17374-26-4Relevant articles and documents
CK2 inhibition, lipophilicity and anticancer activity of new: N 1versus N 2-substituted tetrabromobenzotriazole regioisomers
Abdel-Aal, Abu-Baker M.,Abo-Zeid, Mohammad Nabil,El-Kardocy, Ahmed,Hassan, Nivin A.,Hetta, Helal F.,Mohamed, Noha G.,Mostafa, Yaser A.
, p. 13007 - 13017 (2020)
A new series of antiproliferative casein kinase 2α (CK2α) inhibitors were synthesized incorporating either a hydrophilic group (carboxylic or hydrazide) or a hydrophobic group (ester) at N1 or N2 of 4,5,6,7-tetrabromobenzotriazole (TBBt). New compounds were prepared via N-alkylation of TBBt followed by base-catalysed hydrolysis or hydrazinolysis. All the compounds demonstrated low sub-micromolar inhibition of CK2α and antiproliferative activity against both breast and lung cancer cell lines (MCF-7, and A549, respectively), at low micromolar concentrations with N2-regioisomers exhibiting higher activity than their corresponding N1-isomers. The most active compound incorporates an acetic acid hydrazide moiety at the N2 of the TBBt triazole nucleus with IC50 at 0.131 μM (CK2α), 9.1 μM (MCF-7) and 6.3 μM (A549). It induced apoptosis in the MCF-7 cell line through upregulation of bax (pro-apoptotic gene) four to five times higher than the corresponding ester or acid analogues. Molecular docking suggests that the hydrophilic group at N2 of the TBBt triazole nucleus provides binding with important residues (Asp175, Lys68 and Trp176) in the ATP binding site of the CK2α enzyme. We are the first to experimentally estimate the lipophilicity of TBBt derivatives. Our study demonstrated that TBBt hydrazides are more lipophilic than their corresponding acids in contrast to the contradicting calculated lipophilicity using four well-known software programs. This may explain the higher anticancer activity of the most active hydrazide over its corresponding acid despite their nearly equipotent enzyme inhibition. This journal is
Synthesis of novel chiral TBBt derivatives with hydroxyl moiety. Studies on inhibition of human protein kinase CK2α and cytotoxicity properties
Borowiecki, Pawe?,Wawro, Adam M.,Wińska, Patrycja,Wielechowska, Monika,Bretner, Maria
supporting information, p. 364 - 374 (2014/08/05)
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.
