The beneficial effects of polyphenols, predominantly in the context of oxidative stress-related diseases such as cancer, cardiovascular diseases and neurological conditions including Alzheimer's and ...Parkinson's diseases, have been documented by a number of papers and reviews. The antioxidant/prooxidant properties of phenolic compounds are related mainly to the number and positions of hydroxyl groups and to their redox metal (Cu, Fe) chelating capacity. In this work we studied structurally distinct phenolic molecules such as myricetin, morin, 3',4'-dihydroxy-flavone, taxifolin and 4-hydroxycoumarin, either alone or as interacting with Cu
ions. EPR and UV-Vis spectroscopy confirmed that the effective binding of cupric ions to phenolic compounds requires the presence of the 3-OH and 4-CO groups on the flavonoid C ring and unsaturated C2-C3 bond of the C-ring, which permits through-conjugation with the B-ring. An ABTS assay revealed that radical scavenging activities of phenolic compounds are related to their number of hydroxyl groups, planarity of the molecular skeleton, extent of delocalization and they decrease in the order: myricetin > morin > 3',4'-dihydroxyflavone ~ 4-hydroxy coumarin > taxifolin. Absorption titrations indicate that copper ions can modulate the DNA binding affinity of flavonoids via the formation of their Cu-chelates. Gel electrophoresis measurements indicated that the protective effect of the phenolic compounds decreases in the order: 3',4'-dihydroxyflavone > 4-OH coumarin > morin > taxifolin ~ myricetin. This can be explained by the fact that myricetin, taxifolin and morin form stable Cu(II) complexes capable of causing DNA damage via interaction with DNA and ROS formation via the Fenton reaction. Application of ROS scavengers revealed the formation of singlet oxygen, superoxide and hydroxyl radicals and their concerted synergistic effect on the DNA. The overall results suggest that the most pronounced DNA damage has been observed for flavonoids containing higher number of hydroxyl groups (including 3-OH group of the C ring), such as myricetin (six hydroxyl groups), morin and taxifolin (five hydroxyl groups) in the presence of Cu(II) ions. The proposed mechanism of action by which Cu(II) complexes of myricetin, morin and taxifolin interact with DNA predispose these substances to act as potential anticancer agents. The anticancer activity of phenolic compounds can be explained by their moderate prooxidant properties, which can boost ROS formation and kill cancer cells. Alternatively, slight prooxidant properties may activate antioxidant systems, including antioxidant enzymes and low molecular antioxidants such as glutathione and thus act as preventive anticancer agents.
Kaempferol is a flavonoid that occurs in tea and in many vegetables and fruits, including broccoli, cabbage, beans, grapes, apples, and strawberries. The efficacy of Kaempferol has been demonstrated ...in the treatment of breast, esophageal, cervical, ovarian, and liver cancers and leukemia, which very likely arises from its prooxidant properties and the activation of pro-apoptotic pathways. Indeed, this matter has already been the focus of a number of published studies and reviews. The aim of the present study was to elucidate the antioxidant vs. prooxidant properties of flavonoids in the presence of the redox-active metal, copper (II) ion, by means of the Fenton reaction. The specific motivation of this work is that, since an increased level of Cu(II) ions is known to be associated with many disease states such as neurological conditions (Alzheimer's disease) and cancer, any interaction between these ions and flavonoids might affect the outcome of therapeutic uses of the latter. The structure of the Cu-kaempferol complex in DMSO was investigated by means of low temperature EPR spectroscopy, which confirmed the existence of at least two distinct coordination environments around the copper (II) ion. UV vis-spectra of kaempferol and its Cu(II) complex in DMSO revealed an interaction between the 5-OH (A ring) group and the 4-CO (C ring) group of kaempferol with Cu(II) ions. An ABTS assay confirmed that kaempferol acted as an effective radical scavenger, and that this effect was further enhanced in the form of the Cu(II)-kaempferol complex. Quantitative EPR spin trapping experiments, using DMPO as the spin trap, confirmed suppression of the formation of a mixture of hydroxyl, superoxide, and methyl radicals, in a Fenton reaction system, upon coordination of kaempferol to the redox-active Cu(II) ions, by 80% with respect to the free Cu(II) ions. A viscometric study revealed a better DNA-intercalating ability of the Cu-kaempferol complex than for free kaempferol, essential for conferring anticancer activity of these substances. The results of the viscometric measurements were compared with those from a DNA damage study of Cu-kaempferol complexes in a Fenton reaction system, using gel electrophoresis. At low concentrations of kaempferol (Cu-kaempferol ratios of 1:1 and 1:2), a very weak protective effect on DNA was noted, whereas when kaempferol was present in excess, a significant DNA-protective effect was found. This can be explained if the weakly intercalated kaempferol molecules present at the surface of DNA provide protection against attack by ROS that originate from the Fenton reaction involving intercalated Cu(II)-kaempferol complexes. Following the application of ROS scavengers, L-histidine, DMSO, and SOD, gel electrophoresis confirmed the formation of singlet oxygen, hydroxyl radicals, and superoxide radical anions, respectively. We propose that the prooxidant properties of Cu-kaempferol complexes may provide anticancer activity of these substances. When present in excess, kaempferol displays antioxidant properties under Cu-Fenton conditions. This suggests that kaempferol might prove a suitable candidate for the prevention or treatment of oxidative stress related medical conditions that involve a disturbed metabolism of redox metals such as copper, for example, Menkes disease, and neurological disorders, including Alzheimer's disease. For the potential use of kaempferol in clinical practice, it will be necessary to optimize the dose size and critical age of the patient so that this flavonoid may be beneficial as a preventive drug against cancer and neurological disorders.
Cooper(
) complexes represent a promising group of compounds with antimicrobial and antifungal properties. In the present work, a series of Cu(
) complexes containing the non-steroidal ...anti-inflammatory drugs, tolfenamic acid, mefenamic acid and flufenamic acid as their redox-cycling functionalities, and 1,10-phenanthroline as an intercalating component, has been studied. The antibacterial activities of all three complexes, Cu(tolf-O,O′)
(phen) (
), Cu(mef-O,O′)
(phen) (
) and Cu(fluf-O,O′)
(phen) (
), were tested against the prokaryotic model organisms
(
) and
(
) and their antifungal activities were evaluated towards the yeast,
. The antibacterial activity of both strains has been compared with the antibiotic Neomycin. The calculated IC
values revealed slight differences in the antibacterial activities of the complexes in the order
∼
>
. The most profound growth inhibition of
was observed, at its highest concentration, for the complex
, which contains chlorine atoms in the ligand environment. The trend obtained from IC
values is generally in agreement with the determined MIC values. Similarly, the complex 1 showed the greatest growth inhibition of the yeast
and the overall antifungal activities of the Cu(
) complexes were found to follow the order
>
≫
. However, for complex
, even at the highest concentration tested (150 μM), a 50% decrease in yeast growth was not achieved. It appears that the most potent antimicrobial and antifungal Cu(
) complexes are those containing halogenated NSAIDs. The mechanisms by which Cu(
) complexes cause antibacterial and antifungal activities can be understood on the basis of redox-cycling reactions between cupric and cuprous species which lead to the formation of free radicals. The higher efficacy of the Cu(
) complexes against bacterial cells may be due to an absence of membrane-protected nuclear DNA, meaning that on entering a cell, they can interact directly with its DNA. Contrastingly, for the complexes to interact with the DNA in yeast cells, they must first penetrate through the nuclear membrane.
Copper(II) complexes containing non-steroidal anti-inflammatory drugs (NSAIDs) have been the subject of many research papers and reviews. Here we report the synthesis, spectroscopic study and ...biological activity of novel mixed copper(II) complexes with NSAIDs: tolfenamic (tolf), mefenamic (mef) and flufenamic (fluf) acids and phenanthroline (phen): Cu(tolf-O,O′)2(phen) (1), Cu(mef-O,O′)2(phen) (2), Cu(fluf-O,O′)2(phen) (3). Complexes were characterized by X-ray analysis and EPR spectroscopy. Complexes 1–3 are monomeric, six-coordinate and crystallize in a monoclinic space group. Interaction of Cu(II) complexes with DNA was studied by means of absorption titrations, viscosity measurements and gel electrophoresis. The relative ability of the complexes to cleave DNA even in the absence of hydrogen peroxide is in the order 3 > 2 > 1. Application of the reactive oxygen species (ROS) scavengers, L-histidine, DMSO and SOD confirmed that singlet oxygen, hydroxyl radicals (Fenton reaction) and superoxide radical were formed, respectively. Thus, in addition to mechanism of intercalation, redox-cycling mechanism which in turn lead to the formation of ROS contribute to DNA damage. Cu(II) complexes exhibit excellent SOD-mimetic activity in the order 3~1 > 2. The fluorescence spectroscopy revealed that albumin may act as a targeted drug delivery vehicle for Cu(II) complexes (K~106). The anticancer activities of complexes 1–3 were investigated using an MTS assay (reduction of the tetrazolium compound) against three cancer cell lines (HT-29 human colon adenocarcinoma, HeLa and T-47D breast cancer cells) and mesenchymal stromal cells (MSC). The most promising compound, from the viewpoint of its NSAID biological activity is 3, due to the presence of the three fluorine atoms participating in the formation of weak hydrogen-bonds at the DNA surface.
Proposed orientation of aryl substituents of the Cu(II) complexes 1–3 in their interaction with DNA. The intercalation efficiency of complexes and consequent unwinding of the helix depend on the orientation of remote substituents attached to aromatic rings of the non-steroidal anti-inflammatory drugs (NSAIDs) which can interact with the DNA strand. Display omitted
•Three novel mixed Cu(II) fenamates with phenanthroline were prepared and studied.•Cu(II) complexes are efficient superoxide dismutase-mimetics and DNA intercalators.•Reactive oxygen species-induced DNA damage is a result of a redox-cycling mechanism.•Cu(II) complexes interact with human serum albumin.•Complexes exhibit cytotoxic activity against several cancer cell lines.
Luteolin has been reviewed as a flavonoid possessing potential cardioprotective, anti-inflammatory, anti-cancer activities. Having multiple biological effects, luteolin may act as either an ...antioxidant or a pro-oxidant. In this work, the protective role of copper(II)-chelation by luteolin on DNA damage via the Cu-Fenton reaction was studied. EPR and UV–vis spectroscopic data demonstrated that the luteolin, lacking 3-OH group, chelates to Cu(II) via the 5-OH and 4-CO groups, respectively. EPR spin trapping experiments using DMPO spin trap confirmed that the coordination of luteolin to Cu(II) significantly suppressed formation of hydroxyl and superoxide radicals (by 80%) in a Cu-Fenton system. Absorption titrations showed that the chelation of Cu(II) by luteolin slightly increased the mild intercalation strength of its interaction with DNA, as compared with free luteolin. Comparison with kaempferol and quercetin revealed, that the strength of the interaction between the free flavonoids/Cu-flavonoid complexes with DNA is only mildly affected by the presence/absence of 3-OH group. Due to the differences in the sensitivities of absorption titrations and viscometry, the latter confirmed weaker DNA intercalating efficiency of Cu-luteolin complex than does free luteolin. A dose dependent protective effect of luteolin against ROS-induced DNA damage was observed using gel electrophoresis. This effect was more pronounced compared to quercetin and kaempferol. In conclusion, the administration of luteolin to patients suffering from oxidative stress-related diseases with disturbed Cu-metabolism such as Alzheimer's diseases (antioxidant effect) and certain cancers (prooxidant effect) may have several health benefits.
Display omitted
•Antioxidant/prooxidant properties of luteolin in a Cu-Fenton reaction were studied.•EPR spin trapping experiments confirmed suppressed formation of hydroxyl radicals.•Interaction of Cu-luteolin complex with DNA was studied by absorption titrations.•DNA damage was studied by gel electrophoresis.
•Five new zinc(II) 3-aminobenzoates were synthesized and characterized by infrared spectroscopy and elemental analysis.•Thermal decomposition of all complexes was studied by thermogravimetric ...analysis and differential thermal analysis.•Antimicrobial activity of the prepared complexes against bacteria, yeast and filamentous fungi was evaluated.•Influence of the amino group position on the benzene ring on the antimicrobial activity of aminobenzoates was revealed.
Zinc(II) 3-aminobenzoate (3-NH2benz) as well as four new coordination compounds containing ligands L (thiourea – tu, nicotinamide – nad; isonicotinamide – inad; N,N-diethylnicotinamide – dnad) with general formula of Zn(3-NH2benz)2L2 were synthesized and characterized by elemental analysis and IR spectroscopy. Thermoanalytical methods (TG/DTG, DTA) were used in order to compare the thermal decomposition of synthesized compounds with previously prepared 2- and 4-aminobenzoates. The intermediates and the final product of thermal decomposition were proved by spectroscopic methods. The antimicrobial activity of the zinc(II) 3-aminobenzoate complexes against various strains of bacteria, yeasts and filamentous fungi was determined and compared with 2- and 4-aminobenzoates as well. According to obtained results complexes with thiourea and N,N-diethylnicotinamide exhibit activity towards filamentous fungi R. oryzae, and A. Alternata, yeast C. Albicans, as well as bacteria S. aureus.
New zinc(II) 2-chlorobenzoates of general formula Zn(2-ClC
6
H
4
COO)
2
(
L
)
2
(where
L
= caffeine—
caf
, urea—
u
, methyl-3-pyridylcarbamate—
mpc
, phenazone—
phen
, theophylline—
thp
) were ...synthesised and characterised by elemental analysis and IR spectroscopy. The thermal behaviour of the complexes was studied by TG/DTG and DTA methods in nitrogen and in air atmosphere. During the thermal decomposition of the studied compounds the release of organic ligands take place followed by the decomposition of 2-chlorobenzoate anion. The volatile decomposition intermediates were proved by mass spectrometry. Zinc oxide was found as the final product of the thermal decomposition performed up to 1,000 K. The antimicrobial activity of the zinc(II) complexes against various strains of bacteria, yeasts and filamentous fungi has been investigated. It was found that the prepared compounds decreased the growth of
Staphylococcus aureus
,
Escherichia coli
,
Candida albicans
,
Rhizopus oryzae
and
Microsporum gypseum
, respectively. The most resistant to all tested compounds was probiotic strain of
Lactobacillus plantarum
. The presence of zinc and ligands in the prepared compounds increased the inhibitory effect compared to sodium salt of prepared compounds and free ligands.
The synthesis and characterization of six new 2-methylthionicotinate (2-MeSnic) copper(II) monomeric complexes Cu(2-MeSnic)
2
L
2
(L is furo3,2-cpyridine—fpy, 2-methylfuro3,2-cpyridine—Mefpy, ...2,3-dimethylfuro3,2-cpyridine—Me
2
fpy or benzo4,5furo3,2-cpyridine—Bfp), Cu(2-MeSnic)
2
(fpy)
2
(H
2
O), as well as Cu(2-MeSnic)
2
(CF
3
Phfpy)
2
(H
2
O)
2
(CF
3
Phfpy is 2-(3-trifluoromethylphenyl)furo3,2-cpyridine) are reported. The characterizations were based on elemental analysis, infrared, electronic and EPR spectra. The crystal structure of one of the complexes has been determined. The Cu
II
atoms of Cu(2-MeSnic)
2
(fpy)
2
(H
2
O) are six-coordinated in a highly distorted tetragonal–bipyramidal arrangement by two nitrogen atoms, one from each fpy, in
trans
-positions, by three oxygen atoms of the carboxyl groups of 2-MeSnic ligands (one monodentate, one asymmetrically bidentate), one axial position being occupied by the oxygen of a water molecule. The antimicrobial effects have been tested on various strains of bacteria, yeasts and filamentous fungi. A comparison of the IC
50
and MIC values has shown a decrease of inhibition activities of tested compounds in the order: Cu(2-MeSnic)
2
(Bfp)
2
> Bfp > Cu(2-MeSnic)
2
(CF
3
Phfpy)
2
(H
2
O)
2
> Cu(2-MeSnic)
2
(Me
2
fpy)
2
> CF
3
Phfpy > Cu(2-MeSnic)
2
(Mefpy)
2
> Me
2
fpy > Cu(2-MeSnic)
2
(fpy)
2
(H
2
O) > Cu(2-MeSnic)
2
(H
2
O)
2
> Mefpy > fpy = 2-MeSnicH = CuSO
4
.
The thermal decomposition of the complexes Zn(form) sub(2) times 2phen(I), Zn(ac) sub(2) times 2phen(II), Zn(prop) sub(2) times 2phen(III), Zn(but) sub(2) times 2phen(IV), where phen=phenazone, ...form=formiate,ac=acetate, prop=propionate, but=butyrate has been studied in air by TG/DTGand DTA methods. The possible mechanism of the thermal decomposition was proposed.The final product of thermal decomposition was ZnO. IR data show unidentatecoordination of carboxylate group to Zn(II) ion. The complexes were testedagainst various strains of microorganisms and their efficiency decrease inthe sequence yeasts >bacteria>filamentous fungi.
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