The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells
Abstract
:1. Introduction
2. Results
2.1. Effects of 6-Amino-SPD and 6-Morpholino-SPD on Apoptosis Induction and on Mitochondrial Membrane Potential (ΔΨm) in Leukemia Cells
2.2. Effects of 6-Amino-SPD and 6-Morpholino-SPD on Cytochrome c, Caspase 3, Akt, and CA IX Genes, and microRNA (miRNA) Expression Profiles
2.3. Changes in Protein Synthesis
2.4. ADMET Properties
3. Discussion
4. Materials and Methods
4.1. Cell Culturing
4.2. Annexin V/PI Assay
4.3. Measurement of ΔΨm
4.4. Determination of Intracellular Reactive Oxygen Species (ROS)
4.5. Real-Time Quantitative PCR (qPCR)
4.6. miRNA Expression
4.7. Western Blot
4.8. ADMET Properties Prediction
4.9. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Amino-SPD | Morpholino-SPD | Results Interpretation | |
---|---|---|---|
Medicinal Chemistry | |||
QED | 0.885 | 0.687 | >0.67 attractive compounds; ≤0.67 poor |
Synthetic accessibility score | 3.736 | 2.709 | ≤6 excellent; >6 poor |
Fsp3 | 0.077 | 0.235 | ≥0.42 excellent; <0.42 poor |
Lipinski rule | Accepted | Accepted | |
Absorption | |||
Caco-2 permeability | −5.009 | −4.479 | >−5.15 excellent; <−5.15 poor |
MDCK permeability | 6.5 × 10−6 | 1.70 × 10−5 | >2 × 10−6 cm/s excellent; <2 × 10−6 cm/s poor |
F30% | 0.996 | 0.813 | 0–0.3 excellent; 0.3–0.7 medium; 0.7–1.0 poor |
Distribution | |||
Plasma protein binding | 17.01% | 46.09% | ≤90% excellent; >90% poor |
Volume distribution | 1.121 | 0.812 | 0.04–20 excellent; otherwise poor |
BBB penetration | 0.359 | 0.923 | 0–0.3 excellent; 0.3–0.7 medium; 0.7–1.0 poor |
Fraction unbound in plasma (Fu) | 82.10% | 61.47% | >20% high Fu; 5–20% medium Fu; <5% low Fu |
Metabolism | |||
CYP2C9 substrate | 0.636 | 0.848 | probability of being substrate 0–1 |
Excretion | |||
Clearance of a drug | 4.683 | 6.78 | ≥5 excellent; <5 poor |
Half-life of a drug (T1/2) | 0.657 | 0.456 | 0–0.3 excellent; 0.3–0.7 medium; 0.7–1.0 poor |
Toxicity | |||
hERG blockers | 0.037 | 0.025 | 0–0.3 non-toxic; 0.3–0.7 medium; 0.7–1.0 toxic |
Human hepatotoxicity | 0.488 | 0.806 | probability of being toxic 0–1 |
Drug-induced liver injury | 0.975 | 0.993 | probability of being toxic 0–1 |
AMES toxicity | 0.216 | 0.796 | probability of being toxic 0–1 |
Rat oral acute toxicity | 0.630 | 0.141 | probability of being toxic 0–1 |
Skin sensitization | 0.259 | 0.936 | probability of being toxic 0–1 |
Carcinogenicity | 0.364 | 0.372 | probability of being toxic 0–1 |
Eye irritation | 0.029 | 0.095 | probability of being toxic 0–1 |
Respiratory toxicity | 0.921 | 0.378 | probability of being toxic 0–1 |
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Leventić, M.; Opačak-Bernardi, T.; Rastija, V.; Matić, J.; Pavlović Saftić, D.; Ban, Ž.; Žinić, B.; Glavaš-Obrovac, L. The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells. Molecules 2023, 28, 6136. https://doi.org/10.3390/molecules28166136
Leventić M, Opačak-Bernardi T, Rastija V, Matić J, Pavlović Saftić D, Ban Ž, Žinić B, Glavaš-Obrovac L. The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells. Molecules. 2023; 28(16):6136. https://doi.org/10.3390/molecules28166136
Chicago/Turabian StyleLeventić, Marijana, Teuta Opačak-Bernardi, Vesna Rastija, Josipa Matić, Dijana Pavlović Saftić, Željka Ban, Biserka Žinić, and Ljubica Glavaš-Obrovac. 2023. "The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells" Molecules 28, no. 16: 6136. https://doi.org/10.3390/molecules28166136
APA StyleLeventić, M., Opačak-Bernardi, T., Rastija, V., Matić, J., Pavlović Saftić, D., Ban, Ž., Žinić, B., & Glavaš-Obrovac, L. (2023). The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells. Molecules, 28(16), 6136. https://doi.org/10.3390/molecules28166136