Substituted Piperazines as Novel Potential Radioprotective Agents
Abstract
1. Introduction
2. Results
2.1. Chemistry
2.2. Molecular Docking with Anti-Apoptotic Protein Bcl-2
2.3. In Vitro Cytotoxicity of Newly Synthesized Compounds 2, 3, 4, 5, 6, 7, 8, 9, and 10
2.4. In Vitro Toxicity Determination of New Inhibitors
2.5. Pre-Treatment with Compounds 4, 5, 6, 7, 8, and 10 Reduced Radiation-Induced Apoptosis In Vitro
2.6. The Compounds Administered to Mice at MTD Caused No Pathologies
2.7. Pre-Treatment with the Compounds Increased Survival of Whole-Body Irradiated Mice
3. Discussion
4. Experimental Section
4.1. Synthesis and Analysis
4.2. Molecular Docking
4.3. Cell Culture and Treatment with Novel Compounds
4.4. Cytotoxicity of Novel Compounds In Vitro
4.5. Evaluation of Radioprotection In Vitro
4.6. Safe Use Evaluation In Vivo
4.7. Animals and Gamma Radiation
4.8. Preparation of the Novel Compound Solutions and Evaluation of Radioprotection In Vivo
4.9. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds 2, 3, 4, 5, 6, 7, 8, 9 and 10 are available from the authors. |
Compound | Yield (%) | Melting Point (°C) | *ClogP |
---|---|---|---|
2 | 78 | 172–173 | 2.255 |
3 | 75 | 157–158 | 1.948 |
4 | 79 | 189–190 | 1.478 |
5 | 68 | 185–186 | 0.682 |
6 | 69 | 181–182 | 1.671 |
7 | 61 | 182–183 | 0.524 |
8 | 27 | oil | −2.107 |
9 | 25 | oil | 2.090 |
10 | 90 | 154–155 | −0.009 |
(A) | ||||||||||
Cell line | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | DOX |
Jurkat | 31 ± 14 | 95 ± 9 | 105 ± 5 | 98 ± 4 | 101 ± 1 | 100 ± 5 | 103 ± 5 | 104 ± 5 | 108 ± 7 | 2 ± 0 |
MOLT-4 | 0 ± 0 | 81 ± 13 | 88 ± 6 | 93 ± 9 | 90 ± 7 | 93 ± 3 | 106 ± 8 | 103 ± 8 | 112 ± 6 | 1 ± 0 |
A549 | 27 ± 3 | 94 ± 15 | 100 ± 4 | 86 ± 7 | 103 ± 7 | 95 ± 5 | 97 ± 5 | 107 ± 11 | 105 ± 9 | 42 ± 11 |
HT-29 | 28 ± 6 | 85 ± 11 | 100 ± 2 | 91 ± 2 | 86 ± 4 | 96 ± 3 | 101 ± 1 | 102 ± 5 | 104 ± 11 | 55 ± 18 |
PANC-1 | 39 ± 2 | 78 ± 6 | 97 ± 7 | 86 ± 16 | 92 ± 11 | 99 ± 10 | 98 ± 9 | 93 ± 12 | 95 ± 7 | 78 ± 7 |
A2780 | 44 ± 9 | 84 ± 7 | 98 ± 2 | 93 ± 5 | 74 ± 3 | 94 ± 3 | 104 ± 4 | 90 ± 3 | 103 ± 6 | 8 ± 4 |
HeLa | 25 ± 1 | 104 ± 13 | 106 ± 2 | 100 ± 4 | 108 ± 6 | 96 ± 8 | 103 ± 4 | 99 ± 9 | 110 ± 7 | 76 ± 12 |
MCF-7 | 15 ± 1 | 84 ± 9 | 105 ± 4 | 101 ± 6 | 102 ± 8 | 105 ± 6 | 101 ± 5 | 100 ± 4 | 98 ± 2 | 32 ± 3 |
SAOS-2 | 28 ± 2 | 80 ± 4 | 99 ± 6 | 96 ± 4 | 94 ± 6 | 102 ± 7 | 102 ± 6 | 106 ± 2 | 97 ± 6 | 22 ± 4 |
MRC-5 | 23 ± 2 | 84 ± 2 | 97 ± 8 | 98 ± 7 | 91 ± 4 | 100 ± 3 | 95 ± 7 | 102 ± 8 | 102 ± 3 | 22 ± 2 |
(B) | ||||||||||
Cell line | 2 - not tested | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | DOX |
Jurkat | x | 12 ± 5 | 89 ± 1 | 98 ± 3 | 93 ± 2 | 96 ± 0 | 96 ± 13 | 79 ± 11 | 95 ± 4 | 2 ± 0 |
MOLT-4 | x | 2 ± 0 | 92 ± 6 | 104 ± 7 | 112 ± 4 | 99 ± 3 | 81 ± 6 | 71 ± 4 | 100 ± 4 | 1 ± 0 |
A549 | x | 13 ± 2 | 99 ± 0 | 104 ± 8 | 93 ± 3 | 115 ± 0 | 111 ± 11 | 98 ± 13 | 105 ± 2 | 42 ± 11 |
HT-29 | x | 14 ± 5 | 83 ± 4 | 109 ± 2 | 97 ± 4 | 118 ± 2 | 154 ± 11 | 148 ± 2 | 113 ± 2 | 55 ± 18 |
PANC-1 | x | 30 ± 4 | 111 ± 24 | 115 ± 7 | 111 ± 5 | 116 ± 3 | 117 ± 11 | 118 ± 5 | 111 ± 6 | 78 ± 7 |
A2780 | x | 20 ± 5 | 89 ± 1 | 105 ± 8 | 95 ± 4 | 91 ± 2 | 76 ± 10 | 64 ± 5 | 96 ± 2 | 8 ± 4 |
HeLa | x | 11 ± 3 | 137 ± 5 | 116 ± 10 | 104 ± 7 | 132 ± 3 | 100 ± 18 | 90 ± 14 | 121 ± 3 | 76 ± 12 |
MCF-7 | x | 10 ± 2 | 90 ± 3 | 106 ± 1 | 94 ± 9 | 104 ± 6 | 96 ± 7 | 98 ± 11 | 96 ± 6 | 32 ± 3 |
SAOS-2 | x | 10 ± 2 | 88 ± 4 | 111 ± 6 | 111 ± 4 | 109 ± 2 | 87 ± 7 | 90 ± 4 | 102 ± 2 | 22 ± 4 |
MRC-5 | x | 9 ± 6 | 93 ± 5 | 102 ± 8 | 94 ± 2 | 104 ± 3 | 119 ± 16 | 120 ± 16 | 102 ± 8 | 22 ± 2 |
Compounds | IC50 ± SEM (mM) | MTC (mM) |
---|---|---|
2 | 0.04 ± 0.002 | 0.002 |
3 | 0.14 ± 0.01 | 0.01 |
4 | 0.64 ± 0.03 | 0.05 |
5 | 1.35 ± 0.12 | 0.05 |
6 | 0.45 ± 0.01 | 0.02 |
7 | 2.55 ± 0.21 | 0.39 |
8 | > 25 | 6.25 |
9 | 0.24 ± 0.01 | 0.09 |
10 | 5.06 ± 0.23 | 1.56 |
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Filipova, A.; Marek, J.; Havelek, R.; Pejchal, J.; Jelicova, M.; Cizkova, J.; Majorosova, M.; Muckova, L.; Kucera, T.; Prchal, L.; et al. Substituted Piperazines as Novel Potential Radioprotective Agents. Molecules 2020, 25, 532. https://doi.org/10.3390/molecules25030532
Filipova A, Marek J, Havelek R, Pejchal J, Jelicova M, Cizkova J, Majorosova M, Muckova L, Kucera T, Prchal L, et al. Substituted Piperazines as Novel Potential Radioprotective Agents. Molecules. 2020; 25(3):532. https://doi.org/10.3390/molecules25030532
Chicago/Turabian StyleFilipova, Alzbeta, Jan Marek, Radim Havelek, Jaroslav Pejchal, Marcela Jelicova, Jana Cizkova, Martina Majorosova, Lubica Muckova, Tomas Kucera, Lukas Prchal, and et al. 2020. "Substituted Piperazines as Novel Potential Radioprotective Agents" Molecules 25, no. 3: 532. https://doi.org/10.3390/molecules25030532
APA StyleFilipova, A., Marek, J., Havelek, R., Pejchal, J., Jelicova, M., Cizkova, J., Majorosova, M., Muckova, L., Kucera, T., Prchal, L., Psotka, M., Zivna, N., Koutova, D., Sinkorova, Z., Rezacova, M., & Tichy, A. (2020). Substituted Piperazines as Novel Potential Radioprotective Agents. Molecules, 25(3), 532. https://doi.org/10.3390/molecules25030532