Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Design and In Silico Prediction of PKM-2 Modulators
2.2. Chemistry
2.3. In Vitro Studies
3. Materials and Methods
3.1. In Silico
3.2. Chemistry
3.2.1. General Chemistry Methods
3.2.2. Synthesis Sulfonamides (8a,b)
3.2.3. Synthesis Triazoles (9a–e)
3.2.4. Procedure B
3.3. In Vitro Study
3.3.1. Chemicals
3.3.2. Cell Culture
3.3.3. WST-1 Assay
3.3.4. Quantitative Analysis of Cellular Pyruvate Level
3.3.5. DNA Fragmentation and Cell Cycle Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Compound | PKM2 Structure | |||
---|---|---|---|---|
PDB ID: 4G1N | PDB ID: 4XFX | |||
GOLD Score [a.u.] | ΔG [kcal/mol] | GOLD Score [a.u.] | ΔG [kcal/mol] | |
1 | 75.03 | −10.34 | 65.82 | −9.35 |
2 | 62.95 | −9.04 | 54.05 | −8.08 |
3 | 63.77 | −9.13 | 56.78 | −8.38 |
4 | 62.99 | −9.04 | 62.30 | −8.97 |
5 | 58.05 | −8.51 | 53.64 | −8.04 |
6 | 60.65 | −8.79 | 52.92 | −7.96 |
9a | 78.56 | −10.72 | 76.33 | −10.48 |
9b | 72.64 | −10.08 | 75.57 | −10.40 |
9c | 73.17 | −10.14 | 64.99 | −9.26 |
9d | 70.82 | −9.89 | 61.35 | −8.87 |
9e | 71.35 | −9.94 | 60.36 | −8.76 |
Compound | Analyzed Cell Lines—GI50 | |||||
---|---|---|---|---|---|---|
C32 | COLO 829 | MDA-MB-231 | U87-MG | A549 | NHDF | |
9a | 234 µg/mL (0.520 mM) | 169 µg/mL (0.376 mM) | 274 µg/mL (0.609 mM) | 340 µg/mL (0.756 mM) | 223 µg/mL (0.496 mM) | Negative |
9b | 200 µg/mL (0.441 mM) | 266 µg/mL (0.587 mM) | Negative | 347 µg/mL (0.765 mM) | Negative | Negative |
9c | 269 µg/mL (0.691 mM) | 179 µg/mL (0.460 mM) | Negative | Negative | Negative | 87 µg/mL (0.223 mM) |
9d | 209 µg/mL (0.605 mM) | 130 µg/mL (0.376 mM) | Negative | 328 µg/mL (0.949 mM) | Negative | Negative |
9e | 303 µg/mL (0.373 mM) | Negative | 314 µg/mL (0.386 mM) | Negative | Negative | Negative |
Reference compound | Dacarbazine 9 µg/mL (0.049 mM) [34] | Dacarbazine negative [35] | Cisplatin 4 µg/mL (0.013 mM) | Temozolomide negative [36] | Cisplatin 196 µg/mL (0.653 mM) | N/A |
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Marciniec, K.; Rzepka, Z.; Chrobak, E.; Boryczka, S.; Latocha, M.; Wrześniok, D.; Beberok, A. Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study. Molecules 2023, 28, 2509. https://doi.org/10.3390/molecules28062509
Marciniec K, Rzepka Z, Chrobak E, Boryczka S, Latocha M, Wrześniok D, Beberok A. Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study. Molecules. 2023; 28(6):2509. https://doi.org/10.3390/molecules28062509
Chicago/Turabian StyleMarciniec, Krzysztof, Zuzanna Rzepka, Elwira Chrobak, Stanisław Boryczka, Małgorzata Latocha, Dorota Wrześniok, and Artur Beberok. 2023. "Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study" Molecules 28, no. 6: 2509. https://doi.org/10.3390/molecules28062509