Effects of the substituents of pyrazole/thiazine ligands on the magnetic properties of chloro-bridged Cu(II) complexes

[Abstract] We have synthesised and characterised the dimeric copper(II) complexes [{CuCl(PzTz)}2(μ-Cl)2], [{CuCl(DMPzTz)}2(μ-Cl)2] and [{CuCl(DPhPzTz)}2(μ-Cl)2] and the monomeric complex [CuCl2(DMPzTz)] (PzTz = 2-(1-pyrazolyl)-1,3-thiazine, DMPzTz = 2-(3,5-dimethyl-1-pyrazolyl)-1,3-thiazine and DPhPzTz = 2-(3,5-diphenyl-1-pyrazolyl)-1,3-thiazine). Single crystal X-ray diffraction studies show that the geometry around the copper(II) center in the dimeric units is a distorted squared pyramid, while the monomeric compound presents a distorted squared planar coordination. The electronic and magnetic properties of complexes are discussed on the basis of their X-ray structures and EPR spectral studies combined with DFT calculations. Magnetostructural comparisons with structurally similar copper(II) complexes are also carried out. DFT calculations indicate that the dinuclear species are more stable than the mononuclear ones, although the inclusion of methyl or phenyl substituents provokes an important stabilization of the mononuclear forms. DFT calculations fail to predict the sign of the magnetic coupling constants of the complexes whereas multiconfigurational methods, CASSCF/NEVPT2 calculations, predict the correct sign of the exchange coupling constant.Junta de Extremadura; GR15147Ministerio de Economía y Competitividad; CTQ2015-71211-RED

Capacidad coordinante de ligandos derivados de 2-tiazolina e hidrazona frente a iones metálicos de transición

Synthesis and characterization of (2-acetyl-2-thiazoline) hidrazone (ATH), N-(2- acetyl-2-thiazoline)-N¿-(2-thiazolidin-2-one) azine (ATHTd), (2-acetyl-2-thiazoline) thiosemicarbazone (HATtsc), (2-acetyl-2-thiazoline) semicarbazone (ATsc) and (2-acetyl-2- thiazoline) acetylhidrazone (ATHAc) and of their metallic complexes with Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) have been realized.Se ha realizado la síntesis y caracterización de (2-acetil-2-tiazolina) hidrazona (ATH), N-(2-acetil-2-tiazolina)-N¿-(2-tiazolidín-2-ona) azina (ATHTd), (2-acetil-2-tiazolina) tiosemicarbazona (HATtsc), (2-acetil-2-tiazolina) semicarbazona (ATsc) y (2-acetil-2- tiazolina) acetilhidrazona (ATHAc) y de sus complejos metálicos con Co(II), Ni(II), Cu(II), Zn(II) y Cd(II)

Cobalt(II) complexes derived from a 2-aminobenzimidazole-thiazoline ligand: Synthesis, characterization, crystal structures and antimicrobial activity studies

As part of our ongoing studies related with the coordination chemistry of 2-thiazoline derivatives with transition ions, we report the synthesis of a new class of structurally novel complexes containing in their structures a 2-aminobenzimidazole ring. The resulting compound, 2-(2-aminobenzimidazole-1-yl)-2-thiazoline (BzTn), and two cobalt(II) complexes have been structurally characterized by means of physical measurements. The crystal structures of BzTn, [CoCl2(BzTn)2] (1) and [CoBr2(BzTn)2] (2) have been determined by single crystal X-ray diffraction. In both Co(II) complexes, BzTn acts as a monodentate ligand through nitrogen atom of benzimidazole ring. The distorted tetrahedral environmental around the Co(II) ions is completed with two halide ions. Besides that, the newly synthesized compounds were screened for their antimicrobial activity against 6 strains of bacteria: S. aureus, E. coli, S. epidermidis. B. subtilis, E. faecalis y P. aeruginosa.This work was supported by Junta de Extremadura grants (GR18062 and GR18096) for financial support.peerReviewe

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

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

The utilization of photodynamic therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is sometimes limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted toward the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside tissues and, therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of a DFT guided search for efficient PDT PSs with a substantial spectral red shift toward the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex that causes phototoxicity in the very low micromolar to nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids

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

This manuscript is in Memoriam of Prof. Álvaro Bernalte García, Group Leader of the Coordination Chemistry Research Group.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.The authors appreciate the technical and human support provided by the facilities of Bioscience Applied Techniques and Elemental and Molecular Analysis Service of SAIUEx (financed by UEx, Junta de Extremadura, MICINN, FEDER, and FSE). X-Ray intensity measurements were performed at the Unidade de Raios X (RIAIDT, University of Santiago de Compostela, Spain). This work was supported by Junta de Extremadura grants (ref. GR18040, GR18062 and IB18013). E. Fernández-Delgado holds a research pre-doctoral fellowship from Junta de Extremadura (jointly financed by European Social Fund, ref. PD18020). J. Espino holds a research post-doctoral fellowship from Junta de Extremadura (ref. TA18002).peerReviewe