Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. In Vitro Activity Assays
2.2.1. Anti-Cervical Cancer Activity Assay
2.2.2. Structure–Effect Relationship Analysis
2.2.3. Apoptosis of HeLa Cells
2.2.4. Cell Cycle Experiment of HeLa Cells
2.2.5. Migration and Invasion of HeLa Cells
2.2.6. In Vitro Anti-HeLa/DDP Cell Activities
2.2.7. Apoptosis of HeLa/DDP Cells
2.2.8. Cell Cycle Experiment of HeLa/DDP Cells
2.2.9. Migration and Invasion of HeLa/DDP Cells
2.2.10. Molecular Docking
2.2.11. Immunofluorescence Assay
- (1)
- HeLa cell immunofluorescence assay
- (2)
- HeLa/DDP cell immunofluorescence assay
3. Material and Methods
3.1. Chemistry
3.2. Synthesis and Structural Characterization
3.2.1. (E)-1-(3,4-Dichlorophenyl)-2-methyl-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one(3a)
3.2.2. (E)-1-(3,4-Dichlorophenyl)-2-methyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-One(3b)
3.2.3. (E)-1-(3,4-Dichlorophenyl)-2-methyl-3-(2,3,4-trimethoxyphenyl)prop-2-en-1-one(3c)
3.2.4. (E)-1-(3,4-Dichlorophenyl)-2-methyl-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one(3d)
3.2.5. (E)-1-(2,4-dichlorophenyl)-2-methyl-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one(3e)
3.2.6. (E)-1-(3,4-dichlorophenyl)-3-(2,4-dimethoxyphenyl)-2-methylprop-2-en-1-one(3f)
3.2.7. (E)-1-(3,4-dichlorophenyl)-3-(2,6-dimethoxyphenyl)-2-methylprop-2-en-1-one(3g)
3.2.8. (E)-1-(3,4-Dichlorophenyl)-3-(3,5-dimethoxyphenyl)-2-methylprop-2-en-1-one(3h)
3.2.9. (E)-1-(3,4-Dichlorophenyl)-3-(2,3-dimethoxyphenyl)-2-methylprop-2-en-1-one(3i)
3.2.10. (E)-1-(3,4-Dichlorophenyl)-3-(2,5-dimethoxyphenyl)-2-methylprop-2-en-1-one(3j)
3.2.11. (E)-1-(3,4-Dichlorophenyl)-3-(3,4-dimethoxyphenyl)-2-methylprop-2-en-1-one(3k)
3.2.12. (E)-1-(3,4-Dichlorophenyl)-3-(2-methoxyphenyl)-2-methylprop-2-en-1-one(3l)
3.2.13. (E)-1-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)-2-methylprop-2-en-1-one(3m)
3.2.14. (E)-1-(3,4-Dichlorophenyl)-3-(4-(dimethylamino)phenyl)-2-methylprop-2-en-1-one(3n)
3.2.15. (E)-1-(3,4-Dichlorophenyl)-3-(4-(diethylamino)phenyl)-2-methylprop-2-en-1-one(3o)
3.2.16. (E)-1-(2,4-Dichlorophenyl)-3-(4-(diethylamino)phenyl)-2-methylprop-2-en-1-one(3p)
3.3. Biological Assays
3.3.1. Cell lines and Cell Culture
3.3.2. Anticervical Cancer Activity
3.3.3. Pro-Apoptosis Assay
3.3.4. Western Blotting Analysis
3.3.5. Cell Cycle Experiments
3.3.6. Invasion and Migration Experiments
3.3.7. Anti-Cisplatin-Resistant Cervical Cancer Activity
3.3.8. Pro-Apoptosis Assay (HeLa/DDP)
3.3.9. Cell Cycle Experiments (HeLa/DDP)
3.3.10. Invasion and Migration Experiments (HeLa/DDP)
3.3.11. Molecular Docking
3.3.12. Immunofluorescence Assay
3.3.13. Statistical Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | IC50 48 h (μM) ± SD | |||
---|---|---|---|---|
HeLa | SiHa | C33A | H8 | |
3a | >100 | 23.47 ± 4.55 *** | 69.92 ± 7.18 | >100 |
3b | 43.78 ± 3.68 ** | 28.41 ± 2.37 *** | 56.98 ± 6.27 | 57.72 ± 4.70 ## |
3c | >100 | 41.84 ± 5.10 ** | 33.85 ± 4.99 | >100 |
3d | 97.57 ± 7.61 | >100 | 63.73 ± 2.59 | >100 |
3e | >100 | >100 | >100 | >100 |
3f | >100 | >100 | 23.72 ± 4.07 ** | >100 |
3g | 56.05 ± 4.58 * | >100 | 44.79 ± 2.85 | >100 |
3h | >100 | >100 | 54.36 ± 11.52 | >100 |
3i | >100 | >100 | 30.67 ± 8.84 | >100 |
3j | >100 | >100 | 28.46 ± 3.78 * | >100 |
3k | 9.05 ± 0.53 ***# | 14.54 ± 0.98 ***## | 12.11 ± 2.44 *** | >100 |
3l | >100 | 22.49 ± 1.36 *** | 17.29 ± 2.24 *** | >100 |
3m | 29.75 ± 0.98 *** | 67.71 ± 5.60 | 35.12 ± 4.75 | >100 |
3n | >100 | >100 | 23.43 ± 3.42 ** | >100 |
3o | >100 | >100 | 34.97 ± 4.93 | >100 |
3p | >100 | >100 | 41.35 ± 5.42 | >100 |
Chalcone | 67.03 ± 4.56 | 62.03 ± 1.84 | 37.53 ± 1.50 | 78.45 ± 7.78 |
Cisplatin | 13.03 ± 1.82 | 20.70 ± 1.85 | 6.05 ± 1.15 | 25.23 ± 1.29 |
Target Compound | ± SD | ||
---|---|---|---|
HeLa | HeLa/DDP | RI | |
Cisplatin | 13.03 ± 1.82 | 102.91 ± 3.60 | 7.90 |
Paclitaxel | 22.98 ± 1.33 | 130.10 ± 5.84 | 5.66 |
Doxorubicin | 10.43 ± 1.09 | 38.34 ± 4.57 | 3.68 |
Chalcone | 67.03 ± 4.56 | 87.97 ± 7.27 | 1.31 |
3k | 9.05 ± 0.53 # | 9.72 ± 0.73 ### | 1.07 |
Cisplatin + verapamil (6 μM) | 14.59 ± 1.87 | 39.13 ± 6.05 ### | 2.68 |
Cisplatin + 3k (0.25 μM) | 14.54 ± 1.55 | 98.02 ± 10.83 | 6.74 |
Cisplatin + 3k (0.5 μM) | 14.23 ± 0.45 | 68.84 ± 5.10 ### | 4.84 |
Cisplatin + 3k (1 μM) | 11.68 ± 2.57 | 24.54 ± 1.86 ### | 2.10 |
Ligand | Name of Protein | PDB ID | The Lowest Binding Energy (kcal/mol) | |
---|---|---|---|---|
Compd | Hydrogen Bonds | |||
Chalcone | Tubulin | 1SA0 | −6.4 | - |
P-gp | 7O9W | −8.5 | 1 | |
Compound 3k | Tubulin | 1SA0 | −7.1 | 1 |
P-gp | 7O9W | −7.4 | - | |
CN2 | Tubulin | 1SA0 | −8.8 | 10 |
UIC2-Fab | P-gp | 7O9W | −10.8 | 2 |
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Yang, Z.; Liu, Z.; Ablise, M.; Maimaiti, A.; Aihaiti, A.; Alimujiang, Y. Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells. Molecules 2023, 28, 7697. https://doi.org/10.3390/molecules28237697
Yang Z, Liu Z, Ablise M, Maimaiti A, Aihaiti A, Alimujiang Y. Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells. Molecules. 2023; 28(23):7697. https://doi.org/10.3390/molecules28237697
Chicago/Turabian StyleYang, Zheng, Zhengye Liu, Mourboul Ablise, Aikebaier Maimaiti, Aizitiaili Aihaiti, and Yusupuwajimu Alimujiang. 2023. "Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells" Molecules 28, no. 23: 7697. https://doi.org/10.3390/molecules28237697
APA StyleYang, Z., Liu, Z., Ablise, M., Maimaiti, A., Aihaiti, A., & Alimujiang, Y. (2023). Design and Synthesis of Novel α-Methylchalcone Derivatives, Anti-Cervical Cancer Activity, and Reversal of Drug Resistance in HeLa/DDP Cells. Molecules, 28(23), 7697. https://doi.org/10.3390/molecules28237697