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Tropical Journal of Pharmaceutical Research February 2015; 14 (2): 337-349 ISSN: 1596-5996 (print); 1596-9827 (electronic) © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved.

Available online at http://www.tjpr.org http://dx.doi.org/10.4314/tjpr.v14i2.21 Review Article

Coordination Compounds of M(II) Biometal with Acid- Type Anti-inflammatory Drugs as Ligands – A Review

Nenad S Krstić1, Ružica S Nikolić1, Maja N Stanković1, Nada G Nikolić2 and Dragan M Đorđević1 1Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 2Medical Faculty, University of Niš, Bulevar Dr Zorana Đinđića 81, 18000 Niš, Serbia

*For correspondence: Email: [email protected]; Tel: +38118514882

Received: 14 August 2014 Revised accepted: 16 January 2015

Abstract

The cations of biometals in biological systems easily interact with various moieties of organic and inorganic , either as natural constituents or after introduction into the body via O-, N- and S- donor atoms. Study of the interaction between M(II) biometal–O-donor ligand (drug) is of interest for various reasons: more evenly dosing of medicine and biodistribution of medicine; monitoring of its pharmacokinetics including excretion; reduction of unwanted effects of the medicine; greater antimicrobial activity; synergistic effect of the and medicine; and improved anti-ulcerous, anti- tumor and anti-bacterial activity. This paper offers an overview of the literature of published research on coordination between biometals and anti-inflammatory drugs of the acid type. The that the subject of focus in this review are d-metals with M(II) ions, namely, (Cu), (Zn), cobalt (Co) and (Mn).Those containing molecules with carboxyl functional groups can build complexes with coordinated number of metals of 4 and 6, of various stoichiometric structures, simple or complex, and also behave as monodentate, bidentate or bridge ligands in polynuclear complexes.

Keywords: Biometals M(II), Anti-inflammatory medicine, Coordination, O-Donor ligands, Copper, Cobalt, Manganese, Zinc

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INTRODUCTION development of new methods for determining micro-amounts of active components [1-3]. Biometal cations in biological systems easily interact with molecules of water and various The study of the interaction between M(II) parts of different organic and inorganic biometal–O-donor ligands (the drugs) is biomolecules, as natural constituents or interesting for a variety of aspects, with the aim substances introduced into the . The of: achieving more balanced medicine dosing, complex associates, built via O-, N- and S- donor the biodistribution of the medicine; monitoring its atoms, have an important role in biological pharmacokinetics, excretion; the reduction in the processes. The products of interaction between unwanted responses; improving anti-microbial M(II) metals and medicine are fundamentally activities; synergistic effects of the metals and important for the theory of coordination medicine, and improved anti-ulcerous, anti-tumor chemistry, as well as the significance of the and anti-bacterial activity [4-11].

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The mechanisms of the effects of biometal types [23]. Copper plays an important role in the complexes are diverse. The complex biometal reduction of inflammatory processes, and compounds, in addition to a beneficial have a achieves this role through toxic effect on the body, which often limits their (SOD) [20]. Copper is necessary for application [12]. A pioneer in the study of the the synthesis of hemoglobin [24]. complexes of transition metals and non-steroid anti-inflammatory drugs (NSAIDs) was Sorensen Of the overall content of copper in the human [13]. The literature is replete with numerous data body, most of it is found in the human skeletal on studies on the interaction between M(II) ions system, liver, brain and blood. Under normal physiological conditions, the human body of metals and numerous ligands of contains 80-120 mg of copper [12]. The daily pharmaceuticals and supplements via O-, N-, S- requirements of the human body for copper, on donor atoms, as well as the synthesis of their the basis of the recommendation of the World products and the effects which the obtained Health Organization, ranges in the interval from products lead to [4-11]. 0.9 to 1.3 mg/day [15]. Disorders related to the copper contained in the human body are related M(II) BIOMETALS to the occurrence and development of certain illnesses (aceruloplasminemia, Wilson's disease, Biometals from the series of d-metals with Menkes disease, Alzheimer's, various characteristic M(II) ions can be found in the inflammatory processes in the human body, human body in small amounts, and are mainly tumors, etc) [23]. Approximately 50 % of the the active centers of of various overall intake of copper is absorbed through the functions. They are introduced into the body daily bloodstream, and bound to albumins is through a variety of food, which satisfies the daily transferred to other organs and tissues [25]. requirements (Table 1) [12]. The various roles of this biometal in living Biological role of copper organisms are bound, on the one hand, to its polyvalent nature, and on the other, to the Back in 1920, it was shown for the first time that tendency of its ions to build complex compounds. copper is essential for biological systems. That In the theory of coordination compounds, it is was when it was discovered that anemia among well known that the Cu(II) , d9, builds experimental animals occurs as the result of a coordination compounds with a coordination decreased intake of copper as a part of their number of 4 or 6, including quadri-planar, regular diet. With the addition of copper salts, tetrahedron or deformed octahedron structures. there was a correction in the occurring The content and structure of the chelate products pathological state [20,21]. In the biological depend on the physical-chemical features of the processes of living organisms, copper plays an ions (size, polarizability, ion potential, acidity) important role in the process of binding , and the size of the ligand and the active centers, redox processes, electron-transfer processes, potential atom donors, denticity, etc. The and is a part of the structure of numerous possible content of the complex associates has a enzymes: enzymes for the transport of electrons coordination number of 4 or 6 and can be and the enzymes which take part in processes of matched to the formulas [ML ], [M(L-L) ], oxygenation, among others [3,22]. Copper uses 4 2 [ML X ], [M(L-L) X ]. At the same time they can numerous enzyme systems to participate in the 4 2 2 2 be mononuclear, binuclear or polynuclear. various processes in the human body (hemoglobin formation, the metabolism of Binuclear Cu-active centers play an important carbohydrates, the biosynthesis of role in biological (tyrosinase, catecholamine, antioxidative protection of the hemocyanin, catehol oxidase...) [3,26]. human body, the reduction in reactive oxygen

Table 1: M(II) biometals in the human body (numbers in parenthesis denote references)

Biometal Body content Blood content Target organs Daily requirement (mg/day) Cu 80-120 mg [12] 0.8-1.6 mg/L [14] skeletal system,muscles, brain, liver 0.9-1.3[15] pancreas, bones, teeth, liver, Zn 2-3 g [12] 6.3 mg/L [14] 2-15[15] kidneys Co 3 mg [16] 0.39 µg/L [14] liver, pancreas, kidney, heart 1.5*[17] Mn 12 mg [16] 4-15 µg/L [18] liver, pancreas, kidney, 2-5 [19] In the form of vitamin B12 (egual of 0.006 mg of Co)"

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Biological role of zinc role in detoxification from oxygen free radicals as a of the enzymes , Zinc is a biometal necessary for the growth and and superoxide dismutase. Manganese(II) is also development of , and in the human an active center of the enzyme arginase which body, approximately 2 to 3 g of this metal can be takes part in the cycle of urea as the final product found in the structure of more than twenty of nitrogen metabolism [12]. metalloenzymes (carbohydrase, alcohol dehydrogenase, Cu-Zn superoxide dismutase, The level of the presence of this metal in the etc). Zinc ion along with the Cu(II) and Co(II) ions human body is bound to the occurrence of improves the immune system of humans. If , as free damage to enough zinc is introduced into the human body in mitochondrial DNA [30]. doses larger than the recommended daily dosage, negative effects, such as disorders of The Mn(II) ion of the d5 electron configuration depots and decrease in the life expectancy easily builds complexes with a coordination of erythrocytes which leads to anemia and number 6, but are also only slightly stable and greater use. On the basis of the data found in the easily interact with other molecules, which leads literature, zinc in concentrations greater than 800 to changes in the ligands and building of new mg/daily causes a significant increase in the products [3,26]. amylase and lipase in the serum, and the increase in the level of glucose in the blood [27]. ANTI-INFLAMATORY DRUGS OF THE ACID Based on the size and physical-chemical TYPE features of the Zn(II) ion, of the d10 electron configuration, it easily interacts with parts of the Anti-inflammatory drugs are a group of biomolecules, mainly via the O-donor atoms of chemically varied substances which have amino acids, proteins etc. At the same time, it analgesic, anti-pyretic and anti-inflammatory builds compounds with a coordination number 4. effects. Non-steroidal anti-inflammatory drugs According to the denticity of the ligand, its (NSAIDs) of the acid type with a carboxyl content can be found in an M:L = 1:4 ratio, that functional group are made up of the following is, 1:2, with the possible inclusion of solvent type of chemical class derivates: , molecules [3,26]. phenylalkanoic acids, , anthranilic acids, sulphonamides and furanones. Some of the most Biological role of cobalt widely used NSAIDs include , and paracetamol [20,31]. Cobalt as a micro-element has a role in the metabolism of proteins and amino acids for the The anti-inflammatory activity of non-steroid anti- transfer of methyl groups from the methyl donors inflammatory drugs, as well as most of their other to the methyl acceptors as the constituent parts pharmacological activities, has to do with the of metaloenzymes (methyltransferase and inhibition of the conversion of arachidonic acid to methionine ) [12]. Via vitamin B12 [29], prostaglandin which are the mediators of which plays an important role in the process of inflammatory processes [1]. Non-steroid anti- erythrocyte maturation, Co increases the use of inflammatory drugs are potential inhibitors of iron in bone marrow cells [24]. Absorption of Co cyclooxygenase in vivo and in vitro, significantly from food in the human body depends on the decrease the synthesis of prostaglandin, individual's diet, for example the presence of prostacyclin and thromboxane [32]. Non-steroid amino acids decreases, while iron deficiency anti-inflammatory drugs of the acid type are increases [17,29]. Co(II) ion also causes shown in Table 2. apoptosis of the cells, and in greater concentrations even necrosis with an PRODUCTS OF INTERACTION BETWEEN inflammatory response. In addition, this metal M(II) METALS AND NSAIDs OF THE ACID has a genotoxic influence [29]. Co(II) ion of the TYPE d7 electron configuration, easily interacts with moieties of other molecules and builds complex The coordination and structure of the complex particles with a coordination number 4, as well as associate, which originates as a result of coordination number 6, via O-, but also via N- interaction between M(II) metal ions and ligands donor atom [3,26]. (NSAID of the acid type), depend on the nature of the central metal ion (values of energy of Biological role of manganese ionization, completion of the d-sublevels, ion radius, and polarizability) and the nature of the Manganese is a weakly present element in ligand (electron charge, field-strength of the biological systems, but also has an irreplaceable ligand, duration of the metal-ligand link). All of

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Table 2: Non-steroidal anti-inflammatory drugs of the acid type

Generic name IUPAC name Formula Application References

O Acute and chronic pain, Ibuprofen (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid osteoarthritis, rheumatoid [33,34] OH arthritis HO O

H N Pain, including menstrual 2-(2,3-dimethylphenyl)aminobenzoic acid [35] pain, migraine headaches

F O prostaglandin production

Diflunisal 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid OH inhibition, [36] an anti-pyretic F OH O rheumatoid arthritis, 2-(3-phenoxyphenyl)propanoic acid osteoarthritis, and mild to [37] O OH moderate pain

O

analgesic and anti-pyretic (RS)-2-(3-benzoylphenyl)propanoic acid O [38] effects

OH for relief of a wide variety of (+)-(S)-2-(6-methoxynaphthalen-2-yl) propanoic pain, fever, inflammations, [39,40] acid HO O stiffness O O

2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2- O To reduce fever, pain, Indomethacin [41,42] methyl-1H-indol-3-yl} stiffness, and swelling OH N

Cl

O HO O

H analgesic, anti-inflammatory, 2-[(3-chloro-2-methylphenyl)amino]benzoic acid) N anti-rheumatic, anti-pyretic [43] effect

Cl

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The regulation of hormones O which affect the symptoms

N of swelling, pain, sensitivity, [1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2- stiffness in the case of [44] yl]acetic acid OH osteoarthritis and O rheumatoid arthritis, as well as spondyloarthritis F F N The treatment of F 2-{[3(trifluoromethyl)phenyl]amino} nicotinic acid inflammatory rheumatoid [45]

O HN disorders

OH O OH

relieves minor aches and Aspirin 2-acetoxybenzoic acid O O pains, reduces fever, an [46] anti-inflammatory drug

Cl

OH A cure for inflammatory 2-(2-(2,6-dichlorophenylamino)phenyl)acetic NH processes, an analgesic and [47] acid O a cure for dysmenorrhea Cl

HO O F F Anti-pyretic, analgesic and H N anti-inflammatory effect, 2-{[3-(Trifluoromethyl)phenyl]amino}benzoic acid [48] used for skeletal-muscle F disorders

OH O N-(4-hydroxyphenyl)ethanamide pain reliever, fever reducer, Paracetamol [49] N-(4-hydroxyphenyl)acetamide a slight anti-diuretic effect N H

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Krstic et al these features of M(II) ion and ligand lead to magnetic and molar conductivity measurements different geometry of the complex ion which can [47,77]. be determined by spectroscopic studies and various analytical techniques, including the COMPLEXES OF M(II) BIOMETAL IONS AND following: NSAIDs

UV/VIS spectrophotometry Carboxylate ligands, RCOOH, depending on the size and structure of the R remains, as well as This technique is suitable for determining the the physical-chemical features of metal ions, active substances in pharmaceuticals and behave like ligands of various dentate features, biological samples. This technique offers data on where the bonds are primarily enabled via the O- the energy of the splitting of the d-energy donor atom of the carboxylate anion (Figure 1). sublevels, strength and type of the metal-ligand The denticity of the ligand was determined using bond, geometric distribution of the donor atom of the IR/FTIR specter on the basis of changes in the ligand around the central metal ion, and the assignations of symmetrical and symmetric characteristics of the complex [50-54]. asymmetrical C=O vibrations ΔV = vasym(C=O) – νsym(C=O) of the carboxyl group [55-57]. The IR/FTIR (Infra-red/Fourier transform infra-red) geometric structure of the isolated complexes were determined based on the characteristics This spectroscopic technique is used to obtain bands on the UV/VIS spectrum [50-54], as well information on the type of coordination between as changes registered by means of the X-ray metals and ligands, the denticity of the ligands, diffraction analysis [58-60]. as well as the symmetry of the isolated products [55-57].

X-ray diffraction

This analytical technique is used to determine the structure of the studied compounds of the modelled isolated firm products [48,58-60]. Figure 1: The type of coordination between the M(II) biometal ions and the –COOH group of NSAIDs ESR (Electron spin resonance spectroscopy) NSAIDs as monodentate RCOOH ligands This method is used to obtain data isolated from the products of the interaction between the Not much can be found in the relevant literature on the complexes of the NSAIDs acid type and paramagnetic M(II) metal ions and NSAID 2– ligands on: the of the metal, its biometals of the [ML4] type. In the reaction between ibuprofen and the Cu(II) ion [1] a coordination number, type of ligands, geometric 2- structure and spatial distribution of the donor compound was obtained, [Cu(ibf)4] , whose atom, the strength of the interaction between the structure was determined using an elemental metal and ligand [52,61-64]. analysis, the NMR and UV/VIS technique. Ibuprofen also react, beside Cu(II) ion, with Co(II) ESI-MS (Electrospray ionisation mass ion via O-donor atoms of carboxylic group, as spectrometry) discussed by Nikolić et al [78].

This technique can be used to detect the Mefenamic acid builds complexes with the Co(II) ion as a monodentate ligand (Δ = 224 - 230 cm- products of the interaction between metals and 1 organic ligands in solutions at a micromolar level ),defined as having an octahedron structure (three bands in the UV/VIS spectrum: 733 - 742 [65,66]. 2 4 4 nm ( T1g(F) → T2g), 535 - 565 nm ( T2g(F) → 4 4 4 Useful information on coordination compounds of A2g) and 440 - 475 nm ( T1g(F) → T1g(P)) which metal ions and NSAIDs can also be obtained interacts with the DNA, the albumin serums, and using NMR [67,68], DTA and TGA [69,70] indicates a significant antioxidative feature [72].In analyses. In order to determine the constants of the presence of N,N-donor ligands, mefenamic stability, stoichiometric content, small amounts of acid builds a mixed compound with the Zn(II) ion, metals and ligands, we also use AAS [4,71], which has a distorted octahedral geometry cyclic voltammetry [39,72,73], potentiometric [Zn(mef)2(Hpko)2] and which displays anti- analyses [74], polarography [75], high- inflammatory activity, as well as a good affinity performance liquid chromatography (HPLC) [76], towards bonding with the CT DNA and the albumin serums. In this compound, mefenamic acid behaves as a monodentate ligand which is Trop J Pharm Res, February 2015; 14(2): 342

Krstic et al indicated by the lack of a signal at 12.95 in the NSAIDs as bidentate RCOOH ligands 1H-NMR spectrum and Δ value above 190 cm-1 [77]. A far greater number of complex compounds of NSAIDs are built with bivalent ions of biometals Naproxen builds a compound with the Co(II) ion as bidentate ligands (L–L). At the same time, (three bands in the UV/VIS spectrum: 735 - 740 they build mononuclear or polynuclear 2 4 4 nm ( T1g(F) → T2g), 535 - 570 nm ( T2g(F) → complexes, usually of a mixed type with a 4 4 4 A2g) and 445 - 450 nm ( T1g(F) → T1g(P)) in the coordination number of metals of 4 or 6. presence or absence of the N-donor heterocyclic Complexes of the type [M(L–L)2], [M(L–L)L4], ligands. The same type of behavior can be [M(L–L)2L2], [M(L–L)2(L’–L’)] are built by almost determined for the monodentate ligand (Δ = 204 all ligands of the acid type. - 216 cm-1). The resulting complexes can interact with DNA, albumin serum, and have a significant Mefenamic acid builds complexes with M(II) ions antioxidative activity [39]. as a monodentate ligand [72,77] but can build mixed complexes with the Cu(II) ion as a Niflumic acid as a monodentate ligand (Δ = 217 bidentate ligand (Δ = νasym(C=O) – νsym(C=O) = -1 cm-1),via the O-donor atom of the carboxyl group, 170 cm ) in the presence of N-donor builds a high-spin octahedral complexes with the heterocyclic ligands with a general formula of Mn(II) ion, which easily participates with [M(mef)2(N,N-)]. The obtained octahedral exchange reactions with ligands and builds compounds (UV/VIS bands in the region of 650 – 2 compound associates with the DNA [45]. With 690 nm, which is ascribed to the Eg → 2 this anti-pyretic, even the Co(II) ion builds T2gtransfer) are tetragonally distorted and complex octahedral structures which also take indicate a high antioxidative activity, as well as part in the exchange reactions with ligand and the affinity for DNA and albumin serum [35]. A build compound associates with DNA and complex of similar pharmaceutical and geometric albumin serum [79]. The general formula of the characteristics of mefenamic acid as a bidentate built complexes of Co(II) and Mn(II) ions and ligand is built by Zn(II) ion in the presence of the niflumic acid is [M(nifl)2(MeOH)4]. N-donor ligand bipyridyl [77].

Tolfenamic acid and Co(II) build an octahedral The Cu(II) ion with naproxen and diclofenac as complex (band in the UV/VIS: 680 - 720 nm bidentate ligands in the presence of N,N-donor 2 4 4 4 ( T1g(F) → T2g), 540 - 565 nm ( T2g(F) → A2g) ligands builds compounds which have good anti- 4 4 and 470 - 485 nm ( T1g(F) → T1g(P)) with the tumor and anti-microbial activity[73]. participation of solvent molecules in the first coordinating sphere [M(RCOO)2(L)4], that is Complex compound of the Zn(II) ion with [M(RCOO)2(L-L)(L)2]. In this compound, which naproxen with the aim of decreasing the anti- shows an affinity for the DNA and albumin ulcer effect of this NSAID was synthesized. The serums, tolfenamic acid behaves like the obtained complex with naproxen as a bidentate -1 13 monodentate ligand (Δ = 195 - 204 cm-1) [22]. ligand (IR: Δ = 150 cm ; C NMR: a shift in absorption of –COOH from 177,66 to 179,79 The complex of the octahedral structure which ppm) showed a significant reduction in ulcers as shows a great affinity to binding with the CT DNA compared to that of naproxen and a physical also builds Cu(II) ion with as a mixture of naproxen [77]. monodentate ligand (Δ = 201 - 208 cm-1) [59]. Ibuprofen, as a bidentate ligand, builds Complexes of the type [ML4] of a square planar complexes with the Cu(II) and Zn(II) ion in the structure which manifest anti-cancer activity, presence of solvent molecules or N,N-donor -1 SOD and catalase activity, COX inhibition, DNA ligands. The value of Δ is 160 - 170 cm for the binding properties and nuclease activity, are built complex with the Cu(II) ion [82], that is 130 - 140 by aspirin [80]. With Cu(II),the same compounds for the complexes with the Zn(II) ion, where the have a good tolerance among the studied TGA analysis determined the presence of an patients and did not indicate any kind of H2O molecule in the internal coordination sphere unwanted effects [76]. The square-planar [Zn(ibf)2(H2O)2]. The compounds obtained with complex of Co(II) with aspirin have a good Zn(II) indicate good antibacterial activity and cell antibacterial response to Bacillus substilis, culture and growth inhibitory activity [4,32]. Serratia species and [81]. The stability of the compound of various M(II) ions In the presence of the N-donor ligand with aspirin decreases in the rank order: Cu2+> imidazolefenoprofen behaves as a bidentateO- Co2+> Zn2+ [74]. donor (Δ = 187 cm-1) ligand and builds an octahedral complex (λmax = 660 nm) with the

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Cu(II) ion [Cu(fen)2(im)2], which has significant These binuclear complexes of the Cu(II) have a SOD mimetic activities and moderate catalytic better anti-inflammatory activity than the pure oxidase activity[83]. Complexes with a square- drug [37,41], good affinity for DNA and albumin planar structure (λmax = 580 nm) are built by serum binding [35,59], catechol oxidase mimetic ketoprofen with Cu(II) which has a significant activity [37], SOD mimetic activities [58,83], anti-proliferative activity, while ketoprofen inhibition of polymorphonuclear leukocyte behaves as a bidentate ligand [84]. oxidative metabolism [60].

Tolfenamic acid builds octahedral complex with Ibuprofen, ketoprofen and naproxen with the Co(II) ion, where it behaves as a bidentate Cu(II) ion also build binuclear complexes, and ligand], (Δ = 171 cm-1). The built complex their existence in the physiological conditions indicates a greater affinity for DNA and albumin was determined using the ESI-MS technique serum binding, compared to the complex with [85]. Cu(II) ion also builds binuclear complexes mefenamic acid [28]. with aspirin [Cu2(asp)4], and shows the same anti-thrombotic activity and inhibits the platelet- All the complex NSAIDs with biometals indicate a interaction [86], as the improved anti- better pharmacological activity than the NSAIDs inflammatory effect of aspirin itself [88]. This themselves [4,28,32,37,71]. group of authors determined the existence of bidentate associates on the bases of the peak NSAIDs as O-donor ligands in polynuclear which was determined in the ESI-MS specter of compounds the studied Cu-asp system at 848.10 m/z). Interaction of M(II) metal ions on micromolar The carboxylate anion in pharmaceuticals such level was studied by ESI-MS LOOP- as NSAIDs easily builds polynuclear complexes chromatogram method Area under peaks on with small ions of M(II) metals, in which the LOOP-chromatograms in presence of Cu(II), bridging ligands (µ-L~L) lie between two M–M Co(II), Cd(II)-ions is smaller than the centers. The greatest numbers of these corresponding area for ibuprofen without metal compounds are built with copper. Binuclear ions which shows that there is a significant complexes that are built by Cu(II) ion in interaction M(II)-IB at micromolar level and that coordination with O-donor ligands, namely, the interaction is the most expressed in Co(II)-IB fenoprofen, tetracarboxylates, indomethacin, system [88]. ibuprofen and ketoprofen indicate improved anti- inflammatory effects [41,64]. Using IR/FTIR M(II) Biometal ions complexes with the technique, the denticity of the ligands was NSAIDs derivative, paracetamol determined, while the value of Δ as well as the type of chelate complexes of Cu(II) ions with In terms of use, of all the NSAIDs, paracetamol NSAIDs are shown in Table 3. (PA) holds the first three positions. Relevant literature contains data on the study of the Table 3: Binuclear Cu(II)-NSAIDs complexes and the interaction between M(II) metal ions and the corresponding Δ values of the carboxyl group NSAIDs derivative of carboxylic acids, PA [74,89]. Using CNDO calculations of electronic NSAIDs Complex Δ Ref. energy showed that the isolated compounds of -1 [cm ] M(II) ions of the studied metals (Cu and Zn)

Mefenamic [Cu2(mef)2(H2O)2] 170 [35] along with PA belong to the C2h point group acid symmetry. On the basis of spectroscopic data, Fenoprofen [Cu2(fen)2(DMF)2] 206 [37] the obtained UV/VIS, IR and 1H-NMR, this group [Cu2(fen)2(caf)2] 193 [83] of authors considers the studied M(II) ions to Diflunisal [Cu2(difl)2(dmf)2] 185 [59] build complex quadrangle-planar structures with Ibuprofen [Cu2(ibf)2(H2O)2] 172 Naproxen [Cu (naprox) (H O) ] 201 PA via the N- and O-donor atoms, with a metal- 2 2 2 2 [70] Tolmetin [Cu2(tolm)2(H2O)2] 184 ligand = 1:2 ratio. [89] UV/VIS spectral data of Diclofenac [Cu2(dicl)2(H2O)2] 184 paracetamol complex with Co(II) and Cu(II) ions

Tolfenamic [Cu2(tolf)2L2] 145 [58] in molar ratio M:L = 1:2. (λmax = 593 nm, ε = 2.95 4 3 acid × 10 for Cu-PA and λmax = 574 nm, ε = 0.7 × 10 for Co-PA) indicate the participation of -NH- The internuclear distance between Cu(II)-Cu(II) group of paracetamol in complex formation centers in the built complexes, based on the because λmax for complexes with only O-donor results of the X-ray analysis, ranges in interval ligands have much higher values. IR spectral from 2.6075 Å for tolfenamic acid [58] to 2.661 Å data for the same complexes (M-N at 520 - 530 in the case of diflunisal [59]. cm-1 and M-O at 600 - 610 cm-1, and retention of the strong band corresponding to the stretching

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Krstic et al vibration of O-H group) indicate that phenolic -O- kinetic spectrophotometry. J Serb Chem Soc 2008; H group of paracetamol was not directly involved 73(8-9): 879-890. in the complex formation [90]. 3. Lawrance GA. Introduction to coordination chemistry. Chichester: John Wiley & Sons Ltd; 2010; p 304. Polygraphic method showed that the complex 4. Dendrinou-Samara C, Tsotsou G, Ekateriniadou LV, originated between the Zn(II) ions and Kortsaris AH, Raptopoulou CP, Terzis A, Kyriakidis paracetamol with a stoichiometric composition of DA, Kessissoglou DP. Anti-inflammatory drugs M:L = 1:1, where the paracetamol behaves as a interacting with Zn(II), Cd(II) and Pt(II) metal ions. bidentate O-donor ligand. The obtained JInorgBiochem 1998; 71: 171-179. compound exhibits good analgesic activity, better 5. Andrade A, Namora SF, Woisky RG, Wiezel G, Najjar R, than the pure form of the drug [75]. Co(II)-alkyne SertiéJ AA,de Oliveira SD. Synthesis and complexes derived from acetylsalicylic acid represent a new group of organometallic characterization of a diruthenium–ibuprofenato cytostatics, where the inhibition of the COX plays complex: Comparing its anti-inflammatory activity with the main role [91]. that of a copper(II)–ibuprofenato complex. J InorgBiochem 2000; 81(1–2): 23–27. CONCLUSION 6. Gokhale NH, Padhye SS, Padhye SB, Anson CE,Powell AK. Copper complexes of carboxamidrazone

derivatives as anticancer agents. 3. Synthesis, Biometals achieve interaction with acid-type anti- characterization and crystal structure of inflammatory drugs at micromolar and millimolar [Cu(appc)Cl2], (appc=N1-(2-acetylpyridine)pyridine- levels. R-COOH behaves as monodentate, 2- carboxamidrazone). InorgChimActa 2001; 319(1- bidentate or a bridge ligand, which can be 2): 90–94. reliably determined based ona model system, 7. Trávníček Z, Malon M, Šindelář Z, Doležal K, Rolčík J, where in the complexes are formed with different Kryštof V, Strnad M, Marek J. Preparation, stoichiometric compositions, and the geometric physicochemical properties and biological activity of structures, which can be determined using copper(II) complexes with 6-(2-chlorobenzylamino) various analytical techniques (UV/VIS, FTIR, purine (HL1) or 6-(3-chlorobenzylamino) purine EPR, X-ray, ESI-MS, etc.). The associates (HL2).The single-crystal X-ray structure of obtained are important for the following reasons: [Cu(H+L2)Cl3]Cl×2H2O. J InorgBiochem2001; 84(1- theory of coordination chemistry, significance of 2): 23–32. the development of new methods for determining 8. Chaviara ATH, Christidis PC, Papageorgiou A, micro amounts of active components, to achieve Chrysogelou E, Hadjipavlou-Litina DJ, Bolos CA. In more balanced therapeutic dosing, biodistribution vivo anticancer, anti- inflammatory, and toxicity of medicine, monitoring its pharmacokinetics studies of mixed-ligand Cu(II) complexes of dien and including excretion; reduction of unwanted its Schiff dibases with heterocyclic aldehydes and 2- responses, improvement of anti-microbial amino-2-thiazoline. Crystal structure of activity, synergistic effect of the metals and [Cu(dien)(Br)(2a-2tzn)](Br)(H2O). JInorgBiochem medicine, as well as improved anti-ulcerous, anti- 2005; 99(11): 2102–2109. tumor and anti-bacterial activity. 9. Jiménez-Garrido N, Perelló L, Ortiz R, Alzuet G,

ACKNOWLEDGEMENT González-Alvarez M, Cantón E, Liu-González M, García-Granda S, Pérez-Priede M. Antibacterial

studies, DNA oxidative cleavage, and crystal This work was supported by the Ministry of structures of Cu(II) and Co(II) complexes with two Education and Science of the Republic of Serbia quinolone family members, ciprofloxacin and under grant nos. TR34008 and III43012. The enoxacin. J InorgBiochem 2005; 99(3) :677–689. authors would also like to thank Marta 10. Milacic V, Chen D, Giovagnini L, Diez A, Fregona D, Dou Dimitrijević, MA, for proofreading the text of this QP. Pyrrolidinedithiocarbamate-zinc(II) and - paper. copper(II) complexes induce apoptosis in tumor cells

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