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

The cations of biometals in biological systems easily interact with various moieties of organic and inorganic biomolecules, 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 metal and medicine; and improved anti-ulcerous, antitumor 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 metals that the subject of focus in this review are d-metals with M(II) ions, namely, copper (Cu), zinc (Zn), cobalt (Co) and manganese (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


INTRODUCTION
Biometal cations in biological systems easily interact with molecules of water and various parts of different organic and inorganic biomolecules, as natural constituents or substances introduced into the human body. The complex associates, built via O-, N-and S-donor atoms, have an important role in biological processes. The products of interaction between M(II) metals and medicine are fundamentally important for the theory of coordination chemistry, as well as the significance of the development of new methods for determining micro-amounts of active components [1][2][3].
The study of the interaction between M(II) biometal-O-donor ligands (the drugs) is interesting for a variety of aspects, with the aim of: achieving more balanced medicine dosing, the biodistribution of the medicine; monitoring its pharmacokinetics, excretion; the reduction in the unwanted responses; improving anti-microbial activities; synergistic effects of the metals and medicine, and improved anti-ulcerous, anti-tumor and anti-bacterial activity [4][5][6][7][8][9][10][11].
The mechanisms of the effects of biometal complexes are diverse. The complex biometal compounds, in addition to a beneficial have a toxic effect on the body, which often limits their application [12]. A pioneer in the study of the complexes of transition metals and non-steroid anti-inflammatory drugs (NSAIDs) was Sorensen [13]. The literature is replete with numerous data on studies on the interaction between M(II) ions of metals and numerous ligands of pharmaceuticals and supplements via O-, N-, Sdonor atoms, as well as the synthesis of their products and the effects which the obtained products lead to [4][5][6][7][8][9][10][11].

M(II) BIOMETALS
Biometals from the series of d-metals with characteristic M(II) ions can be found in the human body in small amounts, and are mainly the active centers of enzymes of various functions. They are introduced into the body daily through a variety of food, which satisfies the daily requirements (Table 1) [12].

Biological role of copper
Back in 1920, it was shown for the first time that copper is essential for biological systems. That was when it was discovered that anemia among experimental animals occurs as the result of a decreased intake of copper as a part of their regular diet. With the addition of copper salts, there was a correction in the occurring pathological state [20,21]. In the biological processes of living organisms, copper plays an important role in the process of binding oxygen, redox processes, electron-transfer processes, and is a part of the structure of numerous enzymes: enzymes for the transport of electrons and the enzymes which take part in processes of oxygenation, among others [3,22]. Copper uses numerous enzyme systems to participate in the various processes in the human body (hemoglobin formation, the metabolism of carbohydrates, the biosynthesis of catecholamine, antioxidative protection of the human body, the reduction in reactive oxygen types [23]. Copper plays an important role in the reduction of inflammatory processes, and achieves this role through enzyme superoxide dismutase (SOD) [20]. Copper is necessary for the synthesis of hemoglobin [24].
Of the overall content of copper in the human body, most of it is found in the human skeletal system, liver, brain and blood. Under normal physiological conditions, the human body contains 80-120 mg of copper [12]. The daily requirements of the human body for copper, on the basis of the recommendation of the World Health Organization, ranges in the interval from 0.9 to 1.3 mg/day [15]. Disorders related to the copper contained in the human body are related to the occurrence and development of certain illnesses (aceruloplasminemia, Wilson's disease, Menkes disease, Alzheimer's, various inflammatory processes in the human body, tumors, etc) [23]. Approximately 50 % of the overall intake of copper is absorbed through the bloodstream, and bound to albumins is transferred to other organs and tissues [25].
The various roles of this biometal in living organisms are bound, on the one hand, to its polyvalent nature, and on the other, to the tendency of its ions to build complex compounds. In the theory of coordination compounds, it is well known that the Cu(II) ion, d 9 , builds coordination compounds with a coordination number of 4 or 6, including quadri-planar, tetrahedron or deformed octahedron structures. The content and structure of the chelate products depend on the physical-chemical features of the ions (size, polarizability, ion potential, acidity) and the size of the ligand and the active centers, potential atom donors, denticity, etc. The possible content of the complex associates has a coordination number of 4 or 6 and can be

Biological role of zinc
Zinc is a biometal necessary for the growth and development of mammals, and in the human body, approximately 2 to 3 g of this metal can be found in the structure of more than twenty metalloenzymes (carbohydrase, alcohol dehydrogenase, Cu-Zn superoxide dismutase, etc). Zinc ion along with the Cu(II) and Co(II) ions improves the immune system of humans. If enough zinc is introduced into the human body in doses larger than the recommended daily dosage, negative effects, such as disorders of iron depots and decrease in the life expectancy of erythrocytes which leads to anemia and greater use. On the basis of the data found in the literature, zinc in concentrations greater than 800 mg/daily causes a significant increase in the amylase and lipase in the serum, and the increase in the level of glucose in the blood [27]. Based on the size and physical-chemical features of the Zn(II) ion, of the d 10 electron configuration, it easily interacts with parts of the biomolecules, mainly via the O-donor atoms of amino acids, proteins etc. At the same time, it builds compounds with a coordination number 4. According to the denticity of the ligand, its content can be found in an M:L = 1:4 ratio, that is, 1:2, with the possible inclusion of solvent molecules [3,26].

Biological role of cobalt
Cobalt as a micro-element has a role in the metabolism of proteins and amino acids for the transfer of methyl groups from the methyl donors to the methyl acceptors as the constituent parts of metaloenzymes (methyltransferase and methionine transferase) [12]. Via vitamin B 12 [29], which plays an important role in the process of erythrocyte maturation, Co increases the use of iron in bone marrow cells [24]. Absorption of Co from food in the human body depends on the individual's diet, for example the presence of amino acids decreases, while iron deficiency increases [17,29]. Co(II) ion also causes apoptosis of the cells, and in greater concentrations even necrosis with an inflammatory response. In addition, this metal has a genotoxic influence [29]. Co(II) ion of the d 7 electron configuration, easily interacts with moieties of other molecules and builds complex particles with a coordination number 4, as well as coordination number 6, via O-, but also via Ndonor atom [3,26].

Biological role of manganese
Manganese is a weakly present element in biological systems, but also has an irreplaceable role in detoxification from oxygen free radicals as a cofactor of the enzymes catalase, peroxidase and superoxide dismutase. Manganese(II) is also an active center of the enzyme arginase which takes part in the cycle of urea as the final product of nitrogen metabolism [12].
The level of the presence of this metal in the human body is bound to the occurrence of oxidative stress, as free radical damage to mitochondrial DNA [30].
The Mn(II) ion of the d 5 electron configuration easily builds complexes with a coordination number 6, but are also only slightly stable and easily interact with other molecules, which leads to changes in the ligands and building of new products [3,26].

ANTI-INFLAMATORY DRUGS OF THE ACID TYPE
Anti-inflammatory drugs are a group of chemically varied substances which have analgesic, anti-pyretic and anti-inflammatory effects. Non-steroidal anti-inflammatory drugs (NSAIDs) of the acid type with a carboxyl functional group are made up of the following type of chemical class derivates: salicylic acid, phenylalkanoic acids, oxicams, anthranilic acids, sulphonamides and furanones. Some of the most widely used NSAIDs include ibuprofen, aspirin and paracetamol [20,31].
The anti-inflammatory activity of non-steroid antiinflammatory drugs, as well as most of their other pharmacological activities, has to do with the inhibition of the conversion of arachidonic acid to prostaglandin which are the mediators of inflammatory processes [1]. Non-steroid antiinflammatory drugs are potential inhibitors of cyclooxygenase in vivo and in vitro, significantly decrease the synthesis of prostaglandin, prostacyclin and thromboxane [32]. Non-steroid anti-inflammatory drugs of the acid type are shown in Table 2.

PRODUCTS OF INTERACTION BETWEEN M(II) METALS AND NSAIDs OF THE ACID TYPE
The coordination and structure of the complex associate, which originates as a result of interaction between M(II) metal ions and ligands (NSAID of the acid type), depend on the nature of the central metal ion (values of energy of ionization, completion of the d-sublevels, ion radius, and polarizability) and the nature of the ligand (electron charge, field-strength of the ligand, duration of the metal-ligand link). All of

IR/FTIR (Infra-red/Fourier transform infra-red)
This spectroscopic technique is used to obtain information on the type of coordination between metals and ligands, the denticity of the ligands, 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].

ESR (Electron spin resonance spectroscopy)
This method is used to obtain data isolated from the products of the interaction between the paramagnetic M(II) metal ions and NSAID ligands on: the oxidation state of the metal, its coordination number, type of ligands, geometric structure and spatial distribution of the donor atom, the strength of the interaction between the metal and ligand [52,61-64].

ESI-MS (Electrospray ionisation mass spectrometry)
This technique can be used to detect the products of the interaction between metals and organic ligands in solutions at a micromolar level [

COMPLEXES OF M(II) BIOMETAL IONS AND NSAIDs
Carboxylate ligands, RCOOH, depending on the size and structure of the R remains, as well as the physical-chemical features of metal ions, behave like ligands of various dentate features, where the bonds are primarily enabled via the Odonor atom of the carboxylate anion ( Figure 1). The denticity of the ligand was determined using the IR/FTIR specter on the basis of changes in the assignations of symmetrical and asymmetrical C=O vibrations ΔV = v asym (C=O)ν sym (C=O) of the carboxyl group [55-57]. The geometric structure of the isolated complexes were determined based on the characteristics bands on the UV/VIS spectrum [50-54], as well as changes registered by means of the X-ray diffraction analysis [58-60].

NSAIDs as monodentate RCOOH ligands
Not much can be found in the relevant literature on the complexes of the NSAIDs acid type and biometals of the [ML 4 ] 2type. In the reaction between ibuprofen and the Cu(II) ion [1] a compound was obtained, [Cu(ibf) 4 ] 2-, whose structure was determined using an elemental analysis, the NMR and UV/VIS technique. Ibuprofen also react, beside Cu(II) ion, with Co(II) ion via O-donor atoms of carboxylic group, as discussed by Nikolić et al [78].
Mefenamic acid builds complexes with the Co(II) ion as a monodentate ligand (Δ = 224 -230 cm -1 ),defined as having an octahedron structure (three bands in the UV/VIS spectrum: 733 -742 nm ( 2 T 1g (F) → 4 T 2g ), 535 -565 nm ( 4 T 2g (F) → 4 A 2g ) and 440 -475 nm ( 4 T 1g (F) → 4 T 1g (P)) which interacts with the DNA, the albumin serums, and indicates a significant antioxidative feature [72].In the presence of N,N-donor ligands, mefenamic acid builds a mixed compound with the Zn(II) ion, which has a distorted octahedral geometry [Zn(mef) 2 (Hpko) 2 ] and which displays antiinflammatory activity, as well as a good affinity towards bonding with the CT DNA and the albumin serums. In this compound, mefenamic acid behaves as a monodentate ligand which is In the presence of the N-donor ligand imidazolefenoprofen behaves as a bidentateOdonor (Δ = 187 cm -1 ) ligand and builds an octahedral complex (λ max = 660 nm) with the Cu(II) ion [Cu(fen) 2 (im) 2 ], which has significant SOD mimetic activities and moderate catalytic oxidase activity [83]. Complexes with a squareplanar structure (λ max = 580 nm) are built by ketoprofen with Cu(II) which has a significant anti-proliferative activity, while ketoprofen behaves as a bidentate ligand [84].
Tolfenamic acid builds octahedral complex with Co(II) ion, where it behaves as a bidentate ligand], (Δ = 171 cm -1 ). The built complex indicates a greater affinity for DNA and albumin serum binding, compared to the complex with mefenamic acid [28].

NSAIDs as O-donor ligands in polynuclear compounds
The carboxylate anion in pharmaceuticals such as NSAIDs easily builds polynuclear complexes with small ions of M(II) metals, in which the bridging ligands (µ-L~L) lie between two M-M centers. The greatest numbers of these compounds are built with copper. Binuclear complexes that are built by Cu(II) ion in coordination with O-donor ligands, namely, fenoprofen, tetracarboxylates, indomethacin, ibuprofen and ketoprofen indicate improved antiinflammatory effects [41,64]. Using IR/FTIR technique, the denticity of the ligands was determined, while the value of Δ as well as the type of chelate complexes of Cu(II) ions with NSAIDs are shown in Table 3.