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We report the synthesis, characterization and anticancer activity of a new Schiff base (H2L) derived from the condensation of pyridoxamine with pyridoxal and its novel copper(II) and oxidovanadium(IV) complexes: [Cu(HL)Cl] (1), [Cu(LH2)(phen)]Cl2 (2), [Cu(LH2)(amphen)]Cl2 (3), [VIVO(HL)Cl] (4), and [VIVO(LH2)(phen)]Cl2 (5), where phen is 1,10-phenanthroline and amphen is its 5-amino derivative. All compounds were characterized by analytical and spectroscopic techniques, namely FTIR, UV-vis and EPR spectroscopy. Their stability in aqueous media was evaluated, revealing that the presence of the phen co-ligand significantly increases the stability. The ternary Cu(II) complexes (2 and 3) impaired cell viability of osteosarcoma cells (MG-63) (IC50 values of 3.6 ± 0.6 and 7 ± 1.9 μM for 2 and 3), while 1 and the VIVO complexes did not show relevant anticancer activity. Complexes 2 and 3 are also more active than cisplatin (CDDP). Synergistic studies between 2 and sorafenib showed significant synergism on MG-63 cells for the following combinations: 2 (2.0 μM) + sorafenib (10.0 μM) and 2 (2.5 μM) + sorafenib (12.5 μM), whilst the combination of 2 and CDDP did not show synergy. Complex 2 interacts with DNA, inducing significant genotoxic effects on MG-63 cells from 1.0 to 2.5 μM and it increases the ROS levels 880% over basal. Moreover, 2 induces apoptosis at 1.0 and 2.0 μM, while its combination with sorafenib induces apoptosis and necrosis. Finally, compound 2 reduces the cell viability of MG-63 spheroids showing an IC50 value 7-fold lower than that of CDDP (8.5 ± 0.4 μM vs. 65 ± 6 μM). The combination of 2 and sorafenib also showed synergism on spheroids, suggesting that the combination of these drugs improves the anticancer effect against bone cancer cells. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women, with a high incidence estimated to reach 2.3 million by 2030. Triple-Negative Breast Cancer (TNBC) is the greatest invasive class of breast cancer with a poor prognosis, due to the side-effects exerted by the chemotherapy used and the low effectivity of novel treatments. In this sense, copper compounds have shown to be potentially effective as antitumor agents, attracting increasing interest as alternatives to the usually employed platinum-derived drugs. Therefore, the aim of this work is to identify differentially expressed proteins in MDA-MB-231 cells exposed to two copper(II)-hydrazone complexes using label-free quantitative proteomics and functional bioinformatics strategies to identify the molecular mechanisms through which these copper complexes exert their antitumoral effect in TNBC cells. Both copper complexes increased proteins involved in endoplasmic reticulum stress and unfolded protein response, as well as the downregulation of proteins related to DNA replication and repair. One of the most relevant anticancer mechanisms of action found for CuHL1 and CuHL2 was the down-regulation of gain-of-function-mutant p53. Moreover, we found a novel and interesting effect for a copper metallodrug, which was the down-regulation of proteins related to lipid synthesis and metabolism that could lead to a beneficial decrease in lipid levels. [ABSTRACT FROM AUTHOR]

We report here the synthesis, crystal structure, characterization and anticancer activity of a copper(II)-hydrazone complex, [Cu(MeBHoVa)(H2O)2](NO3) (for short, CuHL), against human breast cancer cells on monolayer (2D) and spheroids/mammospheres (3D). The solid-state molecular structure of the complex has been determined by X-ray diffraction methods. The conformational space was searched and geometries were optimized both in the gas phase and including solvent effects by computational methods based on DFT. The compound has been characterized in the solid state and in solution by spectroscopic (FTIR, Raman, UV-vis) methods. The results were compared with those obtained for the hydrazone ligand and complemented with DFT calculations. Cell viability assays on MCF7 (IC50(CuHL) = 1.7 ± 0.1 μM, IC50(CDDP) = 42.0 ± 3.2 μM) and MDA-MB-231 (IC50(CuHL) = 1.6 ± 0.1 μM, IC50(CDDP) = 131.0 ± 18 μM) demonstrated that the complex displays higher antitumor activity than cisplatin (CDDP) on 2D and 3D human breast cancer cell models. Molecular docking and molecular dynamics simulations showed that CuHL could interacts with DNA, inducing a significant genotoxic effect on both breast cancer cells from 0.5 to 1 μM. On the other hand, CuHL increases the ROS production and induces cell programmed death on breast cancer cells at very low micromolar concentrations (0.5–1.0 μM). Moreover, the compound decreased the amount of breast CSCs on MCF7 and MDA-MB-231 cells reducing the percentage of CD44+/CD24−/low cells from 0.5 to 1.5 μM. In addition, CuHL overcame CDDP with an IC50 value 65-fold lower against breast multicellular spheroids ((IC50(CuHL) = 2.2 ± 0.3 μM, IC50(CDDP) = 125 ± 4.5 μM)). Finally, CuHL reduced mammosphere formation capacity, hence affecting the size and number of mammospheres and showing that the complex exhibits antitumor properties on monolayer (2D) and spheroids (3D) derived from human breast cancer cells. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a frequent bone cancer, affecting largely children and young adults. Cisplatin (CDDP) has been efficacious in the treatment of different cancer such us OS but the development of chemoresistance and important side effects leading to therapeutic failure. Novel therapies including copper compounds have shown to be potentially effective as anticancer drugs and one alternative to usually employed platinum compounds. The goal of this work is the evaluation of the in vitro and in vivo antitumoral activity and dilucidate the molecular target of a Cu(II) cationic complex containing a tridentate hydrazone ligand, CuHL for short, H 2 L=N'-'-(2-hydroxy-3-methoxybenzylidene)thiophene-2-carbohydrazide, against human OS MG-63 cells. Anticancer activity on MG-63 cell line was evaluated in OS monolayer and spheroids. CuHL significantly impaired cell viability in both models (IC 50 2D: 2.1 ± 0.3 μM; 3D: 9.1 ± 1.0 μM) (p < 0.001). Additional cell studies demonstrated the copper compound inhibits cell proliferation and conveys cells to apoptosis, determined by flow cytometry. CuHL showed a great genotoxicity, evaluated by comet assay. Proteomic analysis by Orbitrap Mass Spectometry identified 27 differentially expressed proteins: 17 proteins were found overexpressed and 10 underexpressed in MG-63 cells after the CuHL treatment. The response to unfolded protein was the most affected biological process. In addition, in vivo antitumor effects of the compound were evaluated on human OS tumors xenografted in nude mice. CuHL treatment, at a dose of 2 mg/kg i.p., given three times/week for one month, significantly inhibited the progression of OS xenografts and was associated to a reduction in mitotic index and to an increment of tumor necrosis (p < 0.01). Administration of standard-of-care cytotoxic agent CDDP, following the same treatment schedule as CuHL, failed to impair OS growth and progression. • Copper compounds have shown to be potentially effective as antitumor agents in many tumors. • A novel Cu(II)-acylhydrazone reduced the cell viability on 2D and 3D osteosarcoma cell models. • Response to unfolded protein was the most affected biological process after the treatment with Cu(II)-acylhydrazone. • Cu(II)-acylhydrazone impaired osteosarcoma tumor progression, enhancing necrosis and reducing tumor growth rate. [ABSTRACT FROM AUTHOR]

Two new copper(II)-hydrazone complexes with 2,2́ bipyridine or 1,10 phenanthroline as coligands were synthesized and characterized by spectroscopic methods. Their molecular structures were confirmed by single crystal X-ray diffraction. Both complexes were evaluated as antitumour agents. They showed higher cytotoxic activity against lung, bone and breast cancer cells lines than cisplatin. [Display omitted] • Two ternary Cu(II) hydrazone complexes were synthesized and characterized. • The complexes crystallize in a CuO 2 N 3 distorted square pyramidal environment. • The hydrazone adopts different tautomeric forms in the environment of each compound. • EPR data are consistent with the dx2-y2 ground state determined by XRD. • They are more cytotoxic than cisplatin on lung, bone and breast cancer cells lines. Two new penta-coordinated copper(II) hydrazone coordination compounds with 2,2́ bipyridine (I) or 1,10 phenanthroline (II) as coligands are synthesized and characterized in the solid state and in solution by spectroscopic methods (FTIR, Raman, UV–vis, EPR). Single crystal X-ray studies show that they have closely related molecular structures with the copper center in a distorted square pyramidal O 2 N 3 environment. The N -acylhydrazone, 4-hydroxy-NŃ-(E)2-hydroxy-3-methoxybenzylidene]benzohydrazide, H 2 L, coordinates tridentate through its ONO donor atoms as monoanion (HL-) in the cationic complex (I) , [Cu(HL)(bipy)](NO 3). During the period that takes the synthesis reaction of compound (II) , [Cu(L)(o -phen)] to complete, keto-amine to enol-imine tautomerization of H 2 L occurs and the hydrazone coordinates tridentate as dianionic ligand (L2-). The fivefold coordination sphere of the complexes is completed with the nitrogen atoms of the respective coligands. Cytotoxicity studies against bone (MG-63, IC 50 (I) = 5.6 ± 1.0 , IC 50 (II) = 3.5 ± 0.3), breast (MCF7, IC 50 (I) = 10.8 ± 1.9, IC 50 (II) = 4.0 ± 1.3), (MDA-MB-231, IC 50 (I) = 11.4 ± 0.6, IC 50 (II) = 5.3 ± 0.2) and lung cancer cells (A549, IC 50 (I) = 7.7 ± 0.7, IC 50 (II) = 7.0 ± 0.4) reveals increased effectiveness of both complexes compared with the free ligand, the copper nitrate salt and the reference metallodrug cisplatin (CDDP). [ABSTRACT FROM AUTHOR]

The goal of this work was to display the anticancer and antimetastatic activity of a copper(II) with tropolone (trp), complex [ Cu(trp) 2 ] toward human breast cancer cells in monolayer (2D) and spheroids (3D). Cytotoxicity assays against MCF7 (IC 50(complex) = 5.2 ± 1.8 μM, IC 50(CDDP) = 19.3 ± 2.1 μM) and MDA-MB-231 (IC 50(complex) = 4.0 ± 0.2 μM, IC 50(CDDP) = 27.0 ± 1.9 μM) demonstrate that [ Cu(trp) 2 ] exert greater antitumor potency than cisplatin (CDDP) on 2D and 3D human breast cancer cell models. Besides, [ Cu(trp) 2 ] inhibits cell migration by reducing the metalloproteinases activities and the compound undergoes the breast cancer cells to apoptosis at lower concentrations (2.5–10 μM). Moreover, [ Cu(trp) 2 ] overcame CDDP presenting an IC 50 value 26-fold more lower against breast multicellular spheroids ((IC 50(complex) = 4.9 μM, IC 50(CDDP) = 130 μM)). Also, our results showed that [ Cu(trp) 2 ] inhibited the cell migration and cell invasion of breast multicellular spheroids, showing that [ Cu(trp) 2 ] exhibited antimetastatic properties. On the other hand, [ Cu(trp) 2 ] reduced mammosphere forming capacity affecting the size and number of mammospheres. Taken together, [ Cu(trp) 2 ] exhibited anticancer and antimetastatic properties on monolayer (2D) and spheroids (3D) derived from human breast cancer cells. Copper-tropolone complex impaired cell viability of 2D and 3D breast cancer cell models. Reducing cell migration through inhibiting the metalloproteinases activities. Unlabelled Image • The aim of this work was to show the antitumor actions of a copper(II)-tropolone. • Cytotoxicity studies toward 2D and 3D cell cultured human breast cancer cells. • Complex exerts stronger anticancer activity than cisplatin on breast cancer cell models. • Compound inhibits cell migration through inhibiting the metalloproteinases activities. • Complex reduced mammosphere forming capacity. [ABSTRACT FROM AUTHOR]

Thiosemicarbazone moiety is a valuable scaffold for the synthesis of metallic complexes with anticancer purposes, when bearing N‐heterocyclic the final compounds possess diverse biological activities. Using thiazole as bioisosteres, the resulting thiosemicarbazones can afford synthetic drugs with a variety of pharmacological effects. Trying to elucidate, if metal complexes from α‐N‐heterocyclic thiosemicarbazones can achieve more selectivity versus special tumor lines, we have developed new metal complexes with 1H imidazole‐4‐carboxaldehyde 4 N‐p‐tolyl‐ and 4 N‐phenylthiosemicarbazone (HL1 and HL2 respectively). The solution studies of these ligands showed a tautomeric equilibria in solution and their reaction with Li2PdCl4 proved the stability of both forms affording two mononuclear Pd(II) complexes. Both tautomeric forms are clearly coordinated to palladium center acting as two different bidentate ligands. Palladium complexes' stability in biological buffers was investigated to stablish the optimal conditions for the evaluation of cytotoxicity, that on the triple negative adenocarcinoma cell line showed IC50 values in the low micromolar range. Complexes were also studied with CT DNA (UV‐Visible spectroscopy and viscosity) and with the pBR322 plasmid supercoiled models, indicating non covalent interaction. [ABSTRACT FROM AUTHOR]