Synthesis and biological studies of "Polycerasoidol" and "trans-d-Tocotrienolic acid" derivatives as PPARa and/or PPAR? agonists.

Fecha de publicación: 01/01/2022 Fecha Ahead of Print: 27/11/2021

Autores de INCLIVA

• 

  Laura Vila Dasí

  Autor

• 

  Nuria Cabedo Escrig

  Autor

• Carlos Villarroel Vicente

  Autor

• 

  Maria Jesus Sanz Ferrando

  Autor

• 

  Diego Cortes Martinez

  Autor

Participantes ajenos a INCLIVA

• Garcia, Ainhoa
• Bernabeu, Alvaro
• Hennuyer, Nathalie
• Staels, Bart
• Franck, Xavier
• Figadere, Bruno

Grupos y Plataformas de I+D+i

• Grupo de Investigación en Inflamación

  

  Leading Researcher

  Maria Jesus Sanz Ferrando

• Unidad de Cromatografía Líquida Analítica

  

  Responsable de Plataforma

  Nuria Cabedo Escrig

Abstract

2-Prenylated benzopyrans represent a class of natural and synthetic compounds showing a wide range of significant activities. Polycerasoidol is a natural prenylated benzopyran isolated from the stem bark of Polyalthia cerasoides (Annonaceae) that exhibits dual PPARa/? agonism and an anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium. Herein, we report the synthesis of three new series of prenylated benzopyrans containing one (series 1), two (series 2, "polycerasoidol" analogs) and three (series 3, "trans-d-tocotrienolic acid" analogs) isoprenoid units in the hydrocarbon side chain at the 2-position of the chroman-6-ol (6-hydroxy-dihydrobenzopyran) scaffold. Isoprenoid moieties were introduced through a Grignard reaction sequence, followed by Johnson-Claisen rearrangement and subsequent Wittig olefination. hPPAR transactivation activity and the structure activity relationships (SAR) of eleven novel synthesized 2-prenylated benzopyrans were explored. PPAR transactivation activity demonstrated that the seven-carbon side chain analogs (series 1) displayed selectivity for hPPARa, while the nine-carbon side chain analogs (polycerasoidol analogs, series 2) did so for hPPAR?. The side chain elongation to 11 or 13 carbons (series 3) resulted in weak dual PPARa/? activation. Therefore, 2-prenylated benzopyrans of seven- and nine-carbon side chain (polycerasoidol analogs) are good lead compounds for developing useful candidates to prevent cardiovascular diseases associated with metabolic disorders.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Keywords

• 2-Prenylated benzopyrans; Grignard/Johnson-Claisen rearrangement; Polycerasoidol analogs; Tocotrienol analogs; Wittig olefination; hPPAR activity