Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
Abstract
:1. Introduction
2. Results
2.1. Structural Search for Approved Drugs Similar to Colchicine—Site Antimitotics
2.2. Synthesis of Frentizole and Analogs
2.3. Biology
2.3.1. Antiproliferative Activity
2.3.2. Effect of the Compounds on the Cell Cycle
2.3.3. Cell Death Mechanism Studies
2.3.4. Effects on Cellular Microtubules
2.4. Computational Studies
2.4.1. DFT
2.4.2. Docking Studies
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.1.1. General Chemical Techniques
4.1.2. General Synthetic Methods
General Synthetic Method A1 for Bromination via Bromine
General Synthetic Method A2 for Bromination via N-Bromosuccinimide (NBS)
General Synthetic Method B for Amide Bond Formation
General Synthetic Method C for Urea Bond Formation
General Synthetic Method D for Carbamate Formation
General Synthetic Method E for Methylation
4.1.3. Chemical Synthesis and Characterization (Figure S8)
4-Bromo-6-methylbenzo[d]thiazol-2-amine (1b)
N-(6-methylbenzo[d]thiazol-2-yl)benzamide (3a)
N-(5,6-dimethylbenzo[d]thiazol-2-yl)benzamide (3c)
N-(5,6-dimethylbenzo[d]thiazol-2-yl)-N-methylbenzamide (3ca)
N-(6-methoxybenzo[d]thiazol-2-yl)benzamide (3e)
N-(6-methoxybenzo[d]thiazol-2-yl)-N-methylbenzamide (3ea)
N-(6-methylbenzo[d]thiazol-2-yl)-2-phenylacetamide (4a)
1-(4-Bromo-6-methylbenzo[d]thiazol-2-yl)-3-phenylurea (4b)
1-Ethyl-3-(6-methylbenzo[d]thiazol-2-yl)urea (5a)
1-(4-Bromo-6-methylbenzo[d]thiazol-2-yl)-3-ethylurea (5b)
1-(5,6-Dimethylbenzo[d]thiazol-2-yl)-3-ethylurea (5c)
1-(4-Bromo-5,6-dimethylbenzo[d]thiazol-2-yl)-3-ethylurea (5d)
1-Ethyl-3-(6-methoxybenzo[d]thiazol-2-yl)urea (5e)
1-(4-Bromo-6-methoxybenzo[d]thiazol-2-yl)-3-ethylurea (5f)
1-(6-Methylbenzo[d]thiazol-2-yl)-3-phenylurea (6a)
1-(5,6-Dimethylbenzo[d]thiazol-2-yl)-3-phenylurea (6c)
1-(5,6-Dimethylbenzo[d]thiazol-2-yl)-1-methyl-3-phenylurea (6ca)
1-(6-Methoxybenzo[d]thiazol-2-yl)-3-phenylurea (6e)
1-(6-Methoxybenzo[d]thiazol-2-yl)-1-methyl-3-phenylurea (6ea)
1-Benzyl-3-(6-methylbenzo[d]thiazol-2-yl)urea (7a)
1-Benzyl-3-(4-bromo-6-methylbenzo[d]thiazol-2-yl)urea (7b)
Ethyl (6-methylbenzo[d]thiazol-2-yl)carbamate (8a)
Ethyl (4-bromo-6-methylbenzo[d]thiazol-2-yl)carbamate (8b)
Phenyl (6-methylbenzo[d]thiazol-2-yl)carbamate (9a)
Phenyl (4-bromo-6-methyl-N-phenoxycarbonylbenzo[d]thiazol-2-yl)carbamate (9b)
Benzyl (6-methylbenzo[d]thiazol-2-yl)carbamate (10a)
4.2. Biology
4.2.1. Cell Culture Conditions
4.2.2. Cell Growth Inhibition Assay
4.2.3. Cell Cycle Analysis
4.2.4. Apoptotic Cell Death Quantification
4.2.5. Immunofluorescence Experiments
4.3. Computational Studies
4.3.1. Similarity Calculations
4.3.2. Configurational Calculations
4.3.3. Docking Calculations
4.3.4. Molecular Dynamics Simulations and MMGBSA Re-Scoring
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 | R4 | R5 | R6 | RN | X | R’ | HeLa | A-172 | U-87 MG | HEK-293 | J-774 |
---|---|---|---|---|---|---|---|---|---|---|---|
3a | H | H | Me | H | - | Ph | >10 | >10 | >10 | >10 | >10 |
3c | H | Me | Me | H | - | Ph | >10 | >10 | >10 | 5.68 | 7.73 |
3ca | H | Me | Me | Me | - | Ph | >10 | >10 | >10 | >10 | >10 |
3e | H | H | OMe | H | - | Ph | >10 | >10 | >10 | >10 | >10 |
3ea | H | H | OMe | Me | - | Ph | 0.74 | >10 | >10 | >10 | >10 |
4a | H | H | Me | H | - | Bn | >10 | >10 | >10 | >10 | >10 |
4b | Br | H | Me | H | - | Bn | >10 | >10 | >10 | >10 | >10 |
5a | H | H | Me | H | NH | Et | >10 | >10 | >10 | >10 | >10 |
5b | Br | H | Me | H | NH | Et | 0.49 | >10 | >10 | >10 | >10 |
5c | H | Me | Me | H | NH | Et | >10 | >10 | >10 | >10 | >10 |
5d | Br | Me | Me | H | NH | Et | 1.24 | >10 | >10 | >10 | >10 |
5e | H | H | OMe | H | NH | Et | >10 | >10 | >10 | >10 | >10 |
5f | Br | H | OMe | H | NH | Et | 0.7 | >10 | >10 | >10 | >10 |
6a | H | H | Me | H | NH | Ph | >10 | >10 | >10 | >10 | 1.97 |
6b | Br | H | Me | H | NH | Ph | >10 | >10 | >10 | >10 | >10 |
6c | H | Me | Me | H | NH | Ph | >10 | >10 | >10 | >10 | 0.27 |
6ca | H | Me | Me | Me | N | Ph | >10 | >10 | >10 | >10 | >10 |
6e | H | H | OMe | H | NH | Ph | 1 | >10 | 7.33 | 6.86 | >10 |
6ea | H | H | OMe | Me | N | Ph | >10 | >10 | >10 | >10 | >10 |
7a | H | H | Me | H | NH | Bn | >10 | >10 | >10 | >10 | >10 |
7b | Br | H | Me | H | NH | Bn | >10 | >10 | >10 | >10 | >10 |
8a | H | H | Me | H | O | Et | >10 | >10 | >10 | >10 | 0.26 |
8b | Br | H | Me | H | O | Et | >10 | >10 | >10 | >10 | >10 |
9a | H | H | Me | H | O | Ph | >10 | >10 | >10 | >10 | >10 |
9b 2 | Br | H | Me | H | O | Ph | >10 | >10 | >10 | >10 | >10 |
10a | H | H | Me | H | O | Bn | >10 | >10 | >10 | >10 | +/− |
10b | Br | H | Me | H | O | Bn | >10 | >10 | >10 | >10 | >10 |
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Ramos, S.; Vicente-Blázquez, A.; López-Rubio, M.; Gallego-Yerga, L.; Álvarez, R.; Peláez, R. Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition. Int. J. Mol. Sci. 2023, 24, 17474. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242417474
Ramos S, Vicente-Blázquez A, López-Rubio M, Gallego-Yerga L, Álvarez R, Peláez R. Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition. International Journal of Molecular Sciences. 2023; 24(24):17474. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242417474
Chicago/Turabian StyleRamos, Sergio, Alba Vicente-Blázquez, Marta López-Rubio, Laura Gallego-Yerga, Raquel Álvarez, and Rafael Peláez. 2023. "Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition" International Journal of Molecular Sciences 24, no. 24: 17474. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242417474