title: Discovery of substituted 1,4-dihydroquinolines as novel class of ABCB1 modulators.
abstract: Transmembrane efflux pumps are one main cause for multidrug resistance (mdr) of cancer. One hopeful approach to combate the mdr has been the development of inhibitors of the efflux pump activity. A novel class of small-molecule inhibitors of the most important efflux pump ABCB1 (P-glycoprotein) has been discovered. Inhibitory activities are discussed in relation to substituent effects. Most active compounds have been evaluated in first bioanalytical studies to reverse the mdr of an anticancer drug. Cellular toxicity and ABCB1 substrate properties of the compounds were investigated. A cellular induction of relevant efflux pump protein expressions was not observed under inhibitor application, so that our compounds are perspective candidates for further preclinical studies.
authors.affiliation: Institute of Pharmacy, Martin Luther University, 06120 Halle, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Hemmer
authors.affiliation: Institute of Pharmacy, Martin Luther University, 06120 Halle, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Krawczyk
authors.affiliation: Institute of Pharmacy, Martin Luther University, 06120 Halle, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Simon
authors.affiliation: Institute of Pathology, University Hospital Charité, 10117 Berlin, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Lage
authors.affiliation: Institute of Pharmacy, Martin Luther University, 06120 Halle, Germany. Electronic address: andreas.hilgeroth@pharmazie.uni-halle.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hilgeroth
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D006801:Humans; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C544515:1,4-dihydroquinoline; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D011804:Quinolines
keywords: Drug discovery; Efflux pump inhibition; Inhibitor; Multidrug resistance (MDR); Structure–activity data