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.

Keywords: Silybum marianum; chirality; dehydroflavonolignan; diastereomer; flavonoid; flavonolignan; isosilybin; milk thistle; silibinin; silybin; silychristin; silydianin; silymarin.

Figure 1

Major flavonolignans of silymarin.

Figure 2

Structures and numbering styles of stereomers of silybin and 2,3-dehydrosilybin: The structure of silybin A is numbered according to a proprietary numbering system used in most chemical papers and also used in this review; the structure of silybin B is numbered according to IUPAC systematic numbering, and for the structure of 2,3-dehydrosilybin B, there is a quasi-systematic numbering used by some groups in the USA [12,21,22]; in some papers, the α-β numbering can be swapped. Other numbering systems used in the older literature for silybin only are detailed in the Supplementary Materials of the paper by Napolitano et al. [23].

Figure 3

Chiral separation of natural silybin with immobilized lipase B from C. antarctica (Novozym^® 435), TBME—tert-butyl methyl ether. Silybin B and silybin A 23-O-acetate are separated by conventional flash chromatography; while pure silybin B is obtained directly, silybin A is then deacetylated with Novozym^® 435 under hydrolytic conditions [58].

Figure 4

Molecular models of silybin A and silybin B; color code: red—oxygen; grey—carbon; white—hydrogen. Energy minimized structures prepared in program Gaussview https://gaussian.com/gaussview6/ (accessed 20 January 2021).

Figure 5

cis-trans Isomerizations of the optically pure silybins [25]. (A) Silybin A and silybin B isomerizations into respective 2,3-cis-isomers (DMF, dimethylformamide). (B) Silybin B isomerization in EtOAc (TBME, tert-butyl methyl ether). (C) Isomerization of silybin A in EtOAc.

Figure 5

cis-trans Isomerizations of the optically pure silybins [25]. (A) Silybin A and silybin B isomerizations into respective 2,3-cis-isomers (DMF, dimethylformamide). (B) Silybin B isomerization in EtOAc (TBME, tert-butyl methyl ether). (C) Isomerization of silybin A in EtOAc.

Figure 6

Example of hydnocarpin preparation from flavonolignans using Mitsunobu conditions [89].

Figure 7

Laccase catalyzed dimerization of silybin A [92].

Figure 8

Structure of silybin A conjugate with trehalose linked via phosphate diester bond [102].

Figure 9

(A) Plasma concentration-time profile of free (unconjugated) and total silybin A in rats; (B) free and total silybin B after gastric administration of a single dose of 200 mg-kg⁻¹ body weight (mean of three animals, error bars—standard deviation) [84].

Figure 10

Structure of silybin B metabolite 2,4,6-trihydroxy-2-(3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo[1,4]dioxine-6-carbonyl)benzofuran-3-(2H)-one [84].

Figure 11

Structures of minor silymarin components isosilybin C and isosilybin D [53].

Figure 12

Structure of 7-O-galollylsilybin B, a potent antiangiogenic compound [99].