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

International Journal of Molecular Sciences

卷:22

Patrycja Wińska¹  Paweł Borowiecki¹  Konrad Chojnacki¹  Małgorzata Milner-Krawczyk¹  Maria Bretner¹  Monika Wielechowska¹  Mirosława Koronkiewicz²  Maria Jolanta Rędowicz³  Olena Karatsai³ 

[1] Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, Poland;

[2] Department of Drug Biotechnology and Bioinformatics, National Medicines Institute, 00-725 Warsaw, Poland;

[3] Laboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland;

关键词: protein kinase CK2;    CK2 inhibitors;    breast cancer;    tetrabromobenzimidazole;    apoptosis;    prodrug strategy;   

DOI  :  10.3390/ijms22126261

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown