title: Biological evaluation, structure-activity relationships, and three-dimensional quantitative structure-activity relationship studies of dihydro-beta-agarofuran sesquiterpenes as modulators of P-glycoprotein-dependent multidrug resistance.
abstract: Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, and other important diseases. Here, we report the inhibitory activity of a series of 76 dihydro-beta-agarofuran sesquiterpenes, tested on NIH-3T3 cells expressing the human P-glycoprotein (Pgp) multidrug transporter, to establish quantitative comparisons of their respective abilities to block the drug transport activity. The screening was performed on the basis of the ability of sesquiterpenes to modulate the intracellular accumulation of the classical Pgp substrate daunorubicin. To understand the structural basis for inhibitory activity and guide the design of more potent Pgp inhibitors, we have performed a three-dimensional quantitative structure-activity relationship model using the comparative molecular similarity indices analysis (CoMSIA). The most salient features of these requirements are in the region of the substituents at the C-2, C-3, and C-8 positions, which seem to be critical for determining the overall effectiveness of sesquiterpenes as Pgp inhibitors.
authors.affiliation: Instituto Universitario de Bio-OrgAnica Antonio GonzAlez, Universidad de La Laguna and Instituto Canario de Investigación del CAncer, Avenida Astrofísico Francisco SAnchez, 2, 38206 La Laguna, Tenerife, Spain.
authors.forename: Carolina P
authors.initials: CP
authors.lastname: Reyes
authors.forename: Francisco
authors.initials: F
authors.lastname: Muñoz-Martínez
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Torrecillas
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Mendoza
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.forename: Isabel L
authors.initials: IL
authors.lastname: Bazzocchi
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Núñez
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Mercedes
authors.initials: M
authors.lastname: Campillo
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Jiménez
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D001692:Biological Transport; D029753:Celastraceae / Q000737:chemistry*; D003630:Daunorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005663:Furans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D029755:Maytenus / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D018515:Plant Leaves / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D005663:Furans; D012717:Sesquiterpenes; D003630:Daunorubicin