Elsevier

Journal of Molecular Structure

Volume 1154, 15 February 2018, Pages 319-326
Journal of Molecular Structure

Glycine and metformin as new counter ions for mono and dinuclear vanadium(V)-dipicolinic acid complexes based on the insulin-enhancing anions: Synthesis, spectroscopic characterization and crystal structure

https://doi.org/10.1016/j.molstruc.2017.10.055Get rights and content

Highlights

  • Mono and dinuclear vanadium(V) complexes based on the insulin-enhancing anions.

  • Metformin and glycine as counter ion to form a potentially synergistic compounds.

  • Investigation by IR, NMR, UV–Vis spectroscopic and X-ray crystallography techniques.

Abstract

Complexes [VO(dipic) (H2O)2]·2H2O (1), [H2Met][V2O4(dipic)2] (2) and [HGly][VO2(dipic)] (3), where H2dipic = 2,6-pyridinedicarboxylic acid, Met = Metformin (N,N-dimethylbiguanide) and Gly = glycine, were synthesized. The three complexes were characterized by elemental analysis, FTIR, 1H and 13C NMR, and UV–Vis spectroscopy. Solid-state structures of (2) and (3) were determined by single-crystal X-ray diffraction analysis. The coordination geometry around the vanadium atoms in 2 is octahedral, while the coordination geometry in 3 is between trigonal bipyramidal and squared pyramidal. In the binuclear complex 2 and mononuclear complex 3, metformin and glycine are diprotonated and monoprotonated respectively, and act as a counter ion. The redox behavior of the complexes was also investigated by cyclic voltammetry.

Introduction

In recent years, the combination of separate elements into a more complete system and the formation of desirable compounds for various applications, especially in pharmacological field for the treatment of diseases, has been widely considered [1], [2], [3]. This strategy includes the following methodologies: (I) the combination of different organic compounds with the formation of novel salt based on the proton transfer reactions or the formation of co-crystals with no proton transfer [4], [5], [6], (II) the coordination to metals of suitable ligands with adapted biological properties [7], [8], [9], (III) the insertion as counter ions of suitable organic or inorganic compounds in the outer sphere coordination of adapted complexes [10], [11], [12], [13].

Diabetes mellitus is a heterogeneous disorder which, according to the world sanitary statistics in 2016 emitted by WHO, afflicts over 422 million people worldwide and can lead to cardiovascular disease, blindness, kidney disease, and death [14].

Vanadium has well-documented blood-glucose-lowering properties both in vitro and in vivo [3], [15], [16], [17], [18], [19], [20]. Therefore, the research on vanadium medicinal chemistry has been mainly focused on improving biodistribution and tolerability of the vanadium insulin-enhancing core to treat diabetes. In this regard, a great number of vanadium complexes with different ligands that have biological properties have been studied as potential anti diabetic drugs [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]. The strategy for the design of these compounds can potentially benefits from a synergistic approach, in which the whole complex has more than an additive effect from its individual parts. Among these compounds, vanadium complexes containing dipicolinic acid and its derivatives or metformin are an important task because of their insulin-mimetic properties [12], [13], [26], [27].

Dipicolinic acid (H2dipic, 2,6-pyridinedicarboxylic acid) is a relevant N, O-chelating agent. It is present in many natural compounds, and shows various biological functions and potential pharmacological activity. Regarding the insulin-mimic compounds, it has to be noticed that the insulinlike properties of the [VO2(dipic)] anion and its 4-hydroxydipicolinate derivative, [VO2(dipic)single bondOH], have been determined [[26], and references therein] and results show that vanadium complexes of this compound have enhanced the pharmacological activity as compared with the free ligand.

Metformin, N,N-dimethylbiguanide, is a biguanide antihyperglycemic agent, and has been extensively used throughout the world over the last four decades to treat type-2 diabetes mellitus. Metformin can be administered in the form of one of its pharmaceutically acceptable salts of various organic and inorganic acids, such as the hydrochloride, acetate, benzoate, etc. [[30], and references therein]. It can coordinate to the metal center as monodentate [31], [32], bidentate ligand [33], [34], [35], [36] and can also be found in some complexes as a counter ion [37], [38]. Considering the combination of vanadium with metformin to form a potentially synergistic compound for diabetes treatment, two kinds of complexes has been investigated. In the first case metformin participates as a ligand in the inner sphere of coordination [39] and in the second one metformin is located in the outer sphere of coordination as a counter ion [11], [12], [13], [40], [41], [42], [43].

Glycine (Gly) is the simplest and the only non-chiral amino acid in nature. It can exist in various forms: cationic fully protonated, neutral zwitterion, and anionic deprotonated. Glycine can coordinate to the metal center as monodentate [44], [45], [46], [47], bidentate chelating [48], [49], as well as μ2 bridging over two metal atoms through carboxylate group [50], [51], [52], and it can also be found as a discrete non coordinating cation [53], [54].

Due to the fact that counter ions can affect the properties of the overall compound, a suitable counter ion choice can potentially enhance uptake of anions [55], [56], [57]. In this regard, the combination of insulin-enhancing anions [VO2(dipic)] with the glycine and metformin as counter ion, to form potentially synergistic compounds for diabetic cataract treatment, is very attractive. In particular, the results indicate that the oral administration of glycine significantly delays the onset and the progression of diabetic cataract in rats [58].

Our research group has been mainly focused on the development of vanadium-based agents against diabetes. In order to find a substance that enhances the therapeutic effects of insulin-enhancing anion, and exhibits potential pharmacological activity, we have previously reported the synthesis and characterization of insulin-enhancing anionic complexes with different cations, [H2Pipz][VO2(dipic-OH)]2·2H2O, [H2Met][VO2(dipic-OH)]2·H2O, [HMet][VO2(dipic)]·H2O and [HMet][VO2(dipic-OH)]·H2O. Continuing our research interests, here we wish to report on the synthesis and full characterization in solution as well as in the solid state of mono and dinuclear vanadium(V)–dipicolinic acid anionic complexes containing the glycine and metformin molecules as cations.

Section snippets

General methods and materials

All chemicals and solvents were commercially available in high purity and used without further purification. Metformin hydrochloride, glycine, H2dipic, and VOSO4 and tetrabutylammonium hexafluorophosphate (TBAH) were purchased from Sigma-Aldrich, while solvents were purchased from Merck. Elemental analyses were performed by using a Leco, CHNS-932 elemental analyzer. Fourier transform infrared spectra were recorded on a FT-IR JASCO 680-PLUS spectrometer in the region of 4000–400 cm−1 using KBr

Synthesis and characterization

Vanadium(V) dipicolinate complexes 2 and 3 were prepared in two methods. Scheme 1 presents the synthetic route through which the vanadium complexes were obtained. To obtain complex 2, the reaction of VOSO4 with H2dipic and metformin hydrochloride in water was carried out at 90 °C (method A), and three different crystalline compounds identified as H2dipic, 1 and 2 were obtained by slow evaporation of the solvent at room temperature. In this method, complex 2 was always found mixed with other

Conclusions

The adaptability of the metformin and glycine molecules as a ligand (neutral, protonated, and deprotonated forms) and as a counter-ion along with its antidiabetic properties makes its combination with insulin-enhancing anions worthwhile for further investigations. Our main goal in this research was focusing on the synthesis of new complexes that put these species together. Therefore, salts H2Met2+ and HGly+ cations with vanadium insulin-enhancing were prepared and characterized by various

Acknowledgements

We gratefully acknowledge the support of this work by the Sistan and Baluchestan University.

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