Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine–Thiosemicarbazone Derivatives
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Cytotoxicity Assay
2.3. Human Topoisomerase IIα Inhibition Assay
2.4. Molecular Docking
2.5. DNA Interaction Studies
2.5.1. CT DNA Binding by UV–Vis Absorption Spectroscopy
2.5.2. Circular Dichroism
2.5.3. Fluorescent Studies with EtBr
2.6. Evaluation of the Non-Clinical Toxicity
2.7. Cytotoxicity Assay on Leukemic Normal and Resistant Cells
3. Materials and Methods
3.1. Chemicals, Reagents, and Equipment
3.2. Synthesis of the Novel Derivatives
3.2.1. Synthesis of 9-Chloroacridine Cores
- Route A:
- Route B:
3.2.2. Obtaining Thiosemicarbazone Intermediates
3.2.3. Obtaining Acridine–Thiosemicarbazone Derivatives (CL 01-10 and DL 01-10)
3.2.4. (E)-N-(acridin-9-yl)-2-benzylidenehydrazine-1-carbothioamide (CL-01)
3.2.5. (E)-N-(acridin-9-yl)-2-(4-chlorobenzylidene)hydrazine-1-carbothioamide (CL-02)
3.2.6. (E)-N-(acridin-9-yl)-2-(4-methoxybenzylidene)hydrazine-1-carbothioamide (CL-03)
3.2.7. (E)-N-(acridin-9-yl)-2-(2,4-dichlorobenzylidene)hydrazine-1-carbothioamide (CL-04)
3.2.8. (E)-N-(acridin-9-yl)-2-(4-nitrobenzylidene)hydrazine-1-carbothioamide (CL-05)
3.2.9. (E)-N-(acridin-9-yl)-2-(4-methylbenzylidene)hydrazine-1-carbothioamide (CL-06)
3.2.10. (E)-N-(acridin-9-yl)-2-(4-hydroxybenzylidene)hydrazine-1-carbothioamide (CL-07)
3.2.11. (E)-N-(acridin-9-yl)-2-(3-hydroxybenzylidene)hydrazine-1-carbothioamide (CL-08)
3.2.12. (E)-N-(acridin-9-yl)-2-(4-(dimethylamino)benzylidene)hydrazine-1-carbothioamide (CL-09)
3.2.13. (E)-N-(acridin-9-yl)-2-(4-bromobenzylidene)hydrazine-1-carbothioamide (CL-10)
3.2.14. (E)-2-benzylidene-N-(6-chloro-2-methoxyacridin-9-yl)hydrazine-1-carbothioamide (DL-01)
3.2.15. (E)-N-(6-chloro-2-methoxyacridin-9-yl)-2-(4-chlorobenzylidene)hydrazine-1-carbothioamide (DL-02)
3.2.16. (E)-N-(6-chloro-2-methoxyacridin-9-yl)-2-(4-methoxybenzylidene)hydrazine-1-carbothioamide (DL-03)
3.2.17. (E)-N-(6-chloro-2-methoxyacridin-9-yl)-2-(2,4-dichlorobenzylidene)hydrazine-1-carbothioamide (DL-04)
3.2.18. (E)-N-(6-chloro-2-methoxyacridin-9-yl)-2-(4-nitrobenzylidene)hydrazine-1-carbothioamide (DL-05)
3.2.19. (E)-N-(6-chloro-2-methoxyacridin-9-yl)-2-(4-methylbenzylidene)hydrazine-1-carbothioamide (DL-06)
3.2.20. (E)-N-(6-chloro-2-methoxyacridin-9-yl)-2-(4-hydroxybenzylidene)hydrazine-1-carbothioamide (DL-07)
3.2.21. (E)-N-(6-chloro-2-methoxyacridin-9-yl)-2-(3-hydroxybenzylidene)hydrazine-1-carbothioamide (DL-08)
3.2.22. (E)-N-(6-chloro-2-methoxyacridin-9-yl)-2-(4-(dimethylamino)benzylidene)hydrazine-1-carbothioamide (DL-09)
3.2.23. (E)-2-(4-bromobenzylidene)-N-(6-chloro-2-methoxyacridin-9-yl)hydrazine-1-carbothioamide (DL-10)
3.3. Cytotoxic Activity
3.3.1. Cells
3.3.2. Cytotoxicity Assay
3.4. Interaction with DNA
3.4.1. UV–Visible Spectroscopy
3.4.2. Circular Dichroism
3.4.3. Fluorescence Competition with EtBr
3.5. Human Topoisomerase IIα Inhibition Assay
3.6. Molecular Docking
3.7. Evaluation of the Non-Clinical Toxicity
3.7.1. Acute Toxicity Study (14 Days)
3.7.2. Necropsy, Macroscopic Analysis and Organ Weight
3.8. Cytotoxicity Assay on Leukemic Cells
3.8.1. Cells
3.8.2. Cytotoxicity Assay
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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R | Comp | IC50 (µM) 1 | |||
---|---|---|---|---|---|
HCT116 | HepG2 | B16-F10 | MRC-5 | ||
H | CL-01 | >70.00 | >70.00 | ND | >70.00 |
4-Cl | CL-02 | >70.00 | >70.00 | ND | >70.00 |
4-OCH3 | CL-03 | >70.00 | >70.00 | >70.00 | >70.00 |
2,4-Cl | CL-04 | >60.00 | >60.00 | ND | >60.00 |
4-NO2 | CL-05 | >60.00 | >60.00 | 22.71 | 26.78 |
16.60–31.09 | 22.26–32.19 | ||||
4-CH3 | CL-06 | 64.76 | 58.06 | 23.54 | 28.02 |
44.07–95.16 | 38.93–86.62 | 15.94–28.50 | 21.59–36.31 | ||
4-OH | CL-07 | 39.67 | 50.66 | 19.83 | 43.40 |
19.13–63.40 | 43.24–59.31 | 18.73–29.61 | 36.28–51.89 | ||
3-OH | CL-08 | 39.16 | 49.42 | 21.32 | 33.38 |
17.76–59.53 | 43.99–55.52 | 14.56–27.00 | 27.79–40.07 | ||
4-N(CH3)2 | CL-09 | >60.00 | >60.00 | ND | >60.00 |
4-Br | CL-10 | >60.00 | >60.00 | ND | >60.00 |
H | DL-01 | >60.00 | 21.87 | 39.56 | 36.97 |
15.97–29.97 | 24.11–64.89 | 25.35–53.97 | |||
4-Cl | DL-02 | >60.00 | >60.00 | 30.57 | >60.00 |
21.74–42.99 | |||||
4-OCH3 | DL-03 | >60.00 | >60.00 | >60.00 | >60.00 |
2,4-Cl | DL-04 | >60.00 | >60.00 | >60.00 | >60.00 |
4-NO2 | DL-05 | >60.00 | >60.00 | >60.00 | >60.00 |
4-CH3 | DL-06 | >60.00 | 33.38 | 26.26 | >60.00 |
23.64–47.13 | 14.81–46.53 | ||||
4-OH | DL-07 | 28.46 | 24.84 | 21.12 | 23.64 |
25.13–32.24 | 16.21–38.04 | 16.39–26.72 | 17.06–32.79 | ||
3-OH | DL-08 | 24.22 | 21.28 | 14.79 | 14.36 |
21.32–27.49 | 11.17–40.50 | 11.51–18.99 | 9.61–21.44 | ||
4-N(CH3)2 | DL-09 | >60.00 | >60.00 | 46.04 | >60.00 |
27.68–50.85 | |||||
4-Br | DL-10 | >50.00 | 20.88 | 34.62 | >50.00 |
11.22–38.83 | 25.74–53.55 | ||||
DOX 2 | 0.15 | 0.15 | 0.03 | 2.22 | |
5-FU 3 | 4.1 | 1.3 | 3.5 | 57.9 |
Compounds | mAMSA | DL01 | DL06 | DL07 | DL08 | CL07 |
---|---|---|---|---|---|---|
% of enzyme inhibition | 100 | 77 | - | 74 | 79 | - |
Compounds | Docking Score | Hydrogen Bond | Hydrophobic Interactions | |
---|---|---|---|---|
π-Alkyl | Stacked π–π | |||
CL-07 | 82.02 | T9a G10 * | Arg487 | A12 G13 |
DL-01 | 93.88 | Arg487 | T9 Arg487 | G13 |
DL-06 | 84.01 | - | T9 Arg487 | A12 G13 |
DL-07 | 97.98 | Arg487 T9a Ser464 G10 * | T9 Arg487 | A12 G13 |
DL-08 | 98.06 | Arg487 Asp463 Ser464 | T9 Arg487 | T9 G13 |
mAMSA | 95.21 | Asp463 Ser464 Arg487 | Arg487 | C8 T9 G13 |
Etoposide | 98.35 | Asp463 | T9 Arg487 | G13 Arg487 |
Compounds | Absorptive Properties | ||||
---|---|---|---|---|---|
λ Kb (nm) | ∆λ | R2 | Hypochromic (%) | Kb (104) (M−1) | |
CL-07 | 325 | 3 1 | 0.9586 | 25.52 | 4.51 ± 0.14 |
DL-01 | 320 | 2 2 | 0.9626 | 12.89 | 0.75 ± 0.07 |
DL-08 | 305 | 3 2 | 0.9708 | 14.79 | 1.73 ± 0.23 |
EtBr | 489 | 6 2 | 0.9652 | 35.15 | 5.56 ± 0.19 |
Compounds | Emissive Properties | ||
---|---|---|---|
R2 | Quenching (%) | Ksv (103) (M−1) | |
CL-07 | 0.9903 | 21.71 | 2.6 |
DL-01 | 0.9954 | 15.61 | 1.8 |
DL-08 | 0.9886 | 20.83 | 2.5 |
Toxicity Study | DA/TA | Mortality (%) | Signs of Toxicity |
---|---|---|---|
CL-07 | 0/3 | 0 | None |
DL-01 | 0/3 | 0 | Reduced feed consumption |
DL-08 | 0/3 | 0 | Hepatic steatosis |
NC | 0/3 | 0 | None |
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Sousa, G.; de Almeida, M.C.F.; Lócio, L.L.; dos Santos, V.L.; Bezerra, D.P.; Silva, V.R.; de Almeida, S.M.V.; Simon, A.; Honório, T.d.S.; Cabral, L.M.; et al. Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine–Thiosemicarbazone Derivatives. Pharmaceuticals 2022, 15, 1098. https://doi.org/10.3390/ph15091098
Sousa G, de Almeida MCF, Lócio LL, dos Santos VL, Bezerra DP, Silva VR, de Almeida SMV, Simon A, Honório TdS, Cabral LM, et al. Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine–Thiosemicarbazone Derivatives. Pharmaceuticals. 2022; 15(9):1098. https://doi.org/10.3390/ph15091098
Chicago/Turabian StyleSousa, Gleyton, Maria C. F. de Almeida, Lucas L. Lócio, Vanda L. dos Santos, Daniel P. Bezerra, Valdenizia R. Silva, Sinara M. V. de Almeida, Alice Simon, Thiago da S. Honório, Lucio M. Cabral, and et al. 2022. "Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine–Thiosemicarbazone Derivatives" Pharmaceuticals 15, no. 9: 1098. https://doi.org/10.3390/ph15091098
APA StyleSousa, G., de Almeida, M. C. F., Lócio, L. L., dos Santos, V. L., Bezerra, D. P., Silva, V. R., de Almeida, S. M. V., Simon, A., Honório, T. d. S., Cabral, L. M., Castro, R. N., de Moura, R. O., & Kümmerle, A. E. (2022). Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine–Thiosemicarbazone Derivatives. Pharmaceuticals, 15(9), 1098. https://doi.org/10.3390/ph15091098