Chirality Matters: Biological Activity of Optically Pure Silybin and Its Congeners

Abstract

This review focuses on the specific biological effects of optically pure silymarin flavo-nolignans, mainly silybins A and B, isosilybins A and B, silychristins A and B, and their 2,3-dehydro derivatives. The chirality of these flavonolignans is also discussed in terms of their analysis, preparative separation and chemical reactions. We demonstrated the specific activities of the respective diastereomers of flavonolignans and also the enantiomers of their 2,3-dehydro derivatives in the 3D anisotropic systems typically represented by biological systems. In vivo, silymarin flavonolignans do not act as redox antioxidants, but they play a role as specific ligands of biological targets, according to the “lock-and-key” concept. Estrogenic, antidiabetic, anticancer, antiviral, and antiparasitic effects have been demonstrated in optically pure flavonolignans. Potential application of pure flavonolignans has also been shown in cardiovascular and neurological diseases. Inhibition of drug-metabolizing enzymes and modulation of multidrug resistance activity by these compounds are discussed in detail. The future of “silymarin applications” lies in the use of optically pure components that can be applied directly or used as valuable lead structures, and in the exploration of their true molecular effects.

Silybin and its congeners: from traditional medicine to molecular effects

“…Molecular modeling reveals fundamental structural and steric differences between, e.g., silybin A and B, with silybin A having a curved "banana-shaped" structure while silybin B is more planar. 7 The avonolignans of silymarin suffer from poor aqueous solubility, with silychristin being the most soluble, and therefore poor bioavailability. Numerous in vitro studies have used concentrations that are very difficult or impossible to achieve at the bedside.…”

“…, silybin A and B, with silybin A having a curved “banana-shaped” structure while silybin B is more planar. 7…”

“…The synonym silibinin has thus acquired a different meaning, which is somewhat confusing for the general user of this substance. 7 This problem has another aspect: natural silybin is not an equimolar mixture of silybin A and B, but is dominated by silybin B in a ratio of up to 7 : 3. 8 This ratio depends on the source and processing of silymarin and can also be altered by crystallization.…”

Phosphodiester Silybin Dimers Powerful Radical Scavengers: A Antiproliferative Activity on Different Cancer Cell Lines

“…These studies have mostly disregarded this aspect because of the difficulty separating, on a preparative scale, two diastereoisomers ( 1a and 1b ). In the 2021 a very in-depth study by Kren et al [ 13 ] on the central role of stereochemistry in the pharmacological properties of silybin, highlights how it is necessary to continue studying these flavonolignans, together with the other silymarin flavonolignans, never neglecting their optical purity.…”

Continuous Diastereomeric Kinetic Resolution—Silybins A and B

“…Indeed, Biological structures, such as typical 3D-systems, require stereochemically defined ligands and, therefore, results generated from mixtures have no-or very limited-validity. Indeed, there are significant differences between silybin diastereomers in terms of various biological activities [3], as well as in bioavailability and metabolism [3,7]. Therefore, a single compound is required for biological studies instead of the natural mixture, especially in cases where the composition varies significantly [8][9][10].…”