Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Abstract

Protein kinase CK2 has been considered as an attractive drug target for anti-cancer therapy. The synthesis of N-hydroxypropyl TBBi and 2MeTBBi derivatives as well as their respective esters was carried out by using chemoenzymatic methods. Concomitantly with kinetic studies toward recombinant CK2, the influence of the obtained compounds on the viability of two human breast carcinoma cell lines (MCF-7 and MDA-MB-231) was evaluated using MTT assay. Additionally, an intracellular inhibition of CK2 as well as an induction of apoptosis in the examined cells after the treatment with the most active compounds were studied by Western blot analysis, phase-contrast microscopy and flow cytometry method. The results of the MTT test revealed potent cytotoxic activities for most of the newly synthesized compounds (EC50 4.90 to 32.77 µM), corresponding to their solubility in biological media. We concluded that derivatives with the methyl group decrease the viability of both cell lines more efficiently than their non-methylated analogs. Furthermore, inhibition of CK2 in breast cancer cells treated with the tested compounds at the concentrations equal to their EC50 values correlates well with their lipophilicity since derivatives with higher values of logP are more potent intracellular inhibitors of CK2 with better proapoptotic properties than their parental hydroxyl compounds.

Synthesis and Anticancer Activity of Novel Dual Inhibitors of Human Protein Kinases CK2 and PIM-1

“…Moreover, the cytotoxic activity of the tested compounds corresponds better with their lipophilicity than their inhibitory activity. This correlation is in agreement with our previous findings demonstrating that the most promising compound characterized by a higher log P value can penetrate cell membranes more efficiently, therefore exhibiting improved intracellular inhibition of CK2 [ 40 ]. The present results were supported by molecular docking studies for the most selective compounds, i.e., rac -6 and rac -11.…”

“…Although this structural fragment is located towards the outer part of the CK2 ATP-binding site, it generates additional polar interactions with a catalytic cavity, which increase the affinity toward the kinase receptor. In view of these findings, we also obtained a novel potent dual CK2/PIM-1 inhibitor, namely 3-(4,5,6,7-tetrabromo-2-methyl-1 H -1,3-benzodiazol-1-yl)propan-1-ol ( N 1 -PrOH-TBBi), which, after functionalization into its corresponding acetyl prodrug, turned out to be a very promising anticancer agent toward breast cancer cell lines [ 40 ]. Therefore, we expect that further structural modification of aliphatic substituents possessing efficient hydrogen bond-forming moieties installed at the appropriate distance from the TBBi core structure will enhance the affinity and selectivity of the designed 2-alkanol-TBBi derivatives toward titled kinases.…”

Antitumor activity of the protein kinase inhibitor 1-(β-D-2′-deoxyribofuranosyl)-4,5,6,7-tetrabromo- 1H-benzimidazole in breast cancer cell lines

“…We also described the synthesis of new N-hydroxypropyl TBBi and 2MeTBBi derivatives and their effect on the viability of MCF-7 and MDA-MB-231 cell lines. Derivatives with the methyl group decreased the viability of both cell lines more efficiently than their non-methylated analogs [ 43 ].…”