Terpenoids from Euphorbia pedroi as Multidrug-Resistance Reversers

Ricardo J. Ferreira, Annamária Kincses, Márió Gajdács, G. Spengler, Daniel J.V.A. Dos Santos, J. Molnár, Maria José U. Ferreira

Research output: Contribution to journalArticle

Abstract

The phytochemical study of Euphorbia pedroi led to the isolation of a new tetracyclic triterpenoid with an unusual spiro scaffold, spiropedroxodiol (1), along with seven known terpenoids (2-8). Aiming at obtaining compounds with improved multidrug-resistance (MDR) reversal activity, compound 8, an ent-abietane diterpene, was derivatized by introducing nitrogen-containing and aromatic moieties, yielding compounds 9-14. The structures of compounds were characterized by detailed spectroscopic analysis, including 2D NMR experiments (COSY, HMQC/HSQC, HMBC, and NOESY). Compounds 1-14 were evaluated for their MDR-reversing activity on human ABCB1 gene transfected mouse lymphoma cells (L5178Y-MDR) through a combination of functional and chemosensitivity assays. The natural compounds 1-8 were further evaluated on resistant human colon adenocarcinoma cells (Colo320), and, additionally, their cytotoxicity was assessed on noncancerous mouse (NIH/3T3) and human (MRC-5) embryonic fibroblast cell lines. While spiropedroxodiol (1) was found to be a very strong MDR reversal agent in both L5178Y-MDR and Colo320 cells, the chemical modifications of helioscopinolide E (8) at C-3 positively contributed to increase the MDR reversal activity of compounds 10, 12, and 13. Furthermore, in combination assays, compounds 1 and 7-14 enhanced synergistically the cytotoxicity of doxorubicin. Finally, by means of molecular docking, the key residues and binding modes by which compounds 1-14 may interact with a murine P-glycoprotein model were identified, allowing additional insights on the efflux modulation mechanism of these compounds.

Original languageEnglish
JournalJournal of Natural Products
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Euphorbia
Terpenes
Multiple Drug Resistance
Cytotoxicity
Assays
Abietane Diterpenes
Spectroscopic analysis
Chemical modification
Phytochemicals
P-Glycoprotein
Fibroblasts
Scaffolds
Doxorubicin
Nitrogen
Genes
Cells
Nuclear magnetic resonance
Modulation
Experiments
Human Activities

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

Cite this

Ferreira, R. J., Kincses, A., Gajdács, M., Spengler, G., Dos Santos, D. J. V. A., Molnár, J., & Ferreira, M. J. U. (Accepted/In press). Terpenoids from Euphorbia pedroi as Multidrug-Resistance Reversers. Journal of Natural Products. https://doi.org/10.1021/acs.jnatprod.8b00326

Terpenoids from Euphorbia pedroi as Multidrug-Resistance Reversers. / Ferreira, Ricardo J.; Kincses, Annamária; Gajdács, Márió; Spengler, G.; Dos Santos, Daniel J.V.A.; Molnár, J.; Ferreira, Maria José U.

In: Journal of Natural Products, 01.01.2018.

Research output: Contribution to journalArticle

Ferreira, Ricardo J. ; Kincses, Annamária ; Gajdács, Márió ; Spengler, G. ; Dos Santos, Daniel J.V.A. ; Molnár, J. ; Ferreira, Maria José U. / Terpenoids from Euphorbia pedroi as Multidrug-Resistance Reversers. In: Journal of Natural Products. 2018.
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