title: Synthesis of novel chiral TBBt derivatives with hydroxyl moiety. Studies on inhibition of human protein kinase CK2α and cytotoxicity properties.
abstract: The efficient method for the synthesis of novel 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) derivatives bearing a single stereogenic center has been developed. New compounds with a variety of substituents at the meta- and para-position of the phenyl ring are reported. All of the presented compounds were obtained using classical synthetic methods, such as bromination of benzotriazole, and its subsequent alkylation by monotosylated arylpropane-1,3-diols, which in turn have been synthesized through reduction of the corresponding prochiral β-keto esters, and the selective monotosylation of the primary hydroxyl group. The influence of the new and previously reported N-hydroxyalkyl TBBt derivatives on the activity of human protein kinase CK2α catalytic subunit was examined. The most active were derivatives with N-hydroxyalkyl substituents (IC50 in 0.80-7.35 μM range). A binding mode of (R)-1-(4,5,6,7-tetrabromo-2H-benzotriazol-2-yl)butan-3-ol 7b to hCK2α has been proposed based on in silico docking studies. Additionally, MTT-based cytotoxicity tests demonstrated high activities of novel 1-aryl-3-TBBt-propan-1-ol and 3-TBBt-propan-1,2-diol derivatives against human peripheral blood T lymphoblast (CCRF-CEM), and moderate anti-tumor activities against human breast adenocarcinoma (MCF7) cell lines.
authors.affiliation: Warsaw University of Technology, Faculty of Chemistry, Noakowskiego St. 3, 00-664 Warsaw, Poland. Electronic address: pawel_borowiecki@onet.eu.
authors.forename: Paweł
authors.initials: P
authors.lastname: Borowiecki
authors.affiliation: Warsaw University of Technology, Faculty of Chemistry, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Wawro
authors.affiliation: Warsaw University of Technology, Faculty of Chemistry, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Wińska
authors.affiliation: Warsaw University of Technology, Faculty of Chemistry, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Wielechowska
authors.affiliation: Warsaw University of Technology, Faculty of Chemistry, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Bretner
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C405354:4,5,6,7-tetrabromobenzotriazole; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D047390:Casein Kinase II
keywords: 4,5,6,7-Tetrabromo-1H-benzotriazole; Anti-tumor therapies; Cytotoxicity evaluations; Inhibitors; Molecular docking; Protein kinase CK2