title: The 5-aromatic hydantoin-3-acetate derivatives as inhibitors of the tumour multidrug resistance efflux pump P-glycoprotein (ABCB1): Synthesis, crystallographic and biological studies.
abstract: A series of arylpiperazine derivatives of hydantoin-3-acetate, including previously obtained 5,5-diphenylhydantoin (1-7) and new-synthesized spirofluorene-hydantoin derivatives (8-12), were investigated in the search for new inhibitors of the tumour multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells. Synthesis of new compounds (8-12) was performed. Crystal structures of two compounds (8 and 11) were determined by X-ray diffraction method. The conformations of the investigated molecules (8 and 11) in the crystalline samples are different. The bent conformation seems to be more favourable for biological activity than the extended one. The efflux pump inhibitory properties of the compounds 1-12 were evaluated in the fluorescence uptake assay using rhodamine 123 dye in mouse T-lymphoma model in vitro. Their cytotoxic action was examined, too. All compounds with methyl acetate moiety displayed high potency to inhibit the MDR efflux pump. The most active compound, methyl 2-(1-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-5,5-diphenylhydantoin-3-yl)acetate (5), tested at 1/10 of verapamil concentration displayed the 9-fold higher P-gp inhibitory action.
authors.affiliation: Department of Chemistry, Institute of Biology, Pedagogical University of Cracow, ul. Podchorążych 2, 30-084 Kraków, Poland. Electronic address: zeslawsk@up.krakow.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Żesławska
authors.affiliation: Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Annamária
authors.initials: A
authors.lastname: Kincses
authors.affiliation: Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Spengler
authors.affiliation: Faculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Kraków, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Nitek
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Wyrzuc
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland. Electronic address: j.handzlik@uj.edu.pl.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Handzlik
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000085:Acetates / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D006827:Hydantoins / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000085:Acetates; D006827:Hydantoins
keywords: Crystal structure; Derivatives of hydantoin; Multidrug resistance inhibitors; P-glycoprotein (ABCB1)