Design, Semisynthesis, and Estrogenic Activity of Lignan Derivatives from Natural Dibenzylbutyrolactones

  1. López-Rojas, Priscila
  2. Amesty, Ángel
  3. Guerra-Rodríguez, Miguel
  4. Brito-Casillas, Yeray
  5. Guerra, Borja
  6. Fernández-Pérez, Leandro
  7. Estévez-Braun, Ana
  1. 1 Universidad de La Laguna
    info

    Universidad de La Laguna

    San Cristobal de La Laguna, España

    ROR https://ror.org/01r9z8p25

Revista:
Pharmaceuticals

ISSN: 1424-8247

Any de publicació: 2022

Volum: 15

Número: 5

Pàgines: 585

Tipus: Article

DOI: 10.3390/PH15050585 GOOGLE SCHOLAR lock_openAccés obert editor

Altres publicacions en: Pharmaceuticals

Resum

Based on molecular docking studies on the ERα, a series of lignan derivatives (3–16) were designed and semisynthesized from the natural dibenzylbutyrolactones bursehernin (1) and matairesinol dimethyl ether (2). To examine their estrogenic and antiestrogenic potencies, the effects of these compounds on estrogen receptor element (ERE)-driven reporter gene expression and viability in human ER+ breast cancer cells were evaluated. Lignan compounds induced ERE-driven reporter gene expression with very low potency as compared with the pure agonist E2. However, coincubation of 5 μM of lignan derivatives 1, 3, 4, 7, 8, 9, 11, 13, and 14 with increasing concentrations of E2 (from 0.01 pM to 1 nM) reduced both the potency and efficacy of pure agonists. The binding to the rhERα-LBD was validated by TR-FRET competitive binding assay and lignans bound to the rhERα with IC50 values from 0.16 μM (compound 14) to 6 μM (compound 4). Induced fit docking (IFD) and molecular dynamics (MD) simulations for compound 14 were carried out to further investigate the binding mode interactions. Finally, the in silico ADME predictions indicated that the most potent lignan derivatives exhibited good drug-likeness

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