Silymarin, an extract from milk thistle (Silybum marianum) fruits, is consumed in various food supplements. The metabolism of silymarin flavonolignans in mammals is complex, the exact structure of their metabolites still remains partly unclear and standards are not commercially available. This work is focused on the preparation of sulfated metabolites of silymarin flavonolignans. Sulfated flavonolignans were prepared using aryl sulfotransferase from Desulfitobacterium hafniense and p-nitrophenyl sulfate as a sulfate donor and characterized by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR). Their 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and N,N-dimethyl-p-phenylenediamine (DMPD) radical scavenging; ferric (FRAP) and Folin⁻Ciocalteu reagent (FCR) reducing activity; anti-lipoperoxidant potential; and effect on the nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway were examined. Pure silybin A 20-O-sulfate, silybin B 20-O-sulfate, 2,3-dehydrosilybin-20-O-sulfate, 2,3-dehydrosilybin-7,20-di-O-sulfate, silychristin-19-O-sulfate, 2,3-dehydrosilychristin-19-O-sulfate, and silydianin-19-O-sulfate were prepared and fully characterized. Sulfated 2,3-dehydroderivatives were more active in FCR and FRAP assays than the parent compounds, and remaining sulfates were less active chemoprotectants. The sulfated flavonolignans obtained can be now used as authentic standards for in vivo metabolic experiments and for further research on their biological activity.

Department of Medical Chemistry and Biochemistry Faculty of Medicine and Dentistry Palacký University Hněvotínská 3 77515 Olomouc Czech Republic Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 3 77515 Olomouc Czech Republic

Faculty of Science Charles University Department of Physical and Macromolecular Chemistry Hlavova 2030 8 12843 Prague Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 14220 Prague Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 14220 Prague Czech Republic Faculty of Science Charles University Department of Physical and Macromolecular Chemistry Hlavova 2030 8 12843 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 16610 Prague Czech Republic

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$a Valentová, Kateřina $u Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic. kata.valentova@email.cz.

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$a Sulfated Metabolites of Flavonolignans and 2,3-Dehydroflavonolignans: Preparation and Properties / $c K. Valentová, K. Purchartová, L. Rydlová, L. Roubalová, D. Biedermann, L. Petrásková, A. Křenková, H. Pelantová, V. Holečková-Moravcová, E. Tesařová, J. Cvačka, J. Vrba, J. Ulrichová, V. Křen,

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$a Silymarin, an extract from milk thistle (Silybum marianum) fruits, is consumed in various food supplements. The metabolism of silymarin flavonolignans in mammals is complex, the exact structure of their metabolites still remains partly unclear and standards are not commercially available. This work is focused on the preparation of sulfated metabolites of silymarin flavonolignans. Sulfated flavonolignans were prepared using aryl sulfotransferase from Desulfitobacterium hafniense and p-nitrophenyl sulfate as a sulfate donor and characterized by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR). Their 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and N,N-dimethyl-p-phenylenediamine (DMPD) radical scavenging; ferric (FRAP) and Folin⁻Ciocalteu reagent (FCR) reducing activity; anti-lipoperoxidant potential; and effect on the nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway were examined. Pure silybin A 20-O-sulfate, silybin B 20-O-sulfate, 2,3-dehydrosilybin-20-O-sulfate, 2,3-dehydrosilybin-7,20-di-O-sulfate, silychristin-19-O-sulfate, 2,3-dehydrosilychristin-19-O-sulfate, and silydianin-19-O-sulfate were prepared and fully characterized. Sulfated 2,3-dehydroderivatives were more active in FCR and FRAP assays than the parent compounds, and remaining sulfates were less active chemoprotectants. The sulfated flavonolignans obtained can be now used as authentic standards for in vivo metabolic experiments and for further research on their biological activity.

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$a Purchartová, Kateřina $u Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic. katerina.purchartova@gmail.com. Faculty of Science, Charles University, Department of Physical and Macromolecular Chemistry, Hlavova 2030/8, 12843 Prague, Czech Republic. katerina.purchartova@gmail.com.

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$a Rydlová, Lenka $u Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic. rydlova.l@email.cz. Faculty of Science, Charles University, Department of Physical and Macromolecular Chemistry, Hlavova 2030/8, 12843 Prague, Czech Republic. rydlova.l@email.cz.

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$a Roubalová, Lenka $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 77515 Olomouc, Czech Republic. roubalova.lenka@seznam.cz. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 77515 Olomouc, Czech Republic. roubalova.lenka@seznam.cz.

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$a Biedermann, David $u Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic. biedermann@biomed.cas.cz.

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$a Křenková, Alena $u Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic. alenka.petrickova@gmail.com.

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$a Pelantová, Helena $u Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic. pelantova@biomed.cas.cz.

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$a Holečková-Moravcová, Veronika $u Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic. vholeckov@gmail.com.

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$a Tesařová, Eva $u Faculty of Science, Charles University, Department of Physical and Macromolecular Chemistry, Hlavova 2030/8, 12843 Prague, Czech Republic. eva.tesarova@natur.cuni.cz.

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$a Cvačka, Josef $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16610 Prague, Czech Republic. josef.cvacka@uochb.cas.cz.

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$a Vrba, Jiří $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 77515 Olomouc, Czech Republic. j.vrba@upol.cz. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 77515 Olomouc, Czech Republic. j.vrba@upol.cz.

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$a Ulrichová, Jitka $u Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 77515 Olomouc, Czech Republic. jitkaulrichova@seznam.cz. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 77515 Olomouc, Czech Republic. jitkaulrichova@seznam.cz.

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$a Křen, Vladimír $u Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic. kren@biomed.cas.cz.

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