Chemically engineered extracts of St John's wort as sources of polyprenylated acylphloroglucinols to prevent endothelial dysfunction

Graft rejection remains a serious concern in transplantation therapy. As endothelial dysfunction plays a prominent role in transplant rejection, finding new ways to prevent this process is a huge challenge. Recently, Rouger et al. evidenced the significant anti-inflammatory and immunomodulatory properties of polyphenolic compounds [e.g. polyprenylated acylphloroglucinols (PPAPs)] from tropical Calophyllaceae and Clusiaceae plants on endothelial cells [1,2]. Plants from the Hypericaceae family biosynthesize similar natural products and some species such as St John's wort (Hypericum perforatum) are cultivated thus available in large amounts. To preserve biodiversity and valorize medicinal plants growing in the Loire Valley, the HYPROTEC project attempts to I/improve access to a library of original and bioactive polyphenols by chemical modifications of H. perforatum extracts [3]; II/evaluate their potential for preventing endothelial dysfunction. Preliminary results evaluating the inhibition of VCAM-1 expression on endothelial cells [1] by H. perforatum roots and flowering tops extracts and their fractions, combined with a dereplication study, suggested that hyperforin 1 and its oxidized forms could prevent inflammation and, consequently, endothelial dysfunction. The present work thus describes the synthesis and purification of a small library of PPAPs derivatives from the cyclohexanic flowering tops extract of H. perforatum (1: 3.0% m/m) that was subjected to various oxidation reactions using so-called “green processes”. Data were eventually supplemented by results from biological evaluation. In particular, hyperforin-DCHA 1 (10µM) strongly inhibited TNF-induced VCAM-1 (58%), ICAM-1 (34%) and E-selectin (54%) expression in comparison with the reference compound PDTC (200µM).

Acknowledgements: This work was supported by a grant funded by the Region Pays de la Loire (HYPROTEC project).

Keywords: Endothelial dysfunction, Hypericum perforatum, hyperforin, immunosuppression, inflammation.

References:

[1] Rouger C, Derbré S, Charreau B, Pabois A, Cauchy T, Litaudon M, Awang K, Richomme P. Lepidotol A from Mesua lepidota inhibits inflammatory and immune mediators in human endothelial cells. J Nat Prod 2015; 78: 2187 – 2197.

[2] Rouger C, Pagie S, Derbré S, Ray A-ML, Richomme P, Charreau B. Anti-inflammatory and immunosuppressive effects of polyphenols from Clusiaceae and Calophyllaceae on endothelial cells. PloS One: submitted

[3] Ayelen Ramallo I, Salazar MO, Mendez L, Furlan RLE. Chemically engineered extracts: Source of bioactive compounds. Acc Chem Res 2011; 44: 241 – 250