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Eur J Med Chem. 2014 Sep 12;84:364-74. doi: 10.1016/j.ejmech.2014.07.019. Epub 2014 Jul 11.

Synthesis of novel chiral TBBt derivatives with hydroxyl moiety. Studies on inhibition of human protein kinase CK2α and cytotoxicity properties.

Author information

1
Warsaw University of Technology, Faculty of Chemistry, Noakowskiego St. 3, 00-664 Warsaw, Poland. Electronic address: pawel_borowiecki@onet.eu.
2
Warsaw University of Technology, Faculty of Chemistry, Noakowskiego St. 3, 00-664 Warsaw, Poland.

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.

KEYWORDS:

4,5,6,7-Tetrabromo-1H-benzotriazole; Anti-tumor therapies; Cytotoxicity evaluations; Inhibitors; Molecular docking; Protein kinase CK2

PMID:
25036794
DOI:
10.1016/j.ejmech.2014.07.019
[Indexed for MEDLINE]

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