title: Novel flavonolignan hybrid antioxidants: From enzymatic preparation to molecular rationalization.
abstract: A series of antioxidants was designed and synthesized based on conjugation of the hepatoprotective flavonolignan silybin with l-ascorbic acid, trolox alcohol or tyrosol via a C12aliphatic linker. These hybrid molecules were prepared from 12-vinyl dodecanedioate-23-O-silybin using the enzymatic regioselective acylation procedure with Novozym 435 (lipase B) or with lipase PS. Voltammetric analyses showed that the silybin-ascorbic acid conjugate exhibited excellent electron donating ability, in comparison to the other conjugates. Free radical scavenging, antioxidant activities and cytoprotective action were evaluated. The silybin-ascorbic acid hybrid exhibited the best activities (IC50= 30.2 μM) in terms of lipid peroxidation inhibition. The promising protective action of the conjugate against lipid peroxidation can be attributed to modulated electron transfer abilities of both the silybin and ascorbate moieties, but also to the hydrophobic C12linker facilitating membrane insertion. This was supported experimentally and theoretically by density functional theory (DFT) and molecular dynamics (MD) calculations. The results presented here can be used in the further development of novel multipotent antioxidants and cytoprotective agents, in particular for substances acting at an aqueous/lipid interface.
authors.affiliation: Laboratory of Biotransformation, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 142 20, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Vavříková
authors.affiliation: Laboratory of Biotransformation, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 142 20, Czech Republic.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Křen
authors.affiliation: Laboratory of Biotransformation, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 142 20, Czech Republic.
authors.forename: Lubica
authors.initials: L
authors.lastname: Jezova-Kalachova
authors.affiliation: INSERM U850, Univ. Limoges, School of Pharmacy, 2 rue du Docteur Marcland, 87025 Limoges, France; Department of Biophysics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University, Šlechtitelů 11, 783 71, Olomouc, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Biler
authors.affiliation: INSERM U850, Univ. Limoges, School of Pharmacy, 2 rue du Docteur Marcland, 87025 Limoges, France; Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, tř. 17. listopadu 12, 771 46 Olomouc, Czech Republic.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chantemargue
authors.affiliation: Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc, 775 15, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Pyszková
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, C.N.R., Via Mario Bianco 9, Milano, I-20131, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Riva
authors.affiliation: Laboratory of Biotransformation, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 142 20, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Kuzma
authors.affiliation: Laboratory of Biotransformation, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 142 20, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Valentová
authors.affiliation: Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc, 775 15, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Ulrichová
authors.affiliation: Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc, 775 15, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Vrba
authors.affiliation: INSERM U850, Univ. Limoges, School of Pharmacy, 2 rue du Docteur Marcland, 87025 Limoges, France; Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, tř. 17. listopadu 12, 771 46 Olomouc, Czech Republic.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trouillas
authors.affiliation: Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, Olomouc, 775 15, Czech Republic. Electronic address: jan.vacek@upol.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Vacek
mesh_terms: D000975:Antioxidants / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004579:Electron Transport; D004800:Enzymes, Immobilized; D044947:Flavonolignans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005656:Fungal Proteins; D056945:Hep G2 Cells; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D000077385:Silybin; D012838:Silymarin / Q000737:chemistry
chemical_list: D000975:Antioxidants; D004800:Enzymes, Immobilized; D044947:Flavonolignans; D005656:Fungal Proteins; D012838:Silymarin; D000077385:Silybin; C093667:Novozyme 435; D008049:Lipase
keywords: Cytoprotection; Enzymatic coupling; Lipid peroxidation; Multipotent antioxidant; Silybin; Vitamin C