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. 2019 Dec 25;25(1):90.
doi: 10.3390/molecules25010090.

Ketoprofen-Based Ionic Liquids: Synthesis and Interactions with Bovine Serum Albumin

Paula Ossowicz  1 , Proletina Kardaleva  2 , Maya Guncheva  2 , Joanna Klebeko  1 , Ewelina Świątek  1 , Ewa Janus  1 , Denitsa Yancheva  2 , Ivan Angelov  2
Affiliations

Ketoprofen-Based Ionic Liquids: Synthesis and Interactions with Bovine Serum Albumin

Paula Ossowicz et al. Molecules. .

Abstract

The development of ionic liquids based on active pharmaceutical ingredients (API-ILs) is a possible solution to some of the problems of solid and/or hydrophobic drugs such as low solubility and bioavailability, polymorphism and an alternative route of administration could be suggested as compared to the classical drug. Here, we report for the first time the synthesis and detailed characterization of a series of ILs containing a cation amino acid esters and anion ketoprofen (KETO-ILs). The affinity and the binding mode of the KETO-ILs to bovine serum albumin (BSA) were assessed using fluorescence spectroscopy. All compounds bind in a distance not longer than 6.14 nm to the BSA fluorophores. The estimated binding constants (KA) are in order of 105 L mol-1, which is indicative of strong drug or IL-BSA interactions. With respect to the ketoprofen-BSA system, a stronger affinity of the ILs containing l-LeuOEt, l-ValOBu, and l-ValOEt cation towards BSA is clearly seen. Fourier transformed infrared spectroscopy experiments have shown that all studied compounds induced a rearrangement of the protein molecule upon binding, which is consistent with the suggested static mechanism of BSA fluorescence quenching and formation of complexes between BSA and the drugs. All tested compounds were safe for macrophages.

Keywords: binding constants; bovine serum albumin; ionic liquids; ketoprofen; secondary structure.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
General synthetic procedure for [AAOR][KETO].
Figure 1
Figure 1
Change in the fluorescence emission spectra of BSA in the presence of various concentration of ketoprofen (a); [l-LeuOEt][KETO] (b); [l-ValOEt][KETO] (c); [l-ValOiPr][KETO] (d) [l-ValOPr][KETO] (e) and [l-ValOBu][KETO] (f) in sodium phosphate buffer (pH 7.4, 50 mM) at 25 °C. The insertions represent the Stern–Volmer plot.
Figure 1
Figure 1
Change in the fluorescence emission spectra of BSA in the presence of various concentration of ketoprofen (a); [l-LeuOEt][KETO] (b); [l-ValOEt][KETO] (c); [l-ValOiPr][KETO] (d) [l-ValOPr][KETO] (e) and [l-ValOBu][KETO] (f) in sodium phosphate buffer (pH 7.4, 50 mM) at 25 °C. The insertions represent the Stern–Volmer plot.
Figure 2
Figure 2
Effect of ketoprofen-based ionic liquids (ILs) on the percentage of cell viability in RAW 264.7 macrophages. Control cells were treated with media alone. Values are the mean ± standard error of the mean of three independent experiments. ** p < 0.01, * p < 0.05 indicates.
Scheme 2
Scheme 2
l-Leucine ethyl ester ketoprofenate.
Scheme 3
Scheme 3
l-Valine ethyl ester ketoprofenate.
Scheme 4
Scheme 4
L-valine isopropyl ester ketoprofenate.
Scheme 5
Scheme 5
l-Valine propyl ester ketoprofenate.
Scheme 6
Scheme 6
l-Valine butyl ester ketoprofenate.
Scheme 7
Scheme 7
Ketoprofen.
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