From a Multipotent Stilbene to Soluble Epoxide Hydrolase Inhibitors with Antiproliferative Properties

Article abstract of DOI:10.1002/cmdc.201300057

Inspired by nature: Natural product isopropylstilbene was identified as an inhibitor of soluble epoxide hydrolase exhibiting antiproliferative properties. Following the natural product inspired design approach, a library of (E)-styryl-1H-benzo[d]imidazoles was synthesized and evaluated with recombinant enzyme and on several cancer cell lines. Copyright

Full text of DOI:10.1002/cmdc.201300057

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DOI: 10.1002/cmdc.201300057
From a Multipotent Stilbene to Soluble Epoxide Hydrolase
Inhibitors with Antiproliferative Properties
Estel.la Buscatꢀ,[a] Dominik Bꢁttner,[a] Astrid Brꢁggerhoff,[a] Franca-Maria Klingler,[a]
[a]
[b]
[a]
[b]
[a]
ˇ
´
Julia Weber, Bastian Scholz, Aleksandra Zivkovic, Rolf Marschalek, Holger Stark,
Dieter Steinhilber,[a] Helge B. Bode,[c] and Ewgenij Proschak*[a]
Inhibitors of soluble epoxide hydrolase (sEH) are in the focus
of pharmaceutical research for numerous indications including
cardiovascular disorders, diabetes and inflammatory process-
es.[1–5] sEH is an enzyme located in the branch of the arachi-
donic acid cascade that hydrolyses the epoxyeicosatrienoic
acids (EETs),[6] products resulting from CYP epoxygenases, into
dihydroxyeicosatrienoic acids (DHETs). Although several inhibi-
tors reached clinical trials, the role of EETs and sEH in cancer
growth and metastasis remains rather ambiguous.[7] Using ge-
netic and pharmacological alteration of EET levels, it has been
demonstrated that EETs are critical for primary tumor growth
and metastasis in mouse models of cancer.[8] EETs promote
metastasis by triggering secretion of the vascular endothelial
growth factor (VEGF) by the endothelium, which is critical for
EET cancer stimulating activity. The postulated mechanism[9] for
EETs to promote tumor growth is via epidermal growth factor
receptor/phosphatidylinositol 3 kinase/protein kinase B (EGFR/
PI3K/Akt) and EGFR/mitogen-activated protein kinase (MAPK)
pathways[10] to promote cancer cell survival. However, sorafe-
nib,[11,12] which was originally designed as a multikinase inhibi-
tor,[13] was found to inhibit sEH in the nanomolar concentration
range, which contributes to its profile in vivo.[14,15] Looking at
these studies concisely, EETs act as a double-edged sword in
cancer development and treatment.
targeting several pathways relevant[20] for cancer pathogene-
sis.[21,22] The principle of addressing multiple targets by natural
products can be transferred to synthetic multitarget ligands.[23]
In this study, we intended to discover chemical compounds ex-
hibiting cytotoxic profiles and simultaneously targeting sEH.
We started with a small library of compounds isolated from en-
tomopathogenic bacteria, namely Photorhabdus and Xenorhab-
dus.[24] These bacteria live in symbiosis with soil-dwelling nem-
atodes and together are able to infect and kill different insect
larvae[25,26] using protein toxins but also small molecules. Key
compounds required to evade the insect immune system are
phenoloxidase inhibitors, with rhabduscin as the most promi-
nent example.[27] Assuming that also other insect enzymes, like
juvenile hormone epoxide hydrolase (JHEH),[28] are targeted by
Photorhabdus and Xenorhabdus natural products, we analyzed
our in-house compound library against the JHEH-related target
sEH. We found that the pluripotent isopropylstilbene (IPS, 1)
from Photorhabdus[29] exhibited the desired properties by in-
hibiting sEH with an IC50 value of 10 mm (Table 1, Scheme 1).
Polypharmacological compounds have gained special atten-
tion in the field of cancer treatment due to the complexity of
pathways involved in cancer pathogenesis.[16–18] Natural prod-
ucts are one of the major sources for novel antiproliferative
compounds, exhibiting various modes of cytostatic action.[19]
Often natural products exhibit polypharmacological activity,
Scheme 1. Natural product inspired design of stilbene-derived sEH inhibi-
tors.
Stilbenes like resveratrol[30,31] or erbstatin[32] are known to pos-
sess chemopreventive or antiproliferative properties. Similarly,
IPS exhibited a wide range of antiproliferative properties on
different cancer cell lines, including HepG2 (hepatocarcinoma),
HeLa (cervical cancer), MCF-7 (breast adenocarcinoma), A498
(renal carcinoma) and U937 (histiocytic lymphoma; Table 2).
The synthesis of IPS is not straightforward;[33] therefore, we
followed the natural product inspired approach and intended
to identify compounds with similar properties and simple syn-
thetic accessibility. We screened a small collection of com-
pounds exhibiting the stilbene scaffold (chalcones and resvera-
trol analogues) which was available in-house (Supporting Infor-
mation, SF 3). We identified (E)-styryl-1H-benzo[d]imidazoles as
analogues of IPS that carry a benzimidazole moiety, which was
previously identified as a novel sEH pharmacophore in our
[a] E. Buscatꢀ,+ D. Bꢁttner,+ A. Brꢁggerhoff, F.-M. Klingler, J. Weber,
ˇ
´
Dr. A. Zivkovic, Prof. Dr. H. Stark, Prof. Dr. D. Steinhilber,
Prof. Dr. E. Proschak
Institut fꢁr Pharmazeutische Chemie, Goethe Universitꢂt Frankfurt am Main
Max-von-Laue Str. 9, 60438 Frankfurt am Main (Germany)
E-mail: proschak@pharmchem.uni-frankfurt.de
[b] B. Scholz, Prof. Dr. R. Marschalek
Institut fꢁr Pharmazeutische Biologie
Goethe Universitꢂt Frankfurt am Main
Max-von-Laue Str. 9, 60438 Frankfurt am Main (Germany)
[c] Prof. Dr. H. B. Bode
Merck Stiftungsprofessur fꢁr Molekulare Biotechnologie
Fachbereich Biowissenschaften, Goethe Universitꢂt Frankfurt am Main
Max-von-Laue Str. 9, 60438 Frankfurt am Main (Germany)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201300057.
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carbodiimide (EDC). 4-(Dimethy-
lamino)pyridine (DMAP) and imi-
dazole were used as catalysts.
The resulting amide intermedi-
ates 6, 9, 12, 15, 18, 21, 24, 27,
33, 36, 39, 42, 45, 48, 51, 54, 57,
and 60 were cyclized by heating
under microwave irradiation in
the presence of hydrochloric
acid to yield the target (E)-styryl-
1H-benzo[d]imidazoles 7, 10, 13,
16, 19, 22, 25, 28, 34, 37, 40, 43,
46, 49, 52, 55, 58, and 61 as the
corresponding hydrochloric acid
salt (Scheme 2). The (E)-geome-
try of the styryl double bonds
was confirmed by proton–
proton coupling constants (Sup-
porting Information, SF 1). In
order to introduce an aromatic
residue at the meta position of
the phenyl ring (Scheme 3), 3-
bromo-(E)-cinnamic acid (62) un-
derwent esterification (79%
yield), followed by Suzuki cou-
pling of the key intermediate 63
with the desired aryl boronic
acid (26–49% yield). After hy-
drolysis of 64, 65, and 66, the
condensation with o-phenylene-
diamine (5) led to amide inter-
mediates 70–72, that underwent
subsequent cyclization to yield
compounds 73–75 under micro-
Table 1. IC50 values of synthesized (E)-styryl-1H-benzo[d]imidazoles.[a]
Compd R1
R2 R3 IC50 [mm][b]
Compd R1
R2
R3
IC50 [mm][b]
AUDA
IPS (1)
3
7
10
13
16
19
22
25
28
29
30
–
–
H
–
–
–
–
0.1Æ0.01
10.0Æ0.96
5.9Æ0.60
0.6Æ0.13
2.0Æ0.39
18.3Æ1.35
1.7Æ0.12
2.6Æ0.21
32.1Æ10.10
1.4Æ0.11
4.3Æ0.49
4.6Æ0.03
5.8Æ1.73
1.2Æ0.16
74
75
31
34
37
40
43
46
2
49
52
55
58
61
3-(pyridin-3-yl)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.8Æ0.23
1.5Æ0.36
6.1Æ0.45
6.5Æ0.50
7.5Æ1.52
9.8Æ3.94
17.3Æ3.11
4.3Æ0.57
5.4Æ0.74
9.7Æ0.32
1.9Æ0.16
1.6Æ0.37
2.7Æ0.76
4.9Æ1.10
3-DHBD[c]
4-F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2-CF3
2-NO2
2-OCH3
2-Cl
2-F
2-Br
3-Cl
3-Br
3-NO2
3-OCH3
3-(furan-2-yl)
4-CF3
4-OCH3
4-NO2
2-OCH3
3-OCH3
3-OCH3
4-Cl
2-CF3
2-CF3
2-CF3
2-CF3
5-OCH3
4-OCH3
5-OCH3
2-Cl
H
H
H
H
H
H
3-F
3-CH3
3-Cl
3-OCH3
73
[a] Structures are given in Schemes 2–3 and full chemical names can be found in the Supporting Information.
[b] Data are the meanÆSD of sEH inhibition of three different experiments. IC50 values were determined with
recombinant sEH using PHOME as substrate. [c] DHBD: 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl).
Table 2. Cell-viability EC50 values of selected compounds 16, 19, 74, 75 and IPS (1) for several cancer cell lines.
Compd
EC50 [mm][a]
MCF-7
HepG2
HeLa
A498
U937
IPS (1)
16
19
74
75
4.7Æ0.94
10.4Æ2.00
ia
n.t.
n.t.
n.d. (73.1% Æ14.65)[b]
n.d. (111.8% Æ17.09)[b]
n.d. (96.1% Æ19.23)[b]
2.7Æ0.27
1.1Æ0.11
2.1Æ0.11
10.2Æ0.23
9.2Æ0.51
n.d. (115.1% Æ7.21)[b]
4.7Æ0.25
n.d. (63.3% Æ28.91)[b]
n.d. (18.0% Æ5.20)[b]
18.4Æ5.49
21.8Æ5.31
15.7Æ2.43 n.d. (26.3% Æ1.00)[b]
21.0Æ2.38
19.8Æ3.03
15.1Æ1.04 n.d. (50.7% Æ10.42)[b]
[a] All EC50 values were determined by at least three independent experiments using WST-1 cell viability assay
and are expressed as EC50 ÆSD. Abbreviations: n.d.=not determinable, n.t.=not tested, ia=inactive at 30 mm.
[b] Cell viability [%] at 30 mm.
group.[34] The introduction of a benzimidazole does not abolish
the desired antiproliferative properties, since this class of com-
pounds showed a wide spectrum of pharmacological charac-
teristics,[35] including antiallergic,
wave radiation. Compounds 3, 29, 30 and 31 were purchased.
Inhibitory activity of styryl benzimidazole derivatives was inves-
tigated on human recombinant sEH expressed in E. coli[37]
analgesic, anti-inflammatory and
antibacterial activities. Com-
pound 2 inhibited sEH with an
IC50 value of 5.4 mm and was
used as a starting point for fur-
ther optimization.
For the synthesis of a com-
pound collection based on an
(E)-benzimidazole stilbene scaf-
fold, we used a previously pub-
lished[36] procedure (Scheme 2)
that involves the condensation
of substituted o-phenylenedia-
mine 5, 50, 53, 56, or 59 with
the appropriately substituted (E)-
cinnamic acid derivative 4, 8, 11,
14, 17, 20, 23, 26, 32, 35, 38, 41,
44, or 47 in the presence of 1-
Scheme 2. Synthesis of (E)-styryl-1H-benzo[d]imidazoles. Reagents and conditions: a) EDC (1.5 equiv), DMAP
(0.05 equiv), imidazole (0.05 equiv), RT, 4 h, 21–84%; b) 6m aq HCl, EtOH, 1208C, 10 min, MW, 20–92%. Com-
ethyl-3-(3-dimethylaminopropyl)- pounds 3, 29, 30, and 31 were purchased.
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After exploring the phenyl
moiety, we could conclude that
the best substitution pattern
was ortho-trifluoromethyl (com-
pound 7, IC50 =0.6 mm). There-
fore, derivatives of compounds
bearing altered eastern substitu-
tion were synthetized. Electron-
donating groups as in methoxy-
substituted 61 (IC50 =4.9 mm) ex-
hibited inhibitory activity; how-
ever, 52 (IC50 =1.9 mm), 55 (IC50 =
1.6 mm) and 58 (IC50 =2.7 mm)
Scheme 3. Synthesis of (E)-styryl-1H-benzo[d]imidazoles 73, 74 and 75 through introduction of aromatic residues
at position 3. Reagents and conditions: a) MeOH, H2SO4 (0.1 equiv), reflux, 16 h, 70%; b) R1ÀB(OH)2 (2.0 equiv),
Pd(PPh3)4 (0.1 equiv), 1m aq Na2CO3, toluene/EtOH (4:1), 858C, 16 h, 26–49%; c) KOH (2.85 equiv), MeOH, 258C,
3.5 h, 64–95%; d) EDC (1.5 equiv), DMAP (0.05 equiv), o-phenylenediamine (1.0 equiv), imidazole (0.05 equiv), RT,
4 h, 8–32%; e) 6m aq HCl, EtOH, 1208C, 10 min, MW, 34–63%.
bearing
electron-withdrawing
groups partially restored the ac-
tivity.
The structure–activity relation-
ship (SAR) of the investigated
styryl benzimidazoles on sEH are
using a synthetic epoxide as a substrate (3-phenyl-cyano(6-me-
thoxy-2-naphthalenyl)methyl ester-2-oxiraneacetic acid,
rather flat, which correlates with the possible binding mode
proposed by the molecular docking experiment of the most
potent compound 7 (Figure 1, see the Supporting Information
PHOME).[38] As shown in Table 1, we examined the different
substitutions at the phenyl ring of the styryl moiety (western
part) and the substitutions at the benzimidazole scaffold (east-
ern part). Regarding the western part of the molecule, several
compounds were synthesized bearing ortho, meta and para
substitutions. Ortho-substituted compounds (7, 10, 13, 16, 19)
yielded highest inhibitory activity, with the exception of
bromo-substituted 22. Electron-donating groups like methoxy
(compound 13) were less tolerated (IC50 =18.3 mm), and the
best inhibition was obtained with trifluoromethyl-substituted
compound 7 (IC50 =0.6 mm). Unsubstituted compound 3 result-
ed in a 10-fold loss of potency compared with the best com-
pound 7. With the exception of bromo-substituted 22
(IC50 =32.1 mm), halogen groups in the ortho position exhibited
moderate inhibition with IC50 values in the range of 1.7 to
2.6 mm .
Lower inhibitory activity was observed for 29 and 30, indi-
cating that meta substitution is less favored than ortho substi-
tution. However, we confirmed the tendency concerning the
electron-donating properties of the substituent, as compound
30 decreases the inhibitory activity (IC50 =5.8 mm). The intro-
duction of heterocyclic moieties, such as furane (73), pyridine
(74) or 2,3-dihydrobenzo[b][1,4]dioxine (75), increased the in-
hibitory potency (73: IC50 =1.2 mm, 74: IC50 =0.8 mm, 75: IC50 =
1.5 mm, Table 1). In contrast to the positive substituent effect
observed for ortho-substituted compounds, para-substitution
pattern resulted in a weaker inhibitory activity regardless of
the electron-donating nature of the substituent.
Figure 1. Docking pose of (E)-styryl-1H-benzo[d]imidazole 7 in the binding
pocket of the catalytic domain of sEH (PDB: 3KOO).
for details). Both nitrogen atoms of the benzimidazole core
seem to interact with the catalytic center of sEH (Tyr381,
Asp333, Tyr465). The largest part of the benzimidazole scaffold
is enclosed in the Trp334 niche (15 ꢃ) capable for aryl interac-
tions. The phenyl moiety showed p-stacking with Met419[39]
and His524, and the benzimidazole core showed p-stacking
with Trp334. The additional space around both aromatic cores
correlates with the high tolerability of different substituents, as
demonstrated by the SAR.
Additionally, double substitution at the phenyl moiety was
explored and led to a decrease in the inhibitory activity. 2,5-
Methoxy-substituted compound 43 (IC50 =17.3 mm) exhibited
the lowest inhibitory activity, which could be restored by a 3,4-
dimethoxy (46, IC50 =4.3 mm) or 3,5-dimethoxy substitution
pattern (2, IC50 =5.2 mm). The potency was not completely re-
stored by exchanging the methoxy groups to a 3,4-dichloro
pattern (49, IC50 =9.7 mm).
We evaluated the effect of compounds IPS (1; IC50 =
10.0 mm), 16 (IC50 =1.7 mm), 19 (IC50 =2.6 mm), 74 (IC50 =
1.2 mm) and 75 (IC50 =0.8 mm) on cell viability of several cancer
lines (Table 2). IPS inhibited the proliferation activity of all cell
lines except MCF-7. In the water-soluble tetrazolium salt (WST-
1) assay, EC50 values were in the range of 2.7 to 10.4 mm. Ortho-
substituted compounds 16 and 19 affected the proliferation
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drugs and drug precursors to
templates for fully synthetic bio-
active molecules.
Acknowledgements
This work was supported by the
Deutsche Forschungsgemeinschaft
(DFG)
(PR 1405/2-1),
LOEWE
Schwerpunkt Insektenbiotechnolo-
gie (to H.B.B.), Oncogenic Signal-
ing Frankfurt (OSF), Deutsches
Konsortium fꢁr Translationale
Krebsforschung
(DKTK),
and
Figure 2. Annexin V/PI staining of HepG2 cells incubated with A) 1% DMSO for 48 h, B) 1 (10 mm) for 24 h, C) 19
(10 mm) for 48 h, D) 19 (30 mm) for 48 h, E) 74 (10 mm) for 24 h, F) 75 (10 mm) for 24 h.
LOEWE-Schwerpunkt,
Anwen-
dungsorientierte Arzneimittelfor-
schung. E.B. thanks the Deutscher
Akademischer
Austauschdienst
activity of HeLa and U937 (suspension cells). Ortho-fluoro-sub-
stituted compound 19 inhibited cell proliferation of HepG2
(EC50 =4.7 mm) and U937 (EC50 =2.1 mm) and slightly of HeLa
cells (30 mm, 18%).
(DAAD)-La Caixa, J.W. thanks Beilstein Institute for a fellowship.
Keywords: benzimidazoles · cancer · polypharmacology ·
soluble epoxide hydrolase · stilbenes
Compounds 74 and 75 affected the cell growth of the differ-
ent cancer cell lines to a lesser extent. Compound 74 inhibited
the growth of HepG2 (EC50 =21.8 mm), HeLa (EC50 =18.4 mm),
MCF-7 (EC50 =15.7 mm), U937 (EC50 =10.2 mm), and to some
extent A498 cell lines (resulting in only 26% cell viability at
30 mm). Similarly, compound 75 displayed inhibitory activity on
all cancer cell lines. EC50 values ranged from 9.2 to 21.5 mm
(Table 2). Interestingly all compounds inhibited the cell prolifer-
ation of suspension cells U937.
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Received: February 6, 2013
Published online on April 17, 2013
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