Synthesis of novel (−)-epicatechin derivatives as potential endothelial GPER agonists: Evaluation of biological effects

Viviana Sarmiento, Israel Ramirez-Sanchez, Aldo Moreno-Ulloa, Diego Romero-Perez, Daniel Chávez, Miguel Ortiz, Nayelli Najera, Jose Correa-Basurto, Francisco Villarreal, Guillermo Ceballos

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

© 2018 Elsevier Ltd To potentially identify proteins that interact (i.e. bind) and may contribute to mediate (−)-epicatechin (Epi) responses in endothelial cells we implemented the following strategy: 1) synthesis of novel Epi derivatives amenable to affinity column use, 2) in silico molecular docking studies of the novel derivatives on G protein-coupled estrogen receptor (GPER), 3) biological assessment of the derivatives on NO production, 4) implementation of an immobilized Epi derivative affinity column and, 5) affinity column based isolation of Epi interacting proteins from endothelial cell protein extracts. For these purposes, the Epi phenol and C3 hydroxyl groups were chemically modified with propargyl or mesyl groups. Docking studies of the novel Epi derivatives on GPER conformers at 14 ns and 70 ns demostrated favorable thermodynamic interactions reaching the binding site. Cultures of bovine coronary artery endothelial cells (BCAEC) treated with Epi derivatives stimulated NO production via Ser1179 phosphorylation of eNOS, effects that were attenuated by the use of the GPER blocker, G15. Epi derivative affinity columns yielded multiple proteins from BCAEC. Proteins were electrophoretically separated and inmmunoblotting analysis revealed GPER as an Epi derivative binding protein. Altogether, these results validate the proposed strategy to potentially isolate and identify novel Epi receptors that may account for its biological activity.
Original languageAmerican English
Pages (from-to)658-663
Number of pages591
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StatePublished - 15 Feb 2018

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