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Restoration of Chemosensitivity in P-Glycoprotein-Dependent Multidrug-Resistant Cells by Dihydro-β-agarofuran Sesquiterpenes from Celastrus vulcanicola
- Callies, Oliver, Sánchez-Cañete, María P., Gamarro, Francisco, Jiménez, Ignacio
A., Castanys, Santiago, Bazzocchi, Isabel L.
- Journal of natural products 2015 v.78 no.4 pp. 736-745
- Celastrus, P-glycoproteins, anticarcinogenic activity, circular dichroism spectroscopy, drug therapy, humans, leaves, mass spectrometry, mice, multiple drug resistance, neoplasms, nuclear magnetic resonance spectroscopy, sesquiterpenoids, verapamil, vinblastine
- Multidrug resistance (MDR) caused by the overexpression of ABC drug transporters is a major obstacle in clinical cancer chemotherapy and underlines the urgent need for the development of new, potent, and safe reversal agents. Toward this goal, reported herein are the structure elucidation and biological activity of nine new (1–9) and four known (10–13) dihydro-β-agarofuran sesquiterpenes, isolated from the leaves of Celastrus vulcanicola, as reversers of MDR mediated by human P-glycoprotein expression. The structures of these compounds were elucidated by extensive NMR spectroscopic and mass spectrometric analysis, and their absolute configurations were determined by circular dichroism studies, chemical correlations (1a, 8a, and 8b), and biogenetic means. Four compounds from this series were discovered as potent chemosensitizers for MDR1-G185 NIH-3T3 murine cells (3, 4, 6, and 7), showing higher efficacies than the classical P-glycoprotein inhibitor verapamil, a first-generation chemosensitizer, when reversing resistance to daunomycin and vinblastine at the lowest concentration tested of 1 μM.