H2S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis.

The elevated level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excessive H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@Cu2Cl(OH)3-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H2S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H2S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu9S8) from the TCuH, followed with the release of TPZ. The depletion of H2S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu2+ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H2O2 to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.

Thermodynamically and Kinetically Enhanced Benzene Vapor Sensor Based on the Cu-TCPP-Cu MOF with Extremely Low Limit of Detection.

As a carcinogenic and highly neurotoxic hazardous gas, benzene vapor is particularly difficult to be distinguished in BTEX (benzene, toluene, ethylbenzene, xylene) atmosphere and be detected in low concentrations due to its chemical inertness. Herein, we develop a depth-related pore structure in Cu-TCPP-Cu to thermodynamically and kinetically enhance the adsorption of benzene vapor and realize the detection of ultralow-temperature benzene gas. We find that the in-plane π electronic nature and proper pore sizes in Cu-TCPP-Cu can selectively induce the adsorption and diffusion of BTEX. Interestingly, the theoretical calculations (including density functional theory (DFT) and grand canonical Monte Carlo (GCMC) simulations) exhibit that benzene molecules are preferred to adsorb and array as a consecutive arrangement mode in the Cu-TCPP-Cu pore, while the TEX (toluene, ethylbenzene, xylene) dominate the jumping arrangement model. The differences in distribution behaviors can allow adsorption and diffusion of more benzene molecules within limited room. Furthermore, the optimal pore-depth range (60-65 nm) of Cu-TCPP-Cu allows more exposure of active sites and hinders the gas-blocking process. The optimized sensor exhibits ultrahigh sensitivity to benzene vapor (155 Hz/µg@1 ppm), fast response time (less than 10 s), extremely low limit of detection (65 ppb), and excellent selectivity (83%). Our research thus provides a fundamental understanding to design and optimize two-dimensional metal-organic framework (MOF)-based gas sensors.

Immunogenic Cell Death Induction and Oxygenation by Multifunctional Hollow Silica/Copper-Doped Carbon Dots.

The metastasis and recurrence of cancer are related to immunosuppression and hypoxia in the tumor microenvironment. Activating immune activity and improving the hypoxic environment face essential challenges. This paper reports on a multifunctional nanomaterial, HSCCMBC, that induces immunogenic cell death through powerful photodynamic therapy/chemodynamic therapy synergistic antitumor effects. The tumor microenvironment changed from the immunosuppressive type to immune type, activated the immune activity of the system, decomposed hydrogen peroxide to generate oxygen based on Fenton-like reaction, and effectively increased the level of intracellular O2 with the assistance of 3-bromopyruvate, a cell respiratory inhibitor. The structure and composition of HSCCMBC were characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, infrared spectroscopy, etc. Oxygen probe RDPP was used to investigate the oxygen level inside and outside the cell, and hydroxyl radical probe tetramethylbenzidine was used to investigate the Fenton-like reaction ability. The immunofluorescence method investigated the expression of various immune markers and hypoxia-inducing factors in vitro and in vivo after treatment. In vitro and in vivo experiments indicate that HSCCMBC is an excellent antitumor agent and is expected to be a candidate drug for antitumor immunotherapy.

Cu-doped Fe3O4 nanoparticles for efficient detoxification of epsilon toxin: Toward substituting magnetically recyclable detoxifying agent for formaldehyde.

This research presents the synthesis and characterization of Cu-doped Fe3O4 (Cu-Fe3O4) nanoparticles as a magnetically recoverable and reusable detoxifying agent for the efficient and long-lasting neutralization of bacterial toxins. The nanoparticles were synthesized using the combustion synthesis method and characterized through SEM, XRD, BET, TGA, and VSM techniques. The detoxification potential of Cu-Fe3O4 was compared with traditional formaldehyde (FA) in detoxifying epsilon toxin (ETx) from Clostridium perfringens Type D, the causative agent of enterotoxemia in ruminants. In vivo residual toxicity tests revealed that Cu-Fe3O4 could detoxify ETx at a concentration of 2.0 mg mL-1 within 4 days at room temperature (RT) and 2 days at 37 °C, outperforming FA (12 and 6 days at RT and 37 °C, respectively). Characterization studies using dynamic light scattering (DLS) and circular dichroism (CD) highlighted lower conformational changes in Cu-Fe3O4-detoxified ETx compared to FA-detoxified ETx. Moreover, Cu-Fe3O4-detoxified ETx exhibited exceptional storage stability at 4 °C and RT for 6 months, maintaining an irreversible structure with no residual toxicity. The particles demonstrated remarkable reusability, with the ability to undergo five continuous detoxification batches. This study provides valuable insights into the development of an efficient and safe detoxifying agent, enabling the production of toxoids with a native-like structure. The magnetically recoverable and reusable nature of Cu-Fe3O4 nanoparticles offers practical advantages for easy recovery and reuse in detoxification reactions.

Versatile Fluorescence Lifetime-Based Copper Probe to Quantify Mitochondrial Membrane Potential and Reveal Its Interaction with Protein Aggregation.

Mitochondria play a crucial role in maintaining cellular homeostasis, and the depolarization of mitochondrial membrane potential (MMP) is an important signal of apoptosis. Additionally, protein misfolding and aggregation are closely related to diseases including neurodegenerative diseases, diabetes, and cancers. However, the interaction between MMP changes and disease-related protein aggregation was rarely studied. Herein, we report a novel "turn-on" fluorescent probe MitoRhB that specifically targets to mitochondria for Cu2+ detection in situ. The fluorescence lifetime (τ) of MitoRhB exhibits a positive correlation with MMP changes, allowing us to quantitatively determine the relative MMP during SOD1 (A4 V) protein aggregation. Finally, we found that (1) the increasing concentrations of copper will accelerate the depolarization of mitochondria and reduce MMP; (2) the depolarization of mitochondria can intensify the degree of protein aggregation, suggesting a new routine of copper-induced cell death mediated through abnormal MMP depolarization and protein aggregation.

Realizing Ultrasensitive and Accurate Point-of-Care Profiling for ATP with a Triple-Mode Strategy Based on the ATP-Induced Reassembly of a Copper Coordination Polymer Nanoflower.

New strategies for accurate and reliable detection of adenosine triphosphate (ATP) with portable devices are significant for biochemical analysis, while most recently reported approaches cannot satisfy the detection accuracy and independent of large instruments simultaneously, which are unsuitable for fast, simple, and on-site ATP monitoring. Herein, a unique, convenient, and label-free point-of-care sensing strategy based on novel copper coordination polymer nanoflowers (CuCPNFs) was fabricated for multimode (UV-vis, photothermal, and RGB values) onsite ATP determination with high selectivity, sensitivity, and accuracy. The resulting CuCPNFs with a 3D hierarchical structure exhibit the ATP-triggered decomposition behavior because the competitive coordination between ATP and the copper ions of CuCPNFs can result in the formation of ATP-Cu, which reveals preeminent peroxidase mimics activity and can accelerate the oxidation of 3, 3', 5, 5'-tetramethylbenzidine (TMB) to form oxTMB. During this process, the detection system displayed not only color changes but also a strong NIR laser-driven photothermal effect. Thus, the photothermal and color signal variations are easily monitored by a portable thermometer and a smartphone. This multimode point-of-care platform can meet the requirements of onsite, without bulky equipment, accuracy, and reliability all at once, greatly enhancing its application in practice and paving a new way in ATP analysis.

Design, Synthesis, and Anti-Cancer Evaluation of Novel Water-Soluble Copper(I) Complexes Bearing Terpyridine and PTA Ligands.

This study presents a simple and energy-efficient self-assembly LAG synthetic method for novel water-soluble copper(I) complexes [Cu(terpy)(PTA)][PF6] (1) and [Cu(terpy)(PTA)2][PF6] (2). They were characterized by FT-IR, 1H, and 31P{1H} NMR spectroscopy, elemental analysis, and single-crystal/powder X-ray diffraction (for 2). The X-ray analysis of compound 2 indicates a bidentate coordination mode of terpyridine to the metal center. Variable-temperature NMR tests indicate dynamic properties for terpyridine in the case of both compounds, as well as for the PTA ligands in the case of 2. Additionally, compounds 1 and 2 exhibit interesting cytotoxic activity, which was tested on normal human dermal fibroblasts (NHDFs), human lung carcinoma (A549), human breast adenocarcinoma (MCF-7), and human cervix carcinoma (HeLa) established cell lines. In comparison to the other tested compounds, complexes 1 and 2 seem to have significantly lower IC50 values against cancer cells (A549, HeLa, MCF-7), indicating their potential as prospective anticancer agents. Moreover, both compounds show no significant toxicity towards normal skin cells (NHDFs), suggesting a certain selectivity in their action on cancer cells. Cisplatin as a reference compound also exhibited considerable cytotoxicity against cancer cells but with a low level of selectivity, which could lead to unwanted effects on normal cells. Remarkably, compounds 1 and 2 exhibit up to 30 times the cytotoxic activity of cisplatin, with a six-fold lower toxicity to normal cells. They also interact strongly with human serum albumin, suggesting potential therapeutic applications. Overall, these compounds hold significant promise as potential chemotherapeutic agents.

The Copper Reduction Potential Determines the Reductive Cytotoxicity: Relevance to the Design of Metal-Organic Antitumor Drugs.

Copper-organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu2+ to Cu1+ triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)-organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu+2 → Cu+1 redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper-organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper-organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties.

Recently Reported Biological Activities and Action Targets of Pt(II)- and Cu(II)-Based Complexes.

Most diseases that affect human beings across the world are now treated with drugs of organic origin. However, some of these are associated with side effects, toxicity, and resistance phenomena. For the treatment of many illnesses, the development of new molecules with pharmacological potential is now an urgent matter. The biological activities of metal complexes have been reported to have antitumor, antimicrobial, anti-inflammatory, anti-infective and antiparasitic effects, amongst others. Metal complexes are effective because they possess unique properties. For example, the complex entity possesses the effective biological activity, then the formation of coordination bonds between the metal ions and ligands is controlled, metal ions provide it with extraordinary mechanisms of action because of characteristics such as d-orbitals, oxidation states, and specific orientations; metal complexes also exhibit good stability and good physicochemical properties such as water solubility. Platinum is a transition metal widely used in the design of drugs with antineoplastic activities; however, platinum is associated with side effects which have made it necessary to search for, and design, novel complexes based on other metals. Copper is a biometal which is found in living systems; it is now used in the design of metal complexes with biological activities that have demonstrated antitumoral, antimicrobial and anti-inflammatory effects, amongst others. In this review, we consider the open horizons of Cu(II)- and Pt(II)-based complexes, new trends in their design, their synthesis, their biological activities and their targets of action.

Process and systematic study of gold recovery from flexible printed circuit boards (FPCBs) using a choline chloride-ethylene glycol system.

The traditional hydrometallurgy technology has been widely used to recover precious metals from electronic waste. However, such aqueous recycling systems often employ toxic/harsh chemicals, which may cause serious environmental problems. Herein, an efficient and environment-friendly method using a deep eutectic solvent (DES) mixed system of choline chloride-ethylene glycol-CuCl2·2H2O is developed for gold (Au) recovery from flexible printed circuit boards (FPCBs). The Au leaching and precipitation efficiency can reach approximately 100 % and 95.3 %, respectively, under optimized conditions. Kinetic results show that the Au leaching process follows a nucleation model, which is controlled by chemical surface reactions with an apparent activation energy of 80.29 kJ/mol. The present recycling system has a much higher selectivity for Au than for other base metals; the two-step recovery rate of Au can reach over 95 %, whereas those of copper and nickel are < 2 %. Hydrogen nuclear magnetic resonance spectroscopy (HNMR) and density functional theory (DFT) analyses confirm the formation of intermolecular hydrogen bonds in the DES mixed system, which increase the system melting and boiling points and facilitate the Au leaching process. The Au leaching system can be reused for several times, with the leaching efficiency remaining > 97 % after five cycles. Moreover, ethylene glycol (EG) and choline chloride (ChCl) act as aprotic solvents as well as coordinate with metals, decreasing the redox potential to shift the equilibrium to the leaching side. Overall, this research provides a theoretical and a practical basis for the recovery of metals from FPCBs.

Tumor-targeted delivery of copper-manganese biomineralized oncolytic adenovirus for colorectal cancer immunotherapy.

Oncolytic viral therapy (OVT) is a novel anti-tumor immunotherapy approach, specifically replicating within tumor cells. Currently, oncolytic viruses are mainly administered by intratumoral injection. However, achieving good results for distant metastatic tumors is challenging. In this study, a multifunctional oncolytic adenovirus, OA@CuMnCs, was developed using bimetallic ions copper and manganese. These metal cations form a biomineralized coating on the virus's surface, reducing immune clearance. It is known that viruses upregulate the expression of PD-L1. Copper ions in OA@CuMnCs can decrease the PD-L1 expression of tumor cells, thereby promoting immune cell-related factor release. This process involves antigen presentation and the combination of immature dendritic cells, transforming them into mature dendritic cells. It changes "cold" tumors into "hot" tumors, further inducing immunogenic cell death. While oncolytic virus replication requires oxygen, manganese ions in OA@CuMnCs can react with endogenous hydrogen peroxide. This reaction produces oxygen, enhancing the virus's replication ability and the tumor lysis effect. Thus, this multifunctionally coated OA@CuMnCs demonstrates potent amplification in immunotherapy efficacy, and shows great potential for further clinical OVT. STATEMENT OF SIGNIFICANCE: Oncolytic virus therapy (OVs) is a new anti-tumor immunotherapy method that can specifically replicate in tumor cells. Although the oncolytic virus can achieve a therapeutic effect on some non-metastatic tumors through direct intratumoral injection, there are still three major defects in the treatment of metastatic tumors: immune response, hypoxia effect, and administration route. Various studies have shown that the immune response in vivo can be overcome by modifying or wrapping the surface protein of the oncolytic virus. In this paper, a multifunctional coating of copper and manganese was prepared by combining the advantages of copper and manganese ions. The coating has a simple preparation method and mild conditions, and can effectively enhance tumor immunotherapy.

Promising biomedical systems based on copper nanoparticles: Synthesis, characterization, and applications.

Copper and copper oxide nanoparticles (CuNPs) have unique physicochemical properties that make them highly promising for biomedical applications. This review discusses the application of CuNPs in biomedicine, including diagnosis, therapy, and theranostics. Recent synthesis methods, with an emphasis on green approaches, are described, and the latest techniques for nanoparticle characterization are critically analyzed. CuNPs, including Cu2O, CuO, and Cu, have significant potential as anti-cancer agents, drug delivery systems, and photodynamic therapy enhancers, among other applications. While challenges such as ensuring biocompatibility and stability must be addressed, the state-of-the-art research reviewed here provides strong evidence for the efficacy and versatility of CuNPs. These multifunctional properties have been extensively researched and documented, showcasing the immense potential of CuNPs in biomedicine. Overall, the evidence suggests that CuNPs are a promising avenue for future research and development in biomedicine. We strongly support further progress in the development of synthesis and application strategies to enhance the effectiveness and safety of CuNPs for clinical purposes.

Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases.

Copper transporting P-type (P1B-1-) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P1B-1-ATPases remains poorly understood. In particular, the role of the intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations of a P1B-1-ATPase are combined to reveal that in many eukaryotes the MBD immediately prior to the ATPase core, MBD-1, serves a structural role, remodeling the ion-uptake region. In contrast, the MBD prior to MBD-1, MBD-2, likely assists in copper delivery to the ATPase core. Invariant Tyr, Asn and Ser residues in the transmembrane domain assist in positioning sulfur-providing copper-binding amino acids, allowing for copper uptake, binding and release. As such, our findings unify previously conflicting data on the transport and regulation of P1B-1-ATPases. The results are critical for a fundamental understanding of cellular copper homeostasis and for comprehension of the molecular bases of P1B-1-disorders and ongoing clinical trials.

One-Step Construction of 1,3,4-Oxadiazoles with Anticancer Activity from Tertiary Amines via a Sequential Copper(I)-Catalyzed Oxidative Ugi/aza-Wittig Reaction.

An unparalleled copper(I)-catalyzed synthesis of 1,3,4-oxadiazoles from tertiary amines in one step has been described. The one-pot reactions involving (N-isocyanimine)triphenylphosphorane, tertiary amines, and carboxylic acids resulted in the formation of 1,3,4-oxadiazoles in moderate to good yields through a consecutive oxidative Ugi/aza-Wittig reaction, enabling the direct functionalization of sp3 C-H bonds adjacent to the nitrogen atom. This method offered several notable advantages, including ligands-free, exceptional productivity and a high functional group tolerance. The preliminary biological evaluation demonstrated that compound 4f inhibited hepatoma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

Copper-mediated cyclization of thiosemicarbazones leading to 1,3,4-thiadiazoles: Structural elucidation, DFT calculations, in vitro biological evaluation and in silico evaluation studies.

Cancer's global impact necessitates innovative and less toxic treatments. Thiosemicarbazones (TSCs), adaptable metal chelators, offer such potential. In this study, we have synthesized N (4)-substituted heterocyclic TSCs from syringaldehyde (TSL1, TSL2), and also report the unexpected copper-mediated cyclization of the TSCs to form thiadiazoles (TSL3, TSL4), expanding research avenues. This work includes extensive characterization and studies such as DNA/protein binding, molecular docking, and theoretical analyses to demonstrate the potential of the as-prepared TSCs and thiadiazoles against different cancer cells. The DFT results depict that the thiadiazoles exhibit greater structural stability and reduced reactivity compared to the corresponding TSCs. The docking results suggest superior EGFR inhibition for TSL3 with a binding constant value of - 6.99 Kcal/mol. According to molecular dynamics studies, the TSL3-EGFR complex exhibits a lower average RMSD (1.39 nm) as compared to the TSL1-EGFR complex (3.29 nm) suggesting that both the thiadiazole and thiosemicarbazone examined here can be good inhibitors of EGFR protein, also that TSL3 can inhibit EGFR better than TSL1. ADME analysis indicates drug-likeness and oral availability of the thiadiazole-based drugs. The DNA binding experiment through absorption and emission spectroscopy discovered that TSL3 is more active towards DNA which is quantitatively calculated with a Kb value of 4.74 × 106 M-1, Kq value of 4.04 × 104 M-1and Kapp value of 5 × 106 M-1. Furthermore, the BSA binding studies carried out with fluorescence spectroscopy showed that TSL3 shows better binding capacity (1.64 × 105 M-1) with BSA protein. All the compounds show significant cytotoxicity against A459-lung, MCF-7-breast, and HepG2-liver cancer cell lines; TSL3 exhibits the best cytotoxicity, albeit less effective than cisplatin. Thiadiazoles demonstrate greater cytotoxicity than the TSCs. Overall, the promise of TSCs and thiadiazoles in cancer research is highlighted by this study. Furthermore, it unveils unexpected copper-mediated cyclization of the TSCs to thiadiazoles.

Prednisone and ibuprofen conjugate Janus dendrimers and their anticancer activity.

Drug release from hyperbranched Janus dendrimer-drug conjugates and their subsequent activity are influenced by the different drugs in each dendron and the linker. To understand these effects, we synthetized new Janus-type dendrimers of first and second generation. One dendron with 2,2-Bis(hydroxymethyl)propionic acid functionalized with ibuprofen and the second dendron was obtained with 3-aminopropanol-amidoamine and prednisone. The dendrimers were obtained by copper(I)-catalyzed Click azide-alkyne cycloaddition for the formation of a triazole as a dendrimeric nucleus of Janus dendrimer conjugates are reported. The influence of ibuprofen, prednisone, and spacer on cancer activity of Janus dendrimers conjugates is reported. The IC50 values of the anticancer activity on cancer cell lines the Janus dendrimer of second generation was higher in comparison to the first generation dendrimer. Similarly, the anticancer activity was higher compared to the dendron conjugates. Also, no cytotoxic effects of dendrons and dendrimers on non-cancerous kidney COS-7 cell line was observed. The interesting anticancer activity of the prepared prednisone-ibuprofen Janus dendrimer conjugates suggest that the dendrimers could be of potential use as new anticancer drug.

Copper(II) Complexes with 2,2':6',2″-Terpyridine Derivatives Displaying Dimeric Dichloro-µ-Bridged Crystal Structure: Biological Activities from 2D and 3D Tumor Spheroids to In Vivo Models.

Eight 2,2':6',2″-terpyridines, substituted at the 4'-position with aromatic groups featuring variations in π-conjugation, ring size, heteroatoms, and methoxy groups, were employed to enhance the antiproliferative potential of [Cu2Cl2(R-terpy)2](PF6)2. Assessing the cytotoxicity in A2780 (ovarian carcinoma), HCT116 (colorectal carcinoma), and HCT116DoxR (colorectal carcinoma resistant to doxorubicin) and normal primary fibroblasts revealed that Cu(II) complexes with 4-quinolinyl, 4-methoxy-1-naphthyl, 2-furanyl, and 2-pyridynyl substituents showed superior therapeutic potential in HCT116DoxR cells with significantly reduced cytotoxicity in normal fibroblasts (42-129× lower). Besides their cytotoxicity, the Cu(II) complexes are able to increase intracellular ROS and interfere with cell cycle progression, leading to cell death by apoptosis and autophagy. Importantly, they demonstrated antimetastatic and antiangiogenic properties without in vivo toxicity. In accordance with their nuclear accumulation, the Cu(II) complexes are able to cleave pDNA and interact with bovine serum albumin, which is a good indication of their ability for internalization and transport toward tumor cells.

A new copper(II) complex containing long-chain aliphatic hydrazide and 1,10-phenanthroline upregulates ADP hydrolysis in triple-negative breast cancer cells.

Copper can be opportunely complexed to modulate oncogenic pathways, being a promising strategy for cancer treatment. Herein, three new copper(II) complexes containing long-chain aliphatic hydrazides and 1,10-phenanthroline (1,10-phen), namely, [Cu(octh)(1,10-phen)(H2O)](NO3)21, [Cu(dech)(1,10-phen)(H2O)](NO3)22 and [Cu(dodh)(1,10-phen)(H2O)](NO3)2.H2O 3 (where octh = octanoic hydrazide, dech = decanoic hydrazide, dodh = dodecanoic hydrazide) were successfully prepared and characterized by several physical-chemical methods. Furthermore, X-ray structural analysis of complex 2 indicated that the geometry around the copper(II) ion is distorted square-pyramidal, in which hydrazide and 1,10-phenanthroline act as bidentate ligands. A water molecule in the apical position completes the coordination sphere of the metal ion. All new copper(II) complexes were cytotoxic to breast cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and MDA-MB-157) and selective when compared to the non tumor lineage MCF-10A. In particular, complex 2 showed half-maximal inhibitory concentration (IC50) values ranging between 2.7 and 13.4 µM in MDA-MB231 cells after 24 and 48 h of treatment, respectively. Furthermore, this complex proved to be more selective for tumor cell lines when compared to doxorubicin and docetaxel. Complex 2 inhibited the clonogenicity of MDA-MB231 cells, increasing adenosine diphosphate (ADP) hydrolysis and upregulating ecto-nucleoside triphosphate diphosphohydrolase 1 (ENTPD1) transcriptional levels. In this sense, we suggest that the inhibitory effect on cell proliferation may be related to the modulation of adenosine monophosphate (AMP) levels. Thus, a novel copper(II) complex with increased cytotoxic effects and selectivity against breast cancer cells was obtained, contributing to medicinal chemistry efforts toward the development of new chemotherapeutic agents.

Copper perchlorate catalyzed oxidative cyclisation of a novel bishydrazone ligand, formation of an unusual copper complex and in vitro biological implications.

A novel hexadentate bishydrazone ligand, 1,10-bis(di(2-pyridyl)ketone) adipic acid dihydrazone (H2L1) is synthesized and characterized. With copper perchlorate as a catalytic oxidant, the ligand undergoes oxidative cyclisation and resulted in the formation of an unusual copper complex [Cu(L1a)2Cl]ClO4 (1), where L1a is 3-(2-pyridyl)triazolo[1,5-a]-pyridine. The Cu(II) complex was characterized physicochemically, while the molecular structure was confirmed by single crystal X- ray diffraction. In the complex cation, copper(II) is in a distorted trigonal bipyramidal coordination environment, surrounded by two triazolo nitrogen atoms and two pyridyl nitrogen atoms of L1a and a chloride atom. The relevant non covalent intermolecular interactions of the complex quantified using Hirshfeld surface analysis reveals that the O···H/ H···O (27.2%) contacts has the highest contribution. The solution phase bandgaps of the compounds were calculated using Tauc plot, whereas the solid-state band gaps were calculated by Kubelka-Munk model. DFT studies of the compounds indicate that the theoretical calculations corroborate with the experimental data. DPPH antioxidant activity assay of the synthesized compounds showed that the proligand H2L1 has a lower IC50 value (24.1 µM) than that of complex 1 (29.7 µM). The in vitro antibacterial activity was evaluated against Escherichia coli and Staphylococcus aureus, which revealed that complex 1 have excellent activity against E. coli, much as the standard ciprofloxacin. The cytotoxic efficacy investigation of the compounds against A549 (lung) adenocarcinoma cells suggested that H2L1 has more anticancer activity (IC50 value of 149.08 µM) than that of complex 1(IC50 value of 176.70 µM).

Complex formation of ML324, the histone demethylase inhibitor, with essential metal ions: Relationship between solution chemistry and anticancer activity.

N-(3-(dimethylamino)propyl-4-(8-hydroxyquinolin-6-yl)benzamide (ML324, HL) is a potent inhibitor of the iron-containing histone demethylase KDM4, a recognized potential target of cancer therapeutics. Herein, we report the proton dissociation and complex formation processes of ML324 with essential metal ions such as Fe(II), Fe(III), Cu(II) and Zn(II) using UV-visible, fluorescence, electron paramagnetic resonance and 1H NMR spectroscopic methods. The electrochemical behaviour of the copper and iron complexes was characterized by cyclic voltammetry and spectroelectrochemistry. The solid phase structure of ML324 analysed by X-ray crystallography is also provided. Based on the solution equilibrium data, ML324 is present in solution in H2L+ form with a protonated dimethylammonium moiety at pH 7.4, and this (N,O) donor bearing ligand forms mono and bis complexes with all the studied metal ions and the tris-ligand species is also observed with Fe(III). At pH 7.4 the metal binding ability of ML324 follows the order: Fe(II) < Zn(II) < Cu(II) < Fe(III). Complexation with iron resulted in a negative redox potential (E'1/2 = -145 mV vs. NHE), further suggesting that the ligand has a preference for Fe(III) over Fe(II). ML324 was tested for its anticancer activity in chemosensitive and resistant human cancer cells overexpressing the efflux pump P-glycoprotein. ML324 exerted similar activity in all tested cells (IC50 = 1.9-3.6 µM). Co-incubation and complexation of the compound with Cu(II) and Zn(II) had no impact on the cytotoxicity of ML324, whereas Fe(III) decreased the toxicity in a concentration-dependent manner, and this effect was more pronounced in the multidrug resistant cells.