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

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• 作者：Krzysztof Kochel^a ; ^{kkochel@biol.uni.lodz.pl} ; Mateusz D. Tomczyk^b ; Rui F. Sim&otilde ; es^c ; Tomasz Frączek^d ; Adrian Soboń^e ; Paulo J. Oliveira^c ; Krzysztof Z. Walczak^b ; Aneta Koceva-Chyła^a
• 关键词：Virtual High-Throughput Screening ; Hexokinase II ; P19 cells ; Cytotoxicity ; Mitochondrial membrane potential
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：427-431
• 全文大小：873 K
• 卷排序：27

文摘

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 72 h incubation. Of selected BDTA derivatives, the most active was compound 3b, containing 3-hydroxyphenyl moiety in the para position, being able at 100 μM 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.