title: Restoration of Chemosensitivity in P-Glycoprotein-Dependent Multidrug-Resistant Cells by Dihydro-β-agarofuran Sesquiterpenes from Celastrus vulcanicola.
abstract: 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.
authors.affiliation: †Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica and Instituto Canario de Investigación del Cáncer, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain.
authors.forename: Oliver
authors.initials: O
authors.lastname: Callies
authors.affiliation: ‡Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Parque Tecnológico de la Salud, Avenida del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: María P
authors.initials: MP
authors.lastname: Sánchez-Cañete
authors.affiliation: ‡Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Parque Tecnológico de la Salud, Avenida del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.affiliation: †Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica and Instituto Canario de Investigación del Cáncer, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain.
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Jiménez
authors.affiliation: ‡Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Parque Tecnológico de la Salud, Avenida del Conocimiento s/n, 18016 Granada, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.affiliation: †Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica and Instituto Canario de Investigación del Cáncer, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain.
authors.forename: Isabel L
authors.initials: IL
authors.lastname: Bazzocchi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D031247:Celastrus / Q000737:chemistry*; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D003630:Daunorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004544:El Salvador; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D019906:Nuclear Magnetic Resonance, Biomolecular; D018515:Plant Leaves / Q000737:chemistry; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D012717:Sesquiterpenes; C079978:dihydroagarofuran; D014747:Vinblastine; D003630:Daunorubicin