Evaluation of 4,5,6,7-tetrahalogeno-1H-isoindole-1,3(2H)-diones as inhibitors of human protein kinase CK2

Golub, Andriy G.; Yakovenko, O. S.; Prykhod'ko, A.O.; Lukashov, S. S.; Bdzhola, Volodymyr G.; Yarmoluk, S. M.

doi:10.1016/j.bbapap.2007.10.009

Cited by 44 publications

(27 citation statements)

References 23 publications

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“…The positive effect of the substitution of chlorines with bromines can possibly be ascribed to different factors: better shape complementarity with the active site (better van der Waals interactions); an increase in the hydrophobic effect favouring the binding; and higher efficacy of the two halogen bonds established with the hinge region [104,105]. This trend of a higher potency with the increasing dimensions, hydrophobicity and polarizability, respectively, from Cl to Br to I, was confirmed by the higher efficacy of tetraiodobenzo-imidazole derivatives [unpublished observation] and by an analogous trend observed with the tetrahalogeno-isoindole-dione compounds [106]. K22 (4,5,6,7-tetrabromo-1H,3H-benzimidazol-2-thione), DMAT and K32 (4,5,6,7-tetrabromo-1H,3H-benzimidazol-2-one) (Fig.…”

Section: Tetralogenobenzo Derivativessupporting

confidence: 59%

Protein Kinase CK2 in Health and Disease

Battistutta

2009

Cell. Mol. Life Sci.

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Protein kinase CK2 is involved in many fundamental aspects of normal cell life, but it is also able to establish favourable conditions for tumorigenesis. CK2 is elevated in various cancers, it is a potent suppressor of apoptosis, it strongly promotes cell survival, it strengthens the multi-drug resistant phenotype and can be considered a valuable drug target for cancer therapy. In this review, the structural bases of CK2 inhibition deduced from the analysis of crystal structures of CK2alpha-inhibitor complexes are presented and discussed. The best ATP-competitive inhibitors show an adequate hydrophobic character, an excellent shape complementarity with the unique active site of CK2, and the ability to establish polar interactions with both the hinge region and the positive electrostatic area near the conserved water W1 and the Lys68-Glu81 salt bridge. The state of the art of non-ATP-competitive inhibitors is also presented.

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Section: Tetralogenobenzo Derivativessupporting

confidence: 59%

Protein Kinase CK2 in Health and Disease

Battistutta

2009

Cell. Mol. Life Sci.

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“…The first scaffolds considered, the cinnamic acid and the isoindoldione derivatives (Table II), are structurally related to the poli-bromurated benzoimidazole family. Among the series promising molecules are TID46 (2-(4,5,6,7-tetraiodo-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid), reaching an IC 50 value of 0.15 mM as racemic mixture 167 and the tetrabromo cinnamic acid (TBCA, K i 5 0.077 mM). 140 This last one reduces the viability of Jurkat cells more efficiently than TBB through enhancement of apoptosis.…”

Section: Carboxyl Acid Derivativesmentioning

confidence: 99%

How druggable is protein kinase CK2?

2009

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CK2 is a pleiotropic, ubiquitous, and constitutively active protein kinase (PK), with both cytosolic and nuclear localization in most mammalian cells. The holoenzyme is generally composed of two catalytic (alpha and/or alpha') and two regulatory (beta) subunits, but the free alpha/alpha' subunits are catalytically active by themselves and can be present in cells under some circumstances. CK2 catalyzes the phosphorylation of more than 300 substrates characterized by multiple acidic residues surrounding the phosphor-acceptor amino acid, and, consequently, it plays a key role in several physiological and pathological processes. But how can one kinase orchestrate all these tasks faithfully? How is it possible that one kinase can, despite all pleiotropic characteristics of PKs in general, be involved in so many different biochemical events? Is CK2 a druggable target? Several questions are still to be clearly answered, and this review is an occasion for a fruitful discussion.

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“…Recently, structurally related tetraiodinated-isoindole derivatives were synthesized and found to inhibit protein kinase CK2 in an ATP-competitive manner with IC 50 values ranging between 0.15 and 1.5 lM. 20 The highest efficiency documented in the literature for a CK2 inhibitor belongs to a class of pyrazolo-triazine derivatives reported to affect CK2 with K i values in the nanomolar and subnanomolar range. 21,22 Regrettably, however, the experimental conditions for these assays were not detailed; this hampers reliable comparison with other inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Tetraiodobenzimidazoles are potent inhibitors of protein kinase CK2

Gianoncelli

Cozza

Orzeszko

et al. 2009

Bioorganic & Medicinal Chemistry

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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.

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Evaluation of 4,5,6,7-tetrahalogeno-1H-isoindole-1,3(2H)-diones as inhibitors of human protein kinase CK2

Cited by 44 publications

References 23 publications

Protein Kinase CK2 in Health and Disease

Protein Kinase CK2 in Health and Disease

How druggable is protein kinase CK2?

Tetraiodobenzimidazoles are potent inhibitors of protein kinase CK2

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