tissue damage. 5 ROS are enti- ties containing one or more reactive oxygen atoms including hydroxyl radical ( Å OH), superoxide anion rad- ical (O 2 Å ), and hydrogen peroxide (H 2 O 2 ). Their forma- tion is an unavoidable consequence of respiration in aerobic organisms. These species are very unstable and react rapidly with other substances in the body, leading to cell or tissue injury. Antioxidants are defined as substances that, when present at low concentrations compared with those of an oxidizable substrate, significantly delay or pre- vent oxidation of that substrate. 6 Small-molecule anti- oxidants can be present extra- and intracellularly. Antioxidants work by preventing the formation of new free radical species, by converting existing free radicals into less harmful molecules, and by prevent- ing chain reactions. Organic molecules such as phenolic compounds may stimulate or inhibit oxidative damage to biomolecules and are believed to behave as either antioxidants or pro-oxidants. 7–10 Although, after absorption into the bloodstream, phenolic compounds may undergo chemi- cal modifications such as glycosylation, methylation, and glucuronidation, their availability and ability to exert biological activity remain. 9,10 The cytotoxicity of phenols has been associated with their pro-oxidative activity, which can accelerate oxida- tive damage either to DNA or to proteins and carbohy- drates, depending on the structure, dose, target molecule, and environment. This type of compound has been reported to have antiproliferative and cyto- 0968-0896/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2007.07.013 Abbreviations: ROS, reactive oxygen species; QH 2 , p-hydroquinone(s); Q, quinone(s); LO 2 Å , lipoperoxy radical(s); SQ Å , ubisemiquinone; ESR, electron spin resonance; AUC, area under the curve; ORAC-FL, ox- ygen radical absorbing capacity assay using fluorescein; DPPH, 2,2- diphenyl-2-picrylhydrazyl; BDE, bond dissociation enthalpy; HAT, H atom transfer. Keywords: Antioxidant; Hydroquinone; Electron spin resonance spec- troscopy; Kinetics. * Corresponding author. E-mail: colea@uchile.cl Bioorganic & Medicinal Chemistry 15 (2007) 7058–7065