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The search for anticancer metal-based drugs alternative to platinum derivatives could not exclude zinc derivatives due to the importance of this metal for the correct functioning of the human body. Zinc, the second most abundant trace element in the human body, is one of the most important micro-elements essential for human physiology. Its ubiquity in thousands of proteins and enzymes is related to its chemical features, in particular its lack of redox activity and its ability to support different coordination geometries and to promote fast ligands exchange. Analogously to other trace elements, the impairment of its homeostasis can lead to various diseases and in some cases can be also related to cancer development. However, in addition to its physiological role, zinc can have beneficial therapeutic and preventive effects on infectious diseases and, compared to other metal-based drugs, Zn(II) complexes generally exert lower toxicity and offer few side effects. Zinc derivatives have been proposed as antitumor agents and, among the great number of zinc coordination complexes which have been described so far, this review focuses on the design, synthesis and biological studies of zinc complexes comprising N-donor ligands and that have been reported within the last five years.

Two phenoxy-ketimines ligands, 2-(1-(benzylimino)ethyl)phenol (HLBSMe) and 2-((benzylimino)(phenyl)methyl)phenol (HLBSPh), were synthesized and used as supporting ligands of new copper(II), copper(I), and silver(I) complexes. In order to confer different solubility properties to the metal complexes and to stabilize Cu and Ag in their +1 oxidation state, the lipophilic triphenylphosphine (PPh3) and the hydrophilic 1,3,5-triaza-7-phosphaadamantane (PTA) were selected as co-ligands in the syntheses of the Cu(I) and Ag(I) complexes. All compounds were characterized by CHN analysis, NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS); the molecular structure of the copper(II) complex [Cu(LBSPh)2] was also determined by single-crystal X-ray diffraction. Finally, the antibacterial activity of the metal complexes, the Schiff base ligands and phosphane co-ligands, were assessed by determining the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Gram-negative (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus).

The new 3-monosubstituted acetylacetone ligands, 3-(phenyl(1H-pyrazol-1-yl)methyl)pentane-2,4-dione (HLacPz) and 3-((3,5-dimethyl-1H-pyrazol-1-yl)(phenyl)methyl)pentane-2,4-dione (HLacPzMe), were synthesized and used as supporting ligands for new copper(II) and copper(I) phosphane complexes of the general formulae [Cu(HLacX)2(LacX)2] and [Cu(PPh3)2(HLacX)]PF6 (X = Pz (pyrazole) or PzMe (3,5-dimethylpyrazole)), respectively. In the syntheses of the Cu(I) complexes, the triphenylphosphine coligand (PPh3) was used to stabilize copper in the +1 oxidation state, avoiding oxidation to Cu(II). All compounds were characterized by CHN analysis, 1H-NMR, 13C-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). The ligands HLacPz (1) and HLacPzMe (2) and the copper complex [Cu(PPh3)2(HLacPz)]PF6 (3) were also characterized by X-ray crystallography. The reactivity of these new compounds was investigated and the new compounds 4-phenyl-4-(1H-pyrazol-1-yl)butan-2-one (7) and 4-(3,5-dimethyl-1H-pyrazol-1-yl)-4-phenylbutan-2-one (8) were obtained in basic conditions via the retro-Claisen reaction of related 3-monosubstituted acetylacetone, providing efficient access to synthetically useful ketone compounds. Compound 8 was also characterized by X-ray crystallography.

Copper(II) complexes of bis(pyrazol-1-yl)- and bis(triazol-1-yl)-acetate heteroscorpionate ligands have been synthesized. The copper(II) complexes [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4, [HC(COOH)(pz)2]2Cu(ClO4)2 (pzMe2 = 3,5-dimethylpyrazole; pz = pyrazole) were prepared by the reaction of Cu(ClO4)2·6H2O with bis(3,5-dimethylpyrazol-1-yl)acetic acid (HC(COOH)(pzMe2)2) and bis(pyrazol-1-yl)acetic acid (HC(COOH)(pz)2) ligands in ethanol solution. The copper(II) complex [HC(COOH)(tz)2]2Cu(ClO4)2·CH3OH (tz = 1,2,4-triazole) was prepared by the reaction of Cu(ClO4)2·6H2O with bis(1,2,4-triazol-1-yl)acetic acid (HC(COOH)(tz)2) ligand in methanol solution. The synthesized Cu(II) complexes, as well as the corresponding uncoordinated ligands, were evaluated for their cytotoxic activity in monolayer and 3D spheroid cancer cell cultures with different Pt(II)-sensitivity. The results showed that [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4 was active against cancer cell lines derived from solid tumors at low IC50 and this effect was retained in the spheroid model. Structure and ultra-structure changes of treated cancer cells analyzed by Transmission Electron Microscopy (TEM) highlighted the induction of a cytoplasmic vacuolization, thus suggesting paraptotic-like cancer cell death triggering.

This paper reports the synthesis, structural characterization, and biological evaluation of a novel series of CuI and CuII complexes supported by an amantadine-functionalized bis(pyrazol-1-yl)acetate ligand (LAd) as potential anticancer agents for the treatment of glioblastoma (GBM). Comprehensive spectroscopic and structural investigations, including SR-XPS, XANES/EXAFS, and DFT modeling, confirmed the successful coordination of LAd to copper centers in both oxidation states, affording well-defined molecular architectures with distinct coordination geometries. Among the synthesized compounds, the CuI complexes bearing triphenylphosphine co-ligands (compounds 4 and 5) exhibited the strongest cytotoxicity against U87 MG and LN18 GBM cell lines, showing IC50 values lower than those of cisplatin. These complexes induced a pronounced redox imbalance through reactive oxygen species (ROS) overproduction and glutathione (GSH) depletion, leading to G2/M cell cycle arrest and cell death. Flow cytometry and Western blot analyses demonstrated that cell death occurs via caspase-dependent apoptosis in LN18 cells, as evidenced by PARP cleavage, downregulation of Bcl-xL, release of cytochrome c, and mitochondrial translocation of Bax. Altogether, these findings highlight the potential of lipophilic amantadine-functionalized CuI complexes as promising anticancer candidates targeting glioma cells through mitochondrial dysfunction and redox-mediated pathways.

A new dimeric copper(II) bromide complex, [Cu(LOHex)Br(μ-Br)]2 (1), was prepared by a reaction of CuBr2 with the hexyl bis(pyrazol-1-yl)acetate ligand (LOHex) in acetonitrile solution and fully characterized in the solid state and in solution. The crystal structure of 1 was also determined: the complex is interlinked by two bridging bromide ligands and possesses terminal bromide ligands on each copper atom. The two pyrazolyl ligands in 1 coordinate with the nitrogen atoms to complete the Cu coordination sphere, resulting in a five-coordinated geometry—away from idealized trigonal bipyramidal and square pyramidal geometries—which can better be described as distorted square pyramidal, as measured by the τ and χ structural parameters. The pendant hexyloxy chain is disordered over two arrangements, with final site occupancies refined to 0.705 and 0.295. The newly synthesized complex was evaluated as a catalyst in copper-catalyzed C–H oxidation for allylic functionalization through a Kharasch–Sosnovsky reaction without any external reducing agent. Using 0.5 mol% of this catalyst, and tert-butyl peroxybenzoate (Luperox) as an oxidant, allylic benzoates were obtained with up to 90% yield. The general reaction time was only slightly decreased to 24 h but a very significant decrease in the alkene:Luperox ratio to 3:1 was achieved. These factors show relevant improvements with respect to classical Kharasch–Sosnovsky reactions in terms of rate and amount of reagents. The present study highlights the potential of copper(II) complexes containing functionalized bis(pyrazol-1-yl)acetate ligands as efficient catalysts for allylic oxidations.

Gold nanorods (AuNRs) were synthesized and optimized with the aim of obtaining strongly hydrophilic nanomaterials, suitable as a drug delivery system (DDS) for copper-based drugs. After careful purification, AuNRs were characterized by ultraviolet–visible–near-infrared spectroscopy (UV–Vis–NIR), showing two typical localized surface plasmon resonance (LSPR) bands in the range 550–750 nm. Fourier Transform Infrared (FT-IR) and high-resolution X-ray photoelectron (HR-XPS) spectroscopies verified the surface functionalization. Transmission electron microscopy (TEM) showed AuNRs with regular shape and size, with an aspect ratio (AR) of 2.6. Dynamic Light Scattering (DLS) measurements confirmed the size and the stability in water for up to 3 months. The AuNRs were conjugated with copper(I) drugs, i.e., [Cu(PTA)4]BF4 (PTA = 1,3,5-triaza-7-phosphadamantane). The drug loading procedures and efficiency were optimized, and the best loading was η (%) = 50 ± 7%. The non-covalent interactions of the Cu(I) complex with the AuNRs were studied by means of UV–Vis–NIR, ζ-potential, HR-TEM, FT-IR, synchrotron radiation-induced X-ray photoelectron (SR-XPS), and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy measurements. The MTT assay performed on Vero E6 cells showed that AuNRs and AuNR-Cu(I) conjugates had no significant effect on cell viability, being biocompatible, causing a reduction in cell viability only after prolonged exposure.

In this study, four new N-(alkyl/aryl)imidazolium-borates were prepared, and their deprotonation reactions were investigated. Addition of BH3•THF to N-benzylimidazoles and N-mesitylimidazoles leads to imidazolium-trihydridoborate adducts. Ammonium tetraphenylborate reacts with benzyl- or mesityl-imidazoles with the loss of one of the phenyl groups yielding the corresponding imidazolium-triphenylborates. Their authenticity was confirmed by CHN analysis, 1H-NMR, 13C-NMR, 11B-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). 3-Benzyl-imidazolium-1-yl)trihydridoborate, (HImBn)BH3, and (3-mesityl-imidazolium-1-yl)trihydridoborate, (HImMes)BH3, were also characterized by X-ray crystallography. The reactivity of these new compounds as carbene precursors in an effort to obtain borate-NHC complexes was investigated and a new carbene-borate adduct (which dimerizes) was obtained via a microwave-assisted procedure.

Gold nanoparticles (AuNPs), which are strongly hydrophilic and dimensionally suitable for drug delivery, were used in loading and release studies of two different copper(I)-based antitumor complexes, namely [Cu(PTA)4]+ [BF4]− (A; PTA = 1, 3, 5-triaza-7-phosphadamantane) and [HB(pz)3Cu(PCN)] (B; HB(pz)3 = tris(pyrazolyl)borate, PCN = tris(cyanoethyl)phosphane). In the homoleptic, water-soluble compound A, the metal is tetrahedrally arranged in a cationic moiety. Compound B is instead a mixed-ligand (scorpionate/phosphane), neutral complex insoluble in water. In this work, the loading procedures and the loading efficiency of A and B complexes on the AuNPs were investigated, with the aim to improve their bioavailability and to obtain a controlled release. The non-covalent interactions of A and B with the AuNPs surface were studied by means of dynamic light scattering (DLS), UV–Vis, FT-IR and high-resolution x-ray photoelectron spectroscopy (HR-XPS) measurements. As a result, the AuNPs-A system proved to be more stable and efficient than the AuNPs-B system. In fact, for AuNPs-A the drug loading reached 90%, whereas for AuNPs-B it reached 65%. For AuNPs-A conjugated systems, a release study in water solution was performed over 4 days, showing a slow release up to 10%.

[Cu(thp) 4 ][PF 6 ] (HydroCuP) is a phosphino copper(I) complex highly soluble and stable in physiological media that has been developed as a possible viable alternative to platinum-based drugs for anticancer therapy. HydroCuP potently inhibited the growth of human cancer cells derived from solid tumors by inducing endoplasmatic reticulum (ER) stress thus leading to cell death through paraptosis with a preferential efficacy against cancer rather than non-cancer cells. Aim of the present study was to assess the therapeutic potential of HydroCuP in vivo , in syngenic and xenograft murine models of solid tumors by triggering the Unfolded Protein Response (UPR) pathway. With respect to platinum drugs, HydroCuP induced a markedly higher reduction of tumor growth associated with minimal animal toxicity. In human colorectal cancer xenografts, chemotherapy with HydroCuP was extremely effective in both oxaliplatin-sensitive and resistant models. The favorable in vivo tolerability of HydroCuP was also correlated to an encouraging biodistribution profile. Additionally, no signs of drug-related neurotoxicity and nephrotoxicity were observed. Altogether, these results demonstrate that HydroCuP appears worth of further investigation to evaluate its therapeutic activity towards a broad spectrum of solid malignancies.