np500903a_si_001.pdf (1.92 MB)
Restoration of Chemosensitivity in P‑Glycoprotein-Dependent Multidrug-Resistant Cells by Dihydro-β-agarofuran Sesquiterpenes from Celastrus vulcanicola
journal contribution
posted on 2015-04-24, 00:00 authored by Oliver Callies, María P. Sánchez-Cañete, Francisco Gamarro, Ignacio
A. Jiménez, Santiago Castanys, Isabel L. BazzocchiMultidrug 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.