title: Synthesis, biological evaluation and 3D-QSAR studies of new chalcone derivatives as inhibitors of human P-glycoprotein.
abstract: P-glycoprotein (P-gp) is an ATP-dependent multidrug resistance efflux transporter that plays an important role in anticancer drug resistance and in pharmacokinetics of medicines. Despite a large number of structurally and functionally diverse compounds, also flavonoids and chalcones have been reported as inhibitors of P-gp. The latter share some similarity with the well studied class of propafenones, but do not contain a basic nitrogen atom. Furthermore, due to their rigidity, they are suitable candidates for 3D-QSAR studies. In this study, a set of 22 new chalcone derivatives were synthesized and evaluated in a daunomycin efflux inhibition assay using the CCRF.CEM.VCR1000 cell line. The compound 10 showed the highest activity (IC50=42nM), which is one order of magnitude higher than the activity for an equilipohillic propafenone analogue. 2D- and 3D-QSAR studies indicate the importance of H-bond acceptors, methoxy groups, hydrophobic groups as well as the number of rotatable bonds as pharmacophoric features influencing P-gp inhibitory activity.
authors.affiliation: Institute of Medical Chemistry, Medical University Vienna, Waehringer Strasse 10, 1090 Vienna, Austria; Abdul Wali Khan University Mardan, Malakand Mardan Rd, Mardan, Pakistan.
authors.forename: Zahida
authors.initials: Z
authors.lastname: Parveen
authors.affiliation: University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Gerda
authors.initials: G
authors.lastname: Brunhofer
authors.affiliation: University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Ishrat
authors.initials: I
authors.lastname: Jabeen
authors.affiliation: University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.affiliation: Institute of Medical Chemistry, Medical University Vienna, Waehringer Strasse 10, 1090 Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Chiba
authors.affiliation: University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090 Vienna, Austria. Electronic address: gerhard.f.ecker@univie.ac.at.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D002599:Chalcone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002599:Chalcone
keywords: ABCB1; Chalcones; GRIND; MDR; P-glycoprotein