Cyclic diarylheptanoids as Na+-glucose cotransporter (SGLT) inhibitors from Acer nikoense

Article abstract of DOI:10.1016/j.bmcl.2009.12.036

Two cyclic diarylheptanoids, acerogenins A (1) and B (2) have been isolated from the bark of Acer nikoense as inhibitors of Na⁺-glucose cotransporter (SGLT). Acerogenins A (1) and B (2) inhibited both isoforms, SGLT1 and SGLT2. Structure-activity relationship of acerogenin derivatives on inhibitory activity of SGLT as well as conformational analysis of 1 and 2 on the basis of J-resolved HMBC spectra and X-ray analysis were discussed.

Full text of DOI:10.1016/j.bmcl.2009.12.036

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1070–1074
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Cyclic diarylheptanoids as Na+-glucose cotransporter (SGLT) inhibitors
from Acer nikoense
a
a
b
b
b
Hiroshi Morita a, , Jun Deguchi , Yusuke Motegi , Seizo Sato , Chihiro Aoyama , Jiro Takeo ,
*
Motoo Shiro c, Yusuke Hirasawa a
a Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41 Shinagawa-ku, Tokyo 142-8501, Japan
b Central Research Laboratory, Nippon Suisan Kaisha, Ltd, 559-6 Kitano-machi, Hachioji, Tokyo 192-0906, Japan
c X-ray Research Laboratory, Rigaku Corporation, Akishima, Tokyo 196-8666, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Two cyclic diarylheptanoids, acerogenins A (1) and B (2) have been isolated from the bark of Acer nikoense
as inhibitors of Na+-glucose cotransporter (SGLT). Acerogenins A (1) and B (2) inhibited both isoforms,
SGLT1 and SGLT2. Structure–activity relationship of acerogenin derivatives on inhibitory activity of SGLT
as well as conformational analysis of 1 and 2 on the basis of J-resolved HMBC spectra and X-ray analysis
were discussed.
Received 13 October 2009
Revised 14 November 2009
Accepted 7 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Acerogenin
Acer nikoense
SGLT inhibitor
Conformational analysis
Na+-glucose cotransporter (SGLT) is a membrane protein that
plays an important role in the re-absorption of glucose in the kid-
neys. SGLT is known to have three isoforms (SGLT1, SGLT2, and
SGLT3).1–3 SGLT1 is expressed primarily in the brush border mem-
brane of mature enterocytes in the small intestine, where it ab-
sorbs dietary glucose and galactose from the gut lumen.4 SGLT2
is only expressed in the renal cortex, where it is assumed to be
present in the brush border membrane of the S1 and S2 segments
of the proximal tubule, and to be responsible for the re-absorption
of glucose from the glomerular filtrate.4 It is expected that the inhi-
bition of SGLT could decrease glucose re-absorption resulting in an
increase in urinary sugar excretion and a decrease in blood glucose
level. Thus, SGLT inhibitors have therapeutic potential for type 2
diabetes.5
Our screening study on SGLT inhibitors in traditional medicines
discovered that the bark of methanol extract of Acer nikoense
showed effective SGLT inhibitory activity. The bark of Acer nikoense
(Aceraceae) are used as a Japanese folk medicine for hepatic disor-
ders and eye diseases, which contains a series of acerogenins6,7 and
acerosides8,9 with a range of biological activities such as anti-can-
cer, anti-inflammatory, anti-fungal, and anti-bacterial effects.10
Our efforts on identifying inhibitors that target SGLT1 and SGLT2
resulted in the isolation of two cyclic diarylheptanoids, aceroge-
nins A (1) and B (2) from the bark of Acer nikoense. Our interest
has also been focused on conformation of these cyclic diarylhepta-
noids with SGLT inhibition to clarify structure–activity relation-
ship. This paper describes effects of acerogenins A (1) and B (2)
on inhibition of SGLT and structure–activity relationship of these
cyclic diarylheptanoids as well as conformational analysis of 1
and 2 by J-resolved HMBC spectra and X-ray analysis of 2.
The bark of Acer nikoense (1.0 kg) was extracted with MeOH,
and the extract was partitioned between hexane and water. Hex-
ane-soluble materials (7.3 g) were subjected to a silica gel column
(hexane/EtOAc), in which a bioactive fraction eluted with 10%
EtOAc was purified by an ODS HPLC (70% MeOH) to afford acerog-
enins A6 (1, 268 mg, 0.03% yield) and B7 (2, 99 mg, 0.01% yield) as
SGLT inhibitors. Then, the known related diarylheptanoids such as
aceroside I (3)8 and VII (4)9 were also isolated from water soluble
materials.
In this study, the SGLT inhibitory activities of acerogenins 1–4
and their derivatives 5–20 against [14C]methyl-
a-D-glucopyrano-
side uptake in COS-1 cells expressing hSGLT1 or hSGLT2 were eval-
uated (Table 1).11 It was found that acerogenins A (1) and B (2)
remarkably inhibited SGLT1 [IC50
(lM) 1: 20.0; 2: 26.0], and
weakly against SGLT2 [IC50 M) 1: 94.0; 2: 43.0]. Whereas acero-
(l
side I (3) with a glucose at a phenolic hydroxy group and aceroside
VII (4), acyclic diarylheptanoid with a glucose at C-11, did not show
inhibition of both SGLT1 and SGLT2. Position of a hydorxy group at
C-9 or C-11 and their stereochemistry may not be so influenced for
SGLT inhibition. On the other hand, some derivatives of 1 such as a
methyl ether 5 and a ketone 6 (acerogenin C),12 a ketone of a
* Corresponding author. Tel./fax: +81 354985778.
E-mail address: moritah@hoshi.ac.jp (H. Morita).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.036

H. Morita et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1070–1074
1071
R3
R1
11
7
9
4
5
8
10
19
OGlc
12
3
6
1
18
2
R2O
O 17
13
14
16
15
HO
OH
4 (aceroside VII)
1 : R1 = OH (β), H, R2 = H, R3 = H2 (acerogenin A)
R1 = H2, R2 = H, R3 = OH, H (acerogenin B)
R1 = OH (β), H, R2 = Glc, R3 = H2 (aceroside I)
R1 = OH (β), H, R2 = Me, R3 = H2
R1 = O, R2 = H, R3 = H2 (acerogenin C)
R1 = O, R2 = Me, R3 = H2
2 :
3 :
5 :
6 :
7 :
8 :
9 :
10 :
11 :
12 :
13 :
H
N
O
HO
O
R1 = H2, R2 = Me, R3 = OH, H
R1 = H2, R2 = Me, R3 = O
19
R1 = OAc (β), H, R2 = Ac, R3 = H2
R1 = OBz (β), H, R2 = Bz, R3 = H2
R1 = OCOCH(CH3)2 (β), H, R2 = COCH(CH3)2, R3 = H2
R1 = OBz (p-Cl) (β), H, R2 = Bz (p-Cl), R3 = H2
R1 = OH (β), H, R2 = Bn, R3 = H2
R1 = O, R2 = Ac, R3 = H2
R1 = O, R2 = Bn, R3 = H2
R1 = O, R2 = Bz, R3 = H2
R1 = H2, R2 = H, R3 = H2
14 :
15 :
16 :
17 :
18 :
HO
O
20
sulfonyl chloride and Et3N, and then LiAlH4. Amide derivative 19
was converted from 6 by treatment with NH2OH, followed by
treatment of LiAlH4. Dehydrated derivative 20 was prepared from
1 by treatment with p-TsOH. Among the ester and ether derivatives
at R2 (Table 1), the acetyl and methyl ether derivatives 5, 7, 8, 9,
and 10 exhibited moderate inhibitory activity against SGLT1. The
ketone derivatives at R1 such as 6, 7, and 9 showed more potent
inhibitory activity against SGLT2. Derivatives with bulky substitu-
ents such as benzoyl and benzyl at R1 or R2 showed less effective
against both SGLT1 and SGLT2. Dehydroxylated derivative 18
showed most potent inhibition against both SGLT1 and SGLT2,
indicating that the presence of a hydroxy at C-9 or C-11 may be
not important for the SGLT inhibitory activity. Interestingly, amide
derivative 19 with 16-membered ring system and dehydrated
derivative 20 with Z double bond at C-11 showed less activity than
18. Therefore, the ring conformation of acerogenin derivatives is
important for the SGLT inhibitory activity.
Our interest of SGLT inhibition for cyclic diaryl formation led to
elucidate the three-dimensional structures of acerogenins A (1)
and B (2). The flexibility of cyclic molecules in solution is some-
what difficult to determine the conformation, although the NMR
provides the most reliable information in solution. To elucidate
the conformation of 1 and 2 in solution, complete assignments of
the 1H and 13C signals were made by 2D NMR measurements
(Table 2).
Table 1
Effects of acerogenins and their derivatives on SGLT inhibitory activity
Inhibitiona (%)
SGLT1
SGLT2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
92.7
94.2
18.3
9.7
33.9
54.2
15.0
14.1
29.5
67.8
53.3
62.4
65.4
67.5
À9.7
34.3
16.8
45.3
19.3
19.8
45.2
77.4
76.9
15.3
80.0
67.8
44.9
44.6
77.9
37.7
68.8
À1.7
20.6
15.7
31.4
13.5
3.9
17
18
19
1.4
96.3
46.5
73.7
50.0
20
Phlorizinb
a
All compounds were evaluated at 50 lM.
Phlorizin was evaluated at 0.2 lM.
b
Conformation of acerogenin A (1) as shown in computer gener-
ated 3D drawing (Fig. 1) was deduced from crosspeaks observed in
methyl ether 7, and derivatives of 2 such as a methyl ether 8 and a
ketone of a methyl ether 9 were prepared with diazomethane and/
or Jones reagent. Treatment of acerogenin A (1) and 6 with appro-
priate acid chloride and DMAP in CHCl3 afforded ester derivatives
10–13, 15, and 17. Ether derivatives 14 and 16 were prepared from
1 by use of benzyl bromide. Dehydroxylated derivative 18 was con-
verted from 1 and 6, respectively, by treatment with p-toluene
3
3
the NOESY spectrum, and JH–H and JH–C coupling constants.
NOESY correlations of H-13b/H-15 and H-13a/H-19 suggested that
these four protons were in one plane. J-resolved HMBC technique
enabled to detect long range C–H J couplings of this cyclic struc-
3
3
ture.13 The coupling constants, JH13a/H12b = 3.3 Hz, JH13a/H12a
=
3
3
3
3.5 Hz, JH13b/H12a = 13.2 Hz, JH13b/H12b = 4.2 Hz, JH13a/C11 = 8.6 Hz,

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H. Morita et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1070–1074
Table 2
1H [dH (J, Hz)] and 13C NMR data (dC) of acerogenins A (1) and B (2) in CD3OD at 300K
dH
dC
1
2
1
2
1
2
3
4
5
6
150.5
145.0
116.9
122.2
132.5
116.5
31.6
151.5
145.7
117.8
123.2
133.8
116.7
29.3
7.20 (1H, d, 7.8)
6.73 (1H, dd, 7.8, 1.8)
7.22 (1H, d, 8.4)
6.77 (1H, d, 8.4)
5.95 (1H, d, 1.8)
2.45 (1H, m)
2.45 (1H, m)
1.29 (1H, m)
1.51 (1H, m)
1.00 (1H, m)
1.25 (1H, m)
1.39 (1H, m)
1.12 (1H, m)
5.96 (1H, br s)
7a
7b
8a
8b
9a
9b
10a
10b
11a
11b
12a
12b
13a
13b
14
15
16
17
18
19
2.70 (1H, ddd, 16.8, 4.8, 3.0)
3.03 (1H, ddd, 16.8, 10.8, 3.0)
1.76 (1H, m)
1.67 (1H, m)
3.38 (1H, m)
28.1
24.9
39.4
69.3
40.6
32.3
37.7
71.1
40.0
23.5
31.2
35.7
0.97 (1H, ddd, 11.1, 11.1, 7.2)
1.47 (1H, m)
1.17 (1H, m)
1.47 (1H, m)
1.47 (1H, m)
1.67 (1H, m)
2.64 (1H, ddd, 13.2, 6.0, 4.5)
2.48 (1H, ddd, 13.2, 9.6, 4.8)
3.53 (1H, dddd, 4.2, 4.2, 4.2, 4.2)
1.71 (1H, dddd, 13.2, 13.2, 4.5, 3.5)
2.13 (1H, dddd, 13.2, 4.2, 4.2, 3.3)
2.94 (1H, ddd, 13.2, 3.5, 3.3)
2.76 (1H, ddd, 13.2, 13.2, 4.2)
139.5
131.5
122.7
156.3
123.9
130.0
139.9
132.5
124.1
156.9
123.9
131.3
7.24 (1H, dd, 8.4, 1.8)
7.00 (1H, dd, 8.4, 2.4)
7.13 (1H, dd, 8.4, 1.2)
6.93 (1H, dd, 8.4, 2.4)
7.26 (1H, dd, 8.4, 2.4)
7.31 (1H, dd, 8.4, 1.8)
7.25 (1H, dd, 8.4, 2.4)
7.28 (1H, dd, 8.4, 1.2)
Figure 2. Rotation model for C-11, C-12, C-13, and C-14 of 1.
Figure 1. Selected NOESY correlations and relative stereochemistry for acerogenin
A (1).
3
and JH13b/C11 = 4.7 Hz indicated gauche conformation between C-
14 and C-11 (Fig. 2). Thereto, NOESY correlations of H-12a/H-19
and H-11/H-14 supported the relative stereostructure of 1. Fur-
thermore, NOESY correlations for H-4/H-7, H-6/H2-9 and H-10b,
and H-10b/H-19 indicated the connectivity of C-7–C-12 might be
a zigzag structure as shown in Figure 1. In this conformation, the
aromatic ring (C-14–C-19) is close to H-6 (dH 5.95), H-9a (dH
1.00), and H-10b (dH 1.12) and these protons are expected to be
shielded by the aromatic ring. Thus, the conformation of 1 in solu-
tion was assigned as shown in Figure 1.
Acerogenin B (2) is a C-9 hydroxy isomer of acerogenin A (1).
The gross structure of 2 was elucidated in an uniform manner. Con-
formation of 2 as shown in computer generated 3D drawing (Fig. 3)
was deduced from crosspeaks observed in the NOESY spectrum
and 3J coupling constants. NOESY correlations of H-13b/H-15 and
H-13a/H-19 suggested that these four protons were in one plane.
Figure 3. Selected NOESY correlations and relative stereochemistry for acerogenin
B (2).

H. Morita et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1070–1074
1073
Figure 4. Rotation model for C-5, C-7, C-8, C-9, and C-10, and C-11, C-12, C-13, and C-14 of 2.
The conformations of C-11–C-13 and C-7–C-9 were deduced from
3
3J coupling constants. The coupling constants, JH13a/H12b = 4.5 or
3
3
3
6.0 Hz, JH13a/H12a = 4.5 or 6.0 Hz, JH13b/H12a = 9.6 Hz, JH13b/H12b
=
3
3
4.8 Hz, JH13a/C11 = 5.8 Hz, and JH13b/C11 = 3.9 Hz indicated gauche
conformation between C-14 and C-11. On the other hands, the cou-
3
3
pling constants, JH7a/H8a = 3.0 or 4.8 Hz, JH7a/H8b = 3.0 or 4.8 Hz,
3JH7a/C9 = 6.7 Hz, 3JH7b/H8a = 10.8 Hz, 3JH7b/H8b = 3.0 Hz, and 3JH7b/C9
=
2.2 Hz indicated gauche conformation between C-5 and C-9. NOESY
correlations of H-4/H-7a, H-6/H-8a, H-6/H-9 and H-10a, and H-9/
H-15 supported the relative stereostructure of 2 (Fig. 4). Thereto,
NOESY correlations of H-13b/H-15, H-13a/H-19, H-12a/H-19, and
H-11a/H-15 supported the relative stereostructure of 2 (Fig. 3).
Furthermore, NOESY correlation for H-10a/H-19 indicated the con-
nectivity of C-7–C-12 might be a zigzag structure. H-6 (dH 5.96)
and H-9 (dH 3.38) are expected to be shielded by the aromatic ring
(C-14–C-19). Thus, the conformation of 2 was assigned as shown in
Figure 3. This conformational feature of 2 was also supported by
Monte Carlo (MC) search.14 A total of 3000 MC steps were per-
formed to confirm the reproducibility of calculation results. After
the MC conformational search, each of the resulting conformations
was subjected to the energy-minimization calculation by MMFF
force field.15,16 Low energy conformers belonged to two separate
clusters. Lowest energy one was corresponding with solution con-
former (266.20 kJ/mol) analyzed by NMR in Figure 3 and the next
one was solid state conformer (270.08 kJ/mol) as shown below.
Acerogenin B (2) was crystallized from methanol–water as col-
orless needles and was analyzed by X-ray crystallography.17 The
asymmetric unit contains two molecules of 2, giving a calculated
density of 1.285 gcmÀ3. The ORTEP drawing of 2 were shown in
Figure 5. The configuration at C-9 in 2 obtained from X-ray analysis
corresponded well to that (racemate) proposed previously.7 The
dihedral angles of the backbone of 2 are summarized in Table 3.
Each conformation of 2 in solid and solution state might be differ-
ent in the dihedral angles of the cyclic side chain (C-9–C-13). The
solid conformation of 2 did not take a zigzag conformation like that
in solution. There were no intramolecular hydrogen bonds, which
stabilized the 15-membered cyclic nature. It is a first report for
X-ray structure of acerogenins. The conformation of the two aro-
matic rings (C-1–C-6 and C-14–C-19) is essentially twisted with
extended antiparallel side chains at C-5 and C-14.
Figure 5. ORTEP Drawing for acerogenin B (2).
Table 3
Parts of torsion angles (°) along backbone of acerogenin B (2)
2a
2b
174.5 (2)
C4–C5–C7–C8
C5–C7–C8–C9
170
À70
154
À74.3 (3)
À177.0 (2)
À80.6 (2)
À96.5 (3)
161.2 (3)
À65.3 (3)
À69.0 (2)
C7–C8–C9–C10
C8–C9–C10–C11
C9–C10–C11–C12
C10–C11–C12–C13
C11–C12–C13–C14
C12–C13–C14–C15
179
157
À105
55
À103
Each angle was estimated from 3D structures based on NMR analysis, which was
also supported by MC search, and on X-ray analysis.
a
Angles from molecular modeling based on NMR analysis.
Angles from X-ray crystallographic structure.
b
their conformations may be important to show inhibition of SGLT.
A series of marchantins from the liverworts are similar case pos-
sessing the two aromatic rings with a biphenyl ether linkage.18 Ef-
forts are currently underway to determine the detail structure–
activity relationship for SGLT inhibitory activity of a series of
acerogenins.
Common structural feature among acerogenins is the presence
of two aromatic rings with a biphenyl ether linkage which can be
connected through seven atoms bridge spacer. Orientation of the
two aromatic rings is required to be ca. 125°. Conformational anal-
ysis of 1 and 2 indicated that acerogenins A and B took a similar
conformation each other but did not match with that in solid state.
The appropriate torsion between two aromatic planes as well as
Acknowledgments
This work was partly supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,

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H. Morita et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1070–1074
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14. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield,
C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.
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a = 71.864(4)°, b = 74.168(4)°, c
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