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Preparation of silybin (2,3-dehydrosilybin) derivatives with the inhibitory action on transport proteins (MDR – proteins, P-glycoprotein)

One of the plausible explanations for synergistic effects of silybin and anti-cancer drugs is inhibition of efflux function of dominant multidrug resistance (MDR) transporter P-glycoprotein [].

We have identified effective and relatively non-cytotoxic inhibitors of Pgp derived from 2,3-dehydrosilybin (2) (Fig. 1). Some of them were more effective inhibitors at lower concentrations than a standard Pgp efflux inhibitor cyclosporine A. Another group of 2,3-dehydrosilybin derivatives had also better inhibitory effects on Pgp efflux but a cytotoxicity was comparable with parent 2,3-dehydrosilybin. Structural requirements for improving inhibitory activity and reducing toxicity of 2,3-dehydrosilybin were established. Effect of E-ring substitution as well as an influence of the substituent size at the 7-OH position of A-ring on Pgp-inhibitory activity was evaluated for the first time in this study [].

Figure 1. Structures of the most active inhibitors of Pgp prepared from 2,3-dehydrosilybin (2)

Structures of the most active inhibitors of Pgp prepared from 2,3-dehydrosilybin

Collaboration

Financial support

This work was supported by the Czech Ministry of Education (Research concepts No. MSM 6198959216, MSM 0021620835 and AV0Z50200510) and KONTAKT project No. 7–2006–16.

References

  1. Maitrejean, M.; Comte, G.; Barron, D.; El Kirat, K.; Gwenaelle, C.; Di Pietro, A. Bioorg. Med. Chem. Lett. 2000, 10, 157
  2. Džubák P, Hajdúch M, Gažák R, Svobodová A, Psotová J, Walterová D, Sedmera P, Křen V. New derivatives of silybin and 2,3-dehydrosilybin and their cytotoxic and P-glycoprotein modulatory activity. Bioorg Med Chem 2006;14:3793–3810

Institute of Microbiology - Czech Academy of Sciences