Synthesis and antiproliferative evaluation of 2-hydroxylated (E)-stilbenes

Article abstract of DOI:10.1016/j.bmcl.2014.10.009

A simple synthesis of 2-hydroxylated (E)-stilbenes was accomplished in good yields via oxidative coupling of 2-hydroxystyrenes and arylboronic acids, with Rh(III)-catalyst and Cu(OAc)₂ as oxidant. The antiproliferative evaluation of all the synthesized compounds were assessed on four different human cancer cell lines (Colo-205, MDA-468, HT29, and MGC80-3), and the results showed that several compounds exhibit strong antiproliferative activities (up to IC₅₀ = 35 nM for MGC80-3).

Full text of DOI:10.1016/j.bmcl.2014.10.009

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5470–5472
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiproliferative evaluation of 2-hydroxylated
(E)-stilbenes
⇑
⇑
Yan Zhang , Mingyun Shen , Sunliang Cui , Tingjun Hou
Institute of Materia Medica and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple synthesis of 2-hydroxylated (E)-stilbenes was accomplished in good yields via oxidative
coupling of 2-hydroxystyrenes and arylboronic acids, with Rh(III)-catalyst and Cu(OAc)2 as oxidant.
The antiproliferative evaluation of all the synthesized compounds were assessed on four different human
cancer cell lines (Colo-205, MDA-468, HT29, and MGC80-3), and the results showed that several
compounds exhibit strong antiproliferative activities (up to IC50 = 35 nM for MGC80-3).
Ó 2014 Elsevier Ltd. All rights reserved.
Received 14 August 2014
Revised 30 September 2014
Accepted 2 October 2014
Available online 13 October 2014
Keywords:
Oxidative coupling
2-Hydroxystyrenes
Arylboronic acids
2-Hydroxylated (E)-stilbenes
Antiproliferative
Stilbenes are privileged molecules in medicinal chemistry
because of their wide range of different biological activities.1
Particularly, hydroxylated stilbenes are largely presented in nature
and play a significant role in antioxidant, antitumor and cardiopro-
tection (Fig. 1). Examples are (E)-resveratrol and (Z)-combretasta-
tin A-4. (E)-Resveratrol, which is isolated from edible materials
such as grape skins, peanuts, and red wine, has been suggested
as an anticancer agent acting by the inhibition of cell proliferation.2
(Z)-Combretastatin A-4, from the bark of South African bush wil-
low Combretum caffrum, also showed significant antitumor activ-
ity.3 Therefore, the synthesis and bioactivity evaluation of
hydroxylated stilbene derivatives received much attention and
interests in medicinal chemistry.4
Literature methods for the synthesis of hydroxylated stilbenes
include conventional Wittig reaction, Horner–Wadsworth–
Emmons reaction, and Mizoroki–Heck coupling reaction. Wittig
reaction and Horner–Wadsworth–Emmons reaction suffer from
limitations of slightly low yields, low E/Z selectivity and stoichiom-
etric generation of triphenylphosphine oxide as byproduct.
Respecting to Mizoroki–Heck reaction, this coupling reaction offers
a simple and direct approach toward hydroxylated stilbenes, with
hydroxystyrenes and iodobenzenes as starting materials. Despite
that, the diversity of iodobenzenes is limited.5 The currently
reported Pd-catalyzed oxidative Mizoroki–Heck reaction also offers
an alternative approach to stilbenes, but these reaction are limited
to narrow substrate scope of simple acrylates, and their synthesis
toward hydroxylated (E)-stilbenes has rarely been reported.6
Therefore, the development of simple and distinct methods for con-
struction of hydroxylated stilbenes still remains attention.
While resveratrol and combretastatin A-4 represent 3-hydrox-
ylated stilbenes, the investigation concerning 2-hydroxylated stilb-
enes is attractive and interesting. As
a consequence of our
continued interest in the synthesis of biologically interesting small
molecules via Rh(III)-catalysis,7 herein we report a new strategy for
rapid assembly of 2-hydroxylated (E)-stilbenes, via oxidative
coupling of readily available 2-hydroxystyrenes and arylboronic
acids (Scheme 1), and the antiproliferative evaluation on four
different human cancer cell lines (Colo-205, MDA-468, HT29, and
MGC80-3) showed that several compounds exhibit strong
proliferative inhibition.
Recently, Macareñas and Gulías reported that 2-hydroxysty-
renes could take CÀH activation on the olefin position under
OMe
OH
MeO
OMe
MeO
HO
HO
OH
combretastatin A-4
resveratrol
⇑
Corresponding authors. Tel./fax: +86 571 88981456.
E-mail addresses: slcui@zju.edu.cn (S. Cui), tingjunhou@zju.edu.cn (T. Hou).
Figure 1. Representative structure of pharmaceutical interesting hydroxylated
These authors contributed equally.
stilbenes.
http://dx.doi.org/10.1016/j.bmcl.2014.10.009
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

Y. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5470–5472
5471
OH
reported that the commercial available arylboronic acids could
change to organometallic reagent and serve as arylation source
under Rh(III)-catalysis.9 Therefore, we assumed that the combina-
tion of 2-hydroxystyrenes and arylboronic acids under Rh(III)-
catalysis would probably lead to arylation of 2-hydroxystyrenes,
and this would deliver structural differential 2-hydroxylated
stilbenes.
oxidative
coupling
R1
OH
B(OH)2
R1
+
R2
R2
Scheme 1. Synthesis of 2-hydroxylated (E)-stilbenes via oxidative coupling of
2-hydroxystyrenes and arylboronic acids.
With this mind, the investigation was then carried out. After
optimization, we found that the reaction of 2-hydroxystyrenes
and arylboronic acids could indeed afford the 2-hydroxylated (E)-
stilbenes in good yields upon 2 mol % [Cp*RhCl2]2 catalyst and
equivalent amount of Cu(OAc)2 as oxidant, and the reaction condi-
tion was pretty mild. Interestingly, when Pd(OAc)2 was used as cat-
alyst under this condition, it was inferior to afford only trace
product, thus demonstrating the importance of Rh(III)-catalysis.
As shown in Scheme 2, various arylboronic acids with valuable
functional groups, such as methyl, methoxy, bromo, cyano,
hydroxy were well tolerated in this protocol to generate diverse
products (3a–3i), and differential substituted 2-hydroxystyrenes
regardless of the electron-donating or electron-withdrawing prop-
erties on the aromatic ring, were also well applicable in this oxida-
tive coupling to afford the 2-hydroxylated (E)-stilbenes (3j–3w).
Moreover, the structure was confirmed by single X-ray analysis
of compound 3s,11 identical to characterization. It should be noted
that the starting material 2-hydroxystyrenes was easily prepared
from salicylaldehydes in one-step, and the arylboronic acids were
commercial available. Considering that the reaction condition
was mild and the yields were good, and a gram-scale reaction dem-
onstrated its practicality,12 therefore this synthetic route to 2-
hydroxylated (E)-stilbenes is general and practical.
Control reaction showed that simple styrene was not amenable
in this protocol, which suggested that the hydroxy group is crucial
in this oxidative coupling. A plausible mechanism for this reaction
is outlined in Scheme 3. The initial rhodium acetate is generated
from [Cp*RhCl2]2 and Cu(OAc)2, and then take a transmetalation
with arylboronic acids 2 to form arylrhodium intermediate A.
The subsequent bidentate type coordination of 2-hydroxystyrenes
1 with A affords B and the following insertion generates C. A next
b-hydrogen elimination delivers 2-hydroxylaed (E)-stilbenes 3 and
Rh(I) species. Finally, the oxidation of Rh(I) by Cu(OAc)2 regener-
ates Rh(III) catalysis and enables the catalytic cycle.
OH
[Cp*RhCl2]2
(2 mol%)
OH
R1
B(OH)2
R1
+
R2
Cu(OAc)2 (2 equiv)
MeOH, RT
R2
3
2
1
OMe
OH
OH
R2
R2
(R1 = H)
3a
(R1 = 2-OMe)
3j
2
, 66% yield, R = H
, 85% yield, R2 = 4-OH
3b, 76% yield, R2 = 4-Me
3k, 83% yield, R2 = 4-OMe
3l, 57% yield, R2 = 2,4-(OMe)2
3c, 75% yield, R2 = 4-Br
, 80% yield, R2 = 4-OH
3d
, 71% yield, R2 = 3,5-(OMe)2
, 80% yield, R2 = 3,4,5-(OMe)3
3m
3n
3e, 30% yield, R2 = 4-CN
3f, 53% yield, R2 = 2,4-(OMe)2
, 70% yield, R2 = 3,5-(OH)2
, 72% yield, R2 = 3,5-(OMe)2
3g
3h
3i, 64% yield, R2 = 3,4,5-(OMe)3
OH
MeO
OH
Br
R2
R2
(R1 = 4-Br)
3q
, 75% yield, R2 = 4-OH
(R1 = 3-OMe)
3r,68% yield, R2 = 2,4-(OMe)2
3s, 86% yield, R2 = 3,5-Me2
3o, 58% yield, R2 = 3,5-(OMe)2
, 60% yield, R2 = 3,4,5-(OMe)3
, 65% yield, R2 = 3,5-(OMe)2
3p
3t
3u
, 60% yield, R2 = 3,4,5-(OMe)3
OH
O2N
R2
(R1 = 4-NO2)
3v, 63% yield, R2 = 3,5-(OMe)2
, 64% yield, R2 = 3,4,5-(OMe)3
3w
3s
Scheme 2. Synthesis of 2-hydroxylated (E)-stilbenes.10
All the synthesized compounds (and resveratrol as a standard)
were subjected to in vitro antiproliferative evaluation using the
MTT assay in four human cancer cell lines, including Colo-205
(colon), MDA-468 (breast), HT29 (colon), and MGC80-3 (stomach),
Rh(III)-catalysis,8 which indicated that Rh(III)-catalyzed divergent
functionalization of 2-hydroxystyrenes for access to their biologi-
cal interesting derivatives would be possible. Meanwhile, Miura
[Cp*RhCl2]2
1/2
Cu(OAc)2
Cp*Rh(OAc)2
B(OH)2
R2
Cu(OAc)2
2
Cp*
Rh
OAc
Cp*Rh(I)
R2
A
OH
R1
OH
R2
R1
3
H
O
1
H
O
R2
R1
Rh Cp*
Rh
R1
Cp*
R2
B
C
Scheme 3. Plausible mechanism.

5472
Y. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5470–5472
Table 1
MDA-468, HT29, and MGC80-3), and the results showed that sev-
eral compounds exhibited wide spectrum and good antiprolifera-
tive activities.
Antiproliferative activities of 2-hydroxylated (E)-stilbenes
a
Compd
IC50
MDA-468
(lM)
Colo-205
HT29
MGC80-3
Acknowledgments
3a
3b
3c
3d
3e
3f
3g
3h
3i
—
—
19.3 5.4
21.9 7.3
7.4 1.6
—
—
—
—
—
—
—
—
22.9 5.4
14.4 0.8
33.5 1.7
—
We are grateful to the National Natural Science Foundation of
China (21202143, 21472163) and Zhejiang University for financial
support.
21.1 1.8
—
—
—
—
—
—
3.1 0.3
—
—
6.3 1.2
—
—
—
26.2 7.3
26.2 1.9
—
Supplementary data
12.6 1.1
—
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
6.9 2.8
—
5.1 0.6
—
2.6 1.8
8.4 2.3
5.3 3.6
3.5 3.4
3.7 0.6
7.2 2.6
6.1 3.2
14.2 4.2
—
—
—
—
—
—
—
—
—
—
—
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
10.009.
20.2 3.4
—
—
—
1.1 0.1
0.8 0.2
0.035 0.007
—
3.5 0.7
5
3.3 0.8
4.5 3.1
10.6 2.2
14.7 3.3
42 9.7
—
References and notes
5.3 3.6
—
—
9.7 0.9
26.7 2.1
10 4.7
13.3 8.2
9.5 2.7
18.5 0.1
12.6 0.7
—
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0.3
16.4 4.5
—
—
—
3w
Resveratrol
—
23.5 0.8
45.2 6.9
87.2 7.7
(—) denotes value of testing compound larger than value of standard compound.
Values were obtained from MTT assays after 72 h of treatment; the values were
averaged from three independent experiments.
a
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and IC50 (lM) are listed in Table 1. Many compounds showed
prominent antiproliferative activities. Among them, the com-
pounds 3p and 3t exhibited much higher activities than resveratrol
with broad spectrum of activities. When R1-group was –H, the 2-
hydroxylated (E)-stilbene derivatives (3a–3i) had slightly narrow
spectrum of activities, except for bromo and 3,5-dimethoxy substi-
tuted compounds (3c and 3h), which showed broad spectrum and
high antiproliferative activities. When R1-group was 2-OMe, the
compounds (3j–3n) also had narrow spectrum of antiproliferative
activities, albeit with selective high activities. When R1-group was
3-OMe, the compounds (3o and 3p) showed high activities, espe-
cially when R2-group was 3,4,5-(OMe)3, the compound 3p exhib-
ited extraordinary high and wide spectrum of antiproliferative
activities. The highest antiproliferative activity for the compound
3p was found in stomach cancer cell line (IC50 = 35 nM). When
R1-group was 4-Br, the compounds (3q–3u) were also found to
be broad spectrum and active. When R1-group was 4-NO2, the
compounds (3v–3w) had narrow spectrum of activities against
only one or two tumor cells. The wide range observed for the com-
pounds 3a–3w indicated that the nature of substituents greatly
affected the activity profile of these compounds, while methoxy
and bromo are privileged groups in these 2-hydroxylated (E)-
stilbenes.
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10. Representative procedure for the Rh(III)-catalyzed synthesis of 2-hydroxylated
(E)-stilbenes: [Cp*RhCl2]2 (2.5 mg, 2 mol %), 2-hydroxy styrenes 1a (24 mg,
0.2 mmol), Cu(OAc)2 (80 mg, 0.4 mmol), and phenylboronic acid 2 (48.8 mg,
0.4 mmol) were added to a vial, then MeOH (2 mL) was added via syringe. The
reaction mixture was kept at room temperature. After completion within 2
hours, it was diluted with CH2Cl2 and transferred to a round bottom flask, silica
gel (500 mg) was added to the flask and all the volatiles were evaporated under
vacuum. The purification was performed by flash column chromatography on
silica gel using mixture of ethyl acetate/petroleum ether (v/v, 1:10) as eluent to
give product 3a: white solid; yield 66%; mp 141–143 °C; IR (KBr, v cmÀ1): 3533,
3047, 3018, 1584, 1499, 1456, 1333, 1251, 1196, 1088, 978, 846, 761, 727, 694;
1H NMR (CDCl3, 400 MHz, d ppm): 7.52 (m, 3H), 7.39–7.33 (m, 3H), 7.25 (m,
1H), 7.15–7.09 (m, 2H), 6.94 (t, J = 7.2 Hz, 1H), 6.78 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz,
1H), 5.07 (s, 1H); 13C NMR (CDCl3, 100 MHz, d ppm): 153.1, 137.7, 130.3, 128.8,
127.8, 127.4, 126.7, 124.8, 123.1, 121.3, 116.1; HRMS (EI) (m/z): calcd for
C
14H12O (M+), 196.0888; found, 196.0891.
In summary, we have developed a simple and efficient approach
to synthesize 2-hydroxylated (E)-stilbenes via Rh(III)-catalyzed
oxidative coupling of 2-hydroxystyrenes and arylboronic acids.
Moreover, the antiproliferative activities of these compounds were
evaluated in vitro on four different cancer cell lines (Colo-205,
11. CCDC 995487 contains the supplementary crystallographic data for this Letter.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.ac.uk/data_request/cif.
12. See Supplementary data.