Evaluation of biological properties of 3,3′,4,4′-benzophenonetetracarboxylic dianhydride derivatives and their ability to inhibit hexokinase activity

• Published in: Bioorganic & medicinal chemistry letters 2017-02, Vol.27 (3), p.427-431
• Main Authors: Kochel, Krzysztof, Tomczyk, Mateusz D., Simões, Rui F., Frączek, Tomasz, Soboń, Adrian, Oliveira, Paulo J., Walczak, Krzysztof Z., Koceva-Chyła, Aneta
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Benzophenones - chemistry; Binding Sites; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Cell Line, Tumor; Cytotoxicity; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hexokinase - antagonists & inhibitors; Hexokinase - metabolism; Hexokinase II; Humans; Kinetics; Membrane Potential, Mitochondrial - drug effects; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial membrane potential; Molecular Docking Simulation; P19 cells; Protein Structure, Tertiary; Reactive Oxygen Species - metabolism; Virtual High-Throughput Screening
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.12.055

[Display omitted] 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.