Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Carbonic Anhydrase Inhibition
2.2.2. Antitumor Activity
Antitumor Activity towards 60 Cancer Cell Lines (NCI, USA)
Anti-Proliferative Activity towards Renal Cancer UO-31 Cell Line
Cell Cycle Analysis
Annexin V-FITC Apoptosis Assay
2.3. Molecular Modelling Study
3. Materials and Methods
3.1. Chemistry
3.1.1. General
3.1.2. General Procedure for Preparation of Target Diamide-Based Benzenesulfonamides 5a–h
N-(1-(4-Chlorophenyl)-3-oxo-3-((4-sulfamoylphenyl)amino)prop-1-en-2-yl)benzamide (5a)
N-(1-(2,4-Dichlorophenyl)-3-oxo-3-((4-sulfamoylphenyl)amino)prop-1-en-2-yl)benzamide (5b)
N-(1-(4-Bromophenyl)-3-oxo-3-((4-sulfamoylphenyl)amino)prop-1-en-2-yl)benzamide (5c)
N-(3-Oxo-3-((4-sulfamoylphenyl)amino)-1-(p-tolyl)prop-1-en-2-yl)benzamide (5d)
N-(1-(4-Methoxyphenyl)-3-oxo-3-((4-sulfamoylphenyl)amino)prop-1-en-2-yl)benzamide (5e)
N-(1-(2,4-Dimethoxyphenyl)-3-oxo-3-((4-sulfamoylphenyl)amino)prop-1-en-2-yl)benzamide (5f)
N-(1-(3,4-Dimethoxyphenyl)-3-oxo-3-((4-sulfamoylphenyl)amino)prop-1-en-2-yl)benzamide (5g)
N-(1-(5-Methylfuran-2-yl)-3-oxo-3-((4-sulfamoylphenyl)amino)prop-1-en-2-yl)benzamide (5h)
3.2. Biological Evaluation
3.2.1. CA Inhibitory Assay
3.2.2. Anticancer Activity towards 60 Cancer Cell Lines (NCI, Bethesda, MD, USA)
3.2.3. Antiproliferative Activity towards Renal Cancer UO-31 Cell Line
3.2.4. Cell Cycle Analysis
3.2.5. Annexin V-FITC Apoptosis Assay
3.2.6. Molecular Docking Simulations
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Comp. | R | R1 | R2 | KI (nM)* | |||
---|---|---|---|---|---|---|---|
hCA I | hCA II | hCA IX | hCA XII | ||||
5a | H | H | Cl | 3955.7 | 68.3 | 8.8 | 16.1 |
5b | Cl | H | Cl | 5977.6 | 223.9 | 18.3 | 10.5 |
5c | H | H | Br | 2397.8 | 251.9 | 33.5 | 55.4 |
5d | H | H | CH3 | 796.1 | 94.4 | 62.1 | 60.2 |
5e | H | H | OCH3 | 1006.4 | 127.7 | 78.0 | 42.8 |
5f | OCH3 | H | OCH3 | 5132.7 | 294.2 | 73.7 | 134.5 |
5g | H | OCH3 | OCH3 | 2207.7 | 448.0 | 123.3 | 9.8 |
5h | - | - | - | 8175.4 | 114.8 | 8.3 | 57.9 |
AAZ | - | - | - | 250.0 | 12.0 | 25.0 | 5.7 |
Cmpd | I/IX | II/IX | I/XII | II/XII |
---|---|---|---|---|
5a | 449.5 | 7.8 | 245.7 | 4.2 |
5b | 326.6 | 12.2 | 569.2 | 21.3 |
5c | 71.6 | 7.5 | 43.3 | 4.5 |
5d | 12.8 | 1.5 | 13.2 | 1.7 |
5e | 12.9 | 1.4 | 23.5 | 3 |
5f | 69.9 | 4 | 38.2 | 2.2 |
5g | 17.9 | 3.6 | 225.3 | 45.7 |
5h | 985 | 13.8 | 141.2 | 2 |
AAZ | 10.0 | 0.5 | 43.9 | 2.2 |
Compound | IC50 (μM) a |
---|---|
UO-31 | |
5a | 6.53 ± 0.38 |
5b | 16.68 ± 0.92 |
5h | 4.89 ± 0.22 |
Staurosporine | 7.25 ± 0.43 |
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Abdelrahman, M.A.; Eldehna, W.M.; Nocentini, A.; Bua, S.; Al-Rashood, S.T.; Hassan, G.S.; Bonardi, A.; Almehizia, A.A.; Alkahtani, H.M.; Alharbi, A.; et al. Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights. Int. J. Mol. Sci. 2019, 20, 2484. https://doi.org/10.3390/ijms20102484
Abdelrahman MA, Eldehna WM, Nocentini A, Bua S, Al-Rashood ST, Hassan GS, Bonardi A, Almehizia AA, Alkahtani HM, Alharbi A, et al. Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights. International Journal of Molecular Sciences. 2019; 20(10):2484. https://doi.org/10.3390/ijms20102484
Chicago/Turabian StyleAbdelrahman, Mohamed A., Wagdy M. Eldehna, Alessio Nocentini, Silvia Bua, Sara T. Al-Rashood, Ghada S. Hassan, Alessandro Bonardi, Abdulrahman A. Almehizia, Hamad M. Alkahtani, Amal Alharbi, and et al. 2019. "Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights" International Journal of Molecular Sciences 20, no. 10: 2484. https://doi.org/10.3390/ijms20102484
APA StyleAbdelrahman, M. A., Eldehna, W. M., Nocentini, A., Bua, S., Al-Rashood, S. T., Hassan, G. S., Bonardi, A., Almehizia, A. A., Alkahtani, H. M., Alharbi, A., Gratteri, P., & Supuran, C. T. (2019). Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights. International Journal of Molecular Sciences, 20(10), 2484. https://doi.org/10.3390/ijms20102484