Melatonin Derivative-Conjugated Formulations of Pd(II) and Pt(II) Thiazoline Complexes on Mesoporous Silica to Enhance Cytotoxicity and Apoptosis against HeLa Cells.

The search for alternatives to cisplatin has led to the development of new metal complexes where thiazoline derivatives based on platinum(II) and palladium(II) stand out. In this sense, the Pt(II) and Pd(II) complexes coordinated with the thiazoline derivative ligand 2-(3,4-dichlorophenyl)imino-N-(2-thiazolin-2-yl)thiazolidine (TdTn), with formula [PtCl2(TdTn)] and [PdCl2(TdTn)], have previously shown good results against several cancer lines; however, in this work, we have managed to improve their activity by supporting them on mesoporous silica nanoparticles (MSN). The incorporation of metal compounds with a melatonin derivative (5-methoxytryptamine, 5MT), which is a well-known antioxidant and apoptosis inducer in different types of cancer, has been able to increase the cytotoxic activity of both MSN-supported and isolated complexes with only a very low amount (0.35% w/w) of this antioxidant. The covalently functionalized systems that have been synthesized are able to increase selectivity as well as accumulation in HeLa cells. The final materials containing the metal complexes and 5MT (MSN-5MT-PtTdTn and MSN-5MT-PdTdTn) required up to nine times less metal to achieve the same cytotoxic activity than their corresponding non-formulated counterparts did, thus reducing the potential side effects caused by the use of the free metal complexes.

Cytotoxic Effects of New Palladium(II) Complexes with Thiazine or Thiazoline Derivative Ligands in Tumor Cell Lines.

The synthesis of analogs of cisplatin, which is a widely used chemotherapeutic agent, using other metal centers could be an alternative for cancer treatment. Pd(II) could be a substitute for Pt(II) due to its coordination chemistry similarity. For that reason, six squared-planar Pd(II) complexes with thiazine and thiazoline ligands and formula [PdCl2(L)] were synthesized and characterized in this work. The potential anticarcinogenic ability of the compounds was studied via cytotoxicity assay in three different human tumor cell lines, i.e., epithelial cervix carcinoma (HeLa), promyelocytic leukemia (HL-60), and histiocytic lymphoma (U-937). Data obtained showed that complexes with methyl substitutions did not modify cell viability, while no-methyl substituted compounds had a moderate cytotoxic effect on all three cell lines. The complexes with phenyl substitutions displayed the lowest IC50 values, which ranged between 46.39 ± 3.99 µM and 62.74 ± 6.45 µM. Moreover, Pd accumulation inside the cell was observed after incubation with any of the four complexes mentioned, and the two complexes with phenyl rings were found to induce an increase in the percentage of apoptotic cells. These results suggested that the presence of bulky substitutions on the ligands such as phenyl groups may influence the cytotoxicity of the chemotherapeutic agents synthesized.

Pro-Apoptotic and Anti-Migration Properties of a Thiazoline-Containing Platinum(II) Complex in MDA-MB-231 Breast Cancer Cells: The Role of Melatonin as a Synergistic Agent.

Triple-negative breast cancer (TNBC) is an aggressive cancer insensitive to hormonal and human epidermal growth factor receptor 2 (HER2)-targeted therapies and has a poor prognosis. Therefore, there is a need for the development of convenient anticancer strategies for the management of TNBC. In this paper, we evaluate the antitumoral potential of a platinum(II) complex coordinated with the ligand 2-(3,5-diphenylpyrazol-1-yl)-2-thiazoline (DPhPzTn), hereafter PtDPhPzTn, against the TNBC cell line MDA-MB-231, and compared its effect with both cisplatin and its less lipophilic counterpart PtPzTn, the latter containing the ligand 2-(pyrazol-1-yl)-2-thiazoline (PzTn). Then, the putative potentiating actions of melatonin, a naturally occurring antioxidant with renowned antitumor properties, on the tumor-killing ability of PtDPhPzTn were also checked in TNBC cells. Our results show that PtDPhPzTn presented enhanced cytotoxicity compared to both the classical drug cisplatin and PtPzTn. In addition, PtDPhPzTn was able to induce apoptosis, being more selective for MDA-MB-231 cells when compared to non-tumor breast epithelial MCF10A cells. Likewise, PtDPhPzTn produced moderate S phase arrest and greatly impaired the migration ability of MDA-MB-231 cells. Most importantly, the co-stimulation of TNBC cells with PtDPhPzTn and melatonin substantially enhanced apoptosis and markedly improved the anti-migratory action compared to PtDPhPzTn alone. Altogether, our findings provide evidence that PtDPhPzTn and melatonin could be potentially applied to breast cancer treatment as powerful synergistic agents.

Influence of ligand lipophilicity in Pt(II) complexes on their antiproliferative and apoptotic activities in tumour cell lines.

One of the most widely used strategies for drug development is the coordination of bioactive ligands to transition metals, which could improve biological activity. Moreover, the incorporation of aromatic groups to ligands may allow an enhanced lipophilicity that can influence the cellular uptake and accumulation of the metallodrugs, thus increasing their activity. Herein, we have reported the synthesis and characterization of four Pt(II) complexes [PtCl2(L)], where L = 2-(1-pyrazolyl)-2-thiazoline (PzTn), 2-(1-pyrazolyl)-1,3-thiazine (PzTz), 2-(3,5-diphenyl-1-pyrazolyl)-2-thiazoline (DPhPzTn) or 2-(3,5-diphenyl-1-pyrazolyl)-1,3-thiazine (DPhPzTz). The study was aimed at analysing their potential anticarcinogenic ability in epithelial cervix carcinoma HeLa, human promyelocytic leukemia HL-60 and human histiocytic lymphoma U-937 tumour cell lines as well as checking whether the structural factors of the organic ligand may influence their biological activity. Our findings showed that PtDPhPzTn and PtDPhPzTz were far more effective in terms of cytotoxicity than their less lipophilic counterparts (PtPzTn and PtPzTz), especially in cells derived from solid cervical tumours, thereby suggesting that modulating the lipophilicity of the ligands can help improve the cytotoxic effect of the metal complexes.

Synthesis and structure of a new thiazoline-based palladium(II) complex that promotes cytotoxicity and apoptosis of human promyelocytic leukemia HL-60 cells.

Cisplatin is one of the most widely used chemotherapeutic agents in the treatment of different tumors but has high toxicity and side effects. Therefore, the synthesis of new chemotherapeutic agents is necessary, so that they are effective in the treatment of cancer while avoiding such toxicity. In this study, we have synthesized and characterized a palladium(II) complex, [PdCl2(µ-PyTT)2]Cl2·4H2O (PdPyTT), with 2-(2-pyridyl)imine-N-(2-thiazolin-2-yl)thiazolidine (PyTT) as a ligand; besides, its cytotoxicity and pro-apoptotic capacity was tested in human promyelocytic leukemia HL-60 cell line. Similar to cisplatin, PdPyTT produced a time- and dose-dependent decrease in cell viability. Additionally, the palladium complex increased both the proportion of cells with apoptotic morphology and the activation of caspase-3 and -9. PdPyTT, like cisplatin, also increased intracellular ROS production and DNA oxidative damage. Therefore, our findings demonstrated the promising application of palladium(II) complexes as novel anti-leukemic agents.

Pt(II) and Pd(II) complexes with a thiazoline derivative ligand: Synthesis, structural characterization, antiproliferative activity and evaluation of pro-apoptotic ability in tumor cell lines HT-29 and U-937.

Eluding apoptosis represents the hallmark of tumoral cell behavior. Cisplatin (CisPt) is a very common chemotherapeutic agent to treat cancer by reestablishing apoptotic mechanisms of cell death. However, certain patients acquire resistance to CisPt as well as suffer nephrotoxicity, neurotoxicity, nausea and vomiting. The synthesis of new Pt(II) compounds represents an alternative to CisPt to avoid resistance and undesirable side effects. Pd(II) could be a Pt(II) surrogate given the similarity of coordination chemistry between them, thus widening the spectra of available anticancer drugs. Herein, we have synthesized and characterized two Pt(II) or Pd(II) complexes with TdTn (2-(3,4-dichlorophenyl)imino-N-(2-thiazolin-2-yl)thiazolidine), a thiazoline derivative ligand, with formula [PtCl2(TdTn)] and [PdCl2(TdTn)]. The potential anticancer ability was evaluated in human colon adenocarcinoma HT-29 and human histiocytic lymphoma U-937 cell lines. To that aim, U-937 and HT-29 cells were treated with TdTn, [PtCl2(TdTn)] and [PdCl2(TdTn)] for 24 h. The microscopy monitoring indicated that TdTn, [PtCl2(TdTn)] and [PdCl2(TdTn)] arrested the cell proliferation of U-937 and HT-29 cells with respect to control, in agreement with MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) analysis. Moreover, it is noteworthy that the ligand by its own showed antiproliferative effects in both cell lines. [PtCl2(TdTn)] and [PdCl2(TdTn)] caused caspase-3 activation in U-937 cells, simultaneously with caspase-9 activation due to complexes; however, in HT-29 caspase-3 activation occurred simultaneously with caspase-8 activation induced by the ligand TdTn. Only metal complexes were able to induce ROS (Reactive Oxygen Species) generation in U-937 cells, but not TdTn. In HT-29 cells neither the metal complexes, nor the ligand induced ROS generation.