Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Antiproliferative Screening In Vitro
2.2.2. Effect of Compound 9h and 9u on Cell Growth, Cell Cycle and Apoptosis
2.2.3. 9h Induces Expression and Nuclear Export of Nur77, Which May Mediate 9h-Induced Apoptosis
2.2.4. Molecular Docking Study of 9h and Nur77
3. Experimental Section
3.1. General Information
3.2. Synthesis
3.2.1. Procedure for Preparation of the (E)-3-(Dimethylamino)-1-(6-methoxynaphthalen-2-yl)prop-2-en-1-one (3)
3.2.2. Procedure for Preparation of the Ethyl-6-(6-methoxynaphthalen-2-yl)-2-methylnicotinate (5)
3.2.3. Procedure for Preparation of 6-(6-Methoxynaphthalen-2-yl)-2-methylnicotinohydrazide (7)
3.2.4. Procedure for the Preparation of 9a–9w
3.3. Cell Culture
3.4. Cytotoxicity against Cell Lines
3.5. Western Blot Analysis
3.6. Flow Cytometry Assay
3.7. Colony Formation Assay
3.8. Nuclear-Cytosol Fractionation Assay
3.9. Immunofluorescence
3.10. The Docking Experiments
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 | Structure/R | MTT | ||
---|---|---|---|---|
HeLa | HGC-27 | MCF-7 | ||
9a | 88.39 ± 0.22 | 38.39 ± 0.32 | 60.26 ± 0.11 | |
9b | 30.54 ± 0.40 | 50.26 ± 0.20 | 41.46 ± 0.78 | |
9c | 25.33 ± 0.45 | 23.16 ± 0.20 | 21.13 ± 0.52 | |
9d | 20.65 ± 0.26 | 39.12 ± 0.72 | 35.20 ± 0.60 | |
9e | 24.65 ± 0.24 | 49.24 ± 0.26 | 33.34 ± 0.12 | |
9f | 24.15 ± 0.61 | 29.44 ± 0.31 | 23.30 ± 0.10 | |
9g | 20.22 ± 0.31 | 19.40 ± 0.63 | 18.38 ± 0.21 | |
9h | 4.12 ± 0.08 | 1.40 ± 0.11 | 3.30 ± 0.21 | |
9i | 20.10 ± 0.44 | 19.67 ± 0.31 | 21.38 ± 0.25 | |
9j | 12.10 ± 0.21 | 16.56 ± 0.44 | 16.30 ± 0.34 | |
9k | 10.12 ± 0.69 | 12.40 ± 0.50 | 11.56 ± 0.45 | |
9l | 45.40 ± 0.11 | 38.10 ± 0.21 | 40.20 ± 0.33 | |
9m | 34.54 ± 0.37 | 30.20 ± 0.61 | 35.44 ± 0.41 | |
9n | 25.33 ± 0.10 | 23.16 ± 0.07 | 21.13 ± 0.32 | |
9o | 20.65 ± 0.22 | 39.12 ± 0.21 | 35.20 ± 0.09 | |
9p | 14.65 ± 0.31 | 19.24 ± 0.09 | 23.34 ± 0.21 | |
9q | 14.15 ± 0.22 | 19.44 ± 0.69 | 23.30 ± 0.21 | |
9r | 20.22 ± 0.24 | 19.40 ± 0.11 | 18.38 ± 0.41 | |
9s | 16.12 ± 0.07 | 10.40 ± 0.19 | 19.30 ± 0.30 | |
9t | 10.10 ± 0.61 | 16.67 | 11.38 | |
9u | 6.10 ± 0.50 | 4.56 ± 0.09 | 6.44 ± 0.07 | |
9v | 10.12 ± 0.11 | 12.40 ± 0.25 | 11.56 ± 0.56 | |
9w | 10.66 ± 0.34 | 16.43 ± 0.31 | 10.90 ± 0.42 | |
Cisplatin | 12.45 ± 0.11 | 8.90 ± 0.20 | 10.54 ± 0.31 |
Compound | Cancer Cells (IC50, μM) | Normal Cells (IC50, μM) | |||||
---|---|---|---|---|---|---|---|
HepG2 | A549 | MDA-MB231 | H460 | A875 | MRC-5 | LO2 | |
9h | 5.1 ± 0.01 | 7.3 ± 0.21 | 4.3 ± 0.33 | 9.2 ± 0.24 | >50 | >50 | >50 |
9u | 7.2 ± 0.11 | 11.2 ± 0.46 | 21.0 ± 0.01 | 14.0 ± 0.38 | 15.7 ± 0.11 | 22.1 ± 0.11 | 41.0 ± 0.70 |
Cisplatin | 15.2 ± 0.29 | 9.3 ± 0.11 | 20.2 ± 0.25 | 16.6 ± 0.09 | 21.2 ± 0.08 | >50 | >50 |
RESNR | RESTYPE | DIST | RESNR | RESTYPE | DIST |
---|---|---|---|---|---|
118 | LEU | 3.87 | 179 | VAL | 3.47 |
162 | LEU | 3.36 | 224 | LEU | 3.52 |
165 | LEU | 3.57 | 224 | LEU | 3.61 |
167 | VAL | 3.5 | 224 | LEU | 3.41 |
172 | PHE | 3.57 | 228 | LEU | 3.45 |
175 | LEU | 3.89 | 231 | LEU | 3.46 |
178 | LEU | 3.75 |
RESNR | RESTYPE | SIDECHAIN | DIST_H-A | DIST_D-A | DON_ANGLE | PROTISDON |
---|---|---|---|---|---|---|
(Å) | (Å) | (°) | ||||
114 | GLU | TRUE | 2.36 | 3.17 | 136.65 | FALSE |
179 | VAL | FALSE | 2.54 | 3.49 | 155.72 | FALSE |
179 | VAL | FALSE | 2.53 | 3.44 | 149.64 | FALSE |
232 | ARG | TRUE | 1.85 | 2.8 | 153.65 | TRUE |
232 | ARG | TRUE | 3.39 | 3.96 | 116.77 | TRUE |
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Hu, H.; Huang, J.; Cao, Y.; Zhang, Z.; He, F.; Lin, X.; Wu, Q.; Zhao, S. Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators. Molecules 2022, 27, 1698. https://doi.org/10.3390/molecules27051698
Hu H, Huang J, Cao Y, Zhang Z, He F, Lin X, Wu Q, Zhao S. Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators. Molecules. 2022; 27(5):1698. https://doi.org/10.3390/molecules27051698
Chicago/Turabian StyleHu, Hongyu, Jiangang Huang, Yin Cao, Zhaolin Zhang, Fengming He, Xianfu Lin, Qi Wu, and Shengxian Zhao. 2022. "Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators" Molecules 27, no. 5: 1698. https://doi.org/10.3390/molecules27051698