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
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Inhibition of Recombinant CK2 and PIM1
2.2.2. Cytotoxic Effect of TBBi Derivatives toward Breast Cancer Cells
2.2.3. Intracellular Inhibition of Protein Kinase CK2 in MCF-7 and MDA-MB-231 Cells
2.2.4. Induction of Apoptosis in MCF-7 and MDA-MB-231 Cells
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.1.1. General Methods
4.1.2. General Procedure for N-alkylation of 1 and 4
4.1.3. General Procedure for Esterification of 2 and 5
4.2. Biological Evaluation
4.2.1. Reagents and Antibodies
4.2.2. Inhibition of Recombinant CK2 and PIM1
4.2.3. Cell Culture and Agents Treatment
4.2.4. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT)-Based Viability Assay
4.2.5. Western Blotting
4.2.6. Densitometry
4.2.7. Detection of Apoptosis by Flow Cytometry
4.2.8. Cell Cycle Progression by Flow Cytometry
4.2.9. Statistical Evaluation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cpd. | Residual Activity of the Enzyme [%] | Ki [µM] | |||||||
---|---|---|---|---|---|---|---|---|---|
CK2α | CK2 α2β2 | PIM1 | CK2α | CK2 α2β2 | PIM1 | ||||
5 µM | 10 µM | 5 µM | 10 µM | 5 µM | 10 µM | ||||
1 | 19.3 ± 0.2 | 12.4 ± 0.1 | 9.6 ± 2.6 | 5.0 ± 1.2 | 11.2 ± 0.2 | 5.7 ± 0.5 | 0.58 [57] | 0.15 | 0.27 |
2 | 26.1 ± 5.3 | 18.5 ± 0.3 | 16.0 ± 1.8 | 7.6 ± 0.2 | 17.2 ± 2.3 | 10.1 ± 1.0 | 0.27 [58] | 0.28 ± 0.06 | 0.42 ± 0.02 |
3a | 71.0 ± 9.5 | 59.1 ± 3.7 | 58.0 ± 4.0 | 34.8 ± 3.4 | 65.0 ± 2.8 | 24.4 ± 0.9 | – | – | 2.23 ± 0.07 |
3b | 89.3 ± 8.0 | 83.0 ± 13.0 | 85.5 ± 8.3 | 83.1 ± 7.5 | 85.0 ± 0.1 | 74.2 ± 11.2 | – | – | – |
3c | 86.1 ± 4.2 | 79.2 ± 7.6 | 95.3 ± 2.9 | 92.7 ± 3.5 | 99.1 ± 15.7 | 95.4 ± 4.0 | – | – | – |
4 | 18.8 ± 1.1 | 7.7 ± 3.3 | 6.0 ± 0.9 | 2.9 ± 0.2 | 8.0 ± 0.9 | 4.5 ± 0.2 | 1.11 ± 0.30 [34] | 0.11 ± 0.04 | 0.21 ± 0.02 |
5 | 26.1 ± 3.5 | 16.3 ± 1.0 | 14.2 ± 2.0 | 9.1 ± 0.6 | 9.3 ± 2.6 | 3.4 ± 0.3 | 0.20 ± 0.08 | 0.05 ± 0.01 | 0.15 ± 0.08 |
6a | 81.5 ± 8.0 | 68.4 ± 9.8 | 75.6 ± 5.9 | 49.6 ± 0.8 | 38.8 ± 3.1 | 19.0 ± 0.1 | – | – | 1.94 ± 0.16 |
6b | 76.8 ± 1.9 | 74.3 ± 0.1 | 85.4 ± 0.6 | 71.4 ± 0.2 | 62.4 ± 8.3 | 46.4 ± 2.7 | – | – | – |
6c | 89.9 ± 5.2 | 84.3 ± 10.4 | 90.2 ± 4.7 | 80.8 ± 1.9 | 95.2 ± 9.4 | 79.8 ± 8.6 | – | – | – |
CX-4945 | 0 | 0 | 0 | 0 | 2.3 ± 0.1 | 1.2 ± 0.1 | – | – | – |
Cpd. | EC50 ± SD [μM] | Log P * | Log S * | |||||
---|---|---|---|---|---|---|---|---|
MCF-7 | MDA-MB-231 | |||||||
24 h | 48 h | 72 h | 24 h | 48 h | 72 h | |||
1 | 20.83 ± 1.49 | 18.82 ± 1.60 | 16.86 ± 1.36 | 51.90 ± 14.43 | 25.11 ± 2.04 | 24.92 ± 0.25 | 4.33 | −6.23 |
2 | 24.09 ± 1.39 | 20.08 ± 1.36 | 19.60 ± 1.68 | 54.62 ± 4.32 | 27.19 ± 0.49 | 20.57 ± 0.86 | 3.93 | −5.37 |
3a | 29.34 ± 1.24 | 23.05 ± 0.77 | 21.51 ± 1.86 | 40.80 ± 1.58 | 27.84 ± 1.31 | 24.52 ± 0.48 | 5.51 | −6.55 |
3b | 39.56 ± 1.06 | 28.38 ± 1.71 | 24.77 ± 1.33 | 95.58 ± 20.40 | 32.21 ± 3.26 | 27.30 ± 1.26 | 6.40 | −7.49 |
3c | 24.34 ± 0.25 | 21.14 ± 1.23 | 29.85 ± 1.45 | 45.11 ± 5.43 | 23.68 ± 3.97 | 32.77 ± 3.25 | 7.29 | −8.43 |
3d | >100 | >100 | >100 | >100 | >100 | >100 | 9.07 | −10.28 |
4 | 4.12 ± 0.03 | 4.20 ± 0.29 | 2.66 ± 0.19 | 12.78 ± 6.60 | 5.35 ± 0.82 | 4.73 ± 0.48 | 4.46 | −5.90 |
5 | 17.62 ± 6.35 | 15.96 ± 5.31 | 4.90 ± 2.71 | 57.84 ± 20.79 | 21.03 ± 9.85 | 9.99 ± 0.44 | 4.05 | −5.04 |
6a | 20.15 ± 1.74 | 18.07 ± 0.52 | 16.47 ± 1.13 | 52.17 ± 11.68 | 20.49 ± 1.97 | 16.85 ± 4.07 | 5.64 | −6.21 |
6b | 22.35 ± 1.12 | 18.59 ± 0.18 | 18.31 ± 2.86 | 51.43 ± 8.22 | 21.16 ± 2.40 | 22.06 ± 3.18 | 6.53 | −7.15 |
6c | 25.63 ± 12.30 | 20.46 ± 2.92 | 14.85 ± 2.14 | 61.28 ± 2.23 | 29.83 ± 9.85 | 21.30 ± 2.24 | 7.42 | −8.08 |
6d | >100 | >100 | >100 | >100 | >100 | >100 | 9.19 | −9.92 |
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Chojnacki, K.; Wińska, P.; Karatsai, O.; Koronkiewicz, M.; Milner-Krawczyk, M.; Wielechowska, M.; Rędowicz, M.J.; Bretner, M.; Borowiecki, P. 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. Int. J. Mol. Sci. 2021, 22, 6261. https://doi.org/10.3390/ijms22126261
Chojnacki K, Wińska P, Karatsai O, Koronkiewicz M, Milner-Krawczyk M, Wielechowska M, Rędowicz MJ, Bretner M, Borowiecki P. 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. 2021; 22(12):6261. https://doi.org/10.3390/ijms22126261
Chicago/Turabian StyleChojnacki, Konrad, Patrycja Wińska, Olena Karatsai, Mirosława Koronkiewicz, Małgorzata Milner-Krawczyk, Monika Wielechowska, Maria Jolanta Rędowicz, Maria Bretner, and Paweł Borowiecki. 2021. "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 22, no. 12: 6261. https://doi.org/10.3390/ijms22126261