- Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry
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The self-assembling of the amyloid β (Aβ) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the amyloid hypothesis , many efforts have been devoted to designing molecules able to halt disease progression by inhibiting Aβ self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit Aβ aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment 35MVGGVV40 of Aβ40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments 17LVFF20 and 27NKGAII32 of Aβ40 which shows a high tendency to form bend, turn, and β-sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment 17LVFF20 but lead to the formation of different small-sized, ThT-positive Aβ aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human Aβ indicated that silybin B is the most effective of the four compounds in counteracting Aβ proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics.
- Sciacca, Michele. F. M.,Romanucci, Valeria,Zarrelli, Armando,Monaco, Irene,Lolicato, Fabio,Spinella, Natalia,Galati, Clelia,Grasso, Giuseppe,D'Urso, Luisa,Romeo, Margherita,Diomede, Luisa,Salmona, Mario,Bongiorno, Corrado,Di Fabio, Giovanni,La Rosa, Carmelo,Milardi, Danilo
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p. 1767 - 1778
(2017/08/21)
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- Mechanistic study of the biomimetic synthesis of flavonolignan diastereoisomers in milk thistle
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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.
- Althagafy, Hanan S.,Meza-Avina, Maria Elena,Oberlies, Nicholas H.,Croatt, Mitchell P.
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p. 7594 - 7600
(2013/09/02)
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- Composition for Topical Use
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The use, as a dermatological or cosmetic medicament, of compounds capable of transiently interacting with the AhR receptor (aryl hydrocarbon receptor) as agents for modulating skin functions such as sebaceous function, skin healing, skin atrophy termed “dermatoporosis”, estrogen deprivation and defense against infection, without inducing other toxic effects of the TCDD type. The compounds that interact with the AhR receptor are chosen in that they have a metabolism favorable to the dissociation of these effects, in particular by virtue of in situ production from a precursor and/or metabolization modulated in situ.
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- Enzymatic kinetic resolution of silybin diastereoisomers
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In nature, the flavonolignan silybin (1) occurs as a mixture of two diastereomers, silybin A and silybin B, which in a number of biological assays exhibit different activities. A library of hydrolases (lipases, esterases, and proteases) was tested for separating the silybin A and B diastereomers by selective transesterification or by stereoselective alcoholysis of 23-O-acetylsilybin (2). Novozym 435 proved to be the most suitable enzyme for the preparative production of both optically pure silybins A and B by enzymatic discrimination. Gram amounts of the optically pure substances can be produced within one week, and the new method is robust and readily scalable to tens of grams.
- Monti, Daniela,Gazak, Radek,Marhol, Petr,Biedermann, David,Purchartova, Katerina,Fedrigo, Mirko,Riva, Sergio,Kren, Vladimir
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experimental part
p. 613 - 619
(2010/07/13)
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- Complexes of flavanolignans with phospholipids, preparation thereof and associated pharmaceutical compositions
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The invention relates to novel compounds comprising lipophilic complexes of silybin, silidianin, and silicristin with phospholipids, and the preparation of these complexes by non-conventional methods. Absorption of the novel compounds in the gastrointestinal tract is appreciably greater, resulting in higher plasma levels than for the individual flavanolignans. The resulting improvement in the pharmacokinetic and pharmacological parameters is such that the substances can advantageously be used in the treatment of acute and chronic liver disease of toxic, metabolic or infective origin or of degenerative nature.
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- Bioavailability of silymarin. II. Investigations on the stability of silybin dihemisuccinate
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The kinetics of the hydrolysis of silybin dihemisuccinate at various pH values were investigated. The ester group is not hydrolized in acidic or neutral media. In alkaline solutions, the rate of hydrolysis increases linearly with increasing pH. An HPLC method for the quantitative determination of silybin, its dihemisuccinate, and of two isometric monohemisuccinates is reported.
- Koch,Tscherny,Zinsberger
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p. 385 - 394
(2007/10/02)
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- Benzodioxans by Oxidative Phenol Coupling. Synthesis of Silybin
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Oxidative coupling of substituted catechols with isoeugenol or coniferyl alcohol in the presence of silver oxide affords 2,3-trans-1,4-benzodioxans in good yield.The reaction is highly regioselective when the catechol bears an alkyl substituent, much less
- Merlini, Lucio,Zanarotti, Antonio,Pelter, Andrew,Rochefort, Malcolm P.,Haensel, Rudolf
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p. 775 - 778
(2007/10/02)
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