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. 2022 May 23;61(20):7729-7745.
doi: 10.1021/acs.inorgchem.1c03957. Epub 2022 May 6.

Synthesis and In Vitro Studies of Photoactivatable Semisquaraine-type Pt(II) Complexes

Kevin Morales  1 , Sergi Rodríguez-Calado  2 , Jordi Hernando  1 , Julia Lorenzo  2 , Antonio Rodríguez-Diéguez  3 , Carlos Jaime  1 , Pau Nolis  1 , Mercè Capdevila  1 , Òscar Palacios  1 , Marta Figueredo  1 , Pau Bayón  1
Affiliations

Synthesis and In Vitro Studies of Photoactivatable Semisquaraine-type Pt(II) Complexes

Kevin Morales et al. Inorg Chem. .

Abstract

The synthesis, full characterization, photochemical properties, and cytotoxic activity toward cisplatin-resistant cancer cell lines of new semisquaraine-type Pt(II) complexes are presented. The synthesis of eight semisquaraine-type ligands has been carried out by means of an innovative, straightforward methodology. A thorough structural NMR and X-ray diffraction analysis of the new ligands and complexes has been done. Density functional theory calculations have allowed to assign the trans configuration of the platinum center. Through the structural modification of the ligands, it has been possible to synthesize some complexes, which have turned out to be photoactive at wavelengths that allow their activation in cell cultures and, importantly, two of them show remarkable solubility in biological media. Photodegradation processes have been studied in depth, including the structural identification of photoproducts, thus justifying the changes observed after irradiation. From biological assessment, complexes C7 and C8 have been demonstrated to behave as promising photoactivatable compounds in the assayed cancer cell lines. Upon photoactivation, both complexes are capable of inducing a higher cytotoxic effect on the tested cells compared with nonphotoactivated compounds. Among the observed results, it is remarkable to note that C7 showed a PI > 50 in HeLa cells, and C8 showed a PI > 40 in A2780 cells, being also effective over cisplatin-resistant A2780cis cells (PI = 7 and PI = 4, respectively). The mechanism of action of these complexes has been studied, revealing that these photoactivated platinum complexes would actually present a combined mode of action, a therapeutically potential advantage.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
New semisquaraine-type Pt(II) complexes in this study.
Scheme 1
Scheme 1. Sequential Strategy in the Synthesis of Ligand L1
Scheme 2
Scheme 2. Synthesis of Substituted Pyrrole Motives
Figure 2
Figure 2
MERCURY drawing for L2. Thermal ellipsoids are drawn at the 30% probability level. H atoms are omitted for clarity.
Scheme 3
Scheme 3. Synthesis of Conjugate Pyrrole Ligands L2–8
Figure 3
Figure 3
Configurations of the metal center in model complex C21.
Figure 4
Figure 4
Time evolution of the UV–vis absorption spectra after irradiation of complexes (a) C1 in water/DMSO, 98:2, (b) C2 in water/DMF, 98:2, (c) C3 in water/DMSO, 98:2, (d) C4 in water/DMF, 98:2, (e) C5 in water/DMSO, 98:2, (f) C6 in water/DMF, 98:2, (g) C7 in water, and (h) C8 in water. For C1 λexc = 365 nm (UV lamp) and for C2–8 λexc = 450 nm (LED).
Scheme 4
Scheme 4. Synthesis of Simplified Ligand L22
Scheme 5
Scheme 5. Mechanistic Proposal for the Formation of Butenolide 24 or 25 as the Major Photoproduct
Figure 5
Figure 5
Evaluation of cytotoxicity of compounds C7 and C8 in the absence or presence of blue light (dark/light) in HeLa, A2780, and A2780cis human carcinoma cells after 72 h (24 h internalization) using PrestoBlue assay. Results are representative of three independent experiments with a minimum of three replicates per experiment.
Figure 6
Figure 6
Cytotoxicity assays after 72 h incubation (24 h internalization) in the light and dark in HeLa, A2780, and A2780cis cells with complex C8 and ligand L8, at 100 μM each.
Figure 7
Figure 7
(a) Necrosis and apoptosis assays of A2780 cells untreated (control dark), treated with light only (control light), 1.5 μM C7 (C7 dark), light irradiation in the presence of 1.5 μM C7 (C7 light), 5 μM C8 (C8 dark), and light irradiation in the presence of 5 μM C8 (C8 light). Healthy viable cells were stained with CytoCalcein Violet 450 (blue), late apoptotic/necrotic cells with DNA nuclear green DCS1 (green), and apoptotic cells with phosphatidylserine (red). (b) Representative histograms of stained cells. Results are shown as a percentage of total cells.
Figure 8
Figure 8
ROS formation measured with the DCFDA assay in A2780 cells for cisplatin (CisPt) and complexes C7 and C8 at the corresponding IC50 values for each complex (Table 1) after treatment for 4 h. Results are represented as the percentage over untreated cells. H2O2 (100 μM) was used as the positive control.
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