Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives
Abstract
:1. Introduction
2. Results and Discussion
2.1. Molecular Modeling—Design and Chemical Space Exploration
2.2. Chemistry
2.3. Biological Evaluation
2.4. Analytical Studies
2.4.1. MS, UV, and LC Studies
2.4.2. 1H-NMR Analysis
3. Experimental Section
3.1. Computational Methods
3.2. Chemistry
3.2.1. Materials and Methods
3.2.2. Synthetic Procedures
5,6-Dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide, 1
1H,3H-2,1,3-Benzothiadiazole-2,2-dioxide, 1a
5-Methyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide, 1b
5-(Trifluoromethyl)-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide, 1c
5-Nitro-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide, 1d
5-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-2-nitroaniline, 7
5-Bromo-N-[(4-methoxyphenyl)methyl]-4-methyl-2-nitroaniline, 8
5-Chloro-N1-[(2,4-dimethoxyphenyl)methyl]benzene-1,2-diamine, 9
5-Bromo-N1-[(4-methoxyphenyl)methyl]-4-methylbenzene-1,2-diamine, 10
6-Chloro-1-[(2,4-dimethoxyphenyl)methyl]-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide, 11
6-Bromo-1-[(4-methoxyphenyl)methyl]-5-methyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide, 12
5-Chloro-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide, 1e
5-Bromo-6-methyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide, 2a
1,3-Bis[(4-methoxyphenyl)methyl]-5-nitro-2,1,3-benzothiadiazole-2,2-dioxide, 13
5-Amino-1,3-bis[(4-methoxyphenyl)methyl]-2,1,3-benzothiadiazole-2,2-dioxide, 14
N-{1,3-Bis[(4-methoxyphenyl)methyl]-2,2-dioxo-2,1,3-benzothiadiazol-5-yl}acetamide, 15
N-(2,2-Dioxo-1H,3H-2,1,3-benzothiadiazol-5-yl)acetamide, 1f
4-Bromo-N-[(4-methoxyphenyl)methyl]-2-nitroaniline, 16
4-Bromo-N1-[(4-methoxyphenyl)methyl]benzene-1,2-diamine, 17
5-Bromo-1-[(4-methoxyphenyl)methyl]-3H-2,1,3-benzothiadiazole-2,2-dioxide, 18
5-Bromo-1,3-bis[(4-methoxyphenyl)methyl]-2,1,3-benzothiadiazole-2,2-dioxide, 19
Ethyl (2E)-3-{1,3-bis[(4-methoxyphenyl)methyl]-2,2-dioxo-2,1,3-benzothiadiazol-5-yl} prop-2-enoate, 20
(2E)-3-{1,3-Bis[(4-methoxyphenyl)methyl]-2,2-dioxo-2,1,3-benzothiadiazol-5-yl} prop-2-enoic acid, 21
(2E)-3-{1,3-Bis[(4-methoxyphenyl)methyl]-2,2-dioxo-2,1,3-benzothiadiazol-5-yl}-N-(3-methylbutyl)prop-2-enamide, 22
(2E)-3-{1,3-Bis[(4-methoxyphenyl)methyl]-2,2-dioxo-2,1,3-benzothiadiazol-5-yl}-N-phenylprop-2-enamide, 23
3-(2,2-Dioxo-1H,3H-2,1,3-benzothiadiazol-5-yl)-N-(3-methylbutyl)propanamide, 1g
3-(2,2-Dioxo-1H,3H-2,1,3-benzothiadiazol-5-yl)-N-phenylpropanamide, 1h
1,3-Bis[(4-methoxyphenyl)methyl]-5-phenyl-2,1,3-benzothiadiazole-2,2-dioxide, 24
5-Phenyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide, 1i
1,3-Dibenzyl-2,1,3-benzothiadiazole-2,2-dioxide, 3
1,3,5-Trimethyl-2,1,3-benzothiadiazole-2,2-dioxide, 2b
N-[(2,4-Dimethoxyphenyl)methyl]-2-nitroaniline, 25
N1-[(2,4-Dimethoxyphenyl)methyl]benzene-1,2-diamine, 26
1-[(2,4-Dimethoxyphenyl)methyl]-3H-2,1,3-benzothiadiazole-2,2-dioxide, 27
Ethyl 2-{3-[(2,4-dimethoxyphenyl)methyl]-2,2-dioxo-2,1,3-benzothiadiazol-1-yl}acetate, 28
2-{3-[(2,4-Dimethoxyphenyl)methyl]-2,2-dioxo-2,1,3-benzothiadiazol-1-yl} acetic acid, 29
2-{3-[(2,4-Dimethoxyphenyl)methyl]-2,2-dioxo-2,1,3-benzothiadiazol-1-yl}-N-phenethylacetamide, 30
2-(2,2-Dioxo-3H-2,1,3-benzothiadiazol-1-yl)-N-(2-phenylethyl)acetamide, 4
2,3-Dihydro-1H-1,3-benzodiazol-2-one, 5
3.3. Single Crystal X-ray Analysis
3.4. Biological Evaluation
3.5. Analytical Studies
3.5.1. MS, UV, and LC Analyses
Sample Preparation
MS Method
UV Method
LC Method
3.5.2. 1H-NMR Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the tested compounds (1a–i, 2a–b, 4–6) are available upon request from the authors. |
Compound | Structure | % Inhibition |
---|---|---|
1 | | 96.5 |
I | | 79.0 |
II | | 43.4 |
III | | 85.4 |
| ||
---|---|---|
Compound | Substituents | STAT3 % Inhibition (30 µM) |
1 | R, R1 = CH3; R2, R3 = H | 96.5 ± 1.1 [a] |
1a | R, R1, R2, R3 = H | 16.4 ± 0.8 [b] |
1b | R = H; R1 = CH3; R2, R3 = H | 14.5 ± 0.6 [b] |
1c | R = H; R1 = CF3; R2, R3 = H | 8.2 ± 1.6 [b] |
1d | R = H; R1 = NO2; R2, R3 = H | 56.9 ± 3.6 [c] |
1e | R = H; R1 = Cl; R2, R3 = H | 28.2 ± 1.4 [b] |
1f | R = H; R1 = NHCOCH3; R2, R3 = H | 18.9 ± 2.3 [b] |
1g | R = H; R1 = (CH2)2CONH(CH2)2CH3; R2, R3 = H | 11 ± 2.1 [b] |
1h | R = H; R1 = (CH2)2CONHPh; R2, R3 = H | n.a. |
1i | R = H; R1 = Ph; R2, R3 = H | 6.1 ± 0.9 [b] |
2a | R = CH3; R1 = Br; R2, R3 = H | 25.6 ± 1.2 [b] |
2b | R = H; R1, R2, R3 = CH3 | 8.9 ± 1.1 [b] |
3 | R, R1 = H; R2, R3 = CH2Ph | n.a. |
4 | R, R1, R3 = H; R2 = CH2CONH(CH2)2Ph | 17.3 ± 1.3 [b] |
5 | - | 3.5 ± 5.6 [b] |
6 | - | 11.5 ± 0.8 [b] |
Compound 1 vs. STAT3 | |||
---|---|---|---|
Mutated Cys | IC50 (µM) | Mutated Cys | IC50 (µM) |
WT | 15.8 ± 0.6 | Cys550A | >30 |
Cys468A | >30 | Cys687A | >30 |
Cys542A | >30 | Cys712A | >30 |
Time (min) | 1 mM HCl, pH 3 (A) | ACN (B) |
---|---|---|
0.00 | 95 | 5 |
1.00 | 95 | 5 |
16.00 | 30 | 70 |
16.50 | 30 | 70 |
16.51 | 95 | 5 |
22.00 | 95 | 5 |
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Mori, M.; Gilardoni, E.; Regazzoni, L.; Pedretti, A.; Colombo, D.; Parkinson, G.; Asai, A.; Meneghetti, F.; Villa, S.; Gelain, A. Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives. Molecules 2020, 25, 3509. https://doi.org/10.3390/molecules25153509
Mori M, Gilardoni E, Regazzoni L, Pedretti A, Colombo D, Parkinson G, Asai A, Meneghetti F, Villa S, Gelain A. Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives. Molecules. 2020; 25(15):3509. https://doi.org/10.3390/molecules25153509
Chicago/Turabian StyleMori, Matteo, Ettore Gilardoni, Luca Regazzoni, Alessandro Pedretti, Diego Colombo, Gary Parkinson, Akira Asai, Fiorella Meneghetti, Stefania Villa, and Arianna Gelain. 2020. "Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives" Molecules 25, no. 15: 3509. https://doi.org/10.3390/molecules25153509
APA StyleMori, M., Gilardoni, E., Regazzoni, L., Pedretti, A., Colombo, D., Parkinson, G., Asai, A., Meneghetti, F., Villa, S., & Gelain, A. (2020). Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives. Molecules, 25(15), 3509. https://doi.org/10.3390/molecules25153509