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Discovery of Tricyclic Clerodane Diterpenes as Sarco/Endoplasmic Reticulum Ca2+-ATPase Inhibitors and Structure−Activity Relationships

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Date
2015-05-20
Author
De Ford, Christian
Calderón Castro, Carlos
Sehgal, Pankaj
Fedosova, Natalya U.
Murillo Masís, Renato
Olesen, Claus
Nissen, Poul
Møller, Jesper V.
Merfort, Irmgard
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Abstract
Tricyclic clerodane diterpenes (TCDs) are natural compounds that often show potent cytotoxicity for cancer cells, but their mode of action remains elusive. A computationally based similarity search (CDRUG), combined with principal component analysis (ChemGPS-NP) and docking calculations (GOLD 5.2), suggested TCDs to be inhibitors of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump, which is also the target of the sesquiterpene lactone thapsigargin. Biochemical studies were performed with 11 TCDs on purified rabbit skeletal muscle sarcoplasmic reticulum membranes, which are highly enriched with the SERCA1a isoform. Casearborin D (2) exhibited the highest affinity, with a KD value of 2 μM and giving rise to complete inhibition of SERCA1a activity. Structure–activity relationships revealed that functionalization of two acyl side chains (R1 and R4) and the hydrophobicity imparted by the aliphatic chain at C-9, as well as a C-3,C-4 double bond, play crucial roles for inhibitory activity. Docking studies also suggested that hydrophobic interactions in the binding site, especially with Phe256 and Phe834, may be important for a strong inhibitory activity of the TCDs. In conclusion, a novel class of SERCA inhibitory compounds is presented.
URI
http://hdl.handle.net/10669/75180
External link to the item
10.1021/acs.jnatprod.5b00062
https://pubs.acs.org/doi/10.1021/acs.jnatprod.5b00062
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  • Repositorios universitarios

  • Repositorio del SIBDI-UCR
  • Biblioteca Digital del CIICLA
  • Repositorio Documental Rafael Obregón Loría (CIHAC)
  • Biblioteca Digital Carlos Melendez (CIHAC)
  • Repositorio de Fotografías
  • Colección de videos de UPA-VAS
  • Sitios recomendados

  • Buscador regional de LA Referencia
  • Buscador del Open ROAR
  • Scientific Electronic Library Online (SciELO)
  • Directory of Open Access Journals (DOAJ)
  • Redalyc
  • Redes sociales

  • facebook.com/repositoriokerwa
  • @Ciencia_UCR
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Contact Us | Send Feedback
Repositorio Institucional de la Universidad de Costa Rica. Algunos derechos reservados. Este repositorio funciona con DSpace.
Universidad de Costa Rica