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Preparation of silybin lipophilic derivatives and evaluation of their biological activities

The bioavailability and therapeutic efficacy of silybin is rather limited by its very low solubility in water (430 mg/L). A number of silybin water-soluble semisynthetic derivatives were prepared [], however, an increase in their water-solubility usually led to an impairment of their antioxidant (antiradical) activity in comparison with silybin [4].

On the contrary, non-covalent complex of silybin with phosphatidyl choline – (Silipide, IdB 1016, Indena, IT) [,6], possessed better bioavailability and higher antioxidant activities [7,8] than silybin [9,10]. Moreover, Silipide also exhibits promising anticancer activities [11].

Lipophilization of silybin possibly improves its membrane-stabilizing function – one of the basic molecular mechanisms of silybin activity [,13]. An improvement of the antioxidant activity in heterogeneous systems by lipophilization of the hydrophilic antioxidant has previously been observed: the antioxidant efficiency of retinyl ascorbate [14] as well as ferulates, dihydroferulates, caffeates, dihydrocaffeates and gallates were generally better antioxidants than the parent acids [15–17].

Scheme 1. Reagents and conditions

Table 1. Antioxidant anti-influenza virus A/PR8/34/ (H1N1) activity of silybin and its fatty acid esters

Compound Antioxidant activity Antiviral activity
LPX (a) EC50 (b) (µmol/L)
IC50 (μmol/L) ND
Silybin (1) 58.1 14
7-O-Butanoylsilybin (2a) 100.6 6
7-O-Octanoylsilybin (2b) 116.7 6
7-O-Dodecanoylsilybin (2c) 44.7 ND (c)
7-O-Palmitoylsilybin (2d) 28.9 24
23-O-Butanoylsilybin (3a) 91.7 18
23-O-Octanoylsilybin (3b) 61.1 3
23-O-Dodecanoylsilybin (3c) 50.5 3
23-O-Palmitoylsilybin (3d) 51.9

Conclusion

Two selective acylation methods for silybin esterification with long-chain fatty acids were developed, yielding a series of silybin 7-O- and 23-O-acyl-derivatives of varying acyl chain lengths. These compounds were tested for their (inhibition of lipid peroxidation and DPPH-scavenging) and anti-influenza virus activities. The acyl chain length is an important prerequisite for both biological activities, as they improved with increasing length of the acyl moiety [].

Collaboration

Financial support

This work was supported by grant KJB400200701 from the Grant Agency of the Academy of Sciences of Czech Republic and by institutional research concept AV0Z50200510 and grants OC08049, LC06010 and MSM6198959216 from the Ministry of Education, Youth and Sports of the Czech Republic.

References

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Institute of Microbiology - Czech Academy of Sciences