The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. MTT Antiproliferative Evaluation
2.3. Compounds 4d and 4f Induces G1-Phase Cell Cycle Arrest on MCF-7 Cells
2.4. Apoptosis Quantification
2.5. Effect of Compounds 4d and 4f on Apoptosis Regulatory Markers
2.6. Molecular Docking
3. Experimental
3.1. Chemistry
- 4-(2-Mercapto-8-methoxy-4- oxoquinazolin-3(4H)-yl) benzenesulfonamide (3)
3.2. General Procedure
3.2.1. Method A
3.2.2. Method B
- 2-(4-(8-Methoxy-4-oxo-2-((2-oxo-2-(phenylamino)ethylthio)quinazolin-3(4H)-yl)phenylsul-fonamido)-N-phenylacetamide (4a).
- 2-(4-(8-Methoxy-4-oxo-2-((2-oxo-2-(o-tolylamino)ethylthio)quinazolin-3(4H)-yl)phenylsul-fonamido)-N-(o-tolyl)acetamide (4b).
- 2-(4-(8-Methoxy-4-oxo-2-((2-oxo-2-(m-tolylamino)ethylthio)quinazolin-3(4H)-yl)phenylsul-fonamido)-N-(m-tolyl)acetamide (4c).
- 2-(4-(8-Methoxy-4-oxo-2-((2-oxo-2-(p-tolylamino)ethylthio)quinazolin-3(4H)-yl)phenylsul-fonamido)-N-(p-tolyl)acetamide (4d).
- N-(2-ethylphenyl)-2-((3-(4-(N-(2-((2-ethylphenyl)amino)-2-oxoethyl)sulfamoyl)-phe-nyl)- 8-methoxy-4-oxo-3,4-dihydroquinazolin-2yl) thio)acetamide (4e).
- N-(3-ethylphenyl)-2-((3-(4-(N-(2-((3-ethylphenyl)amino)-2-oxoethyl)sulfamoyl)-phe-nyl)-8-methoxy-4-oxo-3,4-dihydroquinazolin-2yl) thio)acetamide (4f).
- N-(4-ethylphenyl)-2-((3-(4-(N-(2-((4-ethylphenyl)amino)-2-oxoethyl)sulfamoyl)-phenyl)-8-methoxy-4-oxo-3,4-dihydroquinazolin-2yl)thio)acetamide (4g).
- 2-(4-(8-Methoxy-2-((2-((4-methoxyphenyl)amino)-2-oxoethyl)thio)-4-oxoquinazolin-3(4H)-yl)phenylsulfonamido)-N-(4-methoxy-phenyl)acetamide (4h).
- N-(4-Ethoxyphenyl)-2-((3-(4-N-(2((4-ethoxyphenyl)amino)-2-oxoethyl)sulfamoyl)-phenyl-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)acetamide (4i).
- N-(3,5-Dimethoxyphenyl)-2-((3-(4-N-(2((3,5-dimethoxyphenyl)amino)-2-oxoethyl)-sulfa-moyl)phenyl-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)acetamide (4j).
- 2-(4-(8-Methoxy-4-oxo-2-((2-oxo-2-(3,4,5 trimethoxyphenyl)amino)ethyl)thio)quinazolin-3(4H)-yl)phenylsulfonamido)-N-(3,4,5-trimethoxyphenyl)acetamide (4k).
- 2-(4-(8-Methoxy-2-((2-((2-methyl-4-nitrophenyl)amino)-2-oxoethyl)thio)-4-oxoquinazolin-3(4H)-yl)phenylsulfonamido)-N-(2-methyl-4-nitrophenyl)acetamide (4l).
- 2-(4-(8-Methoxy-2-((2-((2-methyl-6-nitrophenyl)amino)-2-oxoethyl)thio)-4-oxoquinazolin-3(4H)-yl)phenylsulfonamido)-N-(2-methyl-6-nitrophenyl)acetamide (4m).
- N-(2,4-dinitrophenyl)-2-((3-(4-N-(2((2,4-dinitrophenyl)amino)-2-oxoethyl)sulfamoyl)phen-yl-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)acetamide (4n).
3.3. Biological Evaluations
3.3.1. MTT Cell Viability Assay
3.3.2. Cell Cycle Analysis
3.3.3. Annexin V-FITC/PI Apoptosis Detection
3.3.4. Analysis of Apoptotic Genes by RT-PCR
3.3.5. Western Blotting to See the Effect of 4d and 4f Compounds
3.3.6. Molecular Docking
3.3.7. Statistical Analysis
4. Conclusions
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 No. | Cell Lines and IC50 (µM) | ||||
---|---|---|---|---|---|
A549 | HepG2 | LoVo | MCF-7 | HUVEC | |
4a | 19.6 ± 1.7 | 35 ± 1.2 | 37.5 ± 1.8 | 14.2 ± 0.4 | 20.9 ± 1 |
4b | 11.36 ± 1.6 | 33.7 ± 0.8 | 35.75 ± 1 | 36.2 ± 2 | 32.7 ± 1.2 |
4c | - | - | - | - | - |
4d | 6.6 ± 0.22 | 9 ± 0.3 | 6.87 ± 0.62 | 2.5 ± 0.2 | 7.8 ± 0.6 |
4e | - | - | - | - | - |
4f | 10.14 ± 0.24 | 11.7 ± 2 | 9.76 ± 1.68 | 5 ± 0.24 | 17.9 ± 0.6 |
4g | - | - | - | - | - |
4h | 13.3 ± 0.85 | 25.4 ± 0.95 | 31.7 ± 1 | 31.62 ± 1.3 | 24.3 ± 0. 56 |
4i | 13.8 ± 0.5 | 20.6 ± 1.6 | 22.04 ± 1.01 | 26.4 ± 0.79 | 18.2 ± 2.2 |
4j | - | - | - | - | - |
4k | - | - | - | - | - |
4l | - | - | - | - | - |
4m | - | - | - | - | - |
4n | - | - | - | - | - |
Doxorubicin | 1.1 ± 0.01 | 2.8 ± 0. 01 | 1.5 ± 0.05 | 1.4 ± 0.3 | 3.7 ± 0.2 |
Donor Atoms | Acceptor Atom | Distance (Å) | Type of Interaction | Binding Free Energy, ΔG (kcal mol−1) | Binding Affinity, Kd (M−1) |
---|---|---|---|---|---|
Bcl-2 and DRO * | |||||
LIG:N ASP70:OD2 MET74:CE LEU96:CD1 LIG:C PHE63 PHE71 LIG:C LIG LIG LIG LIG LIG | ASP70:OD2 LIG LIG LIG TYR67 LIG LIG LEU96 ARG105 ALA108 LEU96 ALA108 VAL92 | 2.9553 4.8135 3.5674 3.8681 3.5199 5.2880 4.9682 4.9539 5.2941 4.4414 5.1674 4.4935 5.0873 | Conventional Hydrogen Bond Electrostatic (Pi-Anion) Hydrophobic (Pi-Sigma) Hydrophobic (Pi-Sigma) Hydrophobic (Pi-Sigma) Hydrophobic (Pi-Pi T-shaped) Hydrophobic (Pi-Pi T-shaped) Hydrophobic (Alkyl) Hydrophobic (Pi-Alkyl) Hydrophobic (Pi-Alkyl) Hydrophobic (Pi-Alkyl) Hydrophobic (Pi-Alkyl) Hydrophobic (Pi-Alkyl) | −10.2 | 3.03 × 107 |
Bcl-2 and Compound (4d) | |||||
LIG: H MET74:CE LEU96:CD1 LIG:C TYR67 ALA108 LIG:C LIG | GLU95:OE1 LIG LIG PHE71 LIG LIG:C MET74 VAL92 | 2.0244 3.4311 3.9269 3.6605 3.8844 3.7959 4.8241 5.3864 | Conventional Hydrogen Bond Hydrophobic (Pi-Sigma) Hydrophobic (Pi-Sigma) Hydrophobic (Pi-Sigma) Hydrophobic (Pi-Pi Stacked) Hydrophobic (Alkyl) Hydrophobic (Alkyl) Hydrophobic (Pi-Alkyl) | −7.8 | 5.25 × 105 |
Bcl-2 and Compound (4f) | |||||
TYR67:HH PHE63 TYR67 GLU95:C,O;LEU96:N ALA108 LIG:C LIG:C LIG LIG | LIG:O LIG LIG LIG LIG:C LEU96 MET74 ARG105 ALA108 | 2.4126 4.8823 5.1361 3.9675 3.7719 4.6857 4.0247 5.4994 5.1493 | Conventional Hydrogen Bond Hydrophobic (Pi-Pi T-shaped) Hydrophobic (Pi-Pi T-shaped) Hydrophobic (Amide-Pi Stacked) Hydrophobic (Alkyl) Hydrophobic (Alkyl) Hydrophobic (Alkyl) Hydrophobic (Pi-Alkyl) Hydrophobic (Pi-Alkyl) | −7.5 | 3.17 × 105 |
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Alqahtani, A.S.; Ghorab, M.M.; Nasr, F.A.; Ahmed, M.Z.; Al-Mishari, A.A.; Attia, S.M. The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study. Molecules 2022, 27, 981. https://doi.org/10.3390/molecules27030981
Alqahtani AS, Ghorab MM, Nasr FA, Ahmed MZ, Al-Mishari AA, Attia SM. The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study. Molecules. 2022; 27(3):981. https://doi.org/10.3390/molecules27030981
Chicago/Turabian StyleAlqahtani, Ali S., Mostafa M. Ghorab, Fahd A. Nasr, Mohammad Z. Ahmed, Abdullah A. Al-Mishari, and Sabry M. Attia. 2022. "The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study" Molecules 27, no. 3: 981. https://doi.org/10.3390/molecules27030981