Cobalt(II) complexes with non-steroidal anti-inflammatory drugs and α-diimines

doi:10.1016/j.jinorgbio.2015.12.015

Journal of Inorganic Biochemistry

Volume 160, July 2016, Pages 125-139

https://doi.org/10.1016/j.jinorgbio.2015.12.015 Get rights and content

Highlights

•
Nine cobalt(II) complexes with non-steroidal anti-inflammatory drugs were synthesized.
•
The crystal structures of five Co-NSAID complexes were determined.
•
The Co-NSAID complexes can bind to human or bovine serum albumins.
•
The complexes show significant radical scavenging activity.
•
Intercalation is the most possible binding mode of the complexes to calf-thymus DNA.

Abstract

Cobalt(II) complexes with a series of non-steroidal anti-inflammatory drugs (diflunisal, flufenamic acid, mefenamic acid and niflumic acid) in the presence of nitrogen-(2,2′-bipyridylamine, 2,2′-bipyridine, 1,10-phenanthroline) and/or oxygen-donor ligands (methanol) have been synthesized and characterized with physicochemical and spectroscopic techniques. The deprotonated NSAID ligands are coordinated to Co(II) ion through their carboxylato groups in diverse binding modes. The crystal structures of complexes [Co(diflunisal-O)₂(methanol)₄], [Co(niflumato-O)₂(methanol)₄], [Co(flufenamato-O,O′)₂(2,2′-bipyridylamine)], [Co(mefenamato-O,O′)₂(2,2′-bipyridylamine)] and [Co₃(flufenamato-O,O′)₄(flufenamato-O,O,O′)₂(2,2′-bipyridine)₂] have been determined by X-ray crystallography. The interaction of the complexes with serum albumins was studied by fluorescence emission spectroscopy and the albumin-binding constants were determined. The ability of the complexes to scavenge 1,1-diphenyl-picrylhydrazyl, 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals was investigated and the complexes were more active than the corresponding free drugs. Spectroscopic (UV and fluorescence), electrochemical (cyclic voltammetry) and physicochemical (viscosity measurements) techniques were employed in order to study the binding mode of the complexes to calf-thymus (CT) DNA and to calculate the corresponding binding constants; for all complexes, intercalation was suggested as the most possible DNA-binding mode.

Graphical abstract

The cobalt(II) complexes with a series of non-steroidal anti-inflammatory drugs (diflunisal, flufenamic acid, mefenamic acid and niflumic acid) and nitrogen-donor (2,2′-bipyridylamine, 2,2′-bipyridine, 1,10-phenanthroline) and/or methanol as ligands were prepared and characterized. The complexes exhibit noteworthy antioxidant activity and significant binding affinity for serum albumins and calf-thymus DNA.

Introduction

The biological interest of cobalt is mainly focused on its presence in vitamin B12 and other proteins as well as in compounds showing biological activity. Being in the active center of vitamin B12, cobalt is indirectly involved in the DNA-synthesis [1]. Furthermore, cobalt is used as a supplement of vitamin B12 [2] and is related to at least eight cobalt-dependent proteins [1]. In 1952, the first studies concerning the biological activity of cobalt compounds were reported [3]; since then, many structurally characterized cobalt compounds have been involved in the hydrolytic cleavage and binding of DNA [4] and/or have been reported as tentative antimicrobial [5], [6], [7], [8], antifungal [9], [10], antiviral [11], [12], antioxidant [13], [14] and antiproliferative [15], [16] agents. Furthermore, doxovir (or CTC-96) is a cobalt complex which has shown an antipsoriatic effect and has successfully completed phase II clinical trials for the treatment of herpes simplex virus [17].

Phenylalkanoic acids, anthranilic acids, oxicams, salicylate derivatives, sulfonamides and furanones constitute the chemical classes of non-steroidal anti-inflammatory drugs (NSAIDs) [18]. The NSAIDs are mainly used as analgesic, anti-inflammatory and antipyretic drugs [19] and their main action is through inhibition of the cyclo-oxygenase (COX)-mediated production of prostaglandins [20]. Diflunisal (Hdifl, Scheme 1(A)) is a difluoro-derivative of salicylic acid and flufenamic acid (Hfluf, Scheme 1(B)), mefenamic acid (Hmef, Scheme 1(C)) and niflumic acid (Hnif, Scheme 1(D)) belong to the derivatives of N-phenylanthranilic acid. Hdifl has good bioavailability and long half-life which may lead to improved adherence to therapy and cost-effectiveness in the case of chronic administration [21]. A thorough survey of the literature has revealed the existence of two structurally characterized copper(II) complexes of diflunisal [22]. Hfluf is used in musculoskeletal and joint disorders and is administered orally and topically [23]. It has channel-regulating ability; it can inhibit nonselective cation channels and can activate potassium channels [24]. A zinc [25], a tin(IV) [26] and few copper(II) flufenamato complexes [27], [28], [29], [30], [31] have been found in the literature. Hmef is widely used as an effective analgesic and antipyretic agent having rather mild side–effects. The crystal structures of a series of tin(IV) [32], copper(II) [33], [34], [35], cobalt(II) [13], zinc(II) [36], manganese(II) [37] and nickel (II) [38] complexes with mefenamato ligands have been found in the literature. Hnif is used to treat inflammatory rheumatoid diseases and relieve acute pain and it is effective against period pains, pain after surgery, and fever [39], [40]. A manganese(II) [41], a silver(I) [42] and four copper(II) complexes [40], [43], [44], [45] complexes of niflumic acid have been reported in the literature. Most of the reported metal–NSAID complexes have shown an enhanced biologic profile in comparison to free NSAID. Most complexes were more active than free NSAID in regard to the DNA- and albumin-binding properties and exhibited pronounced antioxidant activity [46].

A detailed survey of the literature concerning the crystal structures of metal complexes with NSAID ligands bearing carboxylato groups has revealed that among all possible coordination modes of the carboxylato groups to metal [18], [46], the following four ones (Scheme 2) individually and/or in combination were located: (i) monodentate mode (via a carboxylato oxygen, i.e. NSAID-O, Scheme 2(I)) as in a plethora of mononuclear metal-NSAIDs complexes [13], [14], [27], [28], [33], [35], [36], [38], [41], [44], [47], [48], (ii) chelating bidentate mode (via the two carboxylato oxygen atoms to the same metal, i.e. NSAID-O,O´, Scheme 2(II)) as in many mononuclear metal-NSAIDs complexes [22], [31], [35], [36], [38], [47], [48], [49], [50], [51], [52], (iii) bridging bidentate mode (via the two carboxylato oxygen atoms bridging two metals, i.e. μ_1,3-NSAID-O,O′, Scheme 2(III)) as in series of dinuclear copper(II) [22], [29], [31], [34], [40], [43], [53], zinc(II) [52] and molybdenum(II) [54] complexes with the paddlewheel motif, in a polymeric dinuclear manganese(II) complex [55] and in tri- [49] and hexa-nuclear [25] zinc(II) complexes, and (iv) bridging tridentate mode (via the two carboxylato oxygen atoms bridging two metals, i.e. μ_1,1-NSAID-O,O,O′, Scheme 2(IV)) which was not observed individually in a complex but in combination with modes (i)-(iii). Furthermore, there are some structures where more than one of the modes (i)–(iv) exist. A combination of modes: (a) (i) and (ii) was observed in two mononuclear Zn(II) [36] and Mn(II) [55] complexes, (b) (i) and (iii) in a dinuclear Mn(II) [55] and a tetranuclear Sn(IV) [56] complex, (c) (ii) and (iii) in a dinuclear Mn(II) complex [55], (d) (i), (iii) and (iv) in a trinuclear Mn(II) complex [51] and (e) (iii) and (iv) in two tetranuclear Sn(IV) complexes [26], [57] and a polymeric dinuclear Cd(II) complex [58].

As a continuation of our research concerning Co-NSAID complexes [13], [14], [46], [47], we have synthesized and characterized nine novel Co(II) complexes with the NSAIDs diflunisal, flufenamic acid, mefenamic acid and niflumic acid in the presence of the nitrogen-(2,2′-bipyridylamine (bipyam), 2,2′-bipyridine (bipy), 1,10-phenanthroline (phen), Scheme 3) and/or oxygen-donor ligands (methanol (MeOH)). The characterization of the compounds involved physicochemical techniques (elemental analysis, molecular conductivity and room-temperature magnetic measurements), spectroscopies (IR and UV–vis) and cyclic voltammetry. The crystal structures of complexes [Co(difl-O)₂(MeOH)₄], 1, [Co(nif-O)₂(MeOH)₄], 2, [Co(fluf-O,O′)₂(bipyam)], 4, [Co(mef–O,O′)₂(bipyam)], 5 and [Co₃(fluf-O,O′)₄(fluf-O,O,O′)₂(bipy)₂], 6 were determined by X-ray crystallography. The tentative in vitro biological activity of the complexes included the (i) binding of the complexes towards bovine (BSA) and human serum albumin (HSA) studied by fluorescence emission spectroscopy, (ii) the evaluation of the antioxidant activity by determining the scavenging ability of the complexes towards 1,1-diphenyl-picrylhydrazyl (DPPH), 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS⁺ radical dot ) and hydroxyl radicals (OH) and (iii) the interaction of the complexes with calf-thymus (CT) DNA studied by UV spectroscopy, cyclic voltammetry, viscosity measurements and via the ethidium bromide (EB = 3,8-diamino-5-ethyl-6-phenyl-phenanthridinium bromide) displacement from the EB–DNA compound performed by fluorescence emission spectroscopy.

Section snippets

Materials–Instrumentation–Physical measurements

All the chemicals (CoCl₂·6H₂O, Hdifl, Hnif, Hfluf, Hmef, bipy, phen, bipyam, KOH, CT DNA, BSA, HSA, EB, tetraethylammonium perchlorate (TEAP), NaCl, trisodium citrate, DPPH, ABTS, linoleic acid sodium salt, butylated hydroxytoluene (BHT), 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (trolox) and nordihydroguaiaretic (NDGA)) were purchased from Sigma-Aldrich Co and all solvents were purchased from ChemLab. All the chemicals and solvents were reagent grade and were used as purchased

Synthesis and characterization of the complexes

The synthesis of complexes 1–3 was achieved in high yield via the aerobic reaction of the NSAID (HL = Hdifl, Hnif, Hfluf) and KOH with CoCl₂·6H₂O in a 1:2 Co:NSAID ratio according to the equation (Eq. (1)):CoCl₂·6H₂O + 2 HL + 2 KOH + 4 CH₃OH → [Co(L)₂(CH₃OH)₄] + 2KCl + 8 H₂O

Complexes 4–9 were prepared via the aerobic reaction of the NSAID (HL = Hdifl, Hmef, Hfluf) deprotonated by KOH with CoCl₂·6H₂O in the presence of the corresponding N,N′–donor ligand (B = bipy, bipyam, phen) with a 1:2:1 Co:HL:B ratio

Conclusions

The neutral cobalt(II) complexes with the non-steroidal anti-inflammatory drugs diflunisal, flufenamic acid, mefenamic acid and niflumic acid in the presence of the nitrogen-donor heterocyclic ligands 2,2′–bipyridine, 1,10-phenanthroline, 2,2′-bipyridylamine and/or the O-donor ligand methanol were prepared and characterized. The crystal structures of five complexes, namely [Co(diflunisal-O)₂(MeOH)₄], [Co(niflumato-O)₂(MeOH)₄], [Co(flufenamato-O,O′)₂(bipyam)], [Co(mefenamato-O,O′)₂(bipyam)] and

Abbreviations

ABTS

2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radical cation

BHT

butylated hydroxytoluene

bipy

2,2′–bipyridine

bipyam

2,2′–bipyridylamine

broad

BSA

bovine serum albumin

calf-thymus

difl

anion of diflunisal

DMF

N,N-dimethylformamide

DPPH

1,1-diphenyl-picrylhydrazyl

ethidium bromide, 3,8-diamino-5-ethyl-6-phenyl-phenanthridinium bromide

fluf

flufenamato anion

Hdifl

diflunisal, 5-(2,4-difluorophenyl)salicylic acid, 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid

Hfluf

flufenamic acid,

Acknowledgments

This research has been co-financed by the European Social Fund (ESF) and the Greek national funds (National Strategic Reference Framework (NSRF): Archimides III. Financial support from the Slovenian Research Agency (ARRS) through project P1-0175 is gratefully acknowledged. This project was also supported by EU COST ActionCM1105: “Functional metal complexes that bind to biomolecules”.

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Cobalt(II) complexes with non-steroidal anti-inflammatory drugs and α-diimines

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials–Instrumentation–Physical measurements

Synthesis and characterization of the complexes

Conclusions

Abbreviations

Acknowledgments

Adv. Inorg. Chem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Eur. J. Med. Chem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Bioorg. Med. Chem.

J. Inorg. Biochem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Coord. Chem. Rev.

Eur. J. Cancer

Bioorg. Med. Chem. Lett.

J. Inorg. Biochem.

J. Organomet. Chem.

Polyhedron

Polyhedron

J. Inorg. Biochem.

J. Organomet. Chem.

J. Inorg. Biochem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Polyhedron

J. Inorg. Biochem.

Polyhedron

Eur. J. Med. Chem.

J. Inorg. Biochem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Inorg. Chim. Acta

J. Organomet. Chem.

Polyhedron

Polyhedron

Methods Enzymol.

J. Lumin.

J. Inorg. Biochem.

Polyhedron

Inorg. Chim. Acta

J. Inorg. Biochem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

J. Mol. Struct.

J. Mol. Struct.

J. Inorg. Biochem.

J. Inorg. Biochem.

J. Inorg. Biochem.

Dalton Trans.