SAR Study and Molecular Mechanism Investigation of Novel Naphthoquinone-furan-2-cyanoacryloyl Hybrids with Antitumor Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Evaluation of In Vitro Antitumor Activity and Safety
2.2.2. Compound 5c Inhibited HeLa Cell Migration
2.2.3. Compound 5c Inhibited the Colony Formation of HeLa Cells
2.2.4. Compound 5c Blocks HeLa Cells in G2/M Phase
2.2.5. Compound 5c Induced the Generation of Intracellular Reactive Oxygen Species
2.2.6. Effect of Compound 5c on HeLa Cell Apoptosis
2.2.7. Compound 5c Inhibited STAT3 Y705 Phosphorylation in Cell-Based Assays
2.2.8. Kinetic Affinity of Compound 5c against STAT3
2.3. Docking Study of Compound 5c with the STAT3 SH2 Domain
2.4. Molecular Dynamics Simulation Analyses
3. Conclusions
4. Experimental
4.1. Chemistry
4.2. Biological Evaluation
4.2.1. Cell Lines and Cell Culture
4.2.2. Cell Counting Kit-8 (CCK-8) Assay
4.2.3. Hoechst-33342 Staining
4.2.4. Western Blotting Assays
4.2.5. Cell Cycle and Annexin V apoptosis Assays
4.2.6. Wound Healing Assay
4.2.7. Colony Formation Assay
4.2.8. Cellular ROS Detection In Vitro
4.2.9. Biolayer Interferometry (BLI) Assay
4.2.10. Molecular Docking
4.2.11. Molecular Dynamics Simulation
4.3. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Inhibition Rate a (%) at 20 μM | |||
---|---|---|---|---|
HeLa b | PC3 c | A549 d | HCT116 e | |
4a | 13.64 ± 0.15 | 15.47 ± 0.17 | 16.30 ± 0.22 | 5.69 ± 0.23 |
4b | 11.71 ± 0.04 | 3.88 ± 0.13 | 24.2 ± 0.31 | 19.55 ± 0.65 |
4c | 24.23 ± 0.01 | 8.99 ± 0.09 | 11.25 ± 0.05 | 18.78 ± 0.04 |
4d | 11.60 ± 0.79 | 7.17 ± 0.31 | 21.58 ± 0.02 | 10.77 ± 0.49 |
4e | 59.10 ± 0.21 | 15.84 ± 0.33 | 59.49 ± 0.34 | 40.53 ± 0.03 |
4f | 11.49 ± 0.83 | 11.75 ± 0.79 | 25.11 ± 0.79 | 43.69 ± 0.84 |
4g | 16.12 ± 0.17 | 15.38 ± 0.01 | 4.87 ± 0.30 | 7.69 ± 0.02 |
4h | 9.49 ± 0.16 | 19.53 ± 0.17 | 0.25 ± 0.13 | 11.54 ± 0.14 |
4i | 34.99 ± 0.41 | 12.29 ± 0.12 | 13.95 ± 0.87 | 29.05 ± 0.08 |
5a | 10.43 ± 0.41 | 3.70 ± 0.19 | 13.28 ± 0.17 | 8.36 ± 0.26 |
5b | 20.50 ± 0.28 | 17.83 ± 0.33 | 18.40 ± 0.82 | 8.83 ± 0.10 |
5c | 75.78 ± 0.05 | 25.54 ± 0.06 | 24.69 ± 0.04 | 67.67 ± 0.01 |
5d | 5.61 ± 0.24 | 15.51 ± 0.20 | 17.24 ± 0.35 | 26.77 ± 0.94 |
5e | 29.73 ± 0.07 | 19.33 ± 0.28 | 19.84 ± 0.32 | 5.97 ± 95 |
5f | 1.90 ± 0.72 | 11.13 ± 0.03 | 13.88 ± 0.14 | 3.41 ± 0.26 |
5g | 27.98 ± 0.36 | 11.20 ± 0.02 | 32.35 ± 0.95 | 28.25 ± 0.04 |
5h | 17.23 ± 0.11 | 10.12 ± 0.85 | 9.91 ± 0.06 | 3.94 ± 0.03 |
5i | 30.49 ± 0.03 | 16.25 ± 0.19 | 25.03 ± 0.22 | 10.25 ± 0.04 |
6 | 27.00 ± 0.32 | 21.58 ± 0.83 | 21.31 ± 0.45 | 16.78 ± 0.07 |
6a | 26.09 ± 0.66 | 6.93 ± 0.79 | 2.15 ± 0.37 | 17.67 ± 0.06 |
8a | 20.86 ± 0.18 | 15.47 ± 0.29 | 24.06 ± 0.35 | 12.40 ± 0.15 |
8b | 19.33 ± 0.18 | 24.99 ± 0.19 | 7.87 ± 0.11 | 2.17 ± 0.02 |
8c | 9.10 ± 0.21 | 4.65 ± 0.56 | 14.11 ± 0.32 | 4.73 ± 0.47 |
8d | 22.70 ± 0.27 | 22.45 ± 0.05 | 19.35 ± 0.07 | 14.48 ± 0.24 |
8e | 40.58 ± 0.36 | 11.50 ± 0.17 | 14.52 ± 0.25 | 7.70 ± 0.27 |
8f | 30.10 ± 0.39 | 17.72 ± 0.12 | 28.29 ± 0.33 | 27.19 ± 0.15 |
8g | 18.28 ± 0.03 | 7.59 ± 0.72 | 26.89 ± 0.16 | 27.46 ± 0.16 |
8h | 28.47 ± 0.10 | 16.50 ± 0.97 | 21.64 ± 0.39 | 19.61 ± 0.34 |
8i | 55.62 ± 0.12 | 25.11 ± 0.05 | 31.67 ± 0.07 | 47.78 ± 0.19 |
9a | 42.87 ± 0.22 | 2.39 ± 0.09 | 20.73 ± 0.49 | 33.71 ± 0.13 |
9b | 18.65 ± 0.16 | 12.82 ± 0.01 | 8.80 ± 0.04 | 7.22 ± 0.34 |
9c | 5.905 ± 0.29 | 1.45 ± 0.86 | 15.11 ± 0.31 | 37.21 ± 0.08 |
Cell Lines | IC50 (μM) j | |
---|---|---|
5c | WP1066 k | |
HeLa a | 3.10 ± 0.02 | 7.06 ± 1.17 |
PC3 b | 20.50 ± 0.05 | 1.202 ± 0.03 |
HCT116 c | 13.38 ± 0.04 | 7.22 ± 3.14 |
A549 d | 35.27 ± 0.07 | 7.55 ± 0.06 |
MDA-MB-231 e | 40.74 ± 0.12 | 8.17 ± 0.16 |
B16 f | >80 | 24.09 ± 0.70 |
SKOV3 g | 44.6 ± 0.01 | 4.66 ± 0.13 |
Hep3B h | 34.77 ± 0.03 | 4.36 ± 0.05 |
L02 i | 51.7 ± 0.10 | 3.45 ± 0.41 |
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Liu, P.; Fan, D.; Qiao, W.; He, X.; Zhang, L.; Jiang, Y.; Yang, T. SAR Study and Molecular Mechanism Investigation of Novel Naphthoquinone-furan-2-cyanoacryloyl Hybrids with Antitumor Activity. Pharmaceutics 2022, 14, 2104. https://doi.org/10.3390/pharmaceutics14102104
Liu P, Fan D, Qiao W, He X, Zhang L, Jiang Y, Yang T. SAR Study and Molecular Mechanism Investigation of Novel Naphthoquinone-furan-2-cyanoacryloyl Hybrids with Antitumor Activity. Pharmaceutics. 2022; 14(10):2104. https://doi.org/10.3390/pharmaceutics14102104
Chicago/Turabian StyleLiu, Pingxian, Dongmei Fan, Wenliang Qiao, Xinlian He, Lidan Zhang, Yunhan Jiang, and Tao Yang. 2022. "SAR Study and Molecular Mechanism Investigation of Novel Naphthoquinone-furan-2-cyanoacryloyl Hybrids with Antitumor Activity" Pharmaceutics 14, no. 10: 2104. https://doi.org/10.3390/pharmaceutics14102104
APA StyleLiu, P., Fan, D., Qiao, W., He, X., Zhang, L., Jiang, Y., & Yang, T. (2022). SAR Study and Molecular Mechanism Investigation of Novel Naphthoquinone-furan-2-cyanoacryloyl Hybrids with Antitumor Activity. Pharmaceutics, 14(10), 2104. https://doi.org/10.3390/pharmaceutics14102104