Introduction: Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults, with poor prognosis due to relapse, metastasis, and chemoresistance. The search for novel metal-based therapeutics has highlighted copper complexes as promising candidates. Here, we report the in vitro and in vivo antitumor activity of a tetranuclear Cu(II)-hydrazone complex (Cu4L4) derived from (E)-5-chloro-N'-(2-hydroxy-3-methoxybenzylidene)thiophene-2-carbohydrazide. Results: Cytotoxic assays on MG-63 OS cells revealed potent activity with an IC50 of 0.50 ± 0.04 µM, significantly surpassing its free ligand (IC50 = 13.9 ± 1.6 µM) and cisplatin (IC50 = 39.0 ± 1.8 µM). This tetranuclear complex outperforms mononuclear Cu-hydrazones analogs (e.g., 4-fold vs. CuHL1, 2-fold vs. CuHL2, 5-fold vs. CuHL3, 17-fold vs. CuHL4,), and Cu4L4 also exhibits reduced clonogenic survival, induces reactive oxygen species production, and promotes late apoptosis as a main mechanism, being the main mechanism of action involved in anticancer activity. In multicellular tumor spheroids, the complex maintained strong cytotoxicity (IC50 = 4.11 ± 0.12 µM), impaired spheroid integrity, and markedly inhibited cell migration at sub-IC50 concentrations. The tetranuclear architecture confers markedly enhanced antitumor activity relative to the corresponding mononuclear Cu-hydrazone complexes (e.g., 2-fold vs. CuHL1, 4-fold vs. CuHL2, 2-fold vs. CuHL3). In a xenograft model, sustained administration of Cu4L4 (2 mg/kg, i.p., twice weekly) inhibited tumor growth by 43.6%, reduced mitotic index, and increased necrotic area without significant systemic toxicity. Conclusions: Overall, Cu4L4 displayed potent and selective antitumor activity against OS cells in 2D, 3D, and in vivo models, underscoring copper-hydrazone complexes as promising scaffolds for the development of new therapies against OS.

Breast cancer (BC) is the most frequently diagnosed malignancy in women and triple-negative breast cancer (TNBC) is its most aggressive subtype of BC, often associated with poor prognosis due to the limited current therapies. Effective delivery systems for metal-based drugs could improve antitumor efficacy and selectivity. In this study, the copper-complex [Cu(N-N-Fur)(NO3)(H2O)] (CuL1), which has demonstrated anticancer activity, was encapsulated into Eudragit®-based nanoparticles to enhance its effects against TNBC cell lines (MDA-MB-231, 4T1, and Hs 578T). Two nanosystems were prepared by nanoprecipitation followed by ultrasonication, using Eudragit® E100/S100 (ES-CuL1) or Eudragit® E100/NE100D (ENE-CuL1). The physicochemical and morphologic properties were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), fourier transformed infrared spectroscopy (FTIR), and small-angle X-ray scattering/wide-angle X-ray scattering (SAXS/WAXS). Both formulations showed encapsulation efficiencies of CuL1 above 90 % and in vitro controlled drug release over 72 h. Cytotoxicity and apoptosis were evaluated in 2D monolayers and 3D spheroids of TNBC. Notably, ES-CuL1 enhances the cytotoxic activity of CuL1, showing increased cytotoxicity across all 2D cell lines. Consistently, the encapsulated complex significantly reduced clonogenic survival from 0.5 µM onward and induced a higher proportion of late apoptotic cells in all tested lines. In 3D models, ES-CuL1 produced similar effects to the free drug in 4T1 spheroids but elicited a stronger cytotoxic response in Hs 578T spheroids, suggesting improved penetration and retention in tumor-like structures. The superior performance of ES-CuL1 supports its potential as effective nanocarrier for BC therapy and highlights the predictive value of 3D spheroids for nanodrug evaluation.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic treatments. This study evaluates the anticancer activity and mode of action of the copper(II) complex [Cu(HL1)(NO3)H2O]·H2O (CuHL1), derived from (E)-N'-(2-hydroxy-3-methoxybenzylidene)furan-2-carbohydrazide (H2L1), against a panel of TNBC cell lines (MDA-MB-231, MDA-MB-468, MDA-MB-157, HCC1806). CuHL1 exhibits potent cytotoxicity in the low micromolar range (IC50 ≈ 2 µM), surpassing cisplatin by up to 81-fold. In MDA-MB-231 cells, CuHL1 inhibits colony formation and induced reactive oxygen species (ROS) generation in a concentration-dependent manner. Moreover, CuHL1 triggers apoptosis as evidenced by Annexin V/PI staining and the modulation of Bax, Bcl-2, caspase-3, and cleaved caspase-3 protein levels. Label-free quantitative proteomics reveal 34 differentially expressed proteins, implicating pathways related to heat shock response, protein folding, lipid metabolism, and cell migration. Notably, CuHL1 downregulates BCAR3, AJUBA, MPZL1, TP53, FASN, and HMGCS1, suggesting inhibition of prometastatic and lipid biosynthetic processes. Functional assays confirm reduced migratory capacity in MDA-MB-231 cells. These findings position CuHL1 as a promising candidate for TNBC therapy, meriting further in vivo evaluation.

This work deals with the synthesis and characterization of two novel N-acylhydrazones (H2L1 and H2L2) and its Cu(II) complexes [Cu(HL1)2] and [Cu(HL2)2]. The crystal structures of H2L1 and H2L2 were solved by X-ray diffraction and a detailed analysis of the intermolecular interactions that stabilize the crystal packing of both ligands has been performed by Hirshfeld analysis and their associated two-dimensional fingerprint plots. The strength and nature of the intermolecular contacts were evaluated by using different computational tools including the quantum theory of atoms in molecules (QTAIM) and noncovalent (NCI) isosurfaces. Two new Cu(II) complexes were synthesized and characterized by the conjunction of different techniques (FTIR, Elemental Analysis, HRMS, UV-vis spectroscopies and thermogravimetric analysis (TGA)). Cytotoxicity assays of both ligands and its copper(II) complexes against three human tumor cell lines: MG-63 (bone), HCT-116 (colon) and MDA-MB-231 (breast), and non-tumor cell line (L929 cells) revealed an enhancement of the effectiveness as compared with both the ligand and the free metal ion.

This paper describes the synthesis, structural analysis, and magnetic and spectroscopic characterizations of six new dicopper(II) complexes with dinucleating phenol-based ligands containing different thioether and selenoether donor substituents. The compounds appear as a cation complex [Cu2(L)(μ-SO4)]+. Temperature-dependent magnetometry reveals the presence of ferromagnetic coupling for all of the six complexes. The bioinspired catalytic activities of these complexes, related to catechol oxidase, were studied using 3,5-di-tert-butylcatechol as the substrate, and those related to phenoxazinone synthase activity were studied using o-aminophenol. It was observed that the complexes containing withdrawing groups showed the highest values of catalytic efficiency (E). The complexes were cytotoxic against MDA-MB-231 (triple negative breast adenocarcinoma) and MG-63 (human osteosarcoma), surpassing the activity of the metallodrug cisplatin.

This study investigated the use of riboflavin-targeted Nanostructured Lipid Carriers (R-NLCs) to deliver a platinum-based anticancer drug [PtCl(8-O-quinolinate)(dmso)] (8-QO-Pt) to colorectal cancer cells. Three different R-8-QO-Pt-NLC formulations were prepared via hot-homogenization by ultrasonication method. The physicochemical characterizations of NLCs were analyzed by small- and wide-angle X-ray scattering (SAXS/WAXS) and fourier transformed infrared spectroscopy (FTIR). The cytotoxic effects and IC50 values of R-8-QO-Pt-NLC formulations were compared with those of the free 8-QO-Pt. Cellular uptake and apoptosis were evaluated towards HCT 116 cells in monolayer (2D). The liquid overlay technique was used to generate 3D multicellular tumor spheroids, MCTS. The anticancer and antimetastatic activities of the free 8-QO-Pt and R-8-QO-Pt-NLCs were determined in MCTS. The results revealed that R-8-QO-Pt-NLC exhibited greater cytotoxicity and lower IC50 values than free 8-QO-Pt in both 2D and 3D cell cultures. Furthermore, results showed that the volumes of the spheroids were reduced in response to increasing concentrations of R-8-QO-Pt-NLC, showing higher inhibition of cell migration in colorectal cancer spheroids at concentrations of 10.0, 15.0, and 25.0 μM than free 8-QO-Pt. To provide protection against gastric acid conditions, an additional drug delivery system based on alginate (Alg) and gelatin (Gel) beads for R-8-QO-Pt-NLC oral administration was developed. While free and R-NLC encapsulated 8-QO-Pt were practically inactivated at pH 1.2 and 37 °C, it was revealed that the Alg-Gel beads retain 5.7 times the initial activity of the R-8-QO-Pt-NLC. The findings of this research indicate that R-8-QO-Pt-NLC embedded in Alg-Gel beads are promising hydrogels for targeted colorectal delivery systems.

As part of our efforts to develop novel and more effective metallodrugs, we have synthesized and characterized a new coordination complex between the commercially available drug sunitinib (Sun) and the...

This study details the synthesis of a novel ligand, (E)-5-chloro-N'-(2-hydroxy-3-methoxybenzylidene) thiophene-2-carbohydrazide ligand (for short, H2L), and its tetranuclear Cu(II) complex (Cu4L4), together with their X-ray crystal structures and the magnetic properties and EPR spectra of Cu4L4 within the 4-300 K temperature range. Furthermore, we report the spectroscopic characterization (FTIR and UV-Vis) of the compounds and perform a Hirshfeld analysis of their non-covalent interactions, along with certain quantum chemical calculations. H2L crystallizes in the monoclinic space group Cc with Z = 8 molecules per unit cell and the Cu4L4 complex crystallizes in the tetragonal space group P41/a with Z = 4. The complex is at a crystal site of S4 symmetry, conforming to a cubane-like Cu4O4 core. The main pathway for exchange interaction between neighboring copper ions in the core involves a relatively large overlap of the copper d(x2 - y2) electron ground state orbital with the sp2 lone-pair lobes of the bridging oxygen. Magnetic susceptibility in the 5-300 K range, mainly interpreted with the exchange Hamiltonian Ĥex = J(Ŝ1·Ŝ2 + Ŝ2·Ŝ3 + Ŝ3·Ŝ4 + Ŝ4·Ŝ1), confirms the expected relatively strong antiferromagnetic (AF) character of the complex (J = -61.5(1) cm-1). The powder room temperature Q-band EPR spectrum shows a very broad band (ΔBpp = 1980 Gauss) corresponding to a gyromagnetic g-factor of 2.13. The band intensity decreases sharply with temperature, as expected for a Cu(II) tetramer with a well isolated spin singlet (S = 0) ground state.

Focal Adhesion Kinase (FAK) is a key regulator of tumor cell migration and survival, and its persistent overexpression in aggressive cancers has motivated ongoing efforts to identify novel small-molecule inhibitors. Despite this interest, progress in discovering new potent scaffolds has been limited. In this work, we applied a multistep computational workflow followed by experimental testing to refine hit selection and reduce the false positives typically associated with docking. DrugBank and several commercial libraries were screened using Exponential Consensus Ranking (ECR) docking, and molecular dynamics simulations were used to assess pose stability and interaction persistence. A subset of predicted binders was then tested in MG-63 (bone cancer) and MDA-MB-231 (breast cancer) cells using cell viability and wound-healing assays, followed by direct autophosphorylation assays with recombinant FAK. Several repurposed compounds, including clofazimine and tafamidis, produced clear dose-dependent effects on cell migration, although their inhibitory activity in biochemical assays remained weak (IC50 values above 100 μM), far from the potency of the reference inhibitor TAE226. Retrospective analysis of the computational workflow showed that standard MM-GBSA calculations did not correlate with these experimental outcomes. However, incorporating explicit water molecules through the NWAT-MMGBSA approach improved agreement with the biochemical data and helped to rationalize the limited affinity observed experimentally. Taken together, the results underline the relevance of explicit solvation in modeling the FAK active site and suggest that refined solvent-aware protocols may provide more reliable guidance for future screening efforts.

Copper complexes are a class of anticancer compounds studied for the treatment of various types of solid tumors, such as breast, lung, bone, prostate, and ovarian tumors, among others. These compounds have several effects on tumor cell death mechanisms, including apoptosis, necrosis, ferroptosis, and cuproptosis. The chemistry and anticancer activity of copper-based complexes are summarized in this review based on preclinical and clinical research that focuses on structure-activity relationships, molecular targets, and investigation of the mechanism of action and cell death underlying their anticancer activity.

In this work, we evaluated the anticancer activity of compounds 1 (mononuclear) and 2 (dinuclear) copper(ii) coordination compounds over MDA-MB-231 cells, and compared their activities with that of a newly, protonated, dinuclear analogue of 2 (3).

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.

New therapeutic strategies for osteosarcoma (OS) have demonstrated the potential efficacy of copper compounds as anticancer drugs and as a substitute for the often used platinum compounds. OS is a type of bone cancer, primarily affecting young adults and children. The main objective of this work is to discover the molecular targets and cellular pathways related to the antitumor properties of a Cu(II)-hydrazone toward human OS 2D and 3D systems. Cell viability study using MG-63 cells was evaluated in OS monolayer and spheroids. CuHL significantly reduced cell viability in OS models (IC50 2D: 2.6 +/- 0.3 mu M; IC50 3D: 9.9 +/- 1.4 mu M) (p<0.001). Also, CuHL inhibits cell proliferation and it induces cells to apoptosis. The main mechanism of action found for CuHL are the interaction with DNA, genotoxicity, the ROS generation and the proteasome activity inhibition. Besides, 67 differentially expressed proteins were found using proteomic approaches. Of those 67 proteins, 40 were found overexpressed and 27 underexpressed. The response to stress and to unfolded protein, as well as ATP synthesis were the most affected biological process among upregulated proteins, whilst proteins related to DNA replication and redox homeostasis were downregulated.

The anticancer drugs cis-diamminedichloridoplatinum (II) (cisplatin) and oxaliplatin are commonly used to treat patients with a number of cancers including gastrointestinal cancer. While platinum drugs have succeeded in prolonging overall progression-free survival of gastrointestinal cancer patients, treatment with platinum-based chemotherapeutics can cause resistance, and platinum-chemoresistance poses one of the main challenges to gastrointestinal cancer therapy and overall use of platinum-based chemotherapy. In addition to their interactions with DNA, Pt-chemotherapeutics commonly interact with cellular RNA. This manuscript explores the speciation of cisplatin and oxaliplatin, describes their interaction with DNA and RNA, and discusses similarities and differences which cause the different physiological responses of long non-coding RNAs upon treatment with platinum reagents. It explores the aberrant expression of long non-coding RNAs in gastrointestinal cancer including oral cavity cancer, esophageal cancer, gastric cancer, and colorectal cancer. Here we identify several long non-coding RNAs which are aberrantly expressed in platinum-resistant cell lines of gastrointestinal cancers. Although different gastrointestinal cancer cell lines are tested, increased or decreased aberrant expression compared to normal cells is found for the same long non-coding RNAs, suggesting that gene expression and cellular pathways are changed in a similar manner. Indubitably, further understanding of these phenomena will be beneficial to evaluate if these behaviors can be exploited to develop strategies for use in future therapeutic strategies for treatment of gastrointestinal cancer patients.

Metallocompounds are a class of anticancer compounds largely used in the treatment of several types of solid tumors, including bone cancer. Osteosarcoma (OS) is a primary malignant bone tumor that frequently affects children, adolescents and young adults. It is a very invasive type of tumor, so ∼40% of patients develop distant metastases, showing elevated mortality rates. In this review, we present an outline of the chemistry and antitumor properties of metal-based compounds in preclinical (in vitro and in vivo) and clinical OS models, focusing on the relationship between structure–activity, molecular targets and the study of the mechanism of action involved in metallocompound anticancer activity.

Water-soluble crude polysaccharides (WSCPs) were isolated from the fruiting bodies of Ramaria flava (Schaeff.) Qu & eacute;l. (RFCP) and Ramaria cf. aurea (Schaeff.) Qu & eacute;l. (RACP). Species of Ramaria were collected in Boyac & aacute;-Colombia. WSCPs were obtained by hot-water extraction, ethanol precipitation, and dialysis and characterized using UV-Vis spectroscopy, gel permeation chromatography, high-performance liquid chromatography-diode array detector, fourier transform infrared and nuclear magnetic resonance spectroscopy. Different assays evaluated the antioxidant capacity, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-assay was used to determine cytotoxic effects. Chemical compositional analysis revealed that RFCP and RACP are heteropolysaccharides with molecular weights of 407 and 818 kDa, respectively compose mainly of glucose, mannose, galactose, fucose, and glucuronic acid with small amounts of protein and polyphenols. The backbone of RFCP and RACP is composed of beta-D-Glcp-(4 ->,-> 3)-beta-D-Glcp-(1 ->,-> 2,6)-alpha-D-Galp-(1 ->,-> 3,6)-alpha-D-Manp-(1 ->. Antioxidant capacity demonstrated that both crude polysaccharides exhibit reducing power, radical scavenging ability, and a protective effect on lipid-peroxidation. MTT assay showed that RFCP and RACP inhibited the growth of cancer cells HCT 116-(colorectal) and MG-63-(bone) in a concentration-dependent manner. Compared with RFCP, RACP showed better antioxidant capacity and cytotoxic effects due to differences in composition, molecular weight, and triple-helical conformation. Overall, WSCPs exhibited a promising biological effect, highlighting the cultural, nutritional, and medicinal value of wild mushrooms.

Osteosarcoma cancers are becoming more common in children and young adults, and existing treatments have low efficacy and a very high mortality rate, making it pressing to search for new chemotherapies with high efficacy and high selectivity index. Copper complexes have shown promise in the treatment of osteosarcoma. Here, we report the synthesis, characterization, and anticancer activity of [Cu(N-N-Fur)(NO3)(H2O)] complex where N-N-Fur is (E)-N'-(2-hydroxy-3-methoxybenzylidene)furan-2-carbohydrazide. The [Cu(N-N-Fur)(NO3)(H2O)] complex was characterized via X-ray diffraction and electron spin resonance (ESR), displaying a copper center in a nearly squared pyramid environment with the nitrate ligand acting as a fifth ligand in the coordination sphere. We observed that [Cu(N-N-Fur)(NO3)(H2O)] binds to DNA in an intercalative manner. Anticancer activity on the MG-63 cell line was evaluated in osteosarcoma monolayer (IC50 2D: 1.1 ± 0.1 μM) and spheroids (IC50 3D: 16.3 ± 3.1 μM). Selectivity assays using nontumoral fibroblast (L929 cell line) showed that [Cu(N-N-Fur)(NO3)(H2O)] has selectivity index value of 2.3 compared to cis-diamminedichloroplatinum(II) (CDDP) (SI = 0.3). Additionally, flow cytometry studies demonstrated that [Cu(N-N-Fur)(NO3)(H2O)] inhibits cell proliferation and conveys cells to apoptosis. Cell viability studies of MG-63 spheroids (IC50 = 16.3 ± 3.1 μM) showed that its IC50 value is 4 times lower than for CDDP (IC50 = 65 ± 6 μM). Besides, we found that cell death events mainly occurred in the center region of the spheroids, indicating efficient transport to the microtumor. Lastly, the complex showed dose-dependent reductions in spheroid cell migration from 7.5 to 20 μM, indicating both anticancer and antimetastatic effects.

In the war against cancer, two cytotoxic metallic fragments—gold and platinum, symbolically represented as superheroes—join forces in a single molecule. Our research showcases the impressive potency of these molecules against a panel of cancer cell lines, with an emphasis on 2D and 3D triple negative breast cancer models. More information can be found in the Research Article by M. Contel and co-workers (DOI: 10.1002/chem.202302045).