2. Academic Validation
  3. Regioselective synthesis of 7-O-esters of the flavonolignan silibinin and SARs lead to compounds with overadditive neuroprotective effects

Regioselective synthesis of 7-O-esters of the flavonolignan silibinin and SARs lead to compounds with overadditive neuroprotective effects

  • Eur J Med Chem. 2018 Feb 25:146:93-107. doi: 10.1016/j.ejmech.2018.01.036.
Simon Schramm 1,  Guozheng Huang 1,  Sandra Gunesch 1,  Florian Lang 2,  Judit Roa 3,  Petra Högger 2,  Raimon Sabaté 3,  Pamela Maher 4,  Michael Decker 5
Affiliations

Affiliations

  • 1 Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany.
  • 2 Klinische Pharmazie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany.
  • 3 Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, School of Pharmacy, and Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, E-08028 Barcelona, Spain.
  • 4 The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
  • 5 Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany. Electronic address: michael.decker@uni-wuerzburg.de.
PMID: 29407994 DOI: 10.1016/j.ejmech.2018.01.036
Abstract

A series of neuroprotective hybrid compounds was synthesized by conjugation of the flavonolignan silibinin with natural phenolic acids, such as ferulic, cinnamic and syringic acid. Selective 7-O-esterfication without protection groups was achieved by applying the respective acyl chlorides. Sixteen compounds were obtained and SARs were established by evaluating antioxidative properties in the physicochemical FRAP assay, as well as in a cell-based neuroprotection assay using murine hippocampal HT-22 cells. Despite weak activities in the FRAP assay, esters of the α,β-unsaturated acids showed pronounced overadditive effects at low concentrations greatly exceeding the effects of equimolar mixtures of silibinin and the respective acids in the neuroprotection assay. Cinnamic and ferulic acid esters (5a and 6a) also showed overadditive effects regarding inhibition of microglial activation, PC12 cell differentiation, in vitro ischemia as well as anti-aggregating abilities against Aβ42 peptide and τ protein. Remarkably, the esters of ferulic acid with silybin A and silybin B (11a and 11b) showed a moderate but significant difference in both neuroprotection and in their anti-aggregating capacities. The results demonstrate that non-toxic natural Antioxidants can be regioselectively connected as esters with medium-term stability exhibiting very pronounced overadditive effects in a portfolio of biological assays.

Keywords

Esterification; FRAP assay; HT-22 cells; Silybin; Stability.

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