Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis and Characterization of the HQNO2-L-Pro ligand and Its Ru(η6-p-cymene) and Rh(η5-C5Me5) Complexes
2.2. Solution Characterization of the HQNO2-L-Pro
2.3. Complex Formation of the HQNO2-L-Pro Ligand with Essential Metal Ions
2.3.1. Solution Equilibrium of the Fe(III) and Fe(II) Complexes
2.3.2. Solution Equilibrium of the Cu(II) and Zn(II) Complexes
2.4. Solution Speciation of the RhCp* and RuCym Complexes of HQNO2-L-Pro
2.5. Interaction of the RuCym and RhCp* Complexes of HQNO2-L-Pro with HSA
2.6. Cellular Effects
2.6.1. Inhibitory Effect of HQNO2-L-Pro on Organic Anion Transporting Polypeptides
2.6.2. Anticancer Activity of the HQNO2-L-Pro and Its Half-Sandwich Organometallic Complexes
2.6.3. Antibacterial Activity of the HQNO2-L-Pro and Its Half-Sandwich Organometallic Complexes
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 HQNO2-L-Pro
3.3.2. Synthesis of [RuCym(HQNO2-L-Pro)Cl]Cl
3.3.3. Synthesis of [RhCp*(HQNO2-L-Pro)Cl]Cl
3.4. Electrospray Mass Spectrometry
3.5. PH-Potentiometric Measurements
3.6. UV-Visible Spectrophotometry, Spectrofluorometry, and Circular Dichroism Spectroscopy
3.7. NMR and EPR Spectroscopy
3.8. Determination of Distribution Coefficients
3.9. Cyclic Voltammetry
3.10. Capillary Zone Electrophoresis
3.11. OATP Uptake Assay
3.12. In Vitro Cell Studies: Cell Lines and Culture Conditions and Cytotoxicity Assay
3.13. Antibacterial Effect: Bacterial Culture and Determination of MIC Values
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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Method | Ionic Strength (I) | pKa (OH) | pKa (NProH+) | cligand/μM |
---|---|---|---|---|
pH-potentiometry | 0.20 M KNO3 | 5.57 ± 0.09 | 10.68 ± 0.07 | 1700 |
1H NMR | 0.20 M KNO3 | 5.56 ± 0.03 | >10.5 | 1000 |
UV-vis | 0.20 M KNO3 | 5.50 ± 0.03 | 10.78 ± 0.03 | 40 |
UV-vis | 0.10 M KCl | 5.43 ± 0.03 | 10.75 ± 0.03 | 40 |
logβ | Fe(III) | Fe(II) | Cu(II) | Zn(II) |
---|---|---|---|---|
[M(HL)] | 19.75 ± 0.03 | 16.52 ± 0.03 | 19.40 ± 0.03 | 17.36 ± 0.03 |
[M(L)] | − | 8.39 ± 0.03 | 14.45 ± 0.03 | n.d. a |
[M(HL)2] | 38.76 ± 0.03 | 32.74 ± 0.03 | 38.60 ± 0.03 | 33.71 ± 0.06 |
[M(HL)(L)] | − | − | 31.75 ± 0.03 | n.d. a |
[M(L)2] | − | − | 22.99 ± 0.03 | n.d. a |
[M(HL)3] | 55.66 ± 0.03 | 47.60 ± 0.06 | − | − |
RhCp* Complex | RuCym Complex | |
---|---|---|
pKa (1) | 9.33 ± 0.03 | 8.55 ± 0.03 |
pKa (2) | 10.34 ± 0.03 | 10.21 ± 0.03 |
logK’ (H2O/Cl−) a | 2.07 ± 0.03 | 1.47 ± 0.01 |
IC50 (μM) | ||||
---|---|---|---|---|
MES-SA | MES-SA/Dx5 | Colo205 | Colo320 | |
ligand alone | ||||
HQNO2-L-Pro | 226 ± 17 | 97 ± 29 | 34 ± 1 | 32.4 ± 0.4 |
HQNO2-L-Pro + TQ | 223 ± 6 | 219 ± 46 | - | - |
HQCl-L-Pro | 23 ± 4 | 4.3 ± 0.1 | 23 ± 3 a | 9 ± 2 a |
complexes | ||||
RuCym-HQNO2-L-Pro | 166 ± 37 | >400 | >100 | >100 |
RhCp*-HQNO2-L-Pro | 167 ± 38 | 106 ± 8 | 35 ± 1 | 29.8 ± 0.2 |
RuCym-HQCl-L-Pro | - | - | 68 ± 11 a | >100 a |
RhCp*-HQCl-L-Pro | - | - | 26 ± 5 a | 10 ± 1 a |
incubation of HQNO2-L-Pro with metal salts | ||||
+1 equiv. Cu(II) | 40 ± 7 | 25 ± 6 | - | - |
+0.5 equiv. Cu(II) | 49 ± 15 | 35 ± 11 | - | - |
+1 equiv. Zn(II) | 164 ± 24 | >400 | - | - |
+0.5 equiv. Zn(II) | >400 | >400 | - | - |
+1 equiv. Fe(III) | 89 ± 9 | 47 ± 9 | - | - |
+0.33 equiv. Fe(III) | 121 ± 27 | 53 ± 9 | - | - |
doxorubicin | 0.03 ± 0.01 | 4 ± 1 | 0.71 ± 0.02 | 5.4 ± 0.9 |
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Pivarcsik, T.; Pósa, V.; Kovács, H.; May, N.V.; Spengler, G.; Pósa, S.P.; Tóth, S.; Nezafat Yazdi, Z.; Özvegy-Laczka, C.; Ugrai, I.; et al. Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells. Int. J. Mol. Sci. 2023, 24, 593. https://doi.org/10.3390/ijms24010593
Pivarcsik T, Pósa V, Kovács H, May NV, Spengler G, Pósa SP, Tóth S, Nezafat Yazdi Z, Özvegy-Laczka C, Ugrai I, et al. Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells. International Journal of Molecular Sciences. 2023; 24(1):593. https://doi.org/10.3390/ijms24010593
Chicago/Turabian StylePivarcsik, Tamás, Vivien Pósa, Hilda Kovács, Nóra V. May, Gabriella Spengler, Szonja P. Pósa, Szilárd Tóth, Zeinab Nezafat Yazdi, Csilla Özvegy-Laczka, Imre Ugrai, and et al. 2023. "Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells" International Journal of Molecular Sciences 24, no. 1: 593. https://doi.org/10.3390/ijms24010593