Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1<i>H</i>-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties
Protein kinase CK2 has been considered as an attractive drug target for anti-cancer therapy. The synthesis of <i>N</i>-hydroxypropyl TBBi and 2MeTBBi derivatives as well as their respective esters was carried out by using chemoenzymatic methods. Concomitantly with kinetic studies toward...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/12/6261 |
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| author | Konrad Chojnacki Patrycja Wińska Olena Karatsai Mirosława Koronkiewicz Małgorzata Milner-Krawczyk Monika Wielechowska Maria Jolanta Rędowicz Maria Bretner Paweł Borowiecki |
| author_facet | Konrad Chojnacki Patrycja Wińska Olena Karatsai Mirosława Koronkiewicz Małgorzata Milner-Krawczyk Monika Wielechowska Maria Jolanta Rędowicz Maria Bretner Paweł Borowiecki |
| author_sort | Konrad Chojnacki |
| collection | DOAJ |
| description | Protein kinase CK2 has been considered as an attractive drug target for anti-cancer therapy. The synthesis of <i>N</i>-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 (EC<sub>50</sub> 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 EC<sub>50</sub> values correlates well with their lipophilicity since derivatives with higher values of log<i>P</i> are more potent intracellular inhibitors of CK2 with better proapoptotic properties than their parental hydroxyl compounds. |
| first_indexed | 2024-03-10T10:31:06Z |
| format | Article |
| id | doaj.art-4034e2fe881a44e8842d6a457885ffd2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:31:06Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4034e2fe881a44e8842d6a457885ffd22023-11-21T23:36:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012212626110.3390/ijms22126261Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1<i>H</i>-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic PropertiesKonrad Chojnacki0Patrycja Wińska1Olena Karatsai2Mirosława Koronkiewicz3Małgorzata Milner-Krawczyk4Monika Wielechowska5Maria Jolanta Rędowicz6Maria Bretner7Paweł Borowiecki8Chair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, PolandChair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, PolandLaboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandDepartment of Drug Biotechnology and Bioinformatics, National Medicines Institute, 00-725 Warsaw, PolandChair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, PolandChair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, PolandLaboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandChair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, PolandChair of Drug and Cosmetics Biotechnology, Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, PolandProtein kinase CK2 has been considered as an attractive drug target for anti-cancer therapy. The synthesis of <i>N</i>-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 (EC<sub>50</sub> 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 EC<sub>50</sub> values correlates well with their lipophilicity since derivatives with higher values of log<i>P</i> are more potent intracellular inhibitors of CK2 with better proapoptotic properties than their parental hydroxyl compounds.https://www.mdpi.com/1422-0067/22/12/6261protein kinase CK2CK2 inhibitorsbreast cancertetrabromobenzimidazoleapoptosisprodrug strategy |
| spellingShingle | Konrad Chojnacki Patrycja Wińska Olena Karatsai Mirosława Koronkiewicz Małgorzata Milner-Krawczyk Monika Wielechowska Maria Jolanta Rędowicz Maria Bretner Paweł Borowiecki Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1<i>H</i>-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties International Journal of Molecular Sciences protein kinase CK2 CK2 inhibitors breast cancer tetrabromobenzimidazole apoptosis prodrug strategy |
| title | Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1<i>H</i>-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties |
| title_full | Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1<i>H</i>-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties |
| title_fullStr | Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1<i>H</i>-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties |
| title_full_unstemmed | Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1<i>H</i>-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties |
| title_short | Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1<i>H</i>-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties |
| title_sort | synthesis of novel acyl derivatives of 3 4 5 6 7 tetrabromo 1 i h i benzimidazol 1 yl propan 1 ols intracellular tbbi based ck2 inhibitors with proapoptotic properties |
| topic | protein kinase CK2 CK2 inhibitors breast cancer tetrabromobenzimidazole apoptosis prodrug strategy |
| url | https://www.mdpi.com/1422-0067/22/12/6261 |
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