Experimental and DFT study on complexation of the strontium cation with cyclosporin A

doi:10.1016/j.molstruc.2015.06.086

Journal of Molecular Structure

Volume 1100, 15 November 2015, Pages 184-187

https://doi.org/10.1016/j.molstruc.2015.06.086 Get rights and content

Highlights

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Stability of the cyclosporin A–Sr²⁺ complex was determined.
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Quantum mechanical DFT calculations were applied.
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Structure of the resulting cationic complex was predicted.

Abstract

By using extraction experiments and γ-activity measurements, the extraction constant corresponding to the equilibrium Sr²⁺(aq) + 2A⁻(aq) + 1(nb) ⇄ 1·Sr²⁺(nb) + 2A⁻(nb) occurring in the two-phase water-nitrobenzene system (A⁻ = picrate, 1 = cyclosporin A; aq = aqueous phase, nb = nitrobenzene phase) was evaluated as log K_ex (1·Sr²⁺,2A⁻) = 0.1 ± 0.1. Further, the stability constant of the 1·Sr²⁺ complex in nitrobenzene saturated with water was calculated for a temperature of 25 °C: log β_nb (1·Sr²⁺) = 9.2 ± 0.1. Finally, applying quantum mechanical DFT calculations, the most probable structure of the proven 1·Sr²⁺ cationic complex was derived. In the resulting complex, the “central” cation Sr²⁺ is bound by five bonds to the corresponding five oxygen atoms of the parent cyclosporin A ligand. The interaction energy, E(int), of the investigated 1·Sr²⁺ complex, involving the 7-point correction for the basis set superposition error, was calculated as −894.5 kJ/mol.

Graphical abstract

Introduction

Cyclosporin A, a cyclic undecapeptide (see Scheme 1), is an immunosuppressant drug widely used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T cells [1]. It was initially isolated from the fungus Tolypocladium inflatum (Beauveria nivea), found in a soil sample obtained in 1969 from Hardangervidda, Norway, by H. P. Frey [2], [3]. Cyclosporin A was synthesized by a nonribosomal peptide synthetase (i.e., cyclosporin synthetase) [4], [5].

Cyclosporin A binds tightly to cyclophylin [6] and inhibits its peptidylprolyl cis-trans isomerase activity [7], [8]. The conformation of cyclosporin A in the crystal and in solution has been reported by H. R. Loosli et al. [9]. The further conformation of cyclosporin A when bound to cyclophylin [10], [11] and the secondary structure of free [12] and complexed [13], [14] cyclophylin have been determined by NMR. In addition, the X-ray structures of cyclophylin [15] and a cyclophylin–tetrapeptide complex [13] have appeared. Finally, a model of the cyclophylin–cyclosporin A complex that was generated by using the NMR-determined bound conformation of cyclosporin A [11], the X-ray structure of free cyclophylin [15], and intermolecular NOE data, which define how cyclosporin A binds to cyclophylin, have been also presented [16]. It is necessary to emphasize that this cyclosporin A – cyclophylin complex is responsible for the immunosuppressive properties of cyclosporin A [17] by binding to and inhibiting the calcium- and calmodulin-dependent phosphatase, calcineurin [18].

In the current work, the solvent extraction of strontium picrate (abbrev. SrA₂) into nitrobenzene by means of the mentioned cyclosporin A ligand (abbrev. 1; see Scheme 1) was studied. At this point it should be noted that the Sr²⁺ ion is a typical representative of the divalent cations with a large radius. Besides, the radionuclide ⁸⁵Sr²⁺ used (see Experimental) enables relatively fast and very accurate physical-chemical measurements. Therefore, this cation was chosen for the present study. Moreover, the stability constant of the proven 1·Sr²⁺ complex species in the organic phase of the water–nitrobenzene extraction system was determined. Finally, applying DFT calculations, the most probable structure of this cationic complex was predicted.

Section snippets

Experimental

Compound 1 (puriss., ≥99%; see Scheme 1) was purchased from Sigma and it was employed as received. The other chemicals used (Lachema, Brno, Czech Republic) were of reagent grade purity. A solution of strontium picrate (SrA₂) in water was prepared by dissolving a stoichiometric amount of picric acid in an aqueous solution of Sr(OH)₂. The carrier-free radionuclide ⁸⁵Sr²⁺ was obtained from DuPont, Belgium; its radionuclidic purity was 99.9%.

The extraction experiments were carried out in 10 mL

Extraction experiments

Regarding the results of previous papers [19], [20], [21], the two-phase water–SrA₂ (A⁻ = picrate) – nitrobenzene extraction system can be described by the following equilibrium ${Sr}^{2 +} (aq) + 2 A^{-} (aq) ⇄ {Sr}^{2 +} (nb) + 2 A^{-} (nb); K_{ex} ({Sr}^{2 +}, 2 A^{-})$ with the corresponding extraction constant K_ex (Sr²⁺, 2A⁻); aq and nb denote the presence of the species in the aqueous and nitrobenzene phases, respectively. For the constant K_ex (Sr²⁺, 2A⁻) one can write [19], [21]. $\log K_{ex} ({Sr}^{2 +}, 2 A^{-} = \log K_{{Sr}^{2 +}}^{i} + 2 \log K_{A^{-}}^{i}$ where $K_{S r^{2+}}^{i}$ and $K_{A^{-}}^{i}$

Conclusions

In this work, we have demonstrated that the combination of theoretical DFT calculations with an experimental extraction method in the two-phase water–nitrobenzene system can provide relevant data on the bonding interactions of the strontium cation (Sr²⁺) with the cyclosporin A ligand (1). By using this extraction method, the stability constant of the cationic complex 1·Sr²⁺ in nitrobenzene saturated with water was determined as log β_nb (1·Sr²⁺) = 9.2 ± 0.1 (t = 25 °C). On the other hand,

Acknowledgments

This work was supported by the Grant Agency of Faculty of Environmental Sciences, Czech University of Life Sciences, Prague, Project No.: 42900/1312/3114 “Environmental Aspects of Sustainable Development of Society”, and by the Czech Ministry of Education, Youth, and Sports (Project MSM 6046137307).

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Experimental and DFT study on complexation of the strontium cation with cyclosporin A

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Experimental

Extraction experiments

Conclusions

Acknowledgments

J. Biol. Chem.

FEBS Lett.

FEBS Lett.

Cell

Talanta

Chem. Phys. Lett.

Science

Biodivers. Conserv.

Wien. Klin. Wochenschr.

Arch. Microbiol.

Science

Nature

Nature

Helv. Chim. Acta

Biochemistry

Biochemistry

Nature