Antitumoral and Antimetastatic Activity by Mixed Chelate Copper(II) Compounds (Casiopeínas) on Triple-Negative Breast Cancer, In Vitro and In Vivo Models.

Triple-negative breast cancer (TNBC), accounting for 15-20% of all breast cancers, has one of the poorest prognoses and survival rates. Metastasis, a critical process in cancer progression, causes most cancer-related deaths, underscoring the need for alternative therapeutic approaches. This study explores the anti-migratory, anti-invasive, anti-tumoral, and antimetastatic effects of copper coordination compounds Casiopeína IIIia (CasIIIia) and Casiopeína IIgly (CasIIgly) on MDA-MB-231 and 4T1 breast carcinoma cell lines in vitro and in vivo.

Doble synergetic anticancer activity through a combined chemo-photodynamic therapy and bioimaging of a novel Cas-ZnONPs all-in-one system.

A strategy for cancer treatment was implemented, based on chemo-photodynamic therapy, utilizing a novel formulation, low-cost system called Cas-ZnONPs. This system consisted of the incorporation of Casiopeina III-ia (CasIII-ia), a hydrophilic copper coordination compound with well-documented anti-neoplastic activity, on Zinc oxide nanoparticles (ZnONPs) with apoptotic activity and lipophilicity, allowing them to permeate biological barriers. Additionally, ZnONPs exhibited fluorescence, with emission at different wavelengths depending on their agglomeration and enabling real-time tracking biodistribution.

Casiopeina III-ia: A Copper Compound with Potential Use for Treatment of Infections Caused by Leishmania mexicana.

Introduction: Casiopeina III-ia (CasIII-ia) is a mixed chelate copper (II) compound capable of interacting with free radicals generated in the respiratory chain through redox reactions, producing toxic reactive oxygen species (ROS) that compromise the viability of cancer cells, bacteria and protozoa. Due to its remarkable effect on protozoa, this study evaluated the effect of CasIII-ia on Leishmania mexicana amastigotes and its potential use as a treatment for cutaneous leishmaniasis in the murine model.

Methods: We analyzed the leishmanicidal effect of CasIII-ia on L.

Biological activity of mixed chelate copper(II) complexes, with substituted diimine and tridentate Schiff bases (NNO) and their hydrogenated derivatives as secondary ligands: Casiopeína's fourth generation.

We synthesize and characterize nine copper(II) compounds. Four with general formula [Cu(NNO)(NO)] and five mixed chelates [Cu(NNO)(N-N)], where NNO corresponds to asymmetric salen ligands (E)-2-((2-(methylamino)ethylimino)methyl)phenolate (L1) and (E)-3-((2-(methylamino)ethylimino)methyl)naphthalenolate (LN1); and their hydrogenated derivatives 2-((2-(methylamino)ethylamino)methyl)phenolate (LH1) and 3-((2-(methylamino)ethylamino)methyl)naphthalenolate (LNH1); and N-N correspond to 4,4'-dimethyl-2,2'-bipiridyne(dmbpy) or 1,10-phenanthroline (phen). Using EPR, the geometries of the compounds in solution in DMSO were assigned, [Cu(LN1)(NO)] and [Cu(LNH1)(NO)] a square-planar, [Cu(L1)(NO)], [Cu(LH1)(NO)], [Cu(L1)(dmby)] and [Cu(LH1)(dmby)] a square-based pyramid; and [Cu(LN1)(dmby)], [Cu(LNH1)(dmby)] and [Cu(L1)(phen)] and elongated octahedral.

Development and In Vitro and In Vivo Evaluation of an Antineoplastic Copper(II) Compound (Casiopeina III-ia) Loaded in Nonionic Vesicles Using Quality by Design.

In recent decades, the interest in metallodrugs as therapeutic agents has increased. Casiopeinas are copper-based compounds that have been evaluated in several tumor cell lines. Currently, casiopeina III-ia (CasIII-ia) is being evaluated in phase I clinical trials.

Casiopeinas® third generation, with indomethacin: synthesis, characterization, DFT studies, antiproliferative activity, and nanoencapsulation.

Seven new Casiopeinas® were synthesized and properly characterized. These novel compounds have a general formula [Cu(N-N)()]NO, where is deprotonated indomethacin and N-N is either bipyridine or phenanthroline with some methyl-substituted derivatives, belonging to the third generation of Casiopeinas®. Spectroscopic characterization suggests a square-based pyramid geometry and voltammetry experiments indicate that the redox potential is strongly dependent on the N-N ligand.

Self-Assembled Monolayer of Monomercaptoundecahydro--dodecaborate on a Polycrystalline Gold Surface.

In this work, we present an electrochemical study of the boron cage monomercaptoundecahydro--dodecaborate [BHSH] in solution and in a self-assembled monolayer over a polycrystalline gold electrode. Cyclic voltammetry of the anion [BHSH] in solution showed a shift in the peak potentials related to the redox processes of gold hydroxides, which evidences the interaction between the boron cage and the gold surface. For an Au electrode modified with the anion [BHSH], cyclic voltammetry response of the probe Fe(CN)/Fe(CN) showed a ΔEp value typical for a surface modification.

DNA, a target of mixed chelate copper(II) compounds (Casiopeinas®) studied by electrophoresis, UV-vis and circular dichroism techniques.

Casiopeinas are a family of mixed chelate copper(II) complexes with antiproliferative and antineoplastic activities, results that have positioned them as an alternative for cancer treatment. Because DNA is one of their principal targets, it is of our interest to find out the effect of substituents on the diiamine ligands over mode of interaction. Therefore, we studied 21 Casiopeinas upon DNA by gel electrophoresis, UV-vis and circular dichroism (CD) spectroscopic techniques, previously studied by DFT calculations and Quantitative Structure-Activity Relationship (QSAR).

Bridging informatics and medicinal inorganic chemistry: Toward a database of metallodrugs and metallodrug candidates.

Metallodrug discovery has evolved in recent years, yielding several compounds in the clinic for therapeutic and medical imaging diagnostic applications. As reviewed here, several research groups in well-established medicinal inorganic chemistry groups are consistently generating high-quality SAR data representing an ideal starting point in the use of computational methods to advance the development of new drugs. Although there are representative chemical structures of metallodrugs in public databases annotated with biological activity, there is currently no public compound database dedicated to metallodrugs.

Metallodrugs: an approach against invasion and metastasis in cancer treatment.

Cancer is a heterogeneous and multifactorial disease that causes high mortality throughout the world; therefore, finding the most effective therapies is a major research challenge. Currently, most anticancer drugs present a limited number of well-established targets, such as cell proliferation or death; however, it is important to consider that the worse progression of cancer toward pathological stages implies invasion and metastasis processes. Medicinal Inorganic Chemistry (MIC) is a young area that deals with the design, synthesis, characterization, preclinical evaluation, and mechanism of action of new inorganic compounds, called metallodrugs.

H -NMR Metabolomics Study of the Effect of Cisplatin and Casiopeina IIgly on MDA-MB-231 Breast Tumor Cells.

The knowledge of the metabolic processes of designed metallodrugs for cancer treatment is an area that has been not profoundly studied. Casiopeina IIgly (CasIIgly), which belongs to the Casiopeínas family, is a copper (II) coordination compound that has shown good biological activity against several cancer cells, low toxicity in normal cells, and antineoplastic activity in murine and xenografted models. In this work we employed a triple-negative highly metastatic breast carcinoma line (MDA-MB-231), which is one of the cancer types with a great mortality index, for H-NMR metabolomic analysis using cisplatin and CasIIgly, in order to quantify the effect of metallodrugs in the metabolic profile of this cell tumor line as a consequence of treatment at different times.

Intermediate Detection in the Casiopeina-Cysteine Interaction Ending in the Disulfide Bond Formation and Copper Reduction.

A strategy to improve the cancer therapies involves agents that cause the depletion of the endogenous antioxidant glutathione (GSH), increasing its efflux out of cells and inducing apoptosis in tumoral cells due to the presence of reactive oxygen species. It has been shown that Casiopeina copper complexes caused a dramatic intracellular GSH drop, forming disulfide bonds and reducing Cu to Cu. Herein, through the determination of the [Cu]-SH bond before reduction, we present evidence of the adduct between cysteine and one Casiopeina as an intermediate in the cystine formation and as a model to understand the anticancer activity of copper complexes.

Anti-proliferative, pro-apoptotic and anti-invasive effect of the copper coordination compound Cas III-La through the induction of reactive oxygen species and regulation of Wnt/β-catenin pathway in glioma.

Gliomas are the most aggressive neoplasms that affect the central nervous system, being glioblastoma multiforme (GBM) the most malignant. The resistance of GBM to therapies is attributed to its high rate of cell proliferation, angiogenesis, invasion, and resistance to apoptosis; thus, finding alternative therapeutic approaches is vital. In this work, the anti-proliferative, pro-apoptotic, and anti-invasive effect of the copper coordination compound Casiopeina III-La (Cas III-La) on human U373 MG cells was determined and .

Ancillary Ligand in Ternary Cu Complexes Guides Binding Selectivity toward Minor-Groove DNA.

Copper-containing compounds known as Casiopeı́nas are biologically active molecules which show promising antineoplastic effects against several cancer types. Two possible hypotheses regarding the mode of action of the Casiopeı́nas have emerged from the experimental evidence: the generation of reactive oxygen species or the ability of the compounds to bind and interact with nucleic acids. Using robust molecular dynamics simulations, we investigate the interaction of four different Casiopeı́nas with the DNA duplex d(GCACGAACGAACGAACGC).

Theoretical determination of half-wave potentials for phenanthroline-, bipyridine-, acetylacetonate-, and glycinate-containing copper (II) complexes.

We report a protocol for the evaluation of theoretical half-wave potential (E) using a set of 22 mixed chelate copper (II) complexes containing 1,10-phenanthroline and 2,2'-bipyridine derivatives as primary ligands, and acetylacetonate or glycinate as secondary ligands (formally from the Casiopeínas® family) for which accurate experimental values were determined in a 2/5 mixture of ethanol/water. We have calibrated the BP86, PBE, PBE0, B3LYP, M06-2X, and ω-B97XD functionals, using the Los Alamos LANL2DZ and Stuttgart-Köln SDDAll effective core potentials for the Cu and Fe atoms and the 6-311+G* basis set for the C, H, O, and N atoms. To address the solvent effects, we have saturated the first solvation shell with up to 9 water molecules for the explicit model and compared it with the Continuum Like-Polarizable Continuum Model (CPCM) implicit solvent scheme.

Heteroleptic Ni complexes: Synthesis, structural characterization, computational studies and amoebicidal activity evaluation.

In this work, we present the synthesis, characterization, electrochemical studies, DFT calculations, and in vitro amoebicidal effect of seven new heteroleptic Ni coordination compounds. The crystal structures of [H(pdto)](NO) and [Ni(pdto)(NO)]PF are presented, pdto = 2,2'-[1,2-ethanediylbis-(sulfanediyl-2,1-ethanediyl)]dipyridine. The rest of the compounds have general formulae: [Ni(pdto)(NN)](PF) where N-N = 2,2'-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (44dmbpy), 5,5'-dimethyl-2,2'-bipyridine (55dmbpy), 1,10-phenanthroline (phen), 4,7-dimethyl-1,10-phenanthroline (47dmphen) and 5,6-dimethyl-1,10-phenanthroline (56dmphen).

Identification of descriptors for structure-activity relationship in ruthenium (II) mixed compounds with antiparasitic activity.

Herein is presented the synthesis, characterization, electrochemical studies, DFT calculations and in vitro evaluation of amoebicidal activity in trophozoites of Entamoeba histolytica of twenty ruthenium (II) mixed compounds with general formulae: [Ru(pdto)(E-E)]Cl (E-E bidentate, either neutral or negatively charged ligands). For compounds under study, O-O, N-O and N-N auxiliary donor ligands demonstrate to have a crucial impact on the electronic properties and that it is possible to modulate the antiparasitic activity. Among analyzed complexes, only four present a better performance compared to typically used metronidazole drug (IC < 6.

Autophagy Promotes Survival of CHP-212 Neuroblastoma Cells Treated With Casiopeínas®.

Background: Neuroblastoma is the main solid extracranial tumor of childhood. The amplification of N-myc oncogene (MYCN) and 1p deletion are the main molecular alterations. These features are what make treatment impossible, especially in high-risk patients with metastases.

Antigiardiasic activity of Cu(II) coordination compounds: Redox imbalance and membrane damage after a short exposure time.

Giardiasis is a widespread illness that affects inhabitants of underdeveloped countries, being children and seniors the highest risk population. The several adverse effects produced by current therapies besides its increasing ineffectiveness due to the appearance of resistant strains evidence the urgent need for new therapeutic approaches. We present the antigiardiasic effect of eight Cu(II) coordination compounds, which belong to the family Casiopeínas.

Identification of Casiopeina II-gly secondary targets through a systems pharmacology approach.

Casiopeinas are a group of copper-based compounds designed to be used as less toxic, more efficient chemotherapeutic agents. In this study, we analyzed the in vitro effects of Casiopeina II-gly on the expression of canonical biological pathways. Using microarray data from HeLa cell lines treated with Casiopeina II-gly, we identified biological pathways that are perturbed after treatment.

Ex Vivo Cardiotoxicity of Antineoplastic Casiopeinas Is Mediated through Energetic Dysfunction and Triggered Mitochondrial-Dependent Apoptosis.

Casiopeinas are a group of copper-based antineoplastic molecules designed as a less toxic and more therapeutic alternative to cisplatin or Doxorubicin; however, there is scarce evidence about their toxic effects on the whole heart and cardiomyocytes. Given this, rat hearts were perfused with Casiopeinas or Doxorubicin and the effects on mechanical performance, energetics, and mitochondrial function were measured. As well, the effects of Casiopeinas-triggered cell death were explored in isolated cardiomyocytes.

Evaluation of the binding of four anti-tumor Casiopeínas® to human serum albumin.

The metal complexes designated by Casiopeínas® are mixed-ligand Cu-compounds some of them having promising antineoplastic properties. We report studies of binding of Cu(glycinato)(4,7-dimethyl-1,10-phenanthroline) (Cas-II-Gly (1)), Cu(acetylacetonato)(4,7-dimethyl-1,10-phenanthroline) (Cas-III-Ea (2)), Cu(glycinato)(4,4'-dimethyl-2,2'-bipyridine) (Cas-IV-Gly (3)) and Cu(acetylacetonato)(4,4'-dimethyl-2,2'-bipyridine) (Cas-III-ia (4)) to human serum albumin (HSA) by circular dichroism (CD), Electron paramagnetic resonance (EPR) and fluorescence spectroscopy. The results indicate that HSA may bind up to three molecules of the tested Casiopeínas.

Effect of tunable redox behavior of bis chelate substituted 1,10-phenantroline Cu(II) complexes on its reaction with superoxide anion in DMSO. Toward a simple criterion to identify a SOD-like mechanism.

In this work we report a series of Cu(II) complexes [Cu(N-N)(X)], (N-N=substituted 1,10-phenanthroline derivatives and X=Cl or NO), with tunable E for electrochemical reduction [Cu(N-N)(X)]+1e⇌[Cu(N-N)]+X. The disproportion of O was explored in presence of the electro-generated species [Cu(N-N)] using cyclic voltammetry in a non-aqueous media, arising a new simple method to propose a SOD-like mechanism, which can be used as a quick guide test for a compound, before being proven in biological assays. It was found that complexes with high negative half wave potential values (E) for Cu(II)/Cu(I) couple shown a current increment for oxygen reduction, related to the capability of the disproportion of this reactive oxygen species.