5,6-diiodo-1H-benzotriazole: new TBBt analogue that minutely affects mitochondrial activity

Abstract

Abstract4,5,6,7-Tetrabromo-1H-benzotriazole is widely used as the reference ATP-competitive inhibitor of protein kinase CK2. Herein, we study its new analogs: 5,6-diiodo- and 5,6-diiodo-4,7-dibromo-1H-benzotriazole. We used biophysical (MST, ITC) and biochemical (enzymatic assay) methods to describe the interactions of halogenated benzotriazoles with the catalytic subunit of human protein kinase CK2 (hCK2α). To trace the biological activity, we measured their cytotoxicity against four reference cancer cell lines and the effect on the mitochondrial inner membrane potential. The results obtained lead to the conclusion that iodinated compounds are an attractive alternative to brominated ones. One of them retains the cytotoxicity against selected cancer cell lines of the reference TBBt with a smaller side effect on mitochondrial activity. Both iodinated compounds are candidate leaders in the further development of CK2 inhibitors.

Effect of histidine protonation state on ligand binding at the ATP-binding site of human protein kinase CK2

“…For each ligand, at least two independent titration experiments were done. Details of the experimental setup and the analysis algorithm were previously described 49 . For binding of TBBt and 4,5,6-Br 3 Bt by WT and H160A variant, the model of two independent binding sites was applied.…”

“…For binding of TBBt and 4,5,6-Br 3 Bt by WT and H160A variant, the model of two independent binding sites was applied. However, contrary to our previous approach 49 , due to the low heat of binding, the correction for enthalpy of ligand mixing with buffer was constrained to the value determined from the single-binding site model applied to the same system. All the titration data are shown in Supplementary Figs.…”

Benzotriazole scaffold: An overview of antiproliferative potential, mechanisms of action, and structure–activity relationships

“…It was established that the cytotoxic activity rose significantly more than would be predicted based on the inhibitory activity found in the enzymatic assay when the bromine atom was replaced with an iodine atom. [ 56 ]…”

“…[55] Four compounds, namely, 5,6-diiodo-1H-benzotriazole (17a), would be predicted based on the inhibitory activity found in the enzymatic assay when the bromine atom was replaced with an iodine atom. [56] 2.3 | Benzotriazoles as focal adhesion kinase (FAK) inhibitors Different anticancer effects were produced by substituents in different places (ortho > meta > para). [57] To find prospective FAK inhibitor candidates, a virtual screening was done.…”