Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biology
2.2.1. Structure–Activity Relationship Analysis
2.2.2. Cell Growth and Viability
Topotecan Cytotoxicity on HEK293FT Wild Type and TDP1−/− Cells
TDP1 Inhibitors’ Cytotoxicity on HEK293FT TDP1−/− Cells
Activity of 11h and 12k with Topotecan against Tumor Cells
2.2.3. Chemical Space
3. Materials and Methods
3.1. Chemistry
3.1.1. General Procedure (GP)
3.1.2. Reaction of 2-Carene-Containing Mixture and 4-hydroxy-3-methoxybenzaldehyde 10a
3.1.3. Reaction of 2-Carene-Containing Mixture and Crotonaldehyde 10c
3.1.4. Reaction of 2-Carene-Containing Mixture and 2-Thiophenecarbaldehyde 10d
3.1.5. Reaction of 2-Carene-Containing Mixture and 3-methylthiophene-2-carbaldehyde 10e
3.1.6. Reaction of 2-Carene-Containing Mixture and 5-methylthiophene-2-carbaldehyde 10f
3.1.7. Reaction of 2-Carene-Containing Mixture and 4-bromothiophene-2-carbaldehyde 10g
3.1.8. Reaction of 2-Carene-Containing Mixture and 5-bromothiophene-2-carbaldehyde 10h
3.1.9. Reaction of 2-Carene-Containing Mixture and 5-nitrothiophene-2-carbaldehyde 10i
3.1.10. Reaction of 2-Carene-Containing Mixture and 5-nitrofuran-2-carbaldehyde 10j
3.1.11. Reaction of 2-Carene-Containing Mixture and thiophene-3-carbaldehyde 10k
3.1.12. Reaction of Limonene and 2-thiophenecarbaldehyde 10d
3.2. Real-Time Detection of TDP1 Activity
3.3. TDP1 Activity by Gel-Based Assay
3.4. Obtainment of TDP1 Knockout HEK293FT Clones
3.4.1. Plasmid Construction for Human TDP1 Gene Knockout
3.4.2. Knockout HEK293FT Clone Generation
3.4.3. Analysis of CRISPR/Cas9-Mediated Deletions in the TDP1 Gene
3.5. Cell Culture Assay
3.6. Calculation of Molecular Descriptors
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds of structural types 11 and 12 are available from the authors. |
R | RCHO | Product 11 (Yield, (S)-/(R) Ratio) | Products 12 and 13 (Total Yield, %, 12/13) |
---|---|---|---|
4-Hydroxy-3-methoxyphenyl | 10a | 11a (81%, (S)-/(R) = 1:1) | 12a (11%) |
(E)-prop-1-en-1-yl | 10c | 11c (89%, (S)-/(R) = 1.3:1) | |
Thiophen-2-yl | 10d | 11d (78%, (S)-isomer) | 12d, 13d (5%, 7:1) |
3-Methylthiophen-2-yl | 10e | 11e (86%, (S)-isomer) | 12e (2%) |
5-Methylthiophen-2-yl | 10f | 11f (85%, (S)-isomer) | 12f, 13f (2%, 3:1) |
4-Bromothiophen-2-yl | 10g | - | 12g (20%) |
5-Bromothiophen-2-yl | 10h | 11h (73%, (S)-isomer) | 12h (15%) |
5-Nitrothiophen-2-yl | 10i | - | 12i, 13i (18%, 5:1) |
5-Nitrofuran-2-yl | 10j | - | 12j (18%) |
Thiophen-3-yl | 10k | 11k (91%, (S)-/(R) = 1.5:1) | 12k (21%) |
R | Compound 11 | IC501, μM | Compound 12 | IC501, μM |
---|---|---|---|---|
4-Hydroxy-3-methoxyphenyl | 11a | >20 | 12a | >20 |
(E)-prop-1-en-1-yl | 11c | >20 | - | - |
Thiophen-2-yl | 11d | 4.85 ± 1.06 | 12d | 3.35 ± 1.06 |
3-Methylthiophen-2-yl | 11e | 3.6 ± 1.7 | 12e | 2.25 ± 0.63 |
5-Methylthiophen-2-yl | 11f | 4.7 ± 2.0 | - | - |
4-Bromothiophen-2-yl | - | - | 12g | 0.65 ± 0.22 |
5-Bromothiophen-2-yl | 11h | 0.75 ± 0.07 | 12h | 1.75 ± 0.78 |
5-Nitrothiophen-2-yl | - | - | 12i | 14 ± 1 |
5-Nitrofuran-2-yl | - | - | 12j | 28 ± 10 |
Thiophen-3-yl | 11k | 1.60 ± 0.56 | 12k | 1.20 ± 0.14 |
Furamidine | 1.2 ± 0.3 |
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Il’ina, I.V.; Dyrkheeva, N.S.; Zakharenko, A.L.; Sidorenko, A.Y.; Li-Zhulanov, N.S.; Korchagina, D.V.; Chand, R.; Ayine-Tora, D.M.; Chepanova, A.A.; Zakharova, O.D.; et al. Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1. Molecules 2020, 25, 3496. https://doi.org/10.3390/molecules25153496
Il’ina IV, Dyrkheeva NS, Zakharenko AL, Sidorenko AY, Li-Zhulanov NS, Korchagina DV, Chand R, Ayine-Tora DM, Chepanova AA, Zakharova OD, et al. Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1. Molecules. 2020; 25(15):3496. https://doi.org/10.3390/molecules25153496
Chicago/Turabian StyleIl’ina, Irina V., Nadezhda S. Dyrkheeva, Alexandra L. Zakharenko, Alexander Yu. Sidorenko, Nikolay S. Li-Zhulanov, Dina V. Korchagina, Raina Chand, Daniel M. Ayine-Tora, Arina A. Chepanova, Olga D. Zakharova, and et al. 2020. "Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1" Molecules 25, no. 15: 3496. https://doi.org/10.3390/molecules25153496
APA StyleIl’ina, I. V., Dyrkheeva, N. S., Zakharenko, A. L., Sidorenko, A. Y., Li-Zhulanov, N. S., Korchagina, D. V., Chand, R., Ayine-Tora, D. M., Chepanova, A. A., Zakharova, O. D., Ilina, E. S., Reynisson, J., Malakhova, A. A., Medvedev, S. P., Zakian, S. M., Volcho, K. P., Salakhutdinov, N. F., & Lavrik, O. I. (2020). Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1. Molecules, 25(15), 3496. https://doi.org/10.3390/molecules25153496