Synthesis of 1,3,4-Thiadiazole Derivatives and Their Anticancer Evaluation
Abstract
:1. Introduction
2. Results
2.1. Synthesis Procedures
2.2. Anti-Cancer Evaluation
2.2.1. Effects on Cell Viability
2.2.2. Apoptosis Analysis
2.2.3. The Effect on Cell Cycle Phases
2.3. Daphnia Magna Toxicity Assay
2.4. Prediction of the Molecular Mechanism of Action
2.5. Molecular Docking
3. Discussion
4. Materials and Methods
4.1. Analytical Procedures
4.2. Synthesis Procedures
4.2.1. General Procedure for the Synthesis of 5-Aryl-1,3,4-thiadiazole-2-amine Derivatives (2a–g)
4.2.2. 5-Phenyl-1,3,4-thiadiazol-2-amine (2a)
4.2.3. 5-(4-Methylphenyl)-1,3,4-thiadiazol-2-amine (2b)
4.2.4. 5-(3,4-Dihydroxyphenyl)-1,3,4-thiadiazol-2-amine (2c)
4.2.5. 5-(2,5-Dimethoxyphenyl)-1,3,4-thiadiazol-2-amine (2d)
4.2.6. 5-(3,4,5-Trimethoxyphenyl)-1,3,4-thiadiazol-2-amine (2e)
4.2.7. 5-[2-(Phenylthiomethyl)phenyl]-1,3,4-thiadiazol-2-amine (2f)
4.2.8. 5-[2-(Benzenesulfonylmethyl)phenyl]-1,3,4-thiadiazol-2-amine (2g)
4.2.9. Synthesis of N-(5-Phenyl-1,3,4-thiadiazol-2-yl)acetamide (3a)
4.2.10. General Procedure for the Synthesis of 1,3,4-thiadiazol-2-amide Derivatives (3b,c)
4.2.11. N-(5-Phenyl-1,3,4-thiadiazol-2-yl)benzamide (3b)
4.2.12. 2-Phenylthiomethyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzamide (3c)
4.3. Anticancer Evaluation
4.3.1. Reagents
4.3.2. Cell Culture and Treatments
4.3.3. Cytotoxicity Assay
4.3.4. Apoptosis Analysis
4.3.5. Cell Cycle Analysis
4.4. Daphnia Magna Toxicity Assay
4.5. Prediction of the Molecular Mechanism of Action
4.6. Molecular Docking
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Substance | IC50 (24 h) | IC50 (48 h) | ||||
---|---|---|---|---|---|---|
HUVEC | LoVo | MCF-7 | HUVEC | LoVo | MCF-7 | |
2a | >400 | 203.60 | >400 | 83.77 | 62.16 | >400 |
2b | >400 | 133.70 | >400 | 70.92 | 124.5 | >400 |
2c | >400 | 163.3 | >400 | 155.10 | 117.40 | 397.80 |
2d | >400 | 53.64 | 154.30 | 94.80 | 29.16 | 121.50 |
2e | >400 | 107.60 | >400 | 300.30 | 79.19 | >400 |
2f | >400 | >400 | >400 | >400 | 80.70 | >400 |
2g | >400 | 18.08 | 43.34 | 44.55 | 2.44 | 23.29 |
3a | >400 | >400 | >400 | >400 | >400 | >400 |
3b | >400 | 174.10 | >400 | >400 | 62.53 | >400 |
3c | >400 | >400 | >400 | >400 | >400 | >400 |
Cis-Pt | 11.14 | 12.84 | NT * | 8.23 | 80.13 | NT * |
DOX | 1.03 | NT * | 129.10 | 1.35 | NT * | 87.39 |
Substance | Conc. | Total Apoptosis (%) 24 h | Total Apoptosis (%) 48 h | ||||
---|---|---|---|---|---|---|---|
HUVEC | LoVo | MCF-7 | HUVEC | LoVo | MCF-7 | ||
Control | - | 9.4 | 5.2 | 6.1 | 11.2 | 8.7 | 10.3 |
2a | 5 μM | 12.8 | 9.0 | 11.8 | 14.7 | 17.6 | 24.4 |
50 μM | 15.0 | 8.9 | 9.8 | 18.4 | 13.7 | 24.7 | |
2b | 5 μM | 16.7 | 6.9 | 8.0 | 15.7 | 14.0 | 16.7 |
50 μM | 13.6 | 6.3 | 8.4 | 16.6 | 12.3 | 25.4 | |
2c | 5 μM | 16.6 | 7.5 | 11.7 | 15.6 | 13.0 | 26.6 |
50 μM | 12.1 | 6.8 | 7.6 | 12.1 | 13.8 | 15.1 | |
2d | 5 μM | 28.4 | 13.5 | 14.6 | 14.4 | 19.3 | 37.6 |
50 μM | 19.8 | 12.0 | 11.8 | 16.8 | 17.9 | 34.9 | |
2e | 5 μM | 26.3 | 4.9 | 9.1 | 13.1 | 14.3 | 24.6 |
50 μM | 24.3 | 16.4 | 14.9 | 15.5 | 19.9 | 34.2 | |
2f | 5 μM | 19.9 | 14.9 | 22.0 | 15.9 | 27.0 | 44.0 |
50 μM | 18.6 | 8.2 | 12.6 | 14.6 | 17.4 | 45.0 | |
2g | 5 μM | 19.0 | 13.6 | 18.7 | 14.7 | 23.6 | 42.2 |
50 μM | 19.3 | 19.6 | 19.7 | 14.1 | 24.8 | 44.5 | |
3a | 5 μM | 26.6 | 14.9 | 17.6 | 18.2 | 20.1 | 24.9 |
50 μM | 22.6 | 14.5 | 17.9 | 20.1 | 22.3 | 47.9 | |
3b | 5 μM | 17.8 | 12.5 | 19.2 | 15.3 | 22.2 | 43.7 |
50 μM | 17.0 | 12.6 | 16.4 | 15.9 | 20.9 | 41.3 | |
3c | 5 μM | 15.5 | 14.8 | 16.4 | 13.5 | 27.6 | 39.3 |
50 μM | 16.9 | 11.2 | 14.3 | 14.7 | 24.5 | 37.3 | |
Cis-Pt | 5 μM | 15.7 | 15.7 | - | 14.8 | 31.6 | - |
50 μM | 21.7 | 24.5 | - | 17.4 | 38.7 | - | |
DOX | 5 μM | 15.2 | - | 14.8 | 9.5 | - | 33.6 |
50 μM | 18.6 | - | 19.0 | 10.6 | - | 49.0 |
Compound | 24 h | 48 h | ||||
---|---|---|---|---|---|---|
Maximum Average L% | LC50 (µM) | 95%CI of LC50 (µM) | Maximum Average L% | LC50 (µM) | 95%CI of LC50 (µM) | |
2a | 0 | ND | - | 40 | ND | - |
2b | 10 | ND | - | 55 | 143.60 | 21.0–980.0 |
2c | 0 | ND | - | 25 | ND | - |
2d | 40 | 240.80 | 138.7–418.1 | 95 | 50.66 | 31.7–80.9 |
2e | 0 | ND | - | 5 | ND | - |
2f | 5 | ND | - | 10 | ND | - |
2g | 0 | ND | - | 20 | ND | - |
3a | 95 | <6.25 | - | 100 | <6.25 | - |
3b | 5 | ND | - | 45 | 228.30 | 93.53–557.1 |
3c | 10 | ND | - | 55 | 188.5 | 69.59–510.4 |
Target | 2a | 2b | 2c | 2d | 2e | 2f | 2g | 3a | 3b | 3c |
---|---|---|---|---|---|---|---|---|---|---|
Transcription factor STAT inhibitor | 0.45 | 0.48 | 0.39 | 0.37 | 0.37 | 0.47 | 0.23 | 0.67 | 0.73 | 0.64 |
Transcription factor STAT3 inhibitor | 0.44 | 0.48 | 0.39 | 0.38 | 0.38 | 0.35 | – | 0.70 | 0.74 | 0.67 |
Mcl-1 antagonist | 0.44 | 0.40 | 0.44 | 0.32 | 0.37 | 0.43 | 0.31 | 0.49 | 0.55 | 0.46 |
Kinase inhibitor | – | – | 0.38 | – | – | – | – | – | – | – |
Protein kinase AGC family inhibitor | 0.23 | 0.17 | 0.18 | 0.13 | 0.15 | 0.09 | – | 0.22 | 0.24 | 0.14 |
Protein kinase B inhibitor | 0.37 | 0.30 | 0.24 | 0.18 | 0.23 | 0.14 | 0.11 | 0.25 | 0.15 | 0.08 |
Protein kinase B alpha inhibitor | 0.32 | 0.28 | 0.30 | 0.26 | 0.26 | 0.19 | 0.14 | 0.17 | 0.23 | – |
Cyclin-dependent kinase inhibitor | 0.31 | 0.19 | 0.14 | 0.10 | 0.13 | 0.08 | 0.09 | 0.47 | 0.30 | 0.13 |
Cyclin-dependent kinase 2 inhibitor | 0.29 | 0.18 | 0.12 | 0.12 | 0.12 | 0.09 | 0.08 | 0.41 | 0.26 | 0.12 |
CDK9/cyclin T1 inhibitor | 0.47 | 0.43 | 0.46 | 0.36 | 0.35 | 0.36 | 0.32 | – | 0.24 | – |
Pfmrk inhibitor | 0.20 | 0.20 | 0.16 | – | – | – | – | 0.16 | 0.23 | – |
MAP3K5 inhibitor | 0.23 | – | – | – | – | 0.25 | – | 0.35 | 0.35 | 0.30 |
MAP kinase kinase 4 inhibitor | 0.27 | 0.23 | 0.31 | 0.25 | 0.23 | – | – | – | 0.21 | – |
p21-activated kinase 1 inhibitor | 0.20 | – | 0.22 | 0.20 | – | – | – | – | 0.19 | – |
Protein-tyrosine kinase (PTK) inhibitor | 0.32 | 0.26 | 0.25 | 0.37 | 0.24 | 0.13 | 0.15 | 0.18 | 0.28 | 0.14 |
Abl kinase inhibitor | 0.31 | 0.26 | 0.24 | 0.37 | 0.23 | 0.13 | 0.14 | 0.18 | 0.28 | 0.13 |
Tyrosine-protein kinase Fgr inhibitor | – | – | 0.20 | – | – | – | – | – | 0.44 | 0.30 |
Protein-tyrosine kinase p55 (blk) inhibitor | – | – | – | – | – | – | – | – | 0.22 | – |
Focal adhesion kinase inhibitor | 0.20 | 0.18 | – | 0.20 | 0.22 | – | – | 0.21 | 0.28 | 0.19 |
Focal adhesion kinase 2 inhibitor | 0.28 | 0.27 | 0.22 | 0.24 | 0.29 | – | – | 0.27 | 0.37 | 0.27 |
Platelet-derived growth factor receptor kinase inhibitor | – | 0.26 | – | – | – | – | – | – | 0.37 | – |
Proteasome ATPase inhibitor | – | – | – | – | – | – | – | 0.47 | – | – |
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Stecoza, C.E.; Nitulescu, G.M.; Draghici, C.; Caproiu, M.T.; Hanganu, A.; Olaru, O.T.; Mihai, D.P.; Bostan, M.; Mihaila, M. Synthesis of 1,3,4-Thiadiazole Derivatives and Their Anticancer Evaluation. Int. J. Mol. Sci. 2023, 24, 17476. https://doi.org/10.3390/ijms242417476
Stecoza CE, Nitulescu GM, Draghici C, Caproiu MT, Hanganu A, Olaru OT, Mihai DP, Bostan M, Mihaila M. Synthesis of 1,3,4-Thiadiazole Derivatives and Their Anticancer Evaluation. International Journal of Molecular Sciences. 2023; 24(24):17476. https://doi.org/10.3390/ijms242417476
Chicago/Turabian StyleStecoza, Camelia Elena, George Mihai Nitulescu, Constantin Draghici, Miron Teodor Caproiu, Anamaria Hanganu, Octavian Tudorel Olaru, Dragos Paul Mihai, Marinela Bostan, and Mirela Mihaila. 2023. "Synthesis of 1,3,4-Thiadiazole Derivatives and Their Anticancer Evaluation" International Journal of Molecular Sciences 24, no. 24: 17476. https://doi.org/10.3390/ijms242417476