A new glucoside with a potent α-glucosidase inhibitory activity from Lycium schweinfurthii

Article abstract of DOI:10.1080/14786419.2019.1616730

A new glucoside, 3-methoxy-4-O-β-D-glucopyranosyl-methyl benzoate, has been isolated from Lycium schweinfurthii along with five known compounds through bioactivity guided fractionation of the total plant methanolic extract towards α-glucosidase inhibitory activity. All the isolated compounds were tested for their inhibitory effect on α-glucosidase enzyme. As a result, four of them showed a potent inhibitory activity and thus constitute a therapeutic approach to decrease postprandial hyperglycemia in diabetic patients.

Full text of DOI:10.1080/14786419.2019.1616730

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
A new glucoside with a potent α-glucosidase
inhibitory activity from Lycium schweinfurthii
Ahmed Elbermawi, Ahmed F. Halim, El-Sayed S. Mansour, Kadria F. Ahmad,
Ahmed Ashour, Yhiya Amen & Kuniyoshi Shimizu
To cite this article: Ahmed Elbermawi, Ahmed F. Halim, El-Sayed S. Mansour, Kadria F.
Ahmad, Ahmed Ashour, Yhiya Amen & Kuniyoshi Shimizu (2019): A new glucoside with a potent
α-glucosidase inhibitory activity from Lyciumꢀschweinfurthii, Natural Product Research, DOI:
10.1080/14786419.2019.1616730
To link to this article: https://doi.org/10.1080/14786419.2019.1616730
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1616730
A new glucoside with a potent a-glucosidase inhibitory
activity from Lycium schweinfurthii
Ahmed Elbermawia,b, Ahmed F. Halima, El-Sayed S. Mansoura, Kadria F. Ahmada,
Ahmed Ashoura,b, Yhiya Amena,b and Kuniyoshi Shimizub
aDepartment of Pharmacognosy Faculty of Pharmacy, Mansoura University, Mansoura, Egypt;
bDivision of Systematic Forest and Forest Products Sciences, Department of Agro-Environmental
Sciences, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University,
Fukuoka, Japan
ABSTRACT
ARTICLE HISTORY
Received 27 January 2019
Accepted 6 May 2019
A
new glucoside, 3-methoxy-4-O-b-D-glucopyranosyl-methyl
benzoate, has been isolated from Lycium schweinfurthii along with
five known compounds through bioactivity guided fractionation
of the total plant methanolic extract towards a-glucosidase inhibi-
tory activity. All the isolated compounds were tested for their
inhibitory effect on a-glucosidase enzyme. As a result, four of
them showed a potent inhibitory activity and thus constitute a
therapeutic approach to decrease postprandial hyperglycemia in
diabetic patients.
KEYWORDS
Lycium; a-glucosidase;
hyperglycemia
1. Introduction
Diabetes is a chronic metabolic disorder characterized by abnormal high plasma glu-
cose levels, leading to major complications, such as diabetic neuropathy, retinopathy
and cardiovascular diseases (He and King 2004; Krentz et al. 2007). Hydrolysis of diet-
ary carbohydrates such as starch is the major source of glucose in the blood. This
hydrolysis is carried out by a group of hydrolytic enzymes that includes intestinal
a-glucosidases and pancreatic a-amylase (Harris 1992). Inhibition of these enzymes
CONTACT Kuniyoshi Shimizu
shimizu@agr.kyushu-u.ac.jp
Division of Systematic Forest and Forest Products
Sciences, Department of Agro-Environmental Sciences, Graduate School of Bioresource and Bioenvironmental
Sciences, Kyushu University, Fukuoka, 819-0395, Japan.
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1616730.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
A. ELBERMAWI ET AL.
could be an important strategy for management of type II diabetes (Yin et al. 2014),
(Krentz and Bailey 2005), wherein a-glucosidase inhibitors could delay the rapid utiliza-
tion of dietary carbohydrates and thereby suppress postprandial hyperglycemia
(Watanabe et al. 1997). However, currently therapeutic drugs, such as acarbose, are
shown to effectively reduce the intestinal absorption of sugars in humans. However,
some have been associated with abdominal distention, flatulence, meteorism, and pos-
sibly diarrhea (Bishoff 1985).
Lycium schweifurthii is a deciduous Solanaceous shrub that is growing in temperate
to the subtropical regions of North America, North Africa, South America, southern
Africa and Australia (Fukuda et al. 2001). Previous phytochemical investigation of L.
schweinfurthii reported the presence of flavonoids, glycosides and phenolic acids (Abd
El-Maboud et al. 2016). Different species of Lycium are cultivated in the mainland of
China as an important source for health foods, its polysaccharides containing fruits
have proven to promote the differentiation of osteoblasts against postmenopausal
metabolic disorders (Wang et al. 2018). Traditional Chinese Medicine prescriptions
reported the use of some species of Lycium to treat Diabetes (Qian et al. 2017).
Modern pharmacological studies revealed that L. chinense root bark extracts can
decrease serum glucose levels and improve insulin resistance (Behl and Kotwani 2017),
while some of its isolated glycosides exhibited potent antihyperlipidemic activities in
HepG2 cells (Chen et al. 2018). In our ongoing search for a-glucosidase inhibitors, one
new glucoside, 3-methoxy-4-O-b-D-glucopyranosyl-methyl benzoate, along with five
known compounds were isolated. Their structures were elucidated using 1D and 2D
NMR as well as MS analysis. Their a-glucosidase inhibitory activity was screened using
acarbose as a positive control.
2. Results and discussion
2.1. Inhibition of a-glucosidase by different fractions of L. schweinfurthii
methanolic extract
An in vitro a-glucosidase inhibitory assay was performed for the total methanolic
extract showed a promising inhibitory activity, followed by screening of subsequent n-
hexane, methylene chloride, ethyl acetate and n-butanol fractions of L. schweinfurthii
(Figure S1) All the fractions were tested at 100, 50 mg/mL. Ethyl acetate and n-butanol
fractions showed more than 50% inhibition.
2.2. Chemical investigation of the active fractions of L. schweinfurthii
Chemical investigation of the ethyl acetate and n-butanol fractions afforded six
compounds (Figure 1) (1–6). They were identified as diosmetin (1) (Park et al. 2007),
luteolin (2) (Alwahsh et al. 2015), quercetin (3) (Ahmedova et al. 2012), diosmetin-7-O-
b-D-glucoside (4) (Basudan et al. 2005), 3-methoxy-4-O-b-D-glucopyranosyl-methyl
benzoate (5) and 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxy-1-(E)-pro-
penyl)-2-methoxyphenoxy]-propyl-b-D-glucopyranoside (6) (Takara et al. 2002). diosme-
tin-7-O-b-D-glucoside (4) is reported for the first time from Solanaceae, while
diosmetin (1) and 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxy-1-(E)-

NATURAL PRODUCT RESEARCH
3
Figure 1. Structures of isolated compounds from L. schweinfurthii.
propenyl)-2-methoxyphenoxy]-propyl-b-D-glucopyranoside (6) are isolated from L.
schweifurthii species for the first time.
Compound (5) was isolated as a white amorphous powder, with a molecular for-
mula C15H20O9 as established by the cationated molecular ion peak at m/z 367.0981
[M þ Na]þ (calculated, 367.1005) and molecular ion peak at m/z 389.1048 [M þ HCOO]-
1
(calculated, 389.1084) in both positive and negative HRESIMS (Figure S2). The H NMR
1
spectrum together with H-1H COSY correlations (Figures S3 and S4) exhibited an ABX
spin system aromatic protons at dH 7.60 (1H, d, J ¼ 1.8 Hz), 7.22 (1H, d, J ¼ 8.4 Hz) and
7.63 (1H, dd, J ¼ 1.8, 8.4 Hz), two methoxy groups at dH 3.89 (3H, s) and 3.88 (3H, s),
and one anomeric proton at dH 5.02 (1H, d, J ¼ 7.8 Hz) were observed in the upfield
region. The 13C NMR and HSQC spectra (Figures S5 and S6) displayed a total of 15 car-
bon signals; Apart from the sugar moiety signals, one carbonyl at dC 168.3 (C-7), two
oxygenated quaternary carbons at dC 150.5 (C-3) and dC 152.5 (C-4), one quaternary at
dC 125.0 (C-1), three aromatic methines at dC 125.0 (C-6), 116.5 (C-5) and 114.2 (C-2)
two methoxy signals at dC 56.8 and 52.6. The benzoate moiety of the structure was
established through the HMBC correlations (Figure S7 and S8) of H-2 [dH 7.60 (1H, d,
J ¼ 1.8 Hz)] to C-4 [dC 152.5], C-6 [dC 124.6] and C-7 [dC 168.3], as well as H-5 [dH 7.22
(1H, d, J ¼ 8.4 Hz)] to C-1 [dC 125.0], and C-3 [dC 150.5] and H-6 [dH 7.63 (1H, dd, J ¼ 1.
8, 8.4 Hz)] to C-2 [dC 114.2] and C-4 [dC 152.5]. The methoxy groups were confirmed to
be at C-3 and C-7 based on HMBC correlations of the methoxy protons at dH 3.89 and
3.88 with C-3 and C-7, respectively. The HMBC correlation of H-10 [dH 5.02 (1H, d, J ¼ 7.
5 Hz)] with C-4 [dC 152.5] revealed that the sugar unit was attached to C-4. Acid
Hydrolysis of the compound, revealed 4-hydroxy-3-methoxybenzoic acid (vanillic acid)
1
and D-glucose. The aglycone was confirmed by H-NMR and HRMS (Figures S9 and
S10), while the sugar part was deduced from co-chromatography with authentic sug-
ars as D-glucose (Baumeler et al. 2000). Furthermore, the b-configuration of D-

4
A. ELBERMAWI ET AL.
glucopyranose was determined by its anomeric proton coupling constant at [dH 5.02
(1H, d, J ¼ 7.8 Hz)]. Consequently, the compound was identified as, 3-methoxy-4-O-b-D-
glucopyranosyl-methyl benzoate. This compound is isolated for the first time from a
natural source. Nonetheless, tracking the existence of this compound using ethanol as
extracting solvent is necessary to eliminate the possibility of being artifact, so that
LCMS-IT-TOF analysis for the re-extracted plant materials with ethanol was carried out,
resulted in detection of peaks corresponding to compound 5 in both positive
[M þ Na]þ and negative [M þ HCOO]- ion modes, together with TIC chromatogram
(Figure S12 and S13).
2.3. Inhibition of a-glucosidase by compounds isolated from both ethyl acetate
and n-butanol fractions
The six compounds isolated from the active fractions of L. schweinfurthii as well as the
positive control acarbose were tested for their a-glucosidase activity, the results (Table
S14) showed that compounds 1, 2, 3 and 5 exhibited potent a-glucosidase inhibitory
activity with IC50 equal 23.55 2.65, 21.38 1.82, 7.12 0.84 and 22.76 3.67, respect-
ively, while compounds 4 and 6 maintained weak inhibitory activities.
The IC50 values of the isolated flavonoids compounds (1-3) were found to be com-
patible with the reported ones (Watanabe et al. 1997; Lee and Lee 2001).
Hydroxylation at position 3 of flavone was found to enhance the activity (Tadera et al.
2006). Careful investigation of the active compounds from a pharmacokinetic point of
view, it was assumed that 3-methoxy-4-O-b-D-glucopyranosyl-methyl benzoate (5) has
the advantage of being stable in vivo, while the isolated flavonoids are rapidly
degraded within the body into the corresponding phenylacetic acid (Manach and
Jennifer 2004).
3. Experimental section
3.1. General experimental procedure
1H and 13C-NMR spectra were obtained on a Bruker DRX 600 NMR spectrometer
(Bruker Daltonics INC., MA, USA). Chemical shifts (d) were expressed in ppm with refer-
ence to the TMS resonance. HR-ESI-MS was determined using LC–MS–IT–TOF
(Shimadzu, Tokyo, Japan). The MS instrument was operated using an ESI source in
both positive and negative ionization modes with survey scans acquired from m/z
100–2000 for MS and m/z 50–1500 for MS/MS. The ionization parameters were as fol-
lows: probe voltage, 4.5 kV; nebulizer gas flow, 1.5 L/min; CDL temperature, 200 ꢀC;
heat block temperature, 200 ꢀC. Infrared (IR) spectra were obtained by using an FTIR
spectrometer 620, Jasco (Tokyo, Japan). Semi preparative Liquid Chromatography was
R
V
carried out on MPLS-UV-ELSD; BUCHI Reveleris
PREP purification system.
Dimethylsulfoxide (DMSO) and other organic solvents were purchased from Wako Pure
Chemical Industries (Osaka, Japan). Silica gel (75–120 mesh) and RP-C18 silica gel
(38–63 mm) was purchased from Wako Pure Chemical Industries (Osaka, Japan). Thin
layer chromatography (TLC) silica gel 60 F254 was purchased from Merck (Darmstadt,
Germany). The developed chromatograms were visualized under 254 nm. UV light and

NATURAL PRODUCT RESEARCH
5
the spots were made visible by spraying with vanillin/H2SO4 reagent before warming
in an oven pre-heated to 110 ꢀC for 5 min.
3.2. Plant material
L. schweinfurthii Dammer. (Solanaceae), whole plant, was collected from International
coastal road, about fifty kilometres west Gamasa, Egypt on December 2016. The plant
identity was confirmed by Dr. Ibrahim Mashaly, Professor of Ecology, Faculty of
Science, Mansoura University. The fresh collected parts were air dried in shade at
room temperature. A voucher specimen has been deposited at the herbarium of
Pharmacognosy Department, Faculty of Pharmacy, Mansoura University given the
code: LY 01 Mansoura-3.
3.3. Extraction and isolation
The air dried powdered whole plant (1.2 kg) was extracted by maceration with 90%
MeOH at room temperature. The solvent-free extract (107.2 g) was successively fractio-
nated with n-hexane, methylene chloride, ethyl acetate and n-butanol. The EtOAc frac-
tion (15.7 g) was subjected to chromatographic investigation using silica gel column
eluted gradient with n-hexane–EtOAc (100:0 ! 0:100, 64 subfraction), followed by
EtOAc– MeOH (100:0 ! 50:50, 33 subfractions), to give 97 sub-fractions, 250 mL each.
Sub-fractions 7–11 were combined and purified by reversed phase chromatography
using C18 and MPLC gradient elution of H2O-MeOH (50:50 ! 50:100 in 40 min.), to
give compound 1 (7.4 mg). Sub-fractions 17–24 was purified by reversed phase chro-
matography using C18 and MPLC gradient elution of H2O-MeOH (50:50 ! 50:100 in
40 min.), followed by PTLC-RPC18 (on precoated silica gel plates F254) using H2O–MeOH
(30:70) to give compound 2 (11.4 mg). Compound 3 (24 mg) was purified from sub-
fractions 43-50 by PTLC (on pre-coated silica gel plates F254
)
using n-
hexane–EtOAc (30:70).
n-Butanol fraction (20.5 g) was chromatographed on a silica gel column and eluted
with EtOAc–MeOH (100:0!0:100) to yield 86 sub-fractions, 300 mL each. Compound 4
(4.8 mg) was purified from sub-fractions (9–10, 35 mg) by using MPLC eluted with
H2O-MeOH isocratically (70:30, in 20 min.). Sub-fraction (55–64, 968 mg) were subjected
to MPLC eluted with H2O-MeOH (50:50 ! 50:100 in 40 min.), followed by PTLC (on
precoated silica gel plates F254) using H2O–MeOH (50:50) to give compound 5
(1.6 mg). Compounds 6 (2.4 mg) was purified from sub-fractions (82-86, 470 mg) by
PTLC (on pre-coated silica gel plates F254) using H2O–MeOH (50:50).
3.4. Acid hydrolysis
Compound 5 were dissolved in 5 mL MeOH, mixed with equal volume of 5% HCl (v/v),
and the solution was refluxed for 2 h on boiling water bath. Methanol was distilled off
and the hydrolysate was shaken with CH2Cl2 to separate the aglycone. The CH2Cl2
extract was dried over anhydrous sodium sulphate and the solvent was distilled off.
The residue was dissolved in methanol and kept for identification of the aglycone

6
A. ELBERMAWI ET AL.
moiety. The acidic mother liquor was neutralised with silver oxide and the formed pre-
cipitate was filtered off and washed several times with few millilitres of distilled water.
The combined filtrate and washings were evaporated to dryness under reduced pres-
sure. The residue was dissolved in few drops of methanol and used for identification
of the sugar moiety by comparison with authentic sugar samples.
3.5. LC-MS analysis
The compound and the ethanol extract were injected into LC–MS analysis with an IT-
TOF instrument (Shimadzu, Kyoto, Japan). The equipment was fitted with an Agilent
ZORBAX SB-C18 column (1.8 mm, 2.1 ꢁ 150 mm; USA) maintained at 40 ꢀC. The mobile
phase solvents were: solvent A, H2O (0.1% formic acid) and solvent B, acetonitrile
(0.1% formic acid). The gradient program was as follows: 0–20 min (A:B 95:5, v/v),
20–25 min (0:100, v/v). The flow rate was 0.3 mL/min and the injection volume was
2 lL. The Rt of compound 5 was around 9.82 min.
3.6. Spectral data of the new compound (5)
3-methoxy-4-O-b-D-glucopyranosyl-methyl benzoate (5): white amorphous powder, IR
mmax/cmꢂ1: 3446 cmꢂ1 (OH stretching), 1700 cmꢂ1 (C ¼ O stretchinng), 1034 cmꢂ1 (C-O
1
stretching) (Figure S11); HR-ESI-MS m/z [M þ Na]þ 367.0981. H NMR (CD3OD, 600 MHz)
dH 3.40 (1H, m, H-40), 3.46 (2H, m, H-30, 50), 3.57 (1H, m, H-20), 3.69 (1H, m, H-60a), 3.84
(1H, m, H-60b), 3.88 (3H, s, 7-OCH3), 3.89 (3H, s, 4-OCH3), 5.02 (1H, d, J ¼ 7.5 Hz, H-10), 7.
22 (1H, d, J ¼ 8.4 Hz, H-5), 7.60 (1H, d, J ¼ 1.8 Hz, H-2), 7.63 (1H, dd, J ¼ 8.4, 1.8 Hz, H-6).
13C NMR (CD3OD, 150 MHz) dC 52.6 (7-OCH3), 56.8 (4-OCH3), 62.5 (C-60), 71.3 (C-40), 74.8
(C-20), 77.9 (C-30), 78.4 (C-50), 102.0 (C-10), 114.2 (C-2), 116.5 (C-5), 124.6 (C-6), 125.0 (C-
1), 150.5 (C-3), 152.5 (C-4), 168.3 (C-7).
3.7. Inhibition of a-glucosidase activity
The a-glucosidase inhibitory activity was assayed according to a previously described
method (Fatmawati et al. 2011). A 0.1 mL portion of the sample solution or positive
control solution dissolved in DMSO and 0.1 mL of a-glucosidase enzyme (5 units/mL)
in 0.15 M HEPES buffer were added to 0.1 M sucrose solution in 0.15 M HEPES buffer
and then incubated at 37 ꢀC for 30 min. After incubation, the reaction was ended by
heating at 100 ꢀC for 10 min. The formation of glucose was determined by the glucose
oxidase method, using a BF-5S Biosensor (Oji Scientific Instrument, Hyogo, Japan). IC50
values were determined for pure compounds isolated from L. schweinfurthii.
4. Conclusion
In our on-going research for finding a-glucosidase inhibitors from natural sources, L.
schweinfurthii total methanolic extract, fractions and subsequent isolated compounds
were screened for the activity. One new compound, 3-methoxy-4-O-b-D-glucopyrano-
syl-methyl benzoate, together with five known compounds were isolated; from which,

NATURAL PRODUCT RESEARCH
7
quercetin showed excellent inhibition on a-glucosidase with IC50 value of 7.1 mM.
Compounds diosmetin, luteolin and 3-methoxy-4-O-b-D-glucopyranosyl-methyl benzo-
ate exhibited potent inhibition against a-glucosidase with IC50 values of 23.6, 21.3 and
22.8 mM, respectively. 3-methoxy-4-O-b-D-glucopyranosyl-methyl benzoate might have
possessed the advantage of being more stable after being consumed. Regarding the
activity of diosmetin and its glucoside; substitution of hydroxyl group at position 7 of
flavone with sugar seemed to decrease the inhibitory activity.
Acknowledgments
Gratefully, the first author acknowledges the ministry of higher education, Egypt for scholar-
ship support.
The authors are indebted to Dr. Shingo Yokota, Department of Agro-Environmental Sciences,
Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Japan for
carrying out the IR measurement.
The authors are appreciative to Mr. Dedi Satria, Division of Systematic Forest and Forest
Products Sciences, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu
University, Japan for carrying out the LCMS-IT-TOF.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Kuniyoshi Shimizu
http://orcid.org/0000-0001-5960-1503
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