Nanogold-Bound Copper Complexes and Their Various Applications: A Review Article

The term "nano gold," also known as "gold nanoparticles," is commonly used. These particles are extremely small, with a diameter of less than 100 nm, which is only a fraction of the width of a human hair. Due to their tiny size, nano gold particles are often found in a colloidal solution, where they are suspended in a liquid stabilizer. This colloidal gold is essentially another name for nano gold. The main method for producing gold nanoparticles in a colloidal solution is the citrate synthesis technique, which involves combining different solutions to precipitate the gold nanoparticles[1-5]. In biological systems, copper complexes play a significant role at the active sites of many metalloproteins. These complexes have potential applications in various catalytic processes that occur in living organisms, such as electron transfer reactions and the activation of specific antitumor substances. These processes are relevant in the fields of medicinal chemistry and bioinorganic chemistry. The interaction of copper chelates with biological systems and their noteworthy activities against neoplastic, bacterial, fungal, and cancerous cells are also important. Many copper (II) N, S, O / N, N-donor chelators function as effective anticancer agents due to their ability to bind with DNA base pairs[6-10]. Using hydrophilic gold nanoparticles (AuNPs) as carriers for copper complexes is a novel and purposeful strategy that Could raise these compounds' stability and solubility in H 2 O aqueous., thus enhancing their bioavailability. The regulated release of Cu-complexes made possible by this method also creates the possibility for fruitful in vivo and in vitro tests. The definition, significance, and numerous applications of copper complexes in connection to nanogold are presented in this review study[11-15].


Introduction
A variety of frameworks, comprising nanorods, bipyramids, gold nanoshells, nanobowls, spiky nanoshells, terahedra, octahedra, cubes, and cages, could be generated through synthesizing nanogold.A silica nanoparticle core may occasionally be encased in gold, and gold nanoparticles may occasionally have a silver coating.The size and form that are chosen must match the intended use since they have a direct impact on light interacts with the material (Fig. 1) [16][17][18][19][20].

Fig.(1): Different forms of Gold nanoparticles
Copper complexes may possess a variety of geometry with different types and numbers of ligands, ranging from square planar, octahedral, tetrahedral, trigonal planar, and square pyramidal geometry.
Despite the fact that an extensive variety of complexes have been accomplished, the synthesis and design of novel copper complexes by varying the nature of the reactants and synthetic conditions is still under investigation (Fig. 2) [21][22][23][24][25].

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Recently, biomedical research has been concentrating on developing novel metal-based anticancer medicines that can be used in place of Pt(II) compounds.Significant emphasis has been paid to the research of new Cu-based antitumor agents using diverse metals such as gold, ruthenium, silver, and copper.This strategy is motivated by the assumption intrinsic metals may be less hazardous for regular cells than malignant cells.Furthermore, copper(II) complexes containing hexyl bis(pyrazol-1-yl) acetate ligands have recently been investigated as prospective catalysts for improving the efficiency of the Kharasch-reaction, which involves the oxidation of alkenes at the allyl position.The synthesis technique encompasses the utilization of soft donor atom-containing ligands, such as the aromatic sp 2 hybridized nitrogen that exists in pyrazolyl derivatives [26][27][28][29].
Given the restricted solubility of these coordination compounds in aqueous environments, a strategic strategy is required for effective administration of medicines.Conjugating copper complexes with hydrophilic gold nanoparticles provides a strategy for improving their solubility, stability in water, and eventually, their bioavailability.Furthermore, this drug delivery method allows for the regulated and progressive release of copper complexes.In this sense, we utilized SR-XPS and NEXAFS spectroscopy to investigate the molecular and electronic structures of selected Cu(II)-coordination complexes.The investigation involved examining the metal ion's oxidation state and local coordination chemistry employing Cu K-edge XAFS in both near-edge (XANES) and extended (EXAFS) regions.To create a comparison, we additionally glanced at the pristine ligands [30][31][32][33].The deployment of complementary probes, namely XPS-NEXAFS-XAFS, has provided a precise and dependable understanding of the local coordination chemistry and electronic structure of Cu(II)-coordination complexes.Through coupling with hydrophilic AuNPs, these compounds can serve as vital components for the assembly of nanoassemblies.Some members of our team have previously successfully tested this strategy utilizing model systems [34][35][36][37][38].In this paper, we indicate the outcomes of a multidisciplinary assessment of Cu(II)-coordination compounds, in addition to preliminary observations about interactions between coordination compounds and AuNPs.We additionally emphasize future research directions (Fig. 3).

Literature review
In order to assess the anticancer effectiveness of a copper(II) diacetyl-bis(N4-methylthiosemi carbazone) complex and its nano conjugates, Anup Kumar Pramanik and associates carried out a study in 2016, [39].A cleavable disulfide bond that the researchers used to connect the copper(II) complex to a carboxylic acid group allowed for effective distribution.They created highly soluble gold nanoparticles (AuNPs) by mixing copper with amine-terminated lipoic acid and polyethylene glycol (PEG) to increase their solubility in water.To enable focused activity, biotin was added to the gold nanoparticle carrier's surface.The researchers tested HeLa and HaCaT cells to determine the anticancer potency of the copper complex and its conjugates.Surprisingly, whereas the conjugates completely eliminated cancer in HeLa cells, which are derived from cervical carcinoma, they only showed limited effectiveness against HaCaT cells.Due to the breakdown of the disulfide linker in the presence of glutathione (GSH), a reducing chemical frequently present in cancer cells, the conjugates displayed a progressive and controlled release of the complex.It's interesting to note that when tested against HeLa cells, the biotin-added conjugates did not perform better.This conclusion was reinforced by drug uptake tests that demonstrated similar in vitro uptake characteristics for both types of conjugates.The tumor volume of the biotin-conjugated nanoparticle group was shown to be reduced by 3.8 times when compared to the control group, whereas it was only reduced by 2.3 times in the case of the non-biotin conjugates in in vivo study employing a HeLa cell xenograft tumor model.This indicates significant targeting effects.

Scheme (1): A demonstration in which PEG stabilized gold nanoparticles and nano-conjugates are made.
In 2016, Nguyễn Hoàng Ly et al., [40] introduced a novel technique for detecting Cu 2+ ions in environmental and biological solutions.This technique demonstrated high selectivity and sensitivity.The researchers utilized gold nanoparticles (AuNPs) coated with glycine (GLY) in a hydrazine buffer.The dissociative adsorption of GLY on the AuNPs resulted in distinctive CN stretching peaks at approximately 2108 cm -1 .X-ray photoelectron spectroscopy confirmed the presence of Cu species on the AuNPs, while UV-Vis spectra indicated aggregation of the Au particles.Interestingly, the formation of the GLY-Cu 2+ complex caused a noticeable color shift, indicating destabilization.The synthesis of CN variety from GLY on the surface of hydrazinecovered AuNPs was evident from the CN stretching band at around 2108 cm -1 .Importantly, further ions, including Fe 3+ , Fe 2+ , Hg 2+ , Mg 2+ , Mn 2+ , Ni 2+ , Zn 2+ , Cr 3+ , Co 2+ , Cd 2+ , Pb 2+ , Ca 2+ , NH 4+ , Na + , and K + at concentrations as high as 50 µM, did not lead to similar spectral vagaries.The revealing limit for Cu 2+ ions using the CN band was found to be as low as 500nM in distilled water and 1M in river water.Furthermore, the researchers also explored the potential application of this technique for intracellular ion detection in cancer cells, highlighting its practicality (Fig. 4).

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[Cu(2CP-Bz-SMe)] is a copper compound.binds DNA and possesses nuclease activity.Raman scattering investigation validated the functionalization of Fe 3 O 4 @Au with the copper complex through the sulfur atom of the thioether molecule.Despite the gold shell dilution and functionalization with the copper complex, magnetic studies suggested that Fe 3 O 4 @Au@Cu retained its magnetic characteristics.Nuclease studies with Fe 3 O 4 @Au@Cu indicated that the nanomaterial's plasmid DNA nuclease activity was mediated through an oxidative route mediated by H 2 O 2 species in a Fenton-like reaction.The nuclease activity was primarily derived from the HO% species, as indicated by electron paramagnetic resonance spectra (aN = 15.07G, aH = 14.99 G), highlighting the successful transfer of radical production properties from [Cu(2CP-Bz-SMe)] core-shell Au-coated Fe 3 O 4 nanoparticles require.This is the first instance of a Cu-complex immobilized on a Au-coated magnetic nanoparticle producing reactive oxygen species, to the best of our knowledge.,as illustrated in Scheme (2).

Scheme (2): Representative illustration showing the formation of Fe 3 O 4 @Au and its functionalization with [Cu(2CP-Bz-SMe)] 2+ .
In a study conducted in 2019, Ilaria Fratoddi et al., [43]   During the year 2019, a team of researchers led by Shifan Zhao et al., [44] colleagues introduced a novel type of biofuel cells called non-enzymatic biofuel cells (NEFCs) that do not rely on compartments for their functioning.These NEFCs employ an electrografted copper complex of 3,5-diamino-1,2,4-triazole and nanoporous gold nanoparticles as catalysts.What makes these cells remarkable is their ability to operate in a neutral solution and enable self-powered pyrophosphate sensing.This sensing is made possible by the stronger coordination of Cu 2+ with oxygen (O) rather than nitrogen (N) at the cathode.Refer to Figure 7 for a visual representation.

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Cu 2+ ions with Au-crown/carboxylic ions, which results in a color shift from red to blue.A linear association with a correlation value of 0.9814 was obtained at A630/A545 between the reduction in absorbance intensity and the concentration of Cu 2+ ions in the concentration range of 75 nM to 1250 nM.The detection limit was determined to be 150 nM.Notably, among other cations, this sensor assay selectively targets copper ions and provides a simple method for measuring and detecting them in aqueous solutions, as shown in Scheme (3).

Scheme (3): Synthesis of Au-crown/carboxylic ligand.
In 2021, Green LED plasmon excitation (525 nm) was used by Léa Gimeno et al. [47] to graft a copper(II) complex onto colloidal gold nanoparticles (NPs).In this method, nitrobenzaldehyde and nitromethane were present in DMF, resulting in the very efficient synthesis of the equivalent nitroaldol molecule.Kinetic studies employing 1H NMR and Raman spectroscopies demonstrated that when subjected to green light irradiation, the process displayed greater efficiency, particularly in close proximity to the NPs (reaching nearly 100% conversion after 100 minutes).Following the conclusion of the process, the nanocatalyst could be gathered and utilized in two subsequent reactions.Green LED stimulation of the plasmonic nanocatalyst proved to be a simple and efficient technique, dramatically improving the rate of the Henry reaction while needing less energy and shorter reaction times than characteristic applications as shown in Fig. (9).

Fig.(9): grafted green LED plasmon excitation of colloidal gold nanoparticles (NPs)
In 2022, Ahmad Junaid et al. [48] successfully synthesized and characterized a nanogoldcopper(II) complex conjugate [(Cu)(phen)(cys)(H 2 O)]NO 3 n.This complex was subsequently investigated for its ability to inhibit the growth of both breast cancer cells (MCF7) and normal cells

Fig. ( 4 )
Fig. (4): The diagram illustrates the detection process of Cu 2+ ions, which occurs through the redox assets that cause the dissociation of GLY into CN groups on the surfaces of Au-NPs in the occurrence of hydrazine.
investigated the use of hydrophilic gold nanoparticles (AuNPs) for medication delivery.The researchers focused on loading and releasing two copper(I)-based anticancer compounds: compound A ([Cu(PTA)4]+[BF4]), and compound B ([HB(pz)3Cu(PCN)]).Compound A is a water-soluble compound composed of a chemical A is a neutral chemical with a mixed ligand combination that is soluble in water, whereas Compound B is a metal organized in a cationic structure.The study's goal was to evaluate the effectiveness of loading chemicals A and B onto AuNPs in order to increase bioavailability and achieve controlled release.Several methods, including dynamic light dispersion (DLS), UV-Vis, FT-IR, and extreme-resolution X-ray photo-electron spectroscopy (HR-XPS), were used to look into the non-covalent interactions between the chemicals and the surface of AuNPs.According to the findings, the AuNPs-A system outperformed the AuNPs-B system in terms of dependability and efficiency.AuNPs-A had a 90% drug loading effectiveness compared to AuNPs-B's 65%.A four-Sciences Vol.(2)No.(10)………………..……….……….Jun 2023 Journal of Kufa for Chemical 277 day release study employing AuNPs-A was also conducted.conjugated systems in a water solution demonstrated a gradual release of up to 10%, as shown in Fig. 6.

Fig. ( 6 )
Fig. (6): Chemical compositions of the anticancer Cu(I)-complexes retained in this investigation are shown in (a); a loading technique schematic is shown in (b) to produce the conjugated AuNPs-A and AuNPs-B.
Fig.(8): The tetrahedral Cu(I) complex is bound to the surface in two limiting directions by S-Au bonds.The phenanthrene molecular plane is shown by the thick blue line in the smaller insects.The molecular planes of the bipyridine and phenanthrene are both normal to the surface in Figure a.In b), the surface is parallel to the phenanthrene ligand.

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Figure 10, the nano-Au[(Cu)(phen)(cys)(H 2 O)]NO 3 n conjugate exhibited unique antiproliferative and proapoptotic effects in breast cancer cells, demonstrating its potential as a successful anticancer therapy.