title: Evaluation of biological properties of 3,3',4,4'-benzophenonetetracarboxylic dianhydride derivatives and their ability to inhibit hexokinase activity.
abstract: This investigation has explored the properties of 3,3',4,4'-benzophenonetetracarboxylic dianhydride (BDTA) derivatives with regard to their being prospective inhibitors of hexokinase II (HKII). A pluripotent embryonic carcinoma cell line P19 (ECC), was used as the biological target for newly generated potential inhibitors of HKII. The results obtained from Virtual High-Throughput Screening (VHTS), molecular modeling and biological activity studies showed BDTA to be a promising leading structure with a good binding score and simplest functionalization. The inhibitory effect was measured after 72h incubation. Of selected BDTA derivatives, the most active was compound 3b, containing 3-hydroxyphenyl moiety in the para position, being able at 100μM to decrease the mass of differentiated P19dCs cells by 30%, changing both the mitochondrial transmembrane potential and reactive oxygen species level. Under these conditions, only compound 3b had the ability to decrease hexokinase activity in a dose-dependent manner.
authors.affiliation: Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska 141/143, 90-236 Łódź, Poland. Electronic address: kkochel@biol.uni.lodz.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kochel
authors.affiliation: Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland.
authors.forename: Mateusz D
authors.initials: MD
authors.lastname: Tomczyk
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal.
authors.forename: Rui F
authors.initials: RF
authors.lastname: Simões
authors.affiliation: Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Frączek
authors.affiliation: Department of Industrial Microbiology and Biotechnology, Faculty of Biology and Environmental Protection, University of Łódź, Banacha 12/16, 90-237 Łódź, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Soboń
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal.
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Oliveira
authors.affiliation: Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland.
authors.forename: Krzysztof Z
authors.initials: KZ
authors.lastname: Walczak
authors.affiliation: Department of Medical Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska 141/143, 90-236 Łódź, Poland.
authors.forename: Aneta
authors.initials: A
authors.lastname: Koceva-Chyła
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001577:Benzophenones / Q000737:chemistry; D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001577:Benzophenones; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; C047723:benzophenone; D006593:Hexokinase
keywords: Cytotoxicity; Hexokinase II; Mitochondrial membrane potential; P19 cells; Virtual High-Throughput Screening