title: Novel dihydro-beta-agarofuran sesquiterpenes as potent modulators of human P-glycoprotein dependent multidrug resistance.
abstract: P-Glycoprotein (Pgp) overexpression is one factor contributing to multidrug resistance (MDR) in cancer cells and represents one drawback in the treatment of cancer. In an attempt to find more specific and less toxic anticancer MDR-reversal agents, we report herein the isolation, structure elucidation and biological activity of nine new (, and ) and seven known (, and ) dihydro-beta-agarofuran sesquiterpenes from the leaves of Celastrus vulcanicola. Their stereostructures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques, CD studies and biogenetic means. All the compounds were assayed on human MDR1-transfected NIH-3T3 cells, in order to determine their ability to reverse the MDR phenotype due to Pgp overexpression. Six compounds from these series (, , , , and ) showed an effectiveness that was similar to (or higher than) the classical Pgp reversal agent verapamil for the reversal of resistance to daunomycin and vinblastine. The structure-activity relationships are discussed.
authors.affiliation: Departamento de Bioquímica y Contaminación Ambiental, Facultad de Quiímica y Farmacia, Universidad de El Salvador, Final 25 Avenida Norte, El Salvador.
authors.forename: David
authors.initials: D
authors.lastname: Torres-Romero
authors.forename: Francisco
authors.initials: F
authors.lastname: Muñoz-Martínez
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Jiménez
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.forename: Isabel L
authors.initials: IL
authors.lastname: Bazzocchi
mesh_terms: D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents; D031247:Celastrus / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005663:Furans; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D018515:Plant Leaves / Q000737:chemistry; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005663:Furans; D012717:Sesquiterpenes