Metal Chelation Mechanisms Research Articles

Antioxidant and anticancer properties of plant‐based bioactive flavonoids cardamonin and alpinetin: A theoretical insight from •OOH antiradical and Cu (II) chelation mechanisms

AbstractA density functional theory (DFT) study aimed at a comparative investigation on the antioxidant mechanisms of cardamonin and alpinetin, two flavonoid bioactive components derived from plant sources with potential medicinal properties, has been performed through assessment of their •OOH scavenging ability in non‐polar medium and Cu (II) chelation ability in the absence and presence of explicit water molecules stabilising the metal cation. In addition, a comparison of the antioxidant properties of cardamonin with the moiety of phloroglucinol and acylated phloroglucinol has been performed to establish cardamonin's antioxidant potentiality among the phloroglucinol family of compounds. The results of the investigation reveal that alpinetin could be considered a better radical scavenger than cardamonin within the non‐polar lipid bilayer medium of biological systems. However, the role of both compounds as •OOH scavengers may be limited, in comparison to standard antioxidant molecules, such as α‐tocopherol, because of the fact that the bond dissociation enthalpy for the hydrogen atom abstraction mechanism has a positive value, which signifies that the radical scavenging mechanism is not a thermodynamically preferred reaction. Cardamonin is found also to be a weaker antioxidant molecule than phloroglucinol and acylated phloroglucinol moieties. In terms of metal chelation mechanism, cardamonin is a better Cu (II) chelator than alpinetin since it has a higher metal ion affinity than alpinetin upon coordination to the Cu (II) cation. The results obtained could also imply that cardamonin is a better agent in dealing with angiogenesis, tumour growth and metastatis stages of cancer than alpinetin, since the ability of chelating metal cation shown by cardamonin ascribes it a better role as an anticancer agent than alpinetin. Therefore, although alpinetin may prove to play an important role as a promising antioxidant and antiinflamatory agent than cardamonin, by scavenging radical species, cardamonin would prove more valuable in the control of various stages of cancer growth than alpinetin.

Antioxidant and Antiradical Properties of Some Examples of Flavonoids and Coumarins—Potentiometric Studies

A comprehensive study of a range of flavonoids and coumarins is presented in this article. The work uses an approach that evaluates the activity of these compounds by various mechanisms: the electron transfer (ET), the hydrogen atom transfer (HAT), and the mechanism of metal chelation. The studies were carried out using the methods of the cyclic voltammetry and the potentiometry. The electrochemical behavior of these compounds was studied by the method of cyclic voltammetry; the main types of voltammograms, depending on the oxidation mechanisms, were identified. Various versions of potentiometric sensor systems have been used to detect analytical signal in approaches implemented in ET, HAT and metal chelation mechanisms. The antioxidant capacity was studied by the electron-transfer mechanism. Compounds with antioxidant properties were selected; half-reaction periods for these compounds have been determined. It has been shown that electron-donating and complexing properties directly depend on the mutual arrangement of hydroxyl groups in the molecule. The antiradical ability of the compounds has been studied. It was shown that all studied compounds inhibit peroxyl radicals. Series on the change in antioxidant and antiradical properties of compounds have been compiled. There is no correlation between the results of the study of antioxidant properties obtained using sensory systems that reveal various antioxidant mechanisms. The need to use an integrated approach in the study of antioxidant properties is shown.

A new AIEE-active carbazole based colorimetric/fluorimetric chemosensor for ultra-rapid and nano-level determination of Hg2+ and Al3+ in food/environmental samples and living cells

Abstract A new simple carbazole Schiff base (CBS) with typical aggregation-induced emission enhancement (AIEE) property was designed and synthesized based on carbaldehyde and 2-hydroxybenzohydrazide units, which was successfully utilized as a new dual-responsive colorimetric/fluorimetric chemosensor for highly selective and sensitive “turn-off” fluorescence detection of Hg2+ and “turn-on” fluorescence sensing Al3+ in near-perfect aqueous media based on metal chelation mechanism. The low detection limits of CBS for Hg2+ and Al3+ were respectively determined to be 14.7 nM and 47.2 nM, far lower than the WHO guidelines for drinking water, which permitted its nano-level determination in real samples. The CBS for Hg2+/Al3+ sensing displayed outstanding advantages of pH stability, excellent reversibility, ultra-fast response, stronger anti-interference capability and lower cytotoxicity compared with other related chemosensors. The binding mode of CBS with Hg2+/Al3+ was determined to be a 1:1 complexation stoichiometry using Job’s plot analysis and fluorescent titration curve, which further confirmed by FTIR and 1H NMR analysis. Due to its good colorimetric/fluorimetric properties, a simple cost-effective portable on-site test strip was developed that allows for visual, fast, reliable and convenient detecting Hg2+/Al3+ in environmental analysis. Moreover, chemosensor CBS has successful application in building molecular logic gates. Furthermore, the CBS was successfully applied in soil, environmental water, and food samples analysis and live-cell imaging, demonstrated its great potentials in environmental and biological applications.

Proportional coexistence of okanin chalcone glycoside and okanin flavanone glycoside in Bidens pilosa leaves and theoretical investigation on the antioxidant properties of their aglycones

Bidens pilosa plant has been shown to produce okanin flavanone glycoside and its chalcone derivative. In most other plants, due to chalcone isomerase enzyme, the flavanone tends to exist in higher proportions than their chalcone precursors. Herein we have utilized liquid chromatography–mass spectrometry approach and shown that within the leaves of Bidens pilosa plant the two okanin glycosides exist in unusual equal proportional distribution, which indicates that Bidens pilosa plant is an alternative rich source of these highly sought-after antioxidant molecules. The aglycone okanin chalcone (ONC) and okanin flavanone (ONF) have experimentally been shown to exhibit antioxidant activity. However, experimental findings have not conclusively determined which of the two compounds is a more potent antiradical than the other. Herein, the density functional theory (DFT) method is utilized to establish, from structural and thermodynamic energetic considerations, the preferred antioxidant molecule between the two aglycone okanins. A theoretical study on the antioxidant properties of ONC and ONF has been performed by considering their radical scavenging and metal cation (Mn+, where M = Cu(II) or Fe (III)) chelation ability. The study has been performed using B3LYP/6-31 + G(d,p) method. In the case of the metal chelation mechanism, the LANL2DZ pseudo-potential was selected to describe the selected Mn+ cations. The results of the study suggest that ONC is a better radical scavenger than ONF because of the extended electron delocalization on its neutral radical, which is due to the presence of conjugation within the ONC neutral radical after hydrogen atom abstraction. In the metal chelation mechanism, it is noted that the binding energies depend on the media, the nature of the ligand and the cation and the cation coordination site on the ligand. The charge and the spin density on Mn+ decrease on coordination to the ligand. The ability of the ligands to reduce Mn+ cations, coupled with the strong Mn+ binding properties, has significant implication on the antioxidant ability of both okanins. However, since ONC⋅⋅⋅M+n interaction results in higher binding energy than ONF⋅⋅⋅M+n interaction, the implication is that ONC is a preferred free metal ion chelator than ONF.

Structural Basis of Staphylococcus aureus Surface Protein SdrC.

Staphylococcus aureus surface proteins play important roles in host tissue colonization, biofilm formation, and bacterial virulence and are thus essential for successful host infections. The surface protein SdrC from S. aureus induces bacterial biofilm formation via an intermolecular homophilic interaction of its N2 domains. However, the molecular mechanism of how the homophilic interaction is achieved is unknown. Here, we report two crystal structures of SdrC N2N3 domains, revealing two possible homophilic interaction mechanisms: Ca2+-mediated intermolecular metal chelation of N2 domains and intermolecular interaction of N2 and N3 domains. Given the unnecessary role of the N3 domain in the induction of biofilm formation, the N2 domain-mediated metal chelation mechanism is likely the mechanism that facilitates SdrC homophilic interaction. Mutation of key Ca2+-chelating residues differentially reduced the level of protein dimer formation, further supporting the key role of metal chelation in the N2 domain interaction. Together, these results reveal the possible mechanism of the homophilic interaction of SdrC N2 domains and pave the way for the rational development of new strategies against this mechanism.

The use of natural antioxidants to combat lipid oxidation in O/W emulsions

This research investigated the efficacy of four natural antioxidants, quercetin, curcumin, rutin hydrate and ascorbic acid in their ability to combat Lipid Oxidation (LO) within different oil-in-water (O/W) emulsion environments. The free radical scavenging and metal chelating ability of the four antioxidants was first assessed through DPPH and Ferrozine assays respectively and used to help explain each antioxidants efficacy in particular environments. Generally, in emulsions with no added iron, compounds that exhibited the greatest levels of DPPH and Ferrozine inhibition provided the best oxidative stability. In the presence of added iron, antioxidant effectiveness reduced dramatically and in some cases resulted in prooxidant activity. It was concluded that the antioxidant metal chelating mechanism of antioxidants in emulsions with added iron was largely insignificant compared to the prooxidant effect gained by these compounds through their interaction with iron. The most non-polar compounds, curcumin and quercetin provided peroxide value (PV) reductions of 65% and 74% respectively in 5% oil phase volume emulsions compared to just 28% and 43% PV reductions in 40% oil phase volume emulsions; thus providing more evidence of the widely reported ‘polar paradox’. Combinations of ascorbic acid with quercetin or curcumin resulted in antioxidant synergism, whereas other antioxidant combinations led only to additive or antagonistic effects. This research builds on the understanding of the fundamental behaviour of natural antioxidants within different emulsion formulations.

Neuroprotective effect of Costus afer on low dose heavy metal mixture (lead, cadmium and mercury) induced neurotoxicity via antioxidant, anti-inflammatory activities

Humans are constantly exposed to heavy metals due to their ubiquity in the environment. Hence, this study investigated the possible protective effect of Costus afer aqueous leaf extract (CALE) against low dose heavy metal mixture (LDHMM)-induced neurotoxicity. Male albino rats were divided into 6 equal groups. Group 1 served as the normal control receiving only deionized water. Group 2 served as the toxic control receiving on metal mixture (20 mg/kg PbCl2, 1.61 mg/kg CdCl2 and 0.40 mg/kg HgCl2), groups 3, 4 and 5 were co-treated with metal mixture and CALE (750, 1500 and 2250 mg/kg body weight, respectively) and group 6 was treated with metal mixture and ZnCl2. All treatments were administered through oral gavage for 90days. Oxidative stress biomarkers [malondialdehyde (MDA), superoxide dismutase (SOD), glutathione content (GSH) and catalase (CAT)], inflammatory cytokines [interlukin-6 (IL-6) and interlukin-10 (IL-10)], histopathological changes and heavy metal concentration were determined in brain of rats. Results indicated that LDHMM significantly increased (p < 0.05) the lipid peroxidation marker (MDA) and the pro-inflammatory cytokine (IL-6), while lowered levels of the oxidative biomarkers (SOD, CAT and GSH) and anti-inflammatory cytokine (IL-10). Also, LDHMM caused some histopathological changes such as reactive gliosis and glia cell proliferation. LDHMM elevated the lead, cadmium and mercury concentrations in the brain. Severity of the distorted cortical parameters were ameliorated by CALE administration. The CALE induced significant protective effect on LDHMM-mediated neurotoxicity in a dose-dependent manner which may be a result of its antioxidant anti-inflammatory and metal chelation mechanisms.

Novel quinolone-3-carboxylic acid derivatives as anti-HIV-1 agents: design, synthesis, and biological activities

A new series of quinolone-3-carboxylic acids featuring different hydrophobic groups at N-1, C-2, C-7, and C-8 positions were synthesized and evaluated for their activity against single-cycle replicable HIV NL4-3 as inhibition rate of p24 expression in Hela cells cultures. Most of the synthesized compounds showed anti-HIV activity with no significant cytotoxicity at concentration of 100 μM. The most active compounds 4h, 4k, and 4j exhibited anti-HIV activity with an inhibition rate of 55, 71, and 84 %, respectively. A docking study using the crystallographic data available for PFV integrase including its complexes with Mg2+ and Raltegravir revealed that the active compounds could occupy same space near Raltegravir and interact with the Mg2 + ions in the active site. Thus, the anti-HIV activity of the synthesized compounds might involve a metal chelating mechanism.

Treating spinal cord injury via sustained drug delivery from calcium phosphate coatings.

Spinal cord injury (SCI) is a devastating trauma that leaves approximately 10,000 to 20,000 people paralyzed every year in the United States. The majority of these cases are young people that will live to almost a full life expectancy, however, their quality of life is significantly reduced. After SCI there is loss of both sensory and motor function below the level of injury. Due to this loss of function SCI patients are often unable to care for themselves and rely on friends and family to serve as their primary caregivers. The Christopher Reeve Foundation found that more than 50 million people each year provide this care in the U.S., the value of which is estimated to be $306 billion annually. Along with the financial burden, SCI patients have emotional stress and continued health care problems throughout their lives most predominately renal complications and pressure sores. These facts demonstrate the overwhelming need to restore function after SCI.

A theoretical study of the antioxidant properties of phenolic acid amides investigated through the radical-scavenging and metal chelation mechanisms

Phenolic amides have been investigated extensively as efficient antioxidant compounds by means of experimental techniques. However, their mode of action has not been determined through the use of theoretical approaches. In this study, theoretical studies on the conformational and antioxidant properties of phenolic acid amides were performed to investigate factors that contribute to their conformational preferences and to elucidate their antioxidant properties and mechanisms. The antioxidant activity of selected phenolic acid amides has been considered through the ability of the compounds to scavenge free radical species and chelate metal ions. The antiradical mechanisms were investigated using the B3LYP/6-311+G(d,p) method, and the metal chelation mechanism was investigated using the B3LYP/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) method. The results show that the preferred conformers for the neutral and anionic conformers are stabilised by the presence of intramolecular hydrogen bonds (IHBs). The neutral and cationic radical species are stabilised by both IHBs and the spin density delocalisation of the unpaired electron. The preferred Cu complex is one in which the Cu ion interacts simultaneously with the carbonyl group and the benzene ring of the aromatic amine moiety. An estimated metal ion affinity is influenced by the nature of the ligand and the media. In comparison with the isolated Cu(II) ion, the charge on the coordinated metal ion decreases from 2 to ~1 suggesting that the Cu ion is reduced on interaction with the ligand molecule undergoes oxidation.

Conformational, electronic and antioxidant properties of lucidone, linderone and methyllinderone: DFT, QTAIM and NBO studies

Theoretical studies on lucidone, linderone and methyllinderone were performed to investigate factors that contribute to structural stability and to elucidate the antioxidant properties and mechanisms. The study was performed in different media utilising the density functional theory with different functionals and the 6-311+ G(d,p) basis set. The antioxidant activity has been considered through the electron transfer and metal chelation mechanisms. The results show that the stability of the tautomers and conformers is due to the presence of several intramolecular hydrogen bonds. The ionisation potential values suggest that the antiradical activity increases with the increase in the number of OCH3 groups substituted on the cyclopentene-1,3-dione ring. In vacuo, the spin density of the Fe(II) cation upon ligand coordination decreases to 3.0−3.5, whereas the ligand spin density approaches 1, indicating that it is oxidised to a radical cation. The metal ion affinity (MIA) is influenced by the position and number of OCH3 substituted on the acylcyclopentene-1,3-dione ring. A very favourable MIA, in vacuo, is obtained when Fe(II) is chelated between the sp2 O and sp3 O atoms. An estimation of MIA in an aqueous solution shows a remarkable decrease with respect to the results in vacuo.

Investigating the Role of Metal Chelation in HIV-1 Integrase Strand Transfer Inhibitors

HIV-1 integrase (IN) has been validated as an attractive target for the treatment of HIV/AIDS. Several studies have confirmed that the metal binding function is a crucial feature in many of the reported IN inhibitors. To provide new insights on the metal chelating mechanism of IN inhibitors, we prepared a series of metal complexes of two ligands (HL1 and HL2), designed as representative models of the clinically used compounds raltegravir and elvitegravir. Potentiometric measurements were conducted for HL2 in the presence of Mg(II), Mn(II), Co(II), and Zn(II) in order to delineate a metal speciation model. We also determined the X-ray structures of both of the ligands and of three representative metal complexes. Our results support the hypothesis that several selective strand transfer inhibitors preferentially chelate one cation in solution and that the metal complexes can interact with the active site of the enzyme.

Bioassay-guided identification of an anti-inflammatory prenylated acylphloroglucinol from Melicope ptelefolia and molecular insights into its interaction with 5-lipoxygenase

A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC50 value of 0.42μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC4 with an IC50 value of 1.80μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC50 value of 0.40μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of −13.45 (electrostatic) and −5.40kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56Å hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.

Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors

Previously, we discovered linomide analogues as novel HIV-1 integrase (IN) inhibitors. Here, to make possible structure–activity relationships, we report on the design and synthesis of a series of substituted dihydroquinoline-3-carboxylic acids. The crystal structure of the representative compound 2c has also been solved. Among the eight new analogues, 2e showed a potency in inhibiting IN strand transfer catalytic activity similar to the reference diketo acid inhibitor L-731,988 (IC 50 = 0.9 μM vs. 0.54 μM, for 2e and L-731,988, respectively). Furthermore, none of the compounds showed significant cytotoxicity in two tested cancer cell lines. These compounds represent an interesting prototype of IN inhibitors, potentially involved in a metal chelating mechanism, and further optimization is warranted.

Iron-chelation properties of phenolic acids bearing catechol and galloyl groups

In this study, the capacity of seven phenolic acids and hydroxytyrosol for complex formation with iron was quantified. A metal-chelation mechanism was described by means of spectrophotometry and calculating the binding constants of the complexes. The influence of phosphate buffer, Hepes buffer, Tris buffer and water on this mechanism was investigated. UV–Vis absorption spectroscopy showed that the absorption of phenolic acids changes upon the addition of Fe 2+, which resulted in several shifts of their spectra. These batochromic shifts were analyzed and evaluated by calculating binding constants. Furthermore, in the presence of different concentrations of EDTA (0–1 mM), a reduction of the constants was observed. However, not all of the phenolic compounds assessed here showed complex formation, those not bearing catechol or galloyl moiety like vanillic acid, syringic acid and ferulic acid, did not show any complex formation in our study. The ability of the phenolic compounds which chelate iron have been ranked in line with the binding constants in ascending order rendering the protocatechuic acid (1.43 M −1) the weakest chelator, followed by hydroxytyrosol (2.66 M −1), gallic acid (4.78 M −1), caffeic acid (8.12 M −1) and chlorogenic acid (20.13 M −1) as the strongest chelator.

Free radical scavenging and copper chelation: A potentially beneficial action of captopril

Captopril (CpSH), an angiotensin converting enzyme (ACE) inhibitor, is reported to provide protection against free-radical mediated damage. The purpose of this study was to investigate, by means of pulse radiolysis technique, the behaviour of CpSH towards radiation-induced radicals in the absence and in the presence of copper(II) ions, which can play a relevant role in the metal catalysed generation of reactive oxygen species. The results indicate that the -SH group is crucial in determining the radical scavenging action of CpSH and the nature of the resulting CpSH transient products in the absence or in the presence of oxygen.In the presence of Cu(II), the -SH group is still involved in the biological action of the molecule participating both in the one-electron reduction of Cu(II) with formation of CpSSCp, and in Cu(I) chelation. This conclusion is supported by the Raman spectroscopic data which allow to identify the CpSH sites involved in the copper complex at different pH.These results suggest that CpSH may potentially inhibit oxidative damage both through free radical scavenging and metal chelation. Considering the low CpSH concentration in vivo, the metal chelation mechanism, more than the direct radical scavenging, could play the major role in moderating the toxicological effects of free radicals.