title: Overcoming human P-glycoprotein-dependent multidrug resistance with novel dihydro-β-agarofuran sesquiterpenes.
abstract: Sixteen (1-16) dihydro-β-agarofuran sesquiterpenes were isolated from the fruits of Maytenus jelskii and evaluated against mammalian cells with a multidrug resistance phenotype mediated by the overexpression of the human P-glycoprotein. Their stereostructures have been elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques, CD studies, chemical correlations and biogenetic means. Eight compounds from this series were discovered as potent chemosensitizers (1, 2, 4, 6, 8, 9, 11 and 14), showing similar effectiveness to or higher than the classical P-glycoprotein reversal agent verapamil, a first-generation chemosensitizer, when reversing resistance to daunomycin and vinblastine. Detailed structure-activity relationships revealed that aromatic substituents at the 6 and 9-position of the sesquiterpene scaffold were able to modulate the intensity of inhibition.
authors.affiliation: Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain.
authors.forename: Nayra R
authors.initials: NR
authors.lastname: Perestelo
authors.forename: María P
authors.initials: MP
authors.lastname: Sánchez-Cañete
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Jiménez
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Isabel L
authors.initials: IL
authors.lastname: Bazzocchi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005638:Fruit / Q000737:chemistry; D006801:Humans; D029755:Maytenus / Q000737:chemistry*; D008958:Models, Molecular; D012717:Sesquiterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015854:Up-Regulation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012717:Sesquiterpenes