title: Antioxidant, metal-binding and DNA-damaging properties of flavonolignans: a joint experimental and computational highlight based on 7-O-galloylsilybin.
abstract: Besides the well-known chemoprotective effects of polyphenols, their prooxidant activities via interactions with biomacromolecules as DNA and proteins are of the utmost importance. Current research focuses not only on natural polyphenols but also on synthetically prepared analogs with promising biological activities. In the present study, the antioxidant and prooxidant properties of a semi-synthetic flavonolignan 7-O-galloylsilybin (7-GSB) are described. The presence of the galloyl moiety significantly enhances the antioxidant capacity of 7-GSB compared to that of silybin (SB). These findings were supported by electrochemistry, DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activity, total antioxidant capacity (CL-TAC) and DFT (density functional theory) calculations. A three-step oxidation mechanism of 7-GSB is proposed at pH 7.4, in which the galloyl moiety is first oxidized at Ep,1=+0.20V (vs. Ag/AgCl3M KCl) followed by oxidation of the 20-OH (Ep,2=+0.55V) and most probably 5-OH (Ep,3=+0.95V) group of SB moiety. The molecular orbital analysis and the calculation of O-H bond dissociation enthalpies (BDE) fully rationalize the electrooxidation processes. The metal (Cu(2+)) complexation of 7-GSB was studied, which appeared to involve both the galloyl moiety and the 5-OH group. The prooxidant effects of the metal-complexes were then studied according to their capacity to oxidatively induce DNA modification and cleavage. These results paved the way towards the conclusion that 7-O-galloyl substitution to SB concomitantly (i) enhances antioxidant (ROS scavenging) capacity and (ii) decreases prooxidant effect/DNA damage after Cu complexation. This multidisciplinary approach provides a comprehensive mechanistic picture of the antioxidant vs. metal-induced prooxidant effects of flavonolignans at the molecular level, under ex vivo conditions.
authors.affiliation: Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic. jan.vacek@upol.cz
authors.forename: Jan
authors.initials: J
authors.lastname: Vacek
authors.forename: Martina
authors.initials: M
authors.lastname: Zatloukalová
authors.forename: Thomas
authors.initials: T
authors.lastname: Desmier
authors.forename: Veronika
authors.initials: V
authors.lastname: Nezhodová
authors.forename: Jan
authors.initials: J
authors.lastname: Hrbáč
authors.forename: Martin
authors.initials: M
authors.lastname: Kubala
authors.forename: Vladimír
authors.initials: V
authors.lastname: Křen
authors.forename: Jitka
authors.initials: J
authors.lastname: Ulrichová
authors.forename: Patrick
authors.initials: P
authors.lastname: Trouillas
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D004249:DNA Damage; D055664:Electrochemical Techniques; D008163:Luminescent Measurements; D056004:Molecular Dynamics Simulation; D010851:Picrates / Q000378:metabolism; D012838:Silymarin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet
chemical_list: C568966:7-O-galloylsilybin; D000975:Antioxidants; D001713:Biphenyl Compounds; D010851:Picrates; D012838:Silymarin; D003300:Copper; C004931:1,1-diphenyl-2-picrylhydrazyl
keywords: Albumin; Antioxidants; DNA-damage; Flavonolignans; Nucleic acids; Prooxidant effects