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NMR Spectroscopic and Quantum Mechanical Analyses of Enhanced Solubilization of Hesperidin by Theasinensin A

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ABSTRACT

Purpose

The use of hesperidin in the pharmaceutical field is limited by its aqueous insolubility. The effects of natural compounds in tea on the solubility of hesperidin were evaluated and the underlying mechanism was investigated by nuclear-magnetic resonance (NMR) and quantum mechanical calculations.

Methods

The solubility of hesperidin was measured by liquid chromatography time-of-flight mass spectrometry; the structure of the hesperidin/theasinensin A complex was characterized by 1H-NMR, diffusion-ordered NMR spectroscopy, and rotating frame NOE spectroscopy, as well as theoretically by quantum mechanical calculations.

Results

Among the natural compounds in tea, theasinensin A was the most effective in improving hesperidin solubility. The complexation of hesperidin with theasinensin A led to changes in the chemical shift of protons in hesperidin (Δδ: 0.01–0.27 ppm) and diffusion coefficient (ΔD: 0.66–1.32 × 10−10 m2/s) of hesperidin. ROE correlation signals between hesperidin and theasinensin A and quantum mechanical calculations revealed that two hesperidin molecules formed a stable complex with theasinensin A (2:1 complex) with a ΔG energy of −23.5 kJ/mol.

Conclusions

This is the first study that provides insight into the enhanced solubility of hesperidin through interactions with theasinensin A via a 2:1 complex formation between hesperidin and theasinensin A.

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Abbreviations

CAF:

Caffeine

CD:

Cyclodextrin

D value:

Diffusion coefficient value

D2O:

Deuterium oxide

DMSO-d 6 :

Dimethyl sulfoxide-d 6

DOSY-NMR:

Diffusion-ordered-NMR spectroscopy

DSS-d 6 :

3-Trimethylsilyl-1-propanesulfonic acid-d 6

EGC:

(−)-Epigallocatechin

EGCG:

(−)-Epigallocatechin-3-O-gallate

Hesp:

Hesperidin

Nrtn:

Narirutin

QM:

Quantum mechanical

ROESY:

Rotating frame NOE spectroscopy

TSA:

Theasinensin A

TSB:

Theasinensin B

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported in part by Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry in Japan, and by Adaptable and Seamless Technology Transfer Program through target-driven R&D, JST in Japan. The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Division of Bioresources and Biosciences, Faculty of Agriculture, Graduate School of Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581, Japan

    Ruge Cao, Yutaro Kobayashi, Airi Nonaka & Toshiro Matsui

  2. Nagasaki Agricultural and Forestry Technical Development Center, Higashisonogi Tea Research Station, 1414 Nakano-go, Higashisonogi, Nagasaki, 859-3801, Japan

    Yuji Miyata

  3. Department of Nutrition, University of Nagasaki, 1-1-1 Manabino, Nagayo, Nagasaki, 851-2195, Japan

    Kazunari Tanaka

  4. Graduate School of Biochemical Sciences, Nagasaki University, 1-14 Bukyo-machi, Nagasaki, 852-8521, Japan

    Takashi Tanaka

Authors
  1. Ruge Cao
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  2. Yutaro Kobayashi
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  3. Airi Nonaka
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  4. Yuji Miyata
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  5. Kazunari Tanaka
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  6. Takashi Tanaka
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  7. Toshiro Matsui
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Corresponding author

Correspondence to Toshiro Matsui.

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Fig. S1

Change in chemical shift (∆δ, ppm) of protons in narirutin complexed with theasinensin A (Nrtn-TSA) at molar ratios of 1:1 to 1:10 in 10% DMSO-d 6 (a) and in D2O (b) at 25°C. The ∆δ was calculated by the difference between the δ value of narirutin alone and that of narirutin complexed with TSA. Target protons of narirutin were H2, H6′, H5′, H2′, H6, H3′, and H8. (GIF 31 kb)

High Resolution (TIFF 277 kb)

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Cao, R., Kobayashi, Y., Nonaka, A. et al. NMR Spectroscopic and Quantum Mechanical Analyses of Enhanced Solubilization of Hesperidin by Theasinensin A. Pharm Res 32, 2301–2309 (2015). https://doi.org/10.1007/s11095-015-1621-6

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  • DOI: https://doi.org/10.1007/s11095-015-1621-6

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