Curcumin Metal Complexes Research Articles

Metal Complexes of Curcumin: A Comprehensive Approach to Design, Synthesis, Characterization and Assessment of Anti-tubercular Activity

Metal Complexes of Curcumin: A Comprehensive Approach to Design, Synthesis, Characterization and Assessment of Anti-tubercular Activity

The Antitumoral Effect In Ovo of a New Inclusion Complex from Dimethoxycurcumin with Magnesium and Beta-Cyclodextrin.

Breast cancer is one of the leading causes of death in the female population because of the resistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubility and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxycurcumin magnesium complex (DiMeOC-Mg, (4)) with beta-cyclodextrin (DiMeOC-Mg-BCD, (5)) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media phosphate buffer saline (PBS) was improved by a factor of 6x over the free metal complex (4). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and signal transducer and activator of transcription-3 (STAT3) expression levels on MD Anderson metastasis breast-231 cancer (MDA-MB-231) cell lines. Results of an antitumor assay in an in ovo model showed up to 30% inhibition of tumor growth for breast cancer (MDA-MB-231) when using (5) (0.650 mg/kg dose) and 17.29% inhibition with the free homoleptic metal complex (1.5 mg/kg dose, (4)). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new compound (5) exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.

Interaction of gallium, indium, and vanadyl curcumin complexes with hen egg-white lysozyme (HEWL): Mechanistic aspects and evaluation of antiamyloidogenic activity

Many proteins and peptides can aggregate into amyloid fibrils with high-ordered and cross-β rich structure characteristics. Amyloid deposition is a common feature of neurodegenerative diseases called amyloidosis. Various natural polyphenolic compounds such as curcumin exhibited antiamyloidogenic activities, but less researches were focused on the metal complexes of these compounds. In this study, the inhibitory effects of gallium curcumin (Ga(cur)3), indium curcumin (In(cur)3), and vanadyl curcumin (VO(cur)2) on the amyloid fibrillation of hen egg white lysozyme (HEWL) have been investigated. Moreover, the details of binding interactions of these metal complexes with HEWL have been explored. The results of fluorescence quenching analyses revealed that In(cur)3 and VO(cur)2 have much higher binding affinities than Ga(cur)3 toward HEWL. The interactions of these metal complexes were accompanied by partial conformational changes in the tertiary structure of HEWL. The kinetic curves of the fibrillation process demonstrated that In(cur)3 and VO(cur)2 have higher inhibitory effects than Ga(cur)3 on the amyloid fibrillation of HEWL. The strength of binding to HEWL is completely in accordance with inhibitory activities of these metal complexes of curcumin.

The Homoleptic Curcumin-Copper Single Crystal (ML2): A Long Awaited Breakthrough in the Field of Curcumin Metal Complexes.

The first single crystal structure of the homoleptic copper (II) ML2 complex (M=Cu (II), L = curcumin) was obtained and its structure was elucidated by X-ray diffraction showing a square planar geometry, also confirmed by EPR. The supramolecular arrangement is supported by C-H···O interactions and the solvent (MeOH) plays an important role in stabilizing the crystal packing Crystallinity was additionally assessed by XRD patterns. The log P value of the complex (2.3 ± 0.15) was determined showing the improvement in water solubility. The cytotoxic activity of the complex against six cancer cell lines substantially surpasses that of curcumin itself, and it is particularly selective against leukemia (K562) and human glioblastoma (U251) cell lines, with similar antioxidant activity to BHT. This constitutes the first crystal structure of pristine curcumin complexed with a metal ion.

Curcumin-Based β-Diketo Ligands for Ga3+: Thermodynamic Investigation of Potential Metal-Based Drugs

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete 1H/13C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer.

Synthesis, Characterization and Bioactivity Study of Few Metal Complexes of Curcumin with 2-(1H-Benzimidazol-2-yl) Aniline

We have synthesized many metal (II) complexes using curcumin L1 as the major ligand and 2-(1H-Benzimidazol-2-yl) aniline L2 as a supporting ligand. The complexes were characterized by spectroscopy methods such as; molar conductivity, elements microanalysis, Fourier-transform spectroscopy (FT-IR), UV-vis, and mass spectroscopy. Both curcumin ligands and L2 were found to be capable of binding to M(II) and metal ions via their two N atoms, according to the data. The formula for the complexes is the same. [M (L1)(L2)H2OCl], where M is Ni(II), Co(II), Cu(II), Cd(II), and Hg(II) (II). Octahedral complexes are proposed for the prepared compounds. The bio-actives suggested that the complexes are effective against bacteria and fungus on a mild to moderate level.

Bandgap Energy of TiO2/M-Curcumin Material (M = Na+, Mg2+, Cu2+)

Bandgap energy (Egap) of TiO2/curcumin as well as TiO2/M-curcumin (M = Na+, Mg2+, Cu2+) was determined. The material was prepared on transparent conductive oxide as TiO2 film. Then, the curcumin and curcumin derivatives were adsorbed on TiO2 surface by immersing the film in solution of the compounds. The diffuse reflectance UV-Vis spectra of the materials were recorded and utilized to calculate the Egap using the Tauc plot method. The calculation gave the Egap of TiO2 of 3.27 eV that lowers after being deposited with curcumin and metal-curcumin compounds. The Egap of TiO2/curcumin was 2.82 eV, while TiO2/Na+-curcumin, TiO2/Mg2+-curcumin, and TiO2/Cu2+-curcumin were 2.36, 3.11, and 2.15 eV, respectively. Curcumin metal complexes, i.e., TiO2/Cu2+-curcumin, showed high molar absorptivity and effectively deposited on the TiO2 lowers the bandgap energy of TiO2 compared to free-curcumin on TiO2.

Metal - based curcumin and quercetin complexes: cell viability, ROS production and antioxidant activity

Flavonoids, also known as polyphenols, contain carbonyl and hydroxyl groups and are capable of forming complexes with metal ions. In this perspective, complexation of curcumin and quercetin were achieved by using magnesium and calcium divalent cations to enhance the solubilities of curcumin and quercetin. The cell proliferation and antioxidant effects were tested on colon carcinoma cells (HCT-116). Metal complexes of curcumin and quercetin were characterized using XRD analysis, TOF mass spectrometry, FT-IR and UV-Vis spectroscopies. A solubility assay was conducted to demonstrate the improvements in the solubility of curcumin and quercetin. Cell viability was measured by cell viability detection kit-8 (CVDK-8) and imaged by crystal violet assay. 2′,7′-dichlorodihydrofluorescein diacetate fluorogenic (DCFH-DA) dye was used to determine intracellular reactive oxygen species (ROS) production. Radical scavenging activity of metal complexes were analyzed by 2,2-diphenyl-1-picrylhydrazyl radical scavenging (DPPH) assay. Cell viability, reactive oxygen species (ROS) production assays reveal that curcumin and its complexes showed better antiproliferative effect at lower concentrations compared to quercetin complexes. In contrast, quercetin complexes had better radical scavenging activity compared to curcumin complexes based upon DPPH assay. Metal complexes of curcumin and quercetin can be useful to elucidate alternative strategies in cancer prevention and therapy by enhancing their solubilities.

Theoretical study of the impact of metal complexation on the reactivity properties of Curcumin and its diacetylated derivative as antioxidant agents

The chemical behavior of Curcumin and its derivatives as antioxidant and metal chelator has become the subject of intense experimental research. In this work, a theoretical study was conducted with the aim to investigate whether the acetylation of the aromatic group in Curcumin, which makes it more lipophilic, will alter its biological activities. Also, we selected from the literature metal complexes of Curcumin and its diacetylated derivative with Ga(III) and In(III), in order to discriminate the molecular active sites of the investigated molecules in which the oxidative process occurs and to obtain information about their antioxidation mechanisms. The geometrical structures and electronic properties of these compounds have been obtained using the density functional theory (DFT) method, known for its accurate results. As our other objective is to understand the factors driving biological behavior of all the studied compounds as well as the impact of the metal complexation of Curcumin and its diacetylated derivative, we provided here evidences to explain experimental observations from a molecular reactivity perspective.

Metal - Based Curcumin and Quercetin Complexes: Cell Viability, ROS Production and Antioxidant Activity

Flavonoids, also known as polyphenols, contain carbonyl and hydroxyl groups and are capable of forming complexes with metal ions. In this perspective, complexation of curcumin and quercetin were achieved by using magnesium and calcium divalent cations to enhance the solubilities of curcumin and quercetin. The cell proliferation and antioxidant effects were tested on colon carcinoma cells (HCT-116). Metal complexes of curcumin and quercetin were characterized using XRD analysis, TOF mass spectrometry, FT-IR and UV-Vis spectroscopies. A solubility assay was conducted to demonstrate the improvements in the solubility of curcumin and quercetin. Cell viability was measured by cell viability detection kit-8 (CVDK-8) and imaged by crystal violet assay. 2',7'-dichlorodihydrofluorescein diacetate fluorogenic (DCFH-DA) dye was used to determine intracellular reactive oxygen species (ROS) production. Radical scavenging activity of metal complexes were analyzed by 2,2-diphenyl-1-picrylhydrazyl radical scavenging (DPPH) assay. Cell viability, reactive oxygen species (ROS) production assays reveal that curcumin and its complexes showed better antiproliferative effect at lower concentrations compared to quercetin complexes. In contrast, quercetin complexes had better radical scavenging activity compared to curcumin complexes based upon DPPH assay. Metal complexes of curcumin and quercetin can be useful to elucidate alternative strategies in cancer prevention and therapy by enhancing their solubilities.

A novel study on curcumin metal complexes: solubility improvement, bioactivity, and trial burn wound treatment in rats

This paper describes a new technique to enhance the solubility of metal curcumin complexes.

Synthesis, Structural Characterization of 4’,4’’-Dibenzoylcurcumin and Assessment of its Complexation with Fe3+ and Cu2+

The curcumin derivative 4’,4’’-dibenzoylcurcumin (HL) was synthesized by the reaction between curcumin and benzoyl chloride in the presence of pyridine as a supporting base. The composition and structure of HL were characterized by spectroscopic methods such as IR, 1H and 13C NMR spectroscopy. Reactions of HL and transition metal ions, such as Fe3+ and Cu2+, in mixtures of CH3OH and CH2Cl2 gave rise to the corresponding complexes, compositions and structural features of which were studied by thermal analysis and IR spectroscopy. The results strongly suggested the obtained complexes with the compositions of [FeL3] and [CuL2]. In such compounds, metal ions coordinates with the deprotonated ligands L– through the donor sets (O,O) of the keto-enol moieties.
 Keywords: Curcumin, 4’,4’’-dibenzoylcurcumin, β-diketone, Fe(III) complexes, Cu(II) complexes.
 References
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Gallium-68 and scandium-44 labelled radiotracers based on curcumin structure linked to bifunctional chelators: Synthesis and characterization of potential PET radiotracers

Curcumin metal complexes showed widespread applications in medicine and can be exploited as a lead structure for developing new tracers for nuclear medicine application. Herein, the synthesis, chemical characterization and radiolabelling with gallium-68 and scandium-44 of two new targeting vectors based on curcumin scaffolds and linked to the chelators 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA) are reported. Synthesis of the precursors could be achieved with a 13% and 11% yield and radiolabelling generally afforded rapid incorporation under mild conditions (>95%). Stability in physiological media (~75% after 2 h in human blood for [68Ga]Ga−/[44Sc]Sc-AAZTA-PC21 and ~60% for [68Ga]Ga-NODAGA-C21, respectively) are generally enhanced if compared to the previously radiolabelled analogues. MSn fragmentation experiments showed high stability of the AAZTA-PC21 structure mainly due to the pyrazole derivatization of the curcumin keto-enol moiety and a more feasible radiolabelling was noticed both with gallium-68 and scandium-44 mainly due to the AAZTA-chelator properties. [68Ga]Ga-NODAGA-C21 showed the most favorable lipophilicity value (logD = 1.3). Due to these findings, both compounds appear to be promising candidates for the imaging of colorectal cancer, but further studies such as in vitro uptake and in vivo biodistribution experiments are needed.

Enhancing the Solubility of Curcumin Metal Complexes and Investigating Some of Their Biological Activities

This article describes the synthesis of curcumin complexes with metal ions. Properties of these complexes such as spectra IR and UV-Vis and solubility were investigated. The optimum parameters of ultrasound to enhance the solubility was figured out as follows: the capacity of ultrasound: 750 W/g; the time of ultrasound: 7 min; the concentration of the surfactant Tween 80 : 2%. The maximum solubility (mg/ml) of complexes was as follows: Cur-Fe(III): 0.162 ± 0.01; Cur-Zn(II): 0.267 ± 0.02; and Cur-Ca(II): 0.417 ± 0.05. Antioxidant capacity (DPPH, %I) of curcumin complexes was higher than that of curcumin-free complexes. All of these curcumin complexes revealed antimicrobial activities, in which calcium complex had the best resistance against Salmonella, followed by Fe(III) complexes. Meanwhile, the zinc complex was not resistant to this bacterium. These complexes showed antibacterial activity on Staphylococcus aureus, in which Cur-Ca (II) complexes had the highest antibacterial activity. For Escherichia coli, the Cur-Zn (II) complex had no resistance, while the Cur-Ca (II) complex showed the highest antibacterial activity.

Biological properties of metal complexes of curcumin.

Curcumin, a naturally occurring phenolic compound isolated from Curcuma longa, has different pharmacological effects, including antiinflammatory, antimicrobial, antioxidant, and anticancer properties. However, curcumin has been found to have a limited bioavailability because of its hydrophobic nature, low-intestinal absorption, and rapid metabolism. Therefore, there is a need for enhancing the bioavailability and its solubility in water in order to increase the pharmacological effects of this bioactive compound. One strategy is curcumin complexation with transition metals to circumvent the abovementioned problems. Curcumin can undergo chelation with various metal ions to form metallo-complexes of curcumin, which may show greater effects as compared with curcumin alone. Promising results with metal curcumin complexes have been observed with regard to antioxidant, anticancer, and antimicrobial activity, as well as in treatment of Alzheimer's disease. The present review provides a concise summary of the characterization and biological properties of curcumin-metal complexes. © 2019 BioFactors, 45(3):304-317, 2019.

Full Structural Characterization of Homoleptic Complexes of Diacetylcurcumin with Mg, Zn, Cu, and Mn: Cisplatin-level Cytotoxicity in Vitro with Minimal Acute Toxicity in Vivo.

At the present time, scientists place a great deal of effort worldwide trying to improve the therapeutic potential of metal complexes of curcumin and curcuminoids. Herein, the synthesis of four homoleptic metal complexes with diacetylcurcumin (DAC), using a ligand designed to prevent the interaction of phenolic groups, rendering metal complexes through the β-diketone functionality, is reported. Due to their physiological relevance, we used bivalent magnesium, zinc, copper, and manganese for complexation with DAC. The resulting products were characterized by ultraviolet-visible (UV-Vis), fluorescence spectroscopy, infrared spectroscopy (IR), liquid and solid-state nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), magnetic moment, mass spectrometry (MS), single crystal, and powder X-ray diffraction (SCXRD and PXRD). Crystallization was achieved in dimethylsulfoxide (DMSO) or N,N-dimethylformamide (DMF) as triclinic systems with space group P-1, showing the metal bound to the β-diketone function, while the 1H-NMR confirmed the preference of the enolic form of the ligand. Single crystal data demonstrated a 1:2 metal:ligand ratio. The inhibition of lipid peroxidation was evaluated using the thiobarbituric acid reactive substance assay (TBARS). All four metal complexes (Mg, Zn, Cu, and Mn) exhibited good antioxidant effect (IC50 = 2.03 ± 0.27, 1.58 ± 0.07, 1.58 ± 0.15 and 1.24 ± 0.10 μM respectively) compared with butylated hydroxytoluene (BHT) and α-tocopherol. The cytotoxic activity in human cancer cell lines against colon adenocarcinoma (HCT-15), mammary adenocarcinoma (MCF-7), and lung adenocarcinoma (SKLU-1) was found comparable ((DAC)2Mg), or ca. 2-fold higher ((DAC)2Zn) than cisplatin. The acute toxicity assays indicate class 5 toxicity, according to the Organization for Economic Co-operation and Development (OECD) guidelines at doses of 3 g/kg for all complexes. No mortality or changes in the behavior of animals in any of the treated groups was observed. A therapeutic potential can be envisaged from the relevant cytotoxic activity upon human cancer cell lines in vitro and the undetected in vivo acute toxicity of these compounds.

Metal chelating ability and antioxidant properties of Curcumin-metal complexes – A DFT approach

Curcumin, a well-documented phytochemical compound used to treat various diseases because of its more tolerability in the human body and has no side effects. The present study describes the metal chelating ability of Curcumin for Mn2+, Fe2+ and Zn2+ metal ions and their antioxidant properties using density functional theory in both gas and DMSO solvent phases. Results reveal that the carbonyl group at diketo moiety is destabilized due to the metal ion coordination. The interaction energies reveal that CurEN-Zn2+ are the most stable rather than the CurEN-Mn2+ and CurEN-Fe2+ complexes. The AIM analysis confirms that the interaction between the metal ions and Curcumin are to be electrostatic dominant. The HOMO-LUMO orbital analysis shows that the charge transfer interaction is dominant for CurEN-Mn2+ and CurEN-Fe2+ complexes. The DMSO solvent interactions decrease the stability of the CurEN-M2+ cation complexes. The antioxidant mechanism is more reactive for metal complexes than the isolated Curcumin. Since Curcumin possess both metal chelating and antioxidant properties, it can be used in chelation therapy for the cure of Alzheimer’s disease.

Metal complexes of curcumin for cellular imaging, targeting, and photoinduced anticancer activity.

Curcumin is a polyphenolic species. As an active ingredient of turmeric, it is well-known for its traditional medicinal properties. The therapeutic values include antioxidant, anti-inflammatory, antiseptic, and anticancer activity with the last being primarily due to inhibition of the transcription factor NF-κB besides affecting several biological pathways to arrest tumor growth and its progression. Curcumin with all these positive qualities has only remained a potential candidate for cancer treatment over the years without seeing any proper usage because of its hydrolytic instability involving the diketo moiety in a cellular medium and its poor bioavailability. The situation has changed considerably in recent years with the observation that curcumin in monoanionic form could be stabilized on binding to a metal ion. The reports from our group and other groups have shown that curcumin in the metal-bound form retains its therapeutic potential. This has opened up new avenues to develop curcumin-based metal complexes as anticancer agents. Zinc(II) complexes of curcumin are shown to be stable in a cellular medium. They display moderate cytotoxicity against prostate cancer and neuroblastoma cell lines. A similar stabilization and cytotoxic effect is reported for (arene)ruthenium(II) complexes of curcumin against a variety of cell lines. The half-sandwich 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane (RAPTA)-type ruthenium(II) complexes of curcumin are shown to be promising cytotoxic agents with low micromolar concentrations for a series of cancer cell lines. In a different approach, cobalt(III) complexes of curcumin are used for its cellular delivery in hypoxic tumor cells using intracellular agents that reduce the metal and release curcumin as a cytotoxin. Utilizing the photophysical and photochemical properties of the curcumin dye, we have designed and synthesized photoactive curcumin metal complexes that are used for cellular imaging by fluorescence microscopy and damaging the cancer cells on photoactivation in visible light while being minimally toxic in darkness. In this Account, we have made an attempt to review the current status of the chemistry of metal curcumin complexes and present results from our recent studies on curcumin complexes showing remarkable in vitro photocytotoxicity. The undesirable dark toxicity of the complexes can be reduced with suitable choice of the metal and the ancillary ligands in a ternary structure. The complexes can be directed to specific subcellular organelles. Selectivity by targeting cancer cells over normal cells can be achieved with suitable ligand design. We expect that this methodology is likely to provide an impetus toward developing curcumin-based photochemotherapeutics for anticancer treatment and cure.

Reactive Centers of Curcumin and the Possible Role of Metal Complexes of Curcumin as Antioxidants

Curcumin is known as a blood purifier in Ayurveda which has been recently ascribed to its chelating ability with metal, hence reducing the deposition of metal in the body. Curcumin can exhibit keto-enol tautomerism and in the synthesized 1:1 metal complexes, the enolate ion chelate to the metal. The antioxidant activity of the synthesized metal complexes of curcumin was slightly less than the parent curcumin-I. Curcumin in the complexed state retains its antioxidant behavior, consequently establishing importance of phenolic group in deciding its antioxidant activity. The study reveals that the flexibility at the diketo moiety is not a requisite for the radical formation and sufficient scavenging of DPPH occur by phenoxide ion formation.

Synthesis, characterization and antibacterial activity of a curcumin–silver(I) complex

The current study reports the synthesis of a curcumin–silver(I) complex and its preliminary tests against four bacterial strains viz. Staphylococcus aureus, Escherichia coli, Bacillus subtilis, and Bacillus cereus using agar well diffusion method. The results were compared with curcumin by testing it in parallel with the sample. Curcumin showed zones of inhibition against all tested strains of bacteria. Among all bacterial strains, S. aureus was the most sensitive to curcumin with zone of inhibition of 12.2 mm. However, the curcumin–Ag(I) complex did not show the expected enhanced activity against all bacteria. This is perhaps due to the replacement of curcumin phenolic protons by silver ions which might have suppressed the antibacterial property of curcumin. The current research findings suggest that while synthesizing curcumin–metal complexes, the phenolic heads may either be left unaltered or need to be replaced by better substituents than hydroxy groups. Based on the current findings, biologically enhanced models have been provided as future recommendations.