Design, synthesis, and discovery of stilbene derivatives based on lithospermic acid B as potent protein tyrosine phosphatase 1B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.06.016

Dihydroxy stilbene derivatives were designed based on lithospermic acid B and were prepared from 4-(chloromethyl)benzoic acid. The inhibitory activities of the novel compounds against protein tyrosine phosphatase 1B (PTP1B) were evaluated. 3,4-Dihydroxy stilbene carbonyl compounds (7, 11b, 27b) inhibited PTP1B with IC₅₀ values comparable to molybdate, while the conjugation-extended compound (15b) showed inhibition 3-fold better than preclinical RK682. The introduction of electron withdrawing groups or amides into the second phenyl ring, or extension of the conjugation into the stilbene molecule may increase stability of the generated radicals.

Full text of DOI:10.1016/j.bmcl.2007.06.016

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4481–4486
Design, synthesis, and discovery of stilbene derivatives based
on lithospermic acid B as potent protein tyrosine
phosphatase 1B inhibitors
Mankil Jung,a,* Yongnam Lee,a Moonsoo Park,a Hanjo Kim,a Heekyeong Kim,a
Eunyoung Lim,a Jungae Tak,a Minjoo Sim,a Dongeun Lee,a Namsoo Park,a
Won Keun Oh,c Kyu Yeon Hur,b Eun Seok Kangb and Hyun-Chul Leeb
aDepartment of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea
bDivision of Internal Medicine, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea
cCollege of Pharmacy, Chosun University, Gwangju 501-759, Republic of Korea
Received 12 December 2006; revised 15 May 2007; accepted 2 June 2007
Available online 8 June 2007
Abstract—Dihydroxy stilbene derivatives were designed based on lithospermic acid B and were prepared from 4-(chloro-
methyl)benzoic acid. The inhibitory activities of the novel compounds against protein tyrosine phosphatase 1B (PTP1B) were
evaluated. 3,4-Dihydroxy stilbene carbonyl compounds (7, 11b, 27b) inhibited PTP1B with IC50 values comparable to molybdate,
while the conjugation-extended compound (15b) showed inhibition 3-fold better than preclinical RK682. The introduction of
electron withdrawing groups or amides into the second phenyl ring, or extension of the conjugation into the stilbene molecule
may increase stability of the generated radicals.
Ó 2007 Elsevier Ltd. All rights reserved.
Non-insulin-dependent diabetes mellitus (type II) repre-
sents 80–90% of the human population with diabetes,1a
and worldwide estimates approach 215 million cases by
2010.1b However, clinically useful type-II antidiabetic
drugs based on PTP1B inhibition are not available at
the present time. Protein tyrosine phosphatases (PTPs)
act in opposition with protein tyrosine kinases to con-
trol the tyrosine phosphorylation levels of proteins.
Reversible tyrosine phosphorylation plays an important
role in signal transduction and regulation of cell pro-
cesses such as growth, differentiation, and proliferation.2
As anticipated from the importance of tyrosine phos-
phorylation, PTPases are implicated in diverse human
diseases including diabetes, obesity, autoimmune dis-
eases, and neurodegeneration. Type II diabetes is be-
lieved to be associated with a defect in insulin receptor
signaling which begins with the receptor autophospho-
rylation and the receptor tyrosine kinase activation.3a
Insulin signaling is negatively regulated by dephospho-
rylation of the receptor by PTPases and, therefore, the
defect in insulin sensitivity is possibly reversed by the
inhibition of the relevant PTPases.3b The most likely
candidates include PTP1B, LAR, PTPa, and SHP-2.
Among those, protein tyrosine phosphatase 1B (PTP1B)
has been most intensively studied as a target for the
development of inhibitors aiming at the treatment of
type II diabetes and obesity.3c
Recent studies have provided compelling evidence that
one of the main functions of intracellular PTP1B is to
suppress insulin action.4a Reducing PTP1B abundance
in mice not only enhances insulin sensitivity and im-
proves glucose metabolism, but also protects against
obesity induced by high-fat feeding.4b Protein tyrosine
phosphatase 1B functions in the negative regulation of
insulin signaling, and thus establishes PTP1B as an
attractive therapeutic target for diabetes.
Keywords: Lithospermic acid B (LAB); Protein tyrosine phosphatase
(PTP1B); Stilbene derivatives.
Inhibition of PTP1B in insulin sensitive tissues using
novel antisense oligonucleotides has shown enhanced
insulin signaling and glucose tolerance in preclinical
*
Corresponding author. Tel.: +82 2 2123 2648; fax: +82 2 364 7050;
e-mail: mjung@yonsei.ac.kr
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.016

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M. Jung et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4481–4486
models.4c However, there are very few PTPase inhibitors
that have been advanced into clinical trials.
Figure 1 shows the delocalization of spin density of the
phenolic O-centered radical, which was calculated using
Titan program with DFT/6-31G method. The spin den-
sity is delocalized throughout the whole structure of this
compound due to the planarity and the aromaticity of
the structure. Two hydroxyl groups attached to the cen-
tral phenyl ring have been removed to reduce the hydro-
philicity of the compound. Moreover, the terminal
carboxylic acid group can be substituted to make deriv-
atives with improved physical and chemical properties.
It is suitable for assessment by medicinal chemistry, as
it satisfied the lead likeness rule proposed by Teague
et al.7b We can expect high radical scavenging effects
and long half-life for this compound because the spin
density generated at the para position hydroxyl group
through interaction with other radicals can be delocal-
ized throughout the conjugated structure. In addition,
the radical at the para hydroxyl group can be stabilized
to form a hydrogen bond with the meta-position hydroxyl
group. Therefore, we expect this compound and its
derivatives to be useful as potent antioxidants with high
radical scavenging effects that can eventually be devel-
oped as anti-diabetic drug candidates.
Small molecule PTP1B inhibitors may find an important
clinical role as novel insulin sensitizers in the treatment
of type II diabetes.4d,e Lithospermic acid B (LAB)5 1 is
a polyphenol compound extracted from Salvia miltorrhiza
Bunge. Although LAB itself shows no in vitro inhibition
of PTP1B, it was shown to reduce the glomerular pro-
teinuria in in vivo experiments, and to show a strong
in vitro aldose reductase inhibition and has been studied
as an antidiabetic drug candidate.6 In structural aspects,
it is tetramer of caffeic acid with seven phenolic hydroxyl
groups, which cause the antioxidant effect of this
compound.
OH
HO
HO
OH
HO2C
O
OH
O
OH
O
CO2H
O
O
HO
For initial assessment of the structure–activity relation-
ship, the chemical structures of stilbene derivatives were
designed by substitution at various positions of the stil-
bene skeleton as listed in the following Figure 2 and syn-
thesized as shown in Schemes 1–4. Wittig reaction9 of
the protected aromatic aldehyde 5 and the appropriate
aromatic ylide obtained from the phosphonium salt 3
as prepared by literature procedure10,11 afforded the pro-
tected stilbene derivative 612 in 85% yield in the E/Z iso-
mer ratio of 1/1 (Scheme 1). The mixture of E and Z
product isomers was separated by flash chromatogra-
phy. Regiochemistry of E-form of 6 was identified by
higher coupling constant J = 16.3 Hz, doublet at d
6.97, 7.15 compared with lower J = 12.2 Hz, doublet at
d 6.51, 6.61 for Z-form, respectively. Removal of the
tert-butyl dimethylsilyl (TBDMS) groups from E-stil-
bene 611 using tetrabutylammonium fluoride provided
compound 7 (E-form: Rf = 0.10 (hexane/ethyl acetate,
2/1, v/v). d 7.97 (d, 1H, J = 16.25Hz), 7.58 (d, 1H,
J = 16.25Hz). Further reduction of 40-ester of the inter-
mediate E-form 6 with DIBAL-H to 8 and 10 and sub-
sequent deprotection of TBDMS groups of 8, 10 with
TBAF afforded trans compounds 9, 11a, respectively
(Scheme 1).11 Cis form, 26b (Fig. 2), of compound 9
was similarly prepared from Z-form of stilbene 6.
1
In this article, we wish to report the design, synthesis,
and discovery of dihydroxy stilbene derivatives based
on natural lithospermic acid B as potent PTP1B
inhibitors.
Since LAB has high molecular weight and polarity, it
does not satisfy the Lipinski’s rule for potential drug can-
didates with good bioavailability.7a High molecular
weight makes LAB unsuitable for further derivatization,
so we sought a novel simplified lead compound with low
molecular weight that retained high antioxidant effect.
We found that stilbene derivatives (7) inhibited PTP1B
with an IC50 = 25.6 lM in preliminary studies. Recently,
novel stilbene analogs were reported as potent human
cytochrome P450 inhibitors.8 The stilbene derivative is
a neutral molecule without charge, having a structure
well-suited to derivatization. We proposed the lead com-
pound structure 15 to be a derivative of the caffeic acid
dimer, the central part of LAB 1 with two phenolic
hydroxyl groups on the phenyl ring as a stable radical
generator. This molecule is a sort of trans-stilbene, in
which two benzene rings are connected via one double
bond, derived from the core structure of the LAB. It
satisfies the Lipinski’s rule.7a Two phenolic hydroxyl
groups and the conjugation throughout the whole system
may contribute to the expected high radical scavenging
effect by increasing stability of the generated radicals.
Figure 1. Radical-scavenging part/hydrophobic binding part generated
using Titan version 1.0.

M. Jung et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4481–4486
4483
O
O
O
OH
OCH3
R
OCH3
HO
HO
RO
RO
HO
HO
RO
RO
7
: R=H
9
11a : R= H
b : R=NHC6H5
15a : R= CH3
b : R= H
7a : R=CH3
O
O
O
N
H
HO
HO
RO
RO
HO
HO
R
HO
HO
HO
R
26a : R= CH3
b : R= H
16 : R= OH
20a: R= N,N-di C2H5
20b: R= NH-C6H5
27a: cis
28a : R= CO2CH3
b : R= NH2
27b: trans
NO2
O
O
O
O
R1
OCH3
OH
H3CO
HO
R2
R3
O
NO2
HO
OH
30a : R1=R3=H, R2=OH
30b : R1=H,R2=R3=OH
30c : R1=R2=OH, R3=H
31
32
RK- 682
Figure 2. Structures of stilbene derivatives designed, synthesized, and screened against PTP1B.
O
O
OCH3
O
O
H
OH
RO
RO
RO
e
a, b
+
OCH3
R
RO
Cl
2 : R= I
4 : R= H
(E/Z = 1/1)
6 : R= TBDMS
7 : R= H
d
c
f
3 : R= P+Ph3I-
5 : R= TBDMS
OH
OH
RO
RO
HO
HO
HO
g
+
HO
HO
i
8 : R= TBDMS
10 : R= TBDMS
9
26b
6
O
O
H
H
HO
HO
RO
RO
h
11a
Scheme 1. Reagents and conditions: (a) Me2SO4, K2CO3, acetone, 87%; (b) NaI, dry Acetone, reflux, 89%; (c) PPh3, dry ether reflux, 99%; (d)
TBDMSCl, imidazole, DMF, 25 °C, 89%; (e) NaH/THF, 0 °C, 86%; (f–h) TBAF, THF, 0–25 °C, 1 h, 77–90%; (i) DIBAL-H, CH2Cl2, ꢀ78 °C, 87%.
Methyl-(2E)-3-[4-(iodomethyl)phenyl]-2-propenoate 12
was prepared from methyl-4-(chloromethyl)benzoate
via 3a and 4a in the literature procedure.9 Reaction of
12 with triphenylphosphite afforded the phosphonium
salt 13 in 91% yield. Wittig reactions9 of the ylide gener-
ated from 13 with commercially available aromatic alde-
hyde 14 in the presence of n-butyllithium in THF yielded
an olefin compound 158,13 in 62% yield in the E/Z ratio
of 1/1 (Scheme 2). After separation of E- and Z-form of
15 by column chromatography, demethylation of 3,4-
dimethoxy groups of the trans form of compound 15a
by boron tribromide in CH2Cl2 cleanly afforded trans

4484
M. Jung et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4481–4486
O
O
R
OCH3
a
c
OCH3
R
Cl
Cl
4a: R=Cl
12: R=I
13: R=P+Ph3I-
2a: R= CH2OH
3a: R= CHO
d
b
e
O
O
O
H
OCH3
OCH3
H3CO
H3CO
g
13
f
H3CO
H3CO
HO
HO
14
15a : E
c : Z
15b
Scheme 2. Reagents and conditions: (a) DIBAL-H, ꢀ78°C, CH2Cl2, N2, 91%; (b) PCC, 0 °C, CH2Cl2, N2, 90%; (c) (CH3O)2P(O)CH2CO2CH3,
NaOCH3, MeOH, 91%; (d) NaI, N2, acetone, reflux, 90%; (e) TPP, NaOCH3, MeOH, 91%; (f) n-BuLi, THF, 0 °C, 12 h, 62%; (g) BBr3, CH2Cl2, 0 °C,
28%.
O
O
O
d
c
O
O
HO
HO
R1O
R1O
R
R
OR2
16 : R1=R2= H
17 : R1=R2= CH3
18 : R1=CH3, R2=H
20a (26%; R=diethyl amine)
20b (26%; R=aniline)
19a (99%; R=diethyl amine)
19b (72%; R=aniline)
a
b
Scheme 3. Reagents and conditions: (a) CH2N2, Et2O, 0 °C, 40%; (b) 1 N-LiOH, THF/H2O (1/1), rt, 90%; (c) HOBt, EDC, amine, CH2Cl2, rt; (d)
BBr3, CH2Cl2, 0 °C.
NO2
R1
H), d 7.41-7.33 (m, 3H, aromatic H), d 7.20–7.17(m,
R2
2H, aromatic H, vinyl CH), d 7.07–6.91 (m, 2H, aro-
matic H, vinyl CH), d 6.78–6.75 (d, 1H, J = 8.2Hz, aro-
NO2
R3
matic H). IR tmax 3442, 1646, 1600, 1525, 1441 cmꢀ1
.
HRMS (MALDI-TOF): m/z 354.1351 ([M+Na]+,
obsd), 331.1208 (calcd for C21H17NO3) and 27a
(Fig. 2) in 20% yields.
29a : R1=R3=H, R2=OCH3
29b : R1=H, R2=R3=OCH3
29c : R1=R2=OCH3, R3=H
30a (89% : R1=R3=H, R2=OH)
30b (79% : R1=H, R2=R3=OH)
30c (80% : R1=R2=OH,R3=H)
a
For preparation of dihydroxycinnamic acid derivatives,
protection of 3,4-dihydroxycinnamic acid, 16, and selec-
tive hydrolysis of 17 and subsequent amide formation of
18 provided compounds 19a in 99% yield and 19b in
72% yield as the known procedure,10 respectively
(Scheme 3). Final demethylation15 of 19a, 19b by the
boron tribromide in CH2Cl2 cleanly afforded stilbene
derivatives 20a and 20b (26% yields, E-form: d 6.55 (d,
1H, J = 15.6 Hz, trans vinyl CH), and d 7.52 (d, 1H,
J = 15.6 Hz, trans, vinyl CH)).
Scheme 4. Reagents and conditions: (a) BBr3, CH2Cl2, 0 °C, 2 h.
stilbene derivative 15b8,13 [28% yield, a yellow solid:
Rf = 0.47 (hexane/ethyl acetate, 1/1, v/v); 1H NMR
(500 MHz, CD3OD) d 7.72 (d, 1H, J = 16.00 Hz, trans,
vinyl H), d 7.60–7.55 (m, 4H, aromatic H), d 7.20 (d,
J = 16.00, 1H, trans, vinyl H), d 7.07 (s, 1H, aromatic
H), d 6.98 (d, 1H, J = 16.50, vinyl H), d 6.94 (d, 1H,
J = 9.00, aromatic H), d 6.80 (d, 1H, J = 8.50, aromatic
H), d 6.70 (d, 1H, J = 8.50, aromatic H), d 6.55 (d, 1H,
J = 16.50 trans vinyl H), d 3.82 (s, 3H, –OCH3). IR tmax
3413, 3020, 1634, 1439, 1251 cmꢀ1. HRMS (MALDI-
TOF): m/z 297.0743 ([M+H]+, obsd), 296.1049 (calcd
for C18H16O4).
Similarly, demethylation of nitro stilbenes 29a–c by the
boron tribromide15 in CH2Cl2 cleanly afforded stilbene
derivatives 30a–c in 79–89% yields (Scheme 4). 30c:
Rf = 0.13 (hexane/ethyl acetate, 2/1, v/v), E-form d
7.65 (d, 1H, J = 16.2 Hz, trans, vinyl CH), d 7.76 (d,
1H, J = 16.2 Hz, trans vinyl CH). IR tmax 3437,
1633, 1529, 1346. HRMS (MALDI-TOF): m/z
303.0775 ([M+H]+, obsd), 302.0539 (calcd for
C14H10N2O6).
Similarly, demethylation of 15c (Z-form) provided
28a14 (Fig. 2) in 54% yield. Reduction and following
oxidation of the ester group of compound (trans form)
6 and its cis-form, with subsequent amide coupling and
1
deprotection afforded, 11b (60%) as a green solid. H
NMR (250 MHz, CD3OD);
d
7.93–7.89 (d, 2H,
To examine the structure-activity relationships of dihy-
droxy stilbene compounds on PTP1B, a variety of
J = 8.39Hz, aromatic H), d 7.71–7.60 (m, 4H, aromatic

M. Jung et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4481–4486
Table 1. Inhibition against PTP1B of stilbene derivativesa
4485
to phenyl ring (30b and 30c), of the parent stilbene skel-
eton, thus indicating the importance of a hydroxy func-
tion at the C-2 or C-4 positions. Furthermore, addition
of two phenolic hydroxy groups of cis-stilbene (31) to
3,4-dihydroxystilbene (26b) markedly increased the
inhibitory activity. The inhibition by 30b and 30c was
of nearly the same magnitude, with perhaps the presence
of the hydroxy group at position C-4 having an effect on
potency. However, 3,4-dihydroxycinnamic acid 16 and
its amide derivatives, 20a and 20b, show no inhibition,
suggesting necessity of the second phenyl ring connected
through the double bond for PTP1B inhibition.
Compound
IC50 (lM)
7
7a
25.6
c
—
9
11a
260
101
27.2
11b
15a
c
—
14.9
15b
16
c
—
c
20a
20b
—
c
—
c
26a
26b
—
137.5
c
On the basis of these results, it appeared that the 3,4-
dihydroxy motif at the parent phenyl ring and 20,40-
electron withdrawing groups such as ester (7, 15b),
aldehyde (11a), nitro groups (30b and 30c) and amides
(11b, 27b)20 of trans stilbene analogs enhance inhibi-
tory activity of PTP1B. It is noteworthy that trans
derivatives (15b and 27b) are more relatively potent
than cis derivatives (28a and 27a) probably due to
binding suitability with PTP1B. Especially, the amine
derivatives (28b) for future testing are expected to have
higher antioxidant effect than the ester derivatives
because the lone pair of electrons located at the nitrogen
atom of the amide group can be conjugated with
p-bond system better than that of the oxygen atom
of the ester group.20
27a
27b
—
35.4
c
—
28a
30a
c
—
30b
190
168
30c
31 (cis-stilbene)17
32 (curcumin)18
Molybdateb
RK-682b,19
DMSO
—
c
c
—
21
45
c
—
a IC50 values are means and SD of three experiments.
b Positive control(Na2MoO4Æ2H2O).
c Inactive.
trans-stilbene compounds with two hydroxy groups on
phenyl rings of the parent stilbene skeleton were synthe-
sized and the inhibitory activity on PTP1B was deter-
mined.16 All E- and Z-form were separated by using
column silica gel and bioassay was performed as a single
regioisomer form. Using the colorimetric assay based on
the rate of formation of p-nitrophenolate ion indicator,
PTP1B activity was assessed in the presence and absence
of the indicated compounds. IC50 values were calculated
based on the method of Burke et al.16 All measurements
are means and SD of n observations, with a typical var-
iability of 10% among observations. As a positive con-
trol, the effects of the known inhibitors, molybdate
and RK-682, were also evaluated, and the IC50 values
were found to fall within literature values. As shown
in Table 1, 3,4-dimethoxy trans-stilbenes (7a, 15a, and
26a) with protection of 3,4-dihydroxy groups had no
inhibitory effects. This observation supports the idea,
predicted by molecular modeling (Fig. 1), that protec-
tion with methyl group of the 3,4-dihydroxy groups on
phenyl rings inhibits the formation of the stable radical
necessary for inhibition of PTP1B. 3,4-Dihydroxy stilb-
enes (7 and 15b) with a methoxy carbonyl on the second
phenyl ring showed the best and nearly complete inhibi-
tion of PTP1B and had more potency than either 3,4-
dihydroxy trans-stilbene (11a) with 40-aldehyde group
or 3,4-dihydroxy trans-stilbene (9) with 40-alcohol
group. Extension of the conjugated system of 7 to 15b
further increased potency of PTP1B inhibition. The ni-
tro stilbene compounds (30a) with only one hydroxy
group at C-3 position on the phenyl ring of the parent
stilbene skeleton had no inhibitory effects. However,
the inhibitory potency was markedly enhanced by intro-
ducing another hydroxy group at C-2 or C-4 positions
Evaluation of antioxidant activity of stilbene derivatives
7a, 9, 15a, 15b, 30b with xanthine oxidase assay revealed
that there is no direct correlation of radical scavenging
effect with PTP1B inhibition.
In conclusion, we designed, synthesized, and developed
novel stilbene derivatives as potential protein tyrosine
phosphatase 1B inhibitors. Among them, 7, 11b, 15b,
and 27b showed strong inhibitory activities with IC50
values ranging from 14.95 to 35.4 lM against the
PTP1B enzyme. Particularly, compound 7 shows inhib-
itory activity comparable to that of molybdate, while
15b shows a 3-fold lower IC50 than the clinically studied
RK682. Compound 15b deserves further evaluation as a
possible type-2 antidiabetic drug candidate based on the
mechanism of PTP1B inhibition. This result suggests
that introduction of electron withdrawing groups (7),
amide groups (11b, 27b), or extension of the conjugation
(15b) into the stilbene molecule may stabilize the gener-
ated radicals.
Acknowledgments
This research was supported by a research grant from
the Ministry of Health & Welfare (Project No.
B040002), Republic of Korea. We wish to express our
thanks to Professor Jongsun Kim, Yonsei University
College of Medicine, for initial PTP1B screening, and
Bioinformatics & Molecular Design Research Center
(BMDRC) Yonsei University for drug design. Y.L.,
E.L., M.S., D.L., and N.P. acknowledge the fellowship
of the BK 21 program from the Ministry of Education
and Human Resources Development.

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M. Jung et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4481–4486
Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T.
Angew. Chem. Int. Ed. 1999, 38, 3743.
Supplementary data
8. Kim, S.; Ko, H.; Park, J. E.; Jung, S.; Lee, S. K.; Chun,
Y.-J. J. Med. Chem. 2002, 45, 160.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.06.016.
9. Pinney, K. G.; Mejia, M. P.; Villalobos, V. M.; Rosen-
quist, B. E.; Pettit, G. R.; Verdier-Pinard, P.; Hamel, E.
Bioorg. Med. Chem. 2000, 8, 2417; Pettit, G. R.;
Grealish, M. P.; Jung, M. K.; Hamel, E.; Pettit, R. K.;
Chapuis, J.-C.; Schmidt, J. M. J. Med. Chem. 2002, 45,
2534.
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