Chemical constituents and aldose reductase inhibitory activities of Betula alba bark and leaves

Article abstract of DOI:10.1080/14786419.2020.1839455

Systematic phytochemical investigation of the bark and leaves of Betula alba was independently conducted. A new cyclic diarylheptanoid glucoside (1), five diarylheptanoids (2–6), a phenylethanoid (7), a methyl salicylate glycoside (8), a dihydrobenzofuran glucoside (9), an arylbutanoid glycoside (10), two lignan glycosides (11 and 12), a flavanone glucoside (13), and a triterpene (14) were isolated from the bark of B. alba. On the other hand, two cyclic diarylheptanoids (15 and 16), five flavonoids (17–21), a phenylpropanoid (22), a phenylbutanoid glucoside (23), and a monoterpene glucoside (24) were obtained from the leaves of B. alba. The structures of the isolated compounds (1–24) were identified on the basis of one- and two-dimensional NMR spectroscopic data. Compounds 1–24 were subsequently examined for aldose reductase (AR) inhibitory activity. Compounds 14 and 17–20 moderately inhibited AR activity with IC₅₀ values ranging from 6.6 to 34 μM.

Full text of DOI:10.1080/14786419.2020.1839455

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Chemical constituents and aldose reductase
inhibitory activities of Betula alba bark and leaves
Tomoki Iguchi , Minpei Kuroda , Nanami Akiyama , Mariko Hashimoto &
Yoshihiro Mimaki
To cite this article: Tomoki Iguchi , Minpei Kuroda , Nanami Akiyama , Mariko Hashimoto &
Yoshihiro Mimaki (2020): Chemical constituents and aldose reductase inhibitory activities of Betula
alba bark and leaves, Natural Product Research, DOI: 10.1080/14786419.2020.1839455
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1839455
SHORT COMMUNICATION
Chemical constituents and aldose reductase inhibitory
activities of Betula alba bark and leaves
Tomoki Iguchi, Minpei Kuroda, Nanami Akiyama, Mariko Hashimoto and
Yoshihiro Mimaki
Department of Medicinal Pharmacognosy, School of Pharmacy, Tokyo university of Pharmacy and
Life Sciences, Horinouchi, Hachioji, Tokyo, Japan
ABSTRACT
ARTICLE HISTORY
Received 10 July 2020
Accepted 16 October 2020
Systematic phytochemical investigation of the bark and leaves of
Betula alba was independently conducted. A new cyclic diarylhepta-
noid glucoside (1), five diarylheptanoids (2–6), a phenylethanoid (7),
a methyl salicylate glycoside (8), a dihydrobenzofuran glucoside (9),
an arylbutanoid glycoside (10), two lignan glycosides (11 and 12), a
flavanone glucoside (13), and a triterpene (14) were isolated from
the bark of B. alba. On the other hand, two cyclic diarylheptanoids
(15 and 16), five flavonoids (17–21), a phenylpropanoid (22), a phe-
nylbutanoid glucoside (23), and a monoterpene glucoside (24) were
obtained from the leaves of B. alba. The structures of the isolated
compounds (1–24) were identified on the basis of one- and two-
dimensional NMR spectroscopic data. Compounds 1–24 were subse-
quently examined for aldose reductase (AR) inhibitory activity.
Compounds 14 and 17–20 moderately inhibited AR activity with
IC50 values ranging from 6.6 to 34 mM.
KEYWORDS
Betula alba; Betulaceae;
bark; leaf; diarylheptanoid;
aldose reductase
inhibitory activity
1. Introduction
Aldose reductase (AR) metabolizes glucose to sorbitol. Since sorbitol accumulation is
associated with the development of diabetic complications, AR inhibitors may prevent
CONTACT Tomoki Iguchi
iguchit@toyaku.ac.jp
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1839455.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
T. IGUCHI ET AL.
or delay the progression of diabetic complications. Previously, preliminary screening of
37 medicinal plants for AR inhibitory activities was conducted. Among these, the
MeOH extracts of Betula alba bark and leaves were found to inhibit AR activity by 75.5
and 50.4%, respectively (Kuroda et al. 2016). Genus Betula, belonging to the family of
Betulaceae, is distributed across temperate and subarctic climate regions (Tsukamoto
1989). Betula species have been traditionally used not only as a folk medicine to treat
arthritis, rheumatism, and gout but also in cosmetics for hair and skin (Rastogi et al.
2015). B. alba is commonly called “White Birch”, and is known to contain triterpenes
€
such as betulin, betulinic acid, oleanolic acid, erythrodiol, and lupeol (Jager et al. 2008;
Hertrampf et al. 2012). In this study, phytochemical investigation of B. alba bark and
leaves was conducted independently, which resulted in the isolation of 14 (1–14) and
10 (15–24) compounds, respectively. The structures of the isolated compounds (1–24)
were identified on the basis of one- and two-dimensional NMR spectroscopic data.
Compounds 1–24 were subsequently examined for AR inhibitory activity.
2. Results and discussion
B. alba bark (dry weight, 2.0 kg) was extracted with hot MeOH (24 L) and concentrated
using an evaporator. The MeOH extract (230 g) was fractionated using a porous poly-
mer polystyrene resin Diaion HP-20 column to obtain MeOH/H2O (1:4), EtOH, and
EtOAc fractions. The EtOH eluted fraction (175 g) was subjected to silica gel column
chromatography (CC), octadecylsilanized (ODS) silica gel CC, and preparative ODS
HPLC to yield 14 compounds (1–14). The structures of 2–14 were identified as platy-
ꢀ
ꢀ
phyllone (2) (Smite et al. 1993), platyphylloside (3) (Smite et al. 1993), (5S)-5-hydroxy-
1,7-bis-(4-hydroxyphenyl)-3-heptanone 5-O-b-D-apiofuranosyl-(1!2)-b-D-glucopyrano-
ꢀ
side (4) (Smite et al. 1993), betulaplatoside Ia (5) (Matsuda et al. 1998), aceroside VII
(6) (Smite et al. 1993), p-tyrosol (7) (Park et al. 2011), gaultherin (8) (Wang et al. 2011),
ꢀ
fomannoxin acid b-D-glucopyranoside (9) (Zweimuller et al. 1997), apiosylepirhododen-
drin (10) (Pan and Lundgren 1994), massonianoside B (11) (He et al. 2012), (þ)-syrin-
garesinol b-D-glucopyranoside (12) (Deyama et al. 1985), naringenin 7-O-b-D-
glucopyranoside (13) (Shimoda et al. 2010), and betulin (14) (Sholichin et al. 1980)
(Figure 1). The MeOH extract (200 g) of B. alba leaves (dry weight, 800 g) was fractio-
nated by a method similar to that of B. alba bark. The EtOH eluted fraction (80 g) was
separated by silica gel CC, ODS silica gel CC, and preparative ODS HPLC to obtain 10
compounds (15–24). Compounds 15–24 were identified as alnusdiol (15) (Hanawa
et al. 1997), alnusdiol b-D-glucopyranoside (16) (Fuchino et al. 1996), apigenin (17)
(Markham et al. 1978), quercetin (18) (Markham et al. 1978), quercetin 3-O-b-D-galacto-
pyranoside (19) (Markham et al. 1978), quercetin 3-O-a-L-arabinofuranoside (20)
(Lhuillier et al. 2007), chrysosplenol C (21) (Semple et al. 1999), 3-hydroxy-1-(4-hydrox-
yphenyl)-propan-1-one (22) (Jacubert et al. 2010), 4-(40-hydroxy-30-methoxyphenyl)-2-
butanone 40-O-b-D-glucopyranoside (23) (Fan et al. 2001), and betulalbuside A (24)
(Morikawa et al. 2004) (Figure 1). Compounds 2–13, 15, 16, 20, 21, and 23 were iso-
lated from B. alba for the first time.
Compound 1 was obtained as an amorphous powder, and its molecular formula
was determined to be C25H32O9 by HR-ESI-TOF-MS (m/z 499.1943 [M þ Na]þ, calculated

NATURAL PRODUCT RESEARCH
3
Figure 1. Structures of 1–24.
1
for C25H32NaO9: 499.1944) and 13C NMR spectral data. In the H and 13C NMR spectra
of 1, the signals for the following compounds were observed: a 1,2,4-trisubstituted
aromatic ring [dH 6.71 (1H, d, J ¼ 8.2 Hz, H-50), 6.53 (1H, dd, J ¼ 8.2, 2.0 Hz, H-60), and
5.48 (1H, d, J ¼ 2.0 Hz, H-20); dC 134.8, 116.1, 151.9, 144.9, 117.2, and 123.3 (C-10－60)]; a
1,4-disubstituted aromatic ring [dH 7.62 (1H, dd, J ¼ 8.2, 2.2 Hz, H-200), 7.32 (1H, dd,
J ¼ 8.4, 2.2 Hz, H-600), 7.08 (1H, dd, J ¼ 8.2, 2.5 Hz, H-300), and 7.01 (1H, dd, J ¼ 8.4,
2.5 Hz, H-500); dC 142.0, 131.9, 124.3, 157.5, 125.4, and 134.0 (C-100－600)]; and an anome-
1
ric proton/carbon [dH 4.21 (1H, d, J ¼ 7.8 Hz); dC 102.3]. Furthermore, the H-1H COSY
spectrum of 1 revealed the following sequential correlations; dH 2.74 (ddd, J ¼ 16.8,

4
T. IGUCHI ET AL.
10.4, 2.3 Hz, H-1a) and 2.50 (ddd, J ¼ 16.8, 6.8, 2.3 Hz, H-1b)/ dH 1.48 (2H, m, H2-2)/dH
2.81 (dd, J ¼ 12.3, 2.3 Hz, H-3)/ dH 1.66 (m, H-4a) and 1.62 (m, H-4b)/ dH 3.25 (m, H-5)/
dH 2.03 (m, H-6a) and 1.56 (m, H-6b)/dH 2.86 (2H, m, H2-7). The HMQC spectrum of 1
associated the proton signals with the corresponding one-bond coupled carbon
signals at dC 28.8 (C-1), 36.9 (C-2), 68.3 (C-3), 46.3 (C-4), 74.1 (C-5), 41.4 (C-6), and 32.1
1
(C-7). These H and 13C signals indicated the presence of a linear C7 unit bearing an
oxygen atom at C-3 and C-5. The above-mentioned spectral data were closely
related to those of maximowicziol A, a cyclic diarylheptanoid whose aromatic rings are
linked through an oxygen atom (Hanawa et al. 1997). In addition, the signals for
a b-D-glucopyranosyl moiety (Glc) were observed in 1 [dH 4.21 (d, J ¼ 7.8 Hz, H-1000); dH
102.3 (C-1000), 75.3 (C-2000), 78.5 (C-3000), 71.9 (C-4000), 78.2 (C-5000), and 63.0 (C-6000)]. Acid
hydrolysis of 1 with 0.4 M HCl (dioxane/H2O, 1:1) yielded D-glucose. In the HMBC
spectrum of 1, a long-range correlation was observed between H-1000 (dH 4.21) of Glc
and C-5 (dC 74.1) of the aglycone moiety. Therefore,
as maximowicziol A 5-O-b-D-glucopyranoside.
1
was elucidated
The configurations of C-3 and C-5 and the diphenyl ether moiety of 1 have yet to
be determined because of the low yield.
The isolated compounds (1–24) were evaluated for their AR inhibitory activity.
Compounds 14 and 17–20 moderately inhibited AR activity with IC50 values of
34.0 0.69 mM, 9.8 1.2 mM, 15.1 1.1 mM, 21.1 2.6 mM, and 6.6 0.8 mM, respectively.
Epalrestat used as a positive control exhibited an IC50 value of 0.53 0.05 mM. The bark
of B. alba was found to be rich in betulin (14), which is considered to contribute to
the AR inhibitory effect imparted by the MeOH extract of B. alba bark.
3. Experimental
See supplementary material.
4. Conclusions
Systematic phytochemical investigation of the bark and leaves of B. alba afforded 14
compounds (1–14), including a new cyclic diarylheptanoid (1), and 10 compounds
(15–24), respectively. The structures of the isolated compounds (1–24) were identified
on the basis of NMR spectroscopic data. Compounds 1–24 were subsequently exam-
ined for AR inhibitory activity. Compounds 14 and 17–20 moderately inhibited AR
activity with IC50 values ranging from 6.6 to 34 mM.
Disclosure statement
The authors declare no conflict of interest.
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