8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules †
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of HQCl-D-Pro and HQCl-D-hPro, Their Ru(η6-p-cymene) and Rh(η5-C5Me5) Complexes
2.2. Structural Studies of [RhCp*(HQCl-D-hPro)Cl]Cl∙H2O∙CH3OH (1) by X-ray Crystallography
2.3. In Vitro Cytotoxicity and Induction of Apoptosis of the Ligands and Their Complexes
2.4. Solution Chemical Behavior of the Title Ligands and Their Organometallic Complexes
2.4.1. Solution Equilibria and Lipophilicity of HQCl-D-Pro and HQCl-D-hPro
2.4.2. Solution Equilibria and Lipophilicity of the Title Organometallic Complexes
2.5. Binding of the Complexes to Biological Macromolecules
2.5.1. Interaction of the Complexes with Human Serum Albumin
2.5.2. Interaction of the Complexes with DNA
3. Materials and Methods
3.1. Chemicals
3.2. Stock Solutions and Sample Preparation
3.3. Synthesis and Characterization of Ligands and Their Complexes
3.3.1. Synthesis of HQCl-D-Pro
3.3.2. Synthesis of HQCl-D-hPro
3.3.3. Synthesis of [RuCym(HQCl-D-Pro)Cl]Cl
3.3.4. Synthesis of [RhCp*(HQCl-D-Pro)Cl]Cl
3.3.5. Synthesis of [RuCym(HQCl-D-hPro)Cl]Cl
3.3.6. Synthesis of [RhCp*(HQCl-D-hPro)Cl]Cl
3.4. Electrospray Mass Spectrometry
3.5. pH-Potentiometric Measurements
3.6. UV-Visible Spectrophotometry and Determination of Distribution Coefficients
3.7. Circular Dichroism Spectroscopy and Spectrofluorometry
3.8. NMR Spectroscopy
3.9. Capillary Zone Electrophoresis
3.10. X-ray Data Collection, Structure Solution and Refinement for Compound [RhCp*(HQCl-D-hPro)Cl]Cl∙H2O∙CH3OH
3.11. In Vitro Cell Studies
3.11.1. Cell Lines and Culture Conditions
3.11.2. MTT Assay
3.11.3. Assay for Apoptosis Induction
3.12. In Vitro DNA Cleavage Analysis
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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IC50 (μM) | Colo-205 | Colo-320 | MRC-5 |
---|---|---|---|
HQCl-L-Pro a | 20.92 ± 0.80 | 12.87 ± 0.74 | 4.57 ± 0.21 |
HQCl-D-Pro | 17.0 ± 1.0 | 13.41 ± 0.79 | 5.33 ± 0.44 |
HQCl-D-hPro | 18.9 ± 1.1 | 11.9 ± 1.5 | 3.63 ± 0.10 |
RhCp*–HQCl-D-Pro | 31.5 ± 1.4 | 34.3 ± 1.0 | 82.1 ± 5.1 |
RhCp*–HQCl-D-hPro | 21.54 ± 0.60 | 18.90 ± 0.54 | 37.6 ± 2.3 |
RuCym–HQCl-D-Pro | >100 | >100 | >100 |
RuCym–HQCl-D-hPro | >100 | >100 | >100 |
doxorubicin | 0.05 ± 0.01 | 0.19 ± 0.02 | 0.82 ± 0.16 |
Method | Ligand | pKa (NqH+) | pKa (OH) | pKa (NhPro/ProH+) |
---|---|---|---|---|
pH-potentiometry | HQCl-D-Pro a | < 2 | 7.71 ± 0.06 | >11 |
HQCl-D-hPro | 2.42 ± 0.04 | 7.52 ± 0.06 | >11 | |
UV-vis | HQCl-D-Pro | 2.13 ± 0.03 | 7.77 ± 0.04 | >11 |
HQCl-D-hPro | 2.43 ± 0.01 | 7.49 ± 0.04 | 11.43 ± 0.01 | |
1H NMR | HQCl-D-Pro | 2.32 ± 0.03 | 7.75 ± 0.02 | >11 |
HQCl-D-hPro | 2.52 ± 0.03 | 7.54 ± 0.02 | >11 |
Complex | Method | pKa1 | pKa2 | logK′ (H2O/Cl−) |
---|---|---|---|---|
RhCp*–HQCl-D-Pro | UV-vis | 10.08 ± 0.02 | – | 1.72 ± 0.01 |
RhCp*–HQCl-D-hPro | UV-vis | 10.11 ± 0.02 | – | 1.79 ± 0.01 |
1H NMR | 9.82 ± 0.13 a | 10.06 ± 0.06 b | – | |
RuCym–HQCl-D-Pro | UV-vis | 8.96 ± 0.01 | 10.67 ± 0.01 | 1.18 ± 0.01 |
1H NMR | 9.02 ± 0.07 | 10.69 ± 0.06 | – | |
RuCym–HQCl-D-hPro | UV-vis | 8.78 ± 0.01 | 10.03 ± 0.02 | 1.28 ± 0.01 |
1H NMR | 8.77 ± 0.05 | 10.13 ± 0.04 | – |
FHA logKFHA′ | Trp-214 Quenching logKQ′, Site I | DG Displacement logKDG′, Site II | |
---|---|---|---|
RhCp*–HQCl-L-Pro a | 4.7 | 5.5 | 5.6 |
RuCym–HQCl-L-Pro a | 5.1 | 5.7 | 6.1 |
RhCp*–HQCl-D-Pro | 4.4 ± 0.2 | 5.6 ± 0.1 | 5.5 ± 0.1 |
RuCym–HQCl-D-Pro | 4.4 ± 0.3 | 5.5 ± 0.1 | 5.6 ± 0.1 |
RhCp*–HQCl-D-hPro | 4.5 ± 0.2 | 5.6 ± 0.1 | 5.4 ± 0.1 |
RuCym–HQCl-D-hPro | 4.6 ± 0.2 | 5.3 ± 0.1 | 5.7 ± 0.1 |
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Pivarcsik, T.; Dömötör, O.; Mészáros, J.P.; May, N.V.; Spengler, G.; Csuvik, O.; Szatmári, I.; Enyedy, É.A. 8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules. Int. J. Mol. Sci. 2021, 22, 11281. https://doi.org/10.3390/ijms222011281
Pivarcsik T, Dömötör O, Mészáros JP, May NV, Spengler G, Csuvik O, Szatmári I, Enyedy ÉA. 8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules. International Journal of Molecular Sciences. 2021; 22(20):11281. https://doi.org/10.3390/ijms222011281
Chicago/Turabian StylePivarcsik, Tamás, Orsolya Dömötör, János P. Mészáros, Nóra V. May, Gabriella Spengler, Oszkár Csuvik, István Szatmári, and Éva A. Enyedy. 2021. "8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules" International Journal of Molecular Sciences 22, no. 20: 11281. https://doi.org/10.3390/ijms222011281
APA StylePivarcsik, T., Dömötör, O., Mészáros, J. P., May, N. V., Spengler, G., Csuvik, O., Szatmári, I., & Enyedy, É. A. (2021). 8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules. International Journal of Molecular Sciences, 22(20), 11281. https://doi.org/10.3390/ijms222011281