Novel Pyrimidine Derivatives as Potential Anticancer Agents: Synthesis, Biological Evaluation and Molecular Docking Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Lipophilicity and QSAR Study
2.3. Biological Evaluation
2.3.1. Cytotoxicity Assay
2.3.2. Assessment of the Impact on the Transport Function of P-glycoprotein—Accumulation of Rhodamine 123 (Rod-123) in Cells
2.3.3. Verification of Apoptotic and Necrotic Cell Death
2.3.4. Cell Cycle
2.3.5. Cell Migration
2.4. Molecular Docking
3. Conclusions
4. Materials and Methods
4.1. Instruments and Materials
4.2. Synthesis
4.3. Lipophilicity and QSAR Studies
4.4. Tested Compounds
4.4.1. Cell Lines and Conditions
4.4.2. Viability Assay
4.4.3. Assessment of the Impact on the Transport Function of P-glycoprotein—Accumulation of Rhodamine 123 (Rod-123) in Cells
4.4.4. Verification of Apoptotic and Necrotic Cell Death
4.4.5. Cell Cycle
4.4.6. Cell Migration
4.5. Statistical Analysis
4.6. Molecular docking
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 | Lipinski’s Rules | Veber’s Rules | |||||
---|---|---|---|---|---|---|---|
MW ≤ 500 | Log P ≤ 5 | NHD ≤ 5 | NHA ≤ 10 | Violations of Rules | NBR ≤ 10 | TPSA ≤ 140 | |
Doxorubicin | 543.52 | 0.52 | 6 | 12 | 3 | 5 | 206.07 |
4 | 382.50 | 3.14 | 2 | 5 | 0 | 9 | 74.67 |
5 | 354.45 | 2.47 | 2 | 5 | 0 | 7 | 74.67 |
6 | 341.41 | 2.45 | 3 | 5 | 0 | 7 | 91.66 |
7 | 368.48 | 2.77 | 2 | 5 | 0 | 8 | 74.67 |
Compound | Log Po/w | Consensus log Po/w |
---|---|---|
Doxorubicin | –0.18 | 0.52 |
4 | 1.05 | 3.14 |
5 | 1.53 | 2.47 |
7 | 1.25 | 2.77 |
Compound | ΔGbinding (kJ/mol) | Ki (µM) | ΔGint (kJ/mol) | ΔGvdw + ΔGhbond + ΔGdesolv (kJ/mol) | ΔGel (kJ/mol) |
---|---|---|---|---|---|
4 | −30.8 | 4.12 | −42.0 | −41.6 | −0.4 |
5 | −29.0 | 8.56 | −37.7 | −37.5 | −0.2 |
6 | −26.3 | 24.36 | −36.3 | −35.5 | −0.8 |
7 | −27.0 | 15.77 | −37.0 | −36.8 | −0.2 |
Etoposide | −44.6 | 0.02 | −50.9 | −50.6 | −0.3 |
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Tylińska, B.; Wiatrak, B.; Czyżnikowska, Ż.; Cieśla-Niechwiadowicz, A.; Gębarowska, E.; Janicka-Kłos, A. Novel Pyrimidine Derivatives as Potential Anticancer Agents: Synthesis, Biological Evaluation and Molecular Docking Study. Int. J. Mol. Sci. 2021, 22, 3825. https://doi.org/10.3390/ijms22083825
Tylińska B, Wiatrak B, Czyżnikowska Ż, Cieśla-Niechwiadowicz A, Gębarowska E, Janicka-Kłos A. Novel Pyrimidine Derivatives as Potential Anticancer Agents: Synthesis, Biological Evaluation and Molecular Docking Study. International Journal of Molecular Sciences. 2021; 22(8):3825. https://doi.org/10.3390/ijms22083825
Chicago/Turabian StyleTylińska, Beata, Benita Wiatrak, Żaneta Czyżnikowska, Aneta Cieśla-Niechwiadowicz, Elżbieta Gębarowska, and Anna Janicka-Kłos. 2021. "Novel Pyrimidine Derivatives as Potential Anticancer Agents: Synthesis, Biological Evaluation and Molecular Docking Study" International Journal of Molecular Sciences 22, no. 8: 3825. https://doi.org/10.3390/ijms22083825