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Terpenoids from Euphorbia pedroi as Multidrug-Resistance Reversers
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics. Univ Lisbon, Fac Pharm, iMed ULisboa Res Inst Med, Ave Prof Gama Pinto, P-1649003 Lisbon, Portugal.ORCID iD: 0000-0003-2590-8229
Univ Szeged, Fac Med, Dept Med Microbiol & Immunobiol, Dom Ter 10, H-6720 Szeged, Hungary.
Univ Szeged, Fac Med, Dept Med Microbiol & Immunobiol, Dom Ter 10, H-6720 Szeged, Hungary.
Univ Szeged, Fac Med, Dept Med Microbiol & Immunobiol, Dom Ter 10, H-6720 Szeged, Hungary.
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2018 (English)In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 81, no 9, p. 2032-2040Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2018. Vol. 81, no 9, p. 2032-2040
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Pharmaceutical Sciences
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URN: urn:nbn:se:uu:diva-368123DOI: 10.1021/acs.jnatprod.8b00326ISI: 000446276600015PubMedID: 30199257OAI: oai:DiVA.org:uu-368123DiVA, id: diva2:1267605
Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2018-12-03Bibliographically approved

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