Casiopeinas of Third Generations: Synthesis, Characterization, Cytotoxic Activity and Structure–Activity Relationships of Mixed Chelate Compounds with Bioactive Secondary Ligands
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of Curcumin (L1) and Dimethoxycurcumin (L2) Ligands
2.2. Synthesis and Characterization of Copper Complexes [Cu(Dn)(L1)]NO3 and [Cu(Dn)(L2)]NO3
2.2.1. Molar Conductivity, Magnetic Moments and Electron Paramagnetic Resonance (EPR) Spectroscopy
2.2.2. Infrared Spectra
2.2.3. UV-Vis Spectrophotometric Analysis
2.2.4. Mass Spectra
2.2.5. Cyclic Voltammetry Measurements
2.2.6. X-ray
2.3. Biological Assays
Cytotoxicity Activity
Compound | IC50 SKLU-1 (μM) | IC50 HeLa (μM) | IC50 HeLa (μM) of First-Generation Casiopeinas |
---|---|---|---|
L1 | 52.56 ± 2.1 | 50.44 ± 2.3 | - |
D1CuL1 | 41.53 ± 0.5 | N/A | 42 ± 3.1 [25] |
D2CuL1 | 14.36 ± 0.8 | 26.4 9 ± 0.7 | 41.7 ± 0.31 [75] |
D3CuL1 | 8.90 ± 0.2 | 35.78 ± 0.7 | - |
D4CuL1 | 5.29 ± 0.9 | 7.61 ± 0.6 | 10.7 ± 0.9 [25] |
D5CuL1 | 2.68 ± 0.2 | 1.91 ± 0.8 | 3.2 ± 0.03 [75] |
D6CuL1 | 2.60 ± 0.5 | 2.21 ± 0.5 | 2.83 ± 0.09 [75] |
D7CuL1 | 4.48 ± 1.5 | 4.48 ± 0.5 | 2.37 ± 0.4 [75] |
D8CuL1 | 6.25 ± 0.9 | 6.74 ± 0.5 | 4.2 ± 0.6 [25] |
L2 | 56.58 ± 1.8 | 109.05 ± 0.5 | - |
D1CuL2 | 21.82 ± 0.4 | 44.62 ± 1.1 | 42 ± 3.1 [25] |
D2CuL2 | 9.49 ± 1.3 | 37.6 ± 1.9 | 41.7 ± 0.31 [75] |
D3CuL2 | 6.84 ± 1.1 | 30.56 ± 2.5 | - |
D4CuL2 | 4.56 ± 0.6 | 13.26 ± 1.5 | 10.7 ± 0.9 [25] |
D5CuL2 | 1.22 ± 0.1 | 2.01 ± 0.0005 | 3.2 ± 0.03 [75] |
D6CuL2 | 1.19 ± 0.007 | 1.78 ± 0.1 | 2.83 ± 0.09 [75] |
D7CuL2 | 2.68 ± 0.1 | 1.2 ± 0.05 | 2.37 ± 0.4 [75] |
D8CuL2 | 2.38 ± 0.3 | 2.07 ± 0.3 | 4.2 ± 0.6 [25] |
Cisplatin | 9.56 | 5.1 ± 0.4 [25] | 42 ± 3.1 [25] |
2.4. Structure–Activity Relationships
3. Materials and Methods
3.1. Instrumentation
3.2. Syntheses of Ligands and Coordination Compounds
3.2.1. Syntheses of Ligands Curcumin (L1) and Dimethoxycurcumin (L2)
3.2.2. General Synthesis Procedure of Ternary Complexes of [Cu(Dn)(L1)]NO3 and [Cu(Dn)(L2)]NO3
3.3. Cyclic Voltammetry Studies
3.4. X-ray Crystallography
3.5. Biological Assays
Cytotoxicity Activity
3.6. Structure–ActivityRrelationships
3.6.1. Computational Methods
3.6.2. Computational Details
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compound | λmax(nm) π-π* | ε (L/mol cm) | λmax(nm) TCLM | ε (L/mol cm) | λmax(nm) TCML | ε (L/mol cm) |
---|---|---|---|---|---|---|
D1CuL1 | 294 | 31,451 | 430 | 64,287 | 454 | 62,853 |
D2CuL1 | 292 | 22,776 | 430 | 42,317 | 454 | 41,947 |
D3CuL1 | 304 | 28,563 | 426 | 36,928 | 448 | 33,804 |
D4CuL1 | 266 | 48,706 | 430 | 57,630 | 454 | 56,402 |
D5CuL1 | 268 | 51,897 | 430 | 59,041 | 454 | 56,908 |
D6CuL1 | 276 | 42,400 | 428 | 35,698 | 452 | 32,659 |
D7CuL1 | 274 | 34,157 | 432 | 33,142 | 456 | 32,775 |
D8CuL1 | 282 | 53,109 | 430 | 42,733 | 454 | 40,475 |
D1CuL2 | 313 | 22,461 | 430 | 24,832 | 458 | 23,216 |
D2CuL2 | 310 | 25,161 | 430 | 23,350 | 458 | 21,809 |
D3CuL2 | 321 | 17,513 | 430 | 20,741 | 458 | 19,205 |
D4CuL2 | 275 | 42,754 | 433 | 33,220 | 458 | 30,807 |
D5CuL2 | 276 | 52,001 | 433 | 34,631 | 458 | 32,386 |
D6CuL2 | 284 | 44,217 | 433 | 33,226 | 458 | 31,128 |
D7CuL2 | 282 | 49,471 | 433 | 32,936 | 458 | 30,671 |
D8CuL2 | 290 | 53,569 | 436 | 11,448 | 460 | 10,582 |
Compound | Molecular Weight (g/mol) | Molecular Ion (Theoretical m/z) | Molecular Ion (Obtained m/z) |
---|---|---|---|
Curcumin (L1) | 368.37 | 368 | 369.2 |
[Cu(2,2′-bipyridine)(curcumina)]NO3 (D1CuL1) | 649.01 | 586.1 | 586.9 |
[Cu(4,4′-dimethyl-2,2′-bipyridine)(curcumin)]NO3 (D2CuL1) | 695.17 | 614.4 | 615.0 |
[Cu(5,5′-dimethyl-2,2′-bipyridine)(curcumin)]NO3 (D3CuL1) | 695.17 | 614.4 | 614.0 |
[Cu(1,10-phenanthroline)(curcumin)]NO3 (D4CuL1) | 673.12 | 610.1 | 610.9 |
[Cu(4,7-dimethyl-1,10-phenanthroline)(curcumin)]NO3 (D5CuL1) | 719.19 | 638.1 | 638.0 |
[Cu(5,6-dimetyl-1,10-phenanthroline)(curcumin)]NO3 (D6CuL1) | 701.18 | 638.1 | 638.0 |
[Cu(3,4,7,8-tetrametyl-1,10-phenanthroline)(curcumin)]NO3 (D7CuL1) | 747.24 | 666.1 | 667.1 |
[Cu(4,7-diphenyl-1,10-phenanthroline)(curcumin)]NO3 (D8CuL1) | 825.32 | 762.1 | 762.1 |
Dimethoxycurcumin (L2) | 396.43 | 396.4 | 397.7 |
[Cu(2,2′-bipyridine)(dimethoxycurcumin)]NO3 (D1CuL2) | 677.16 | 614.1 | 615.3 |
[Cu(4,4′-dimethyl-2,2′-bipyridine)(dimethoxycurcumin)]NO3 (D2CuL2) | 723.22 | 642.1 | 643.2 |
[Cu(5,5′-dimethyl-2,2′-bipyridine)(dimethoxycurcumin)]NO3 (D3CuL2) | 723.22 | 642.1 | 642.1 |
[Cu(1,10-phenanthroline)(dimethoxycurcumin)]NO3 (D4CuL2) | 737.21 | 638.1 | 638.0 |
[Cu(4,7-dimethyl-1,10-phenanthroline)(dimethoxycurcumin)]NO3 (D5CuL2) | 729.23 | 666.1 | 668.2 |
[Cu(5,6-dimethyl-1,10-phenanthroline)(dimethoxycurcumin)]NO3 (D6CuL2) | 729.23 | 666.1 | 668.2 |
[Cu(3,4,7,8-tetramethyl-1,10-phenanthroline)(dimethoxycurcumin)]NO3 (D7CuL2) | 757.28 | 694.2 | 696.1 |
[Cu(4,7-diphenyl-1,10-phenanthroline)(dimethoxycurcumin)]NO3 (D8CuL2) | 853.37 | 790.2 | 791.5 |
Compound | Epc (V) | Epa (V) | ΔE (V) | E1/2 (V) (Fc+/Fc) |
---|---|---|---|---|
L1 | −0.978 | 0.488 | 1.467 | --- |
D1CuL1 | −0.429 | 0.130 | 0.560 | −0.668 |
D2CuL1 | −0.484 | 0.023 | 0.507 | −0.758 |
D3CuL1 | −0.474 | 0.067 | 0.542 | −1.164 |
D4CuL1 | −0.407 | 0.140 | 0.547 | −0.665 |
D5CuL1 | −0.440 | 0.123 | 0.563 | −0.712 |
D6CuL1 | −0.611 | −0.04 | 0.571 | −0.705 |
D7CuL1 | −0.405 | 0.154 | 0.560 | −0.679 |
D8CuL1 | −0.491 | 0.126 | 0.617 | −0.657 |
L2 | −1.05 | --- | --- | --- |
D1CuL2 | −0.444 | 0.139 | 0.623 | −0.656 |
D2CuL2 | −0.469 | 0.117 | 0.586 | −0.709 |
D3CuL2 | −0.390 | 0.162 | 0.552 | −0.656 |
D4CuL2 | −0.373 | 0.168 | 0.541 | −0.656 |
D5CuL2 | −0.447 | 0.088 | 0.535 | −0.701 |
D6CuL2 | −0.388 | 0.158 | 0.546 | −0.682 |
D7CuL2 | −0.396 | 0.096 | 0.492 | −0.690 |
D8CuL2 | −0.171 | 0.122 | 0.293 | −0.559 |
Compound | Bond Atom-Atom (A°) | Lengths | Bond Atom-Atom (A°) | Angles (°) |
---|---|---|---|---|
D5CuL2 square planar geometry | Cu-N1 | 1.977 | O1-Cu-O2 | 94.68 |
Cu-N2 | 1.993 | N1-Cu-N2 | 81.84 | |
Cu-O1 | 1.906 | O1-Cu-N1 | 92.37 | |
Cu-O2 | 1.886 | O2-Cu-N2 | 89.45 | |
Cu-O (H2O) | 5.456 | O1-Cu-N2 | 168.51 | |
Cu-O (NO3) | 6.582 | O2-Cu-N1 | 166.09 | |
D6CuL2 square-based pyramid geometry | Cu-N1 | 2.013 | O1-Cu-O2 | 94.68 |
Cu-N2 | 2.022 | N1-Cu-N2 | 81.84 | |
Cu-O1 | 1.921 | O1-Cu-N1 | 92.37 | |
Cu-O2 | 1.911 | O2-Cu-N2 | 89.45 | |
Cu-O (H2O) | 2.260 | O1-Cu-N2 | 168.51 | |
Cu-O (NO3) | 4.958 | O2-Cu-N1 | 166.09 |
Compound | Molar Volume (cm3/mol) | IE (eV) | EA (eV) | E1/2 (V) |
---|---|---|---|---|
D1CuL1 | 383.712 | 8.04749134 | 2.82789556 | −0.878171 |
D2CuL1 | 462.274 | 7.99361656 | 2.76906755 | −0.930038 |
D3CuL1 | 466.413 | 8.00534368 | 2.7998987 | −0.872582 |
D4CuL1 | 410.031 | 8.10950385 | 2.87669331 | −0.725702 |
D5CuL1 | 437.24 | 8.04221051 | 2.80906527 | −0.749246 |
D6CuL1 | 417.529 | 8.07647188 | 2.85005565 | −0.849173 |
D7CuL1 | 373.335 | 8.01205011 | 2.79094547 | −0.907115 |
D8CuL1 | 492.824 | 8.07950481 | 2.86419938 | −0.873203 |
D1CuL2 | 451.839 | 8.07429826 | 2.84794598 | −0.836537 |
D2CuL2 | 450.172 | 8.01993014 | 2.78888151 | −0.858569 |
D3CuL2 | 386.932 | 8.03231631 | 2.82004192 | −0.840938 |
D4CuL2 | 393.699 | 8.13593635 | 2.8959002 | −0.728105 |
D5CuL2 | 422.974 | 8.06659075 | 2.82811977 | −0.809915 |
D6CuL2 | 466.821 | 8.10139715 | 2.86922906 | −0.782915 |
D7CuL2 | 545.631 | 8.03569891 | 2.8086884 | −0.799709 |
D8CuL2 | 536.71 | 8.09949401 | 2.87311289 | −0.452801 |
Collection Parameters | D5CuL2 | D6CuL2 |
---|---|---|
Empirical formula | C37H35N3O9Cu | C37H35N3O9Cu |
Formula weight | 729.23 g/mol | 729.23 g/mol |
Temperature (K) | 100 | 100 |
Wavelength (Ǻ) | 1.5417 | 0.71073 |
Crystal system | Triclinic | Triclinic |
Space group | P-1 | P-1 |
a (Ǻ) | 7.7004 (7) | 10.0604 (7) |
b (Ǻ) | 13.7026 (12) | 13.6229 (9) |
c (Ǻ) | 17.1812 (15) | 14.0129 (9) |
α (°) | 110.132 (5) | 70.5193 (12) |
β(°) | 94.503 (6) | 76.4453 (13) |
γ(°) | 91.987 (6) | 71.7320 (13) |
Volume (Ǻ3) | 1693.2 (3) | 1701.1 (2) |
Z | 2 | 1 |
Dcalc (mg/m3) | 1.466 | 1.485 |
Absorption coefficient (mm−1) | 1.462 | 0.709 |
F(000) | 778 | 793 |
Crystal size (mm3) | 0.300 × 0.041 × 0.036 | 0.150 × 0.092 × 0.056 |
Theta range for data collection (°) | 2.752 to 68.243 | 1.558 to 27.442 |
Index ranges | −9 ≤ h ≤ 9, −16 ≤ k ≤ 16, −20 ≤ 1 ≤ 20 | −13 ≤ h ≤ 13, −17 ≤ k ≤ 17, −18 ≤ l ≤ 18 |
Reflections collected | 45,131 | 27,234 |
Independent reflections | 5817 [R(int) = 0.0466] | 7773 [R(int) = 0.0363] |
Refinement method | Full-matrix least-squares on F2 | Full-matrix least-squares on F2 |
Data/restraints/parameters | 5818/563/584 | 7773/360/582 |
Goodness-of-fit on F2 | 1.086 | 1.040 |
Final R indices (I > 2sigma(I)) | R1 = 0.0538, wR2 = 0.1580 | R1 = 0.0355, wR2 = 0.0889 |
R indices (all data) | R1 =0.0588, wR2 = 0.1637 | R1 = 0.0477, wR2 = 0.0889 |
Largest diff. peak and hole e Ǻ−3 | 0.878 and −0.651 | 0.366 and −0.520 |
Extinction coefficient | n/a | n/a |
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Figueroa-DePaz, Y.; Pérez-Villanueva, J.; Soria-Arteche, O.; Martínez-Otero, D.; Gómez-Vidales, V.; Ortiz-Frade, L.; Ruiz-Azuara, L. Casiopeinas of Third Generations: Synthesis, Characterization, Cytotoxic Activity and Structure–Activity Relationships of Mixed Chelate Compounds with Bioactive Secondary Ligands. Molecules 2022, 27, 3504. https://doi.org/10.3390/molecules27113504
Figueroa-DePaz Y, Pérez-Villanueva J, Soria-Arteche O, Martínez-Otero D, Gómez-Vidales V, Ortiz-Frade L, Ruiz-Azuara L. Casiopeinas of Third Generations: Synthesis, Characterization, Cytotoxic Activity and Structure–Activity Relationships of Mixed Chelate Compounds with Bioactive Secondary Ligands. Molecules. 2022; 27(11):3504. https://doi.org/10.3390/molecules27113504
Chicago/Turabian StyleFigueroa-DePaz, Yeshenia, Jaime Pérez-Villanueva, Olivia Soria-Arteche, Diego Martínez-Otero, Virginia Gómez-Vidales, Luis Ortiz-Frade, and Lena Ruiz-Azuara. 2022. "Casiopeinas of Third Generations: Synthesis, Characterization, Cytotoxic Activity and Structure–Activity Relationships of Mixed Chelate Compounds with Bioactive Secondary Ligands" Molecules 27, no. 11: 3504. https://doi.org/10.3390/molecules27113504