Tetraiodobenzimidazoles are potent inhibitors of protein kinase CK2

Abstract

a b s t r a c tA series of novel iodinated benzimidazoles have been prepared by iodination of respective benzimidazole with iodine and periodic acid in sulfuric acid solution. Additionally several 2-substituted-and N-1-carboxymethyl-substituted derivatives of 4,5,6,7-tetraiodobenzimidazole (TIBI) were obtained. For sake of comparison, some new 4,5,6,7-tetrabromobenzimidazoles were also synthesized. The ability of the new compounds to inhibit protein kinase CK2 has been evaluated. The results show that 4,5,6,7-tetraiodobenzimidazoles are more powerful inhibitors of CK2 than their tetrabrominated analogs. Molecular modeling supports the experimental data showing that tetraiodobenzimidazole moiety fills better the binding pocket than respective tetrabromo and tetrachlorocompounds. To note that 4,5,6,7-tetraiodobenzimidazole (TIBI) is one of the most efficient CK2 inhibitors (K i = 23 nM) described to date.

Proapoptotic effects of novel pentabromobenzylisothioureas in human leukemia cell lines

“…We decided to synthesize modified pentabromobenzylisothioureas in a search for new inhibitors of the antiapoptotic enzyme casein kinase 2 (CK2), structurally similar to such known polyhalogenobenzimidazole CK2 inhibitors as 4,5,6,7-tetrabromobenzimidazole (TBI) or 4,5,6,7-tetrabromo-2-dimethylaminobenzimidazole (DMAT) (Szyszka et al ., 1995; Pagano et al ., 2004; Gianoncelli et al ., 2009). We expected that the new compounds would show the advantage of increased water solubility while retaining high CK2 inhibitory activity.…”

Targeting the Protein Quality Control (PQC) Machinery

“…Its structural optimization leads to a tetrabromobenzimidazole (TBBz, 2.69a) [221], its 2-dimethylamino substituted analog (DMAT, 2.69b) [222], a tetraiodobenzimidazole (TIBI, 2.69c) [223], and a tetrabromobenzotriazole (TBBt, 2.70) [224]. Compound 2.68 is a weak CK2 inhibitor, while compounds 2.69a,b and 2.70 are potent and relatively selective, as measured on a panel of 76 kinases [225].…”

Halogen and Hydrogen Bonding in Multicomponent Crystals of Tetrabromo-1H-Benzotriazole

“…Over the years, several analogues of TBBT have been studied with the aim of improving the potency, selectivity, and solubility in water of this API. Unfortunately, only small improvements have been obtained, despite considerable synthetic efforts to prepare and test libraries of TBBT analogues [6,7,11,12]. The study of analogues of a therapeutically relevant drug is not the only viable strategy when an improved drug solubility and dissolution kinetics are pursued.…”