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Nicholas H Oberlies - One of the best experts on this subject based on the ideXlab platform.
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Chemoenzymatic Synthesis, Characterization, and Scale-Up of Milk Thistle Flavonolignan Glucuronides
Drug metabolism and disposition: the biological fate of chemicals, 2015Co-Authors: Brandon T Gufford, Nicholas H Oberlies, Tyler N. Graf, Noemi D. Paguigan, Mary F PaineAbstract:Plant-based therapeutics, including herbal products, continue to represent a growing facet of the contemporary health care market. Mechanistic descriptions of the pharmacokinetics and pharmacodynamics of constituents composing these products remain nascent, particularly for metabolites produced following herbal product ingestion. Generation and characterization of authentic metabolite standards are essential to improve the quantitative mechanistic understanding of herbal product disposition in both in vitro and in vivo systems. Using the model herbal product, milk thistle, the objective of this work was to biosynthesize multimilligram quantities of glucuronides of select constituents (Flavonolignans) to fill multiple knowledge gaps in the understanding of herbal product disposition and action. A partnership between clinical pharmacology and natural products chemistry expertise was leveraged to optimize reaction conditions for efficient glucuronide formation and evaluate alternate enzyme and reagent sources to improve cost effectiveness. Optimized reaction conditions used at least one-fourth the amount of microsomal protein (from bovine liver) and cofactor (UDP glucuronic acid) compared with typical conditions using human-derived subcellular fractions, providing substantial cost savings. Glucuronidation was Flavonolignan-dependent. Silybin A, silybin B, isosilybin A, and isosilybin B generated five, four, four, and three monoglucuronides, respectively. Large-scale synthesis (40 mg of starting material) generated three glucuronides of silybin A: silybin A-7-O-β-d-glucuronide (15.7 mg), silybin A-5-O-β-d-glucuronide (1.6 mg), and silybin A-4´´-O-β-d-glucuronide (11.1 mg). This optimized, cost-efficient method lays the foundation for a systematic approach to synthesize and characterize herbal product constituent glucuronides, enabling an improved understanding of mechanisms underlying herbal product disposition and action.
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large scale isolation of Flavonolignans from silybum marianum extract affords new minor constituents and preliminary structure activity relationships
Natural Product Updates, 2015Co-Authors: Tyler N. Graf, Nicholas H OberliesAbstract:The gram-scale isolation of the major Flavonolignan diastereoisomers from milk thistle (Silybum marianum) extract provided an entre into the isolation of two related analogs that are present in extremely minute quantities. The isolation and structure elucidation of these two new compounds, which we have termed isosilybin C and isosilybin D due to their structural similarities to isosilybin A and isosilybin B, respectively, afforded a preliminary analysis of structure-activity relationships toward prostate cancer growth, survival, and apoptotic endpoints.
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Flavonolignans from Aspergillus iizukae, a Fungal Endophyte of Milk Thistle (Silybum marianum)
Journal of natural products, 2014Co-Authors: Tamam El-elimat, Huzefa A. Raja, Tyler N. Graf, Stanley H. Faeth, Nadja B. Cech, Nicholas H OberliesAbstract:Silybin A (1), silybin B (2), and isosilybin A (3), three of the seven Flavonolignans that constitute silymarin, an extract of the fruits of milk thistle (Silybum marianum), were detected for the first time from a fungal endophyte, Aspergillus iizukae, isolated from the surface-sterilized leaves of S. marianum. The Flavonolignans were identified using a UPLC-PDA-HRMS-MS/MS method by matching retention times, HRMS, and MS/MS data with authentic reference compounds. Attenuation of Flavonolignan production was observed following successive subculturing of the original Flavonolignan-producing culture, as is often the case with endophytes that produce plant-based secondary metabolites. However, production of 1 and 2 resumed when attenuated spores were harvested from cultures grown on a medium to which autoclaved leaves of S. marianum were added. The cycle of attenuation followed by resumed biosynthesis of these Flavonolignans was replicated in triplicate.
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Flavonolignans from Aspergillus iizukae, a Fungal Endophyte of Milk Thistle (Silybum marianum)
2014Co-Authors: Tamam El-elimat, Huzefa A. Raja, Tyler N. Graf, Stanley H. Faeth, Nadja B. Cech, Nicholas H OberliesAbstract:Silybin A (1), silybin B (2), and isosilybin A (3), three of the seven Flavonolignans that constitute silymarin, an extract of the fruits of milk thistle (Silybum marianum), were detected for the first time from a fungal endophyte, Aspergillus iizukae, isolated from the surface-sterilized leaves of S. marianum. The Flavonolignans were identified using a UPLC-PDA-HRMS-MS/MS method by matching retention times, HRMS, and MS/MS data with authentic reference compounds. Attenuation of Flavonolignan production was observed following successive subculturing of the original Flavonolignan-producing culture, as is often the case with endophytes that produce plant-based secondary metabolites. However, production of 1 and 2 resumed when attenuated spores were harvested from cultures grown on a medium to which autoclaved leaves of S. marianum were added. The cycle of attenuation followed by resumed biosynthesis of these Flavonolignans was replicated in triplicate
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mechanistic study of the biomimetic synthesis of Flavonolignan diastereoisomers in milk thistle
Journal of Organic Chemistry, 2013Co-Authors: Hanan S Althagafy, Nicholas H Oberlies, Maria Elena Mezaavina, Mitchell P CroattAbstract:The mechanism for the biomimetic synthesis of Flavonolignan diastereoisomers in milk thistle is proposed to proceed by single-electron oxidation of coniferyl alcohol, subsequent reaction with one of the oxygen atoms of taxifolin’s catechol moiety, and finally, further oxidation to form four of the major components of silymarin: silybin A, silybin B, isosilybin A, and isosilybin B. This mechanism is significantly different from a previously proposed process that involves the coupling of two independently formed radicals.
Vladimír Křen - One of the best experts on this subject based on the ideXlab platform.
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Preparation of Retinoyl-Flavonolignan Hybrids and Their Antioxidant Properties.
Antioxidants (Basel Switzerland), 2019Co-Authors: Christopher S Chambers, David Biedermann, Kateřina Valentova, Marek Kuzma, Lucie Petraskova, Jitka Viktorova, Vladimír KřenAbstract:Antioxidants protect the structural and functional components in organisms against oxidative stress. Most antioxidants are of plant origin as the plants are permanently exposed to oxidative stress (UV radiation, photosynthetic reactions). Both carotenoids and flavonoids are prominent antioxidant and anti-radical agents often occurring together in the plant tissues and acting in lipophilic and hydrophilic milieu, respectively. They are complementary in their anti-radical activity. This study describes the synthesis of a series of hybrid ester conjugates of retinoic acid with various Flavonolignans, such as silybin, 2,3-dehydrosilybin and isosilybin. Antioxidant/anti-radical activities and bio-physical properties of novel covalent carotenoid-flavonoid hybrids, as well as various mixtures of the respective parent components, were investigated. Retinoyl conjugates with silybin—which is the most important Flavonolignan in silymarin complex—(and its pure diastereomers) displayed better 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity than both the parent compounds and their equimolar mixtures.
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2,3-Dehydroderivatives of Silymarin Flavonolignans: Prospective Natural Compounds for the Prevention of Chronic Diseases
Proceedings, 2019Co-Authors: Kateřina Valentova, David Biedermann, Vladimír KřenAbstract:Silybum marianum fruit extract silymarin displays various biological activities, which are attributed mostly to its major component silybin. However, silymarin contain several other isomeric Flavonolignans (isosilybin, silychristin, silydianin) and their oxidation products, the 2,3-dehydroFlavonolignans (2,3-dehydrosilybin, 2,3-dehydrosilychristin, 2,3-dehydrosilydianin). The latter compounds were found to be 1-2 orders of magnitude more efficient radical scavengers, reducing, chelating, cytoprotective, anti-aging, anti-cancer and anti-angiogenic agents than the parent Flavonolignans. Although 2,3-dehydroFlavonolignans occur in silymarin as minorities, they seem to be responsible for the majority of the biological activity and therefore have potential for the prevention of chronic diseases.
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Oxidation of Natural Bioactive Flavonolignan 2,3-Dehydrosilybin. An Electrochemical and Spectral Study
The journal of physical chemistry. B, 2017Co-Authors: Romana Sokolova, David Biedermann, Jan Vacek, Jana Kocábová, Petr Marhol, Jan Fiedler, Vladimír KřenAbstract:The electrochemical oxidation of the natural antioxidant 2,3-dehydrosilybin (DHS) was investigated in acetonitrile. The spectral changes during two electron and two proton oxidation registered by in situ IR spectroelectrochemistry show that the electron transfer is followed by a subsequent chemical reaction with traces of water. A benzofuranone derivative (BF) is formed by ECEC (electron transfer–chemical reaction–electron transfer–chemical reaction) process at the potential of the first oxidation wave. A minor difference in the chemical structures of Flavonolignans DHS and silybin, the presence of a double bond between atoms C-2 and C-3 in the DHS molecule, causes the formation of completely different oxidation products. BF was for the first time identified as the product of the oxidation of Flavonolignan DHS. Its formation was proved by electroanalytical, chromatographic, and spectroelectrochemical techniques. Molecular orbital calculations support the experimental findings.
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Unconventional application of the Mitsunobu reaction: Selective Flavonolignan dehydration yielding hydnocarpins
Beilstein journal of organic chemistry, 2016Co-Authors: Guozheng Huang, David Biedermann, Vladimír Křen, Simon Schramm, Jörg Heilmann, Michael DeckerAbstract:Various Mitsunobu conditions were investigated for a series of Flavonolignans (silybin A, silybin B, isosilybin A, and silychristin A) to achieve either selective esterification in position C-23 or dehydration in a one-pot reaction yielding the biologically important enantiomers of hydnocarpin D, hydnocarpin and isohydnocarpin, respectively. This represents the only one-pot semi-synthetic method to access these Flavonolignans in high yields.
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Oxidation of the Flavonolignan Silybin. In situ EPR Evidence of the Spin-Trapped Silybin Radical
Electrochimica Acta, 2016Co-Authors: Romana Sokolova, Jan Vacek, Eva Vavříková, Jana Kocábová, Petr Marhol, Jan Fiedler, Ján Tarábek, Barbora Papoušková, Vladimír KřenAbstract:Abstract Oxidation of natural Flavonolignan silybin in an aprotic environment was studied by electrochemical methods, electron paramagnetic resonance (EPR), UV–vis and IR in situ spectroelectrochemistry and chromatographic techniques. The presence of electrochemically generated silybin radical was proven using in situ EPR spectroelectrochemistry by spin trapping method with 5-tert-butoxycarbonyl-5-methyl-1-pyrroline-N-oxide (BMPO) as a spin trap reagent. The adduct of the silybin radical with BMPO was additionally unambiguously identified by UPLC-ESI-MS/MS. For the first time, the Flavonolignan radical was detected upon electrochemical oxidation under such conditions. The one-electron oxidation of silybin leads to a hydroxylated silybin derivative. Its specific redox behaviour can reflect its bioefficiency.
David Biedermann - One of the best experts on this subject based on the ideXlab platform.
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Preparation of Retinoyl-Flavonolignan Hybrids and Their Antioxidant Properties.
Antioxidants (Basel Switzerland), 2019Co-Authors: Christopher S Chambers, David Biedermann, Kateřina Valentova, Marek Kuzma, Lucie Petraskova, Jitka Viktorova, Vladimír KřenAbstract:Antioxidants protect the structural and functional components in organisms against oxidative stress. Most antioxidants are of plant origin as the plants are permanently exposed to oxidative stress (UV radiation, photosynthetic reactions). Both carotenoids and flavonoids are prominent antioxidant and anti-radical agents often occurring together in the plant tissues and acting in lipophilic and hydrophilic milieu, respectively. They are complementary in their anti-radical activity. This study describes the synthesis of a series of hybrid ester conjugates of retinoic acid with various Flavonolignans, such as silybin, 2,3-dehydrosilybin and isosilybin. Antioxidant/anti-radical activities and bio-physical properties of novel covalent carotenoid-flavonoid hybrids, as well as various mixtures of the respective parent components, were investigated. Retinoyl conjugates with silybin—which is the most important Flavonolignan in silymarin complex—(and its pure diastereomers) displayed better 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity than both the parent compounds and their equimolar mixtures.
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2,3-Dehydroderivatives of Silymarin Flavonolignans: Prospective Natural Compounds for the Prevention of Chronic Diseases
Proceedings, 2019Co-Authors: Kateřina Valentova, David Biedermann, Vladimír KřenAbstract:Silybum marianum fruit extract silymarin displays various biological activities, which are attributed mostly to its major component silybin. However, silymarin contain several other isomeric Flavonolignans (isosilybin, silychristin, silydianin) and their oxidation products, the 2,3-dehydroFlavonolignans (2,3-dehydrosilybin, 2,3-dehydrosilychristin, 2,3-dehydrosilydianin). The latter compounds were found to be 1-2 orders of magnitude more efficient radical scavengers, reducing, chelating, cytoprotective, anti-aging, anti-cancer and anti-angiogenic agents than the parent Flavonolignans. Although 2,3-dehydroFlavonolignans occur in silymarin as minorities, they seem to be responsible for the majority of the biological activity and therefore have potential for the prevention of chronic diseases.
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Skin Protective Activity of Silymarin and its Flavonolignans.
Molecules, 2019Co-Authors: Jitka Vostalova, Eva Tinková, David Biedermann, Pavel Kosina, Alena Rajnochova SvobodovaAbstract:Silybum marianum (L.) is a medicinal plant traditionally used in treatment of liver disorders. In last decades, silymarin (SM), a standardized extract from S. marianum seeds has been studied for its dermatological application, namely for UVB-protective properties. However, information on SM and its polyphenols effect on activity of enzymes participating in the (photo)aging process is limited. Therefore, evaluation of SM and its Flavonolignans potential to inhibit collagenase, elastase, and hyaluronidase in tube tests was the goal of this study. The antioxidant and UV screening properties of SM and its Flavonolignans silybin, isosilybin, silydianin, silychristin and 2,3-dehydrosilybin (DHSB) were also evaluated by a DPPH assay and spectrophotometrical measurement. DHSB showed the highest ability to scavenge DPPH radical and also revealed the highest UVA protection factor (PF-UVA) that corresponds with its absorption spectrum. SM and studied Flavonolignans were found to exhibit anti-collagenase and anti-elastase activity. The most potent Flavonolignan was DHSB. None of studied Flavonolignans or SM showed anti-hyaluronidase activity. Our results suggest that SM and its Flavonolignans may be useful agents for skin protection against the harmful effects of full-spectrum solar radiation including slowing down skin (photo)aging.
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In-Vitro Activity of Silybin and Related Flavonolignans against Leishmania infantum and L. donovani.
Molecules (Basel Switzerland), 2018Co-Authors: Ana Isabel Olías-molero, David Biedermann, María Dolores Jiménez-antón, María Jesús Corral, José María AlundaAbstract:Flavonolignans from the seeds of the milk thistle (Silybum marianum) have been extensively used in folk medicine for centuries. Confirmation of their properties as hepatoprotective, antioxidant and anticancer has been obtained using standardized extracts and purified Flavonolignans. Information on their potential effect on Leishmania is very scarce. We have investigated the effect of silymarin, silybin and related Flavonolignans on the multiplication of promastigotes in vitro and ex vivo on intracellular amastigotes of L. infantum (Li) and L. donovani (Ld), causative agents of human and canine visceral leishmaniasis (VL). In addition, the potential synergistic effect of the most active molecule and well-established antileishmanial drugs against promastigotes was explored. Dehydroisosilybin A elicited the highest inhibition against Ld and Li promastigotes with an approximate IC50 of 90.23 µM. This molecule showed a moderate synergism with amphotericin B (AmB) but not with SbIII or paromomycin, although it was ineffective against amastigotes. Antileishmanial activity on intracellular amastigotes of the two diastereoisomers of dehydrosilybin (10 µM) was comparable to that elicited by 0.1 µM AmB. Antiproliferative activity and safety of Flavonolignans suggest the interest of exploring their potential value in combination therapy against VL.
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Sulfated Metabolites of Flavonolignans and 2,3-DehydroFlavonolignans: Preparation and Properties
MDPI AG, 2018Co-Authors: Kateřina Valentova, David Biedermann, Lenka Roubalová, Lucie Petraskova, Kateřina Purchartová, Lenka Rydlová, Alena Křenková, Helena Pelantová, Veronika Holečková-moravcová, Eva TesařováAbstract: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
Tyler N. Graf - One of the best experts on this subject based on the ideXlab platform.
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Chemoenzymatic Synthesis, Characterization, and Scale-Up of Milk Thistle Flavonolignan Glucuronides
Drug metabolism and disposition: the biological fate of chemicals, 2015Co-Authors: Brandon T Gufford, Nicholas H Oberlies, Tyler N. Graf, Noemi D. Paguigan, Mary F PaineAbstract:Plant-based therapeutics, including herbal products, continue to represent a growing facet of the contemporary health care market. Mechanistic descriptions of the pharmacokinetics and pharmacodynamics of constituents composing these products remain nascent, particularly for metabolites produced following herbal product ingestion. Generation and characterization of authentic metabolite standards are essential to improve the quantitative mechanistic understanding of herbal product disposition in both in vitro and in vivo systems. Using the model herbal product, milk thistle, the objective of this work was to biosynthesize multimilligram quantities of glucuronides of select constituents (Flavonolignans) to fill multiple knowledge gaps in the understanding of herbal product disposition and action. A partnership between clinical pharmacology and natural products chemistry expertise was leveraged to optimize reaction conditions for efficient glucuronide formation and evaluate alternate enzyme and reagent sources to improve cost effectiveness. Optimized reaction conditions used at least one-fourth the amount of microsomal protein (from bovine liver) and cofactor (UDP glucuronic acid) compared with typical conditions using human-derived subcellular fractions, providing substantial cost savings. Glucuronidation was Flavonolignan-dependent. Silybin A, silybin B, isosilybin A, and isosilybin B generated five, four, four, and three monoglucuronides, respectively. Large-scale synthesis (40 mg of starting material) generated three glucuronides of silybin A: silybin A-7-O-β-d-glucuronide (15.7 mg), silybin A-5-O-β-d-glucuronide (1.6 mg), and silybin A-4´´-O-β-d-glucuronide (11.1 mg). This optimized, cost-efficient method lays the foundation for a systematic approach to synthesize and characterize herbal product constituent glucuronides, enabling an improved understanding of mechanisms underlying herbal product disposition and action.
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large scale isolation of Flavonolignans from silybum marianum extract affords new minor constituents and preliminary structure activity relationships
Natural Product Updates, 2015Co-Authors: Tyler N. Graf, Nicholas H OberliesAbstract:The gram-scale isolation of the major Flavonolignan diastereoisomers from milk thistle (Silybum marianum) extract provided an entre into the isolation of two related analogs that are present in extremely minute quantities. The isolation and structure elucidation of these two new compounds, which we have termed isosilybin C and isosilybin D due to their structural similarities to isosilybin A and isosilybin B, respectively, afforded a preliminary analysis of structure-activity relationships toward prostate cancer growth, survival, and apoptotic endpoints.
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Flavonolignans from Aspergillus iizukae, a Fungal Endophyte of Milk Thistle (Silybum marianum)
Journal of natural products, 2014Co-Authors: Tamam El-elimat, Huzefa A. Raja, Tyler N. Graf, Stanley H. Faeth, Nadja B. Cech, Nicholas H OberliesAbstract:Silybin A (1), silybin B (2), and isosilybin A (3), three of the seven Flavonolignans that constitute silymarin, an extract of the fruits of milk thistle (Silybum marianum), were detected for the first time from a fungal endophyte, Aspergillus iizukae, isolated from the surface-sterilized leaves of S. marianum. The Flavonolignans were identified using a UPLC-PDA-HRMS-MS/MS method by matching retention times, HRMS, and MS/MS data with authentic reference compounds. Attenuation of Flavonolignan production was observed following successive subculturing of the original Flavonolignan-producing culture, as is often the case with endophytes that produce plant-based secondary metabolites. However, production of 1 and 2 resumed when attenuated spores were harvested from cultures grown on a medium to which autoclaved leaves of S. marianum were added. The cycle of attenuation followed by resumed biosynthesis of these Flavonolignans was replicated in triplicate.
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Flavonolignans from Aspergillus iizukae, a Fungal Endophyte of Milk Thistle (Silybum marianum)
2014Co-Authors: Tamam El-elimat, Huzefa A. Raja, Tyler N. Graf, Stanley H. Faeth, Nadja B. Cech, Nicholas H OberliesAbstract:Silybin A (1), silybin B (2), and isosilybin A (3), three of the seven Flavonolignans that constitute silymarin, an extract of the fruits of milk thistle (Silybum marianum), were detected for the first time from a fungal endophyte, Aspergillus iizukae, isolated from the surface-sterilized leaves of S. marianum. The Flavonolignans were identified using a UPLC-PDA-HRMS-MS/MS method by matching retention times, HRMS, and MS/MS data with authentic reference compounds. Attenuation of Flavonolignan production was observed following successive subculturing of the original Flavonolignan-producing culture, as is often the case with endophytes that produce plant-based secondary metabolites. However, production of 1 and 2 resumed when attenuated spores were harvested from cultures grown on a medium to which autoclaved leaves of S. marianum were added. The cycle of attenuation followed by resumed biosynthesis of these Flavonolignans was replicated in triplicate
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semisynthesis cytotoxicity antiviral activity and drug interaction liability of 7 o methylated analogues of Flavonolignans from milk thistle
Bioorganic & Medicinal Chemistry, 2013Co-Authors: Hanan S Althagafy, Tyler N. Graf, Arlene A Sycordero, Brandon T Gufford, Mary F Paine, Jessica Wagoner, Stephen J Polyak, Mitchell P Croatt, Nicholas H OberliesAbstract:Silymarin, an extract of the seeds of milk thistle (Silybum marianum), is used as an herbal remedy, particularly for hepatoprotection. The main chemical constituents in silymarin are seven Flavonolignans. Recent studies explored the non-selective methylation of one Flavonolignan, silybin B, and then tested those analogues for cytotoxicity and inhibition of both cytochrome P450 (CYP) 2C9 activity in human liver microsomes and hepatitis C virus infection in a human hepatoma (Huh7.5.1) cell line. In general, enhanced bioactivity was observed with the analogues. To further probe the biological consequences of methylation of the seven major Flavonolignans, a series of 7-O-methylFlavonolignans were generated. Optimization of the reaction conditions permitted selective methylation at the phenol in the 7-position in the presence of each metabolite’s 4–5 other phenolic and/or alcoholic positions without the use of protecting groups. These 7-O-methylated analogues, in parallel with the corresponding parent compounds, were evaluated for cytotoxicity against Huh7.5.1 cells; in all cases the monomethylated analogues were more cytotoxic than the parent compounds. Moreover, parent compounds that were relatively non-toxic and inactive or weak inhibitors of hepatitis C virus infection had enhanced cytotoxicity and anti-HCV activity upon 7-O-methylation. Also, the compounds were tested for inhibition of major drug metabolizing enzymes (CYP2C9, CYP3A4/5, UDP-glucuronsyltransferases) in pooled human liver or intestinal microsomes. Methylation of Flavonolignans differentially modified inhibitory potency, with compounds demonstrating both increased and decreased potency depending upon the compound tested and the enzyme system investigated. In total, these data indicated that monomethylation modulates the cytotoxic, antiviral, and drug interaction potential of silymarin Flavonolignans.
Kateřina Valentova - One of the best experts on this subject based on the ideXlab platform.
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Preparation of Retinoyl-Flavonolignan Hybrids and Their Antioxidant Properties.
Antioxidants (Basel Switzerland), 2019Co-Authors: Christopher S Chambers, David Biedermann, Kateřina Valentova, Marek Kuzma, Lucie Petraskova, Jitka Viktorova, Vladimír KřenAbstract:Antioxidants protect the structural and functional components in organisms against oxidative stress. Most antioxidants are of plant origin as the plants are permanently exposed to oxidative stress (UV radiation, photosynthetic reactions). Both carotenoids and flavonoids are prominent antioxidant and anti-radical agents often occurring together in the plant tissues and acting in lipophilic and hydrophilic milieu, respectively. They are complementary in their anti-radical activity. This study describes the synthesis of a series of hybrid ester conjugates of retinoic acid with various Flavonolignans, such as silybin, 2,3-dehydrosilybin and isosilybin. Antioxidant/anti-radical activities and bio-physical properties of novel covalent carotenoid-flavonoid hybrids, as well as various mixtures of the respective parent components, were investigated. Retinoyl conjugates with silybin—which is the most important Flavonolignan in silymarin complex—(and its pure diastereomers) displayed better 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity than both the parent compounds and their equimolar mixtures.
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2,3-Dehydroderivatives of Silymarin Flavonolignans: Prospective Natural Compounds for the Prevention of Chronic Diseases
Proceedings, 2019Co-Authors: Kateřina Valentova, David Biedermann, Vladimír KřenAbstract:Silybum marianum fruit extract silymarin displays various biological activities, which are attributed mostly to its major component silybin. However, silymarin contain several other isomeric Flavonolignans (isosilybin, silychristin, silydianin) and their oxidation products, the 2,3-dehydroFlavonolignans (2,3-dehydrosilybin, 2,3-dehydrosilychristin, 2,3-dehydrosilydianin). The latter compounds were found to be 1-2 orders of magnitude more efficient radical scavengers, reducing, chelating, cytoprotective, anti-aging, anti-cancer and anti-angiogenic agents than the parent Flavonolignans. Although 2,3-dehydroFlavonolignans occur in silymarin as minorities, they seem to be responsible for the majority of the biological activity and therefore have potential for the prevention of chronic diseases.
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Sulfated Metabolites of Flavonolignans and 2,3-DehydroFlavonolignans: Preparation and Properties
MDPI AG, 2018Co-Authors: Kateřina Valentova, David Biedermann, Lenka Roubalová, Lucie Petraskova, Kateřina Purchartová, Lenka Rydlová, Alena Křenková, Helena Pelantová, Veronika Holečková-moravcová, Eva TesařováAbstract: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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the silymarin composition and why does it matter
Food Research International, 2017Co-Authors: Christopher S Chambers, David Biedermann, Kateřina Valentova, Veronika Holeckova, Lucie Petraskova, Martin BuchtaAbstract:Abstract The extract from milk thistle (Silybum marianum (L.) Gaertn. (Asteraceae)), known as silymarin, contains a variety of Flavonolignans and displays antioxidant, anti-inflammatory, immunomodulatory and hepatoprotective properties. As silybin is the main component of silymarin, the literature mainly focuses on this compound, ignoring all other components. This leads to problems in reproducibility of scientific results, as the exact composition of silymarin is often unknown and can vary to a certain degree depending on the processing, chemo-variety of the plant used and climatic conditions during the plant growth. There are studies dealing with the analytical separation and quantification of silymarin components as well as studies focused on silymarin content in clinically used drugs, in various plant parts, seasons, geographic locations etc. However, no comparison of detail Flavonolignan profiles in various silymarin preparations is available to date. Also, as a result of the focus on the Flavonolignans; the oil fraction, which contains linoleic, oleic and palmitic acids, sterols, tocopherol (vitamin E) and phospholipids, has been neglected. Due to all these factors, the whole plant is used e.g. as animal feed, the leaves can be eaten in salads and seed oil, besides culinary uses, can be also utilized for biodiesel or polymer production. Various HPLC separation techniques for the determination of the content of the Flavonolignans have been vastly summarized in the present review.
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Flavonolignan 2 3 dehydroderivatives preparation antiradical and cytoprotective activity
Free Radical Biology and Medicine, 2016Co-Authors: Michaela Pyszkova, David Biedermann, Jiří Vrba, Michal Biler, Kateřina Valentova, Marek Kuzma, Romana Sokolova, Milos Mojovic, Ana PopovicbijelicAbstract:Abstract The protective constituents of silymarin, an extract from Silybum marianum fruits, have been extensively studied in terms of their antioxidant and hepatoprotective activities. Here, we explore the electron-donor properties of the major silymarin Flavonolignans. Silybin (SB), silychristin (SCH), silydianin (SD) and their respective 2,3-dehydroderivatives (DHSB, DHSCH and DHSD) were oxidized electrochemically and their antiradical/antioxidant properties were investigated. Namely, Folin–Ciocalteau reduction, DPPH and ABTS+ radical scavenging, inhibition of microsomal lipid peroxidation and cytoprotective effects against tert-butyl hydroperoxide-induced damage to a human hepatocellular carcinoma HepG2 cell line were evaluated. Due to the presence of the highly reactive C3-OH group and the C-2,3 double bond (ring C) allowing electron delocalization across the whole structure in the 2,3-dehydroderivatives, these compounds are much more easily oxidized than the corresponding Flavonolignans SB, SCH and SD. This finding was unequivocally confirmed not only by experimental approaches, but also by density functional theory (DFT) calculations. The hierarchy in terms of ability to undergo electrochemical oxidation (DHSCH~DHSD>DHSB > > SCH/SD>SB) was consistent with their antiradical activities, mainly DPPH scavenging, as well as in vitro cytoprotection of HepG2 cells. The results are discussed in the context of the antioxidant vs. prooxidant activities of Flavonolignans and molecular interactions in complex biological systems.