Synthesis and Investigation of S-Substituted 2-Mercaptobenzoimidazoles as Inhibitors of Hedgehog Signaling

Article abstract of DOI:10.1021/acsmedchemlett.7b00100

Due to the arising resistance of common drugs targeting the Hedgehog signaling pathway, the identification of new compound classes with inhibitory effect is urgently needed. We were able to identify S-alkylated 2-mercaptobenzoimidazoles as a new compound

Full text of DOI:10.1021/acsmedchemlett.7b00100

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Letter
Synthesis and Investigation of S-substituted 2
Mercaptobenzoimidazoles as Inhibitors of Hedgehog Signaling
Simone Graessle, Steven Susanto, Sonja Sievers, Emel Tavsan, Martin Nieger, Nicole Jung, and Stefan Bräse
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00100 • Publication Date (Web): 28 Jul 2017
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Synthesis and Investigation of S-substituted 2-Mercaptobenzoimid-
azoles as Inhibitors of Hedgehog Signaling
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Simone Gräßle,a Steven Susanto,a Sonja Sievers,c Emel Tavsan,a Martin Niegerd, Nicole Junga,b and
Stefan Bräsea,b
aInstitute of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus North, Hermann-von-Helmholtz-Platz 1,
76344 Eggenstein-Leopoldshafen, Germany; bInstitute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Ha-
ber-Weg 6, 76131 Karlsruhe, Germany; cMax Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dort-
mund; d Department of Chemistry, University of Helsinki, P.O. Box 55, FI-00014 University of Helsinki, Finland.
KEYWORDS. Hedgehog signaling, cancer, small molecules, 2-mercaptobenzoimidazoles
ABSTRACT: Due to the arising resistance of common drugs targeting the Hedgehog signaling pathway, the identification of new
compound classes with inhibitory effect is urgently needed. We were able to identify S-alkylated 2-mercaptobenzimidazoles as a new
compound class that exhibits Hedgehog signaling activity in a low micromolar range. The scope of the 2-mercaptobenzimidazole
motif has been investigated by the syntheses of diverse derivatives, revealing that the elongation of the linker unit and the exchange
of particular substitution patterns are tolerable with respect to the activity of the compound class.
The Hedgehog (Hh) signaling pathway acts as a key mediator of
many fundamental processes, such as cell fate specification, prolif-
eration and patterning, as well as tissue morphogenesis and home-
ostasis.[1] Pathway activation is initiated by the binding of one of
the three secreted and lipid-modified ligands to Patched
(PTCH1),[2] a 12-pass transmembrane-spanning receptor. In the ab-
sence of a ligand, PTCH constitutively represses the activity of
Smoothened (SMO), a 7-pass transmembrane-spanning protein
with homology to G-protein-coupled receptors.[3] Following Hh
ligand binding to PTCH1, the repression on SMO is released, and
the expression and post-translational processing of the three GLI
zinc-finger transcription factors is modulated. Misregulation of Hh
signaling has been described in many malignancies, including can-
cers of the skin (basal cell carcinoma) and the brain (medulloblas-
toma) where activating mutations of Hh signaling components have
been found.[4] Furthermore, there are emerging roles for Hh signal-
ing also in other cancer types such as breast, ovarian and prostate
cancer, while the particular contribution and effect of Hh signalling
on different cancer types is still unclear.[5-7] Synthetic small mole-
cule inhibitors of Hh signaling like Vismodegib (1),[8-11] Sonidegib
(2),[12,13] and BMS-833923 (3)[14] (Figure 1) with a high chemical
diversity are in clinical use or in clinical trials. In addition, natural
small molecules like Berberine,[15] Calcitriol[16] and others[17-19]
which have been recently found to influence Hh signaling are of
interest for the search of new inhibitors that may overcome the de-
veloping resistance against currently available drugs.[20,21] Search-
ing for new structures with potential to inhibit Hh signaling, an in-
house library of 940 compounds[22] has been screened resulting in
the identification of 2-mercaptobenzoimidazoles as new lead struc-
tures. The class of 2-mercaptobenzoimidazoles has been shown to
include potent heterocycles in medicinal chemistry due to their
presence in drugs like omeprazole (4)[23-25] or fabomotizole (5).[26]
In particular, 2-(phenoxyalkylthio)-1H-benzoimidazoles were re-
ported as a promising compound class towards the targeting of
Binding Function 3 (BF3)-site of the androgen receptor (Figure 2,
6).[27,28] To the best of our knowledge, no activity of 2-mercapto-
benzoimidazoles with respect to the Hh signaling pathway has been
reported before.
Figure 1 Known inhibitors of the Hedgehog pathway.[3-6]
Figure 2 Structures of selected drugs including a 2-mercapto-
benzoimidazole core (4, 5
[23-26], the potent BF3-inhibitor 6[28]
and a selected library member
[R1 = (CH2)3 CO2Et].[29]
)
7
Recently, we were able to present a solid supported strategy
for the synthesis of diverse S,N-dialkylated 2-mercaptobenzoim-
idazoles by immobilization and derivatization of mercaptobenzo-
]
imidazole on solid supports.[29 The cleavage of the immobilized
precursors yielded N-alkylated target compounds with different
lengths of the alkyl side chain (7) (Figure 2) which were investi-
gated towards their activity in Hh signaling along with a diverse set
of compounds from academic research projects. Most of the tested
N,S-dialkylated 2-mercaptobenzoimidazoles showed no significant
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reduction of the Hh signaling, only the results of the derivative 7
methylphenoxy derivative 10b gave the best results in the
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3
4
5
6
7
8
suggested a slight inhibitory effect (12% inhibition). In order to
find 2-mercaptobenzoimidazoles with higher activity than given for
the N-alkylated compound 7, a library of S-alkylated mercaptoben-
zoimidazoles was synthesized.[30] Therefore a literature-known
procedure without functionalization of the NH-group was success-
fully used.[28] The library consisted of five main types of com-
pounds (10 to 14) (Table 1 to Table 3), which differ in the type or
position of the heteroatoms N, O and S and the length of the bridg-
ing linker unit (Scheme 1). All compounds were tested towards
their activity in the Hedgehog signaling pathway and have been
screening of the 2-mercaptobenzimidazole library, a threefold
decrease of the inhibition was detected for very similar com-
pounds like the 1,4-dimethylphenoxy-derivative 10l (Table 1).
Altogether, eight compounds of the series of type 10 yielding
IC50 values ≤ 3 µM (10a–10h) were identified as potent new
candidates for the inhibition of Hedgehog signaling. Thereby,
compound 10a showed the strongest inhibition of the Hh sig-
nal (Figure 3 shows the dose dependent inhibition of the Hh
signal). While all compounds 10 rely on the same core struc-
9
ture, compounds of type 11–14 were examined to elucidate the
evaluated in comparison to the Hh inhibitor Vismodegib (
1
),
influence of structural changes on the Hh signaling activity.
The effect of structural changes on the main compound core
was exemplarily investigated in order to define the scope of
further modifications of the given 2-mercaptobenzimidazole
10
11
12
13
14
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being a benchmark drug for the inhibition of Hh signaling with
an IC50 of approximately 0.1 µM in the herein described oste-
ogenesis assay (Table 1).
lead structure. The results for compounds 11a–11c (Table 2)
show, at least for this small set of synthesized compounds, that
the exchange of the phenolic part with a thiophenolic part does
not induce a loss of activity if a suitable substitution pattern is
chosen. Contrary, the exchange of the benzoimidazole core
(e.g. 10c, Table 1) with a methyl-benzothiazol-2-amine based
core as given in compound 12a,b (Table 2) caused loss of ac-
tivity.
Scheme 1 General scheme for the synthesis of compounds 10–
14 and crystal structures for selected examples (10c, 11b).
Table 1 O-aryl-type C2-based mercaptobenzoimidazoles
10a–10q.
A.
B.
Hh IC50
[µM]a
VIA IC50
[µM]b,c
R1
R2
R3
R4
R5
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
1
Me
H
H
H
F
H
Me
H
H
H
Me
H
Me
H
NO2
-(CH)4-
H
H
H
H
H
H
H
H
H
OH
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
iPr
H
Me
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
1.76±0.07
2.08±0.15
2.22±0.09
2.23±0.41
2.32±0.13
2.57±0.02
2.61±0.08
2.90±0.50
4.26±0.86
4.47±0.18
4.49±0.44
6.41±1.41
9.17±1.23
inact
inact
inact
inact
7.12
inact
inact
inact
inact
inact
inact
inact
inact
inact
inact
inact
inact
inact
inact
H
OMe
Me
Me
H
H
Me
H
A: two different conformers of 10c; B: asymmetric unit of 11b, show-
ing the two crystallographic independent molecules (displacement pa-
rameter are draw at 50% probability level).
H
H
Ph
H
Me
H
For investigating signal transduction through the Hh pathway,
mouse embryonic mesodermal fibroblast C3H/10T1/2 cells
were used in the osteogenesis assay. These multipotent mes-
enchymal progenitor cells can differentiate into osteoblasts
upon treatment with the SMO agonist Purmorphamine.[31,32]
During differentiation osteoblast specific genes such as alka-
line phosphatase (ALK) which plays an essential role in bone
formation are highly expressed. The activity of ALK can be
monitored by following substrate hydrolysis yielding a highly
luminescent product. An inhibition of the pathway results in
reduction of luminescence. The screening of the library of 2-
H
iPr
NO2
H
H
H
> 10
inact
inact
0.14±0.1
CO2Me
aHh inhibiting activity was determined using mesodermal
stem cells C3H/10T1/2 in the osteogenesis assay; b VIA = vi-
ability, inact = inactive; cell viability was determined using
Cell Titer Glo assay; cCompounds were scored inactive if the
viability of the cells was higher than 80% (compared to the
DMSO control).
(aryloxyalkylthio)-1H-benzoimidazoles 10–14 revealed a sig-
nificantly higher inhibition of the Hh pathway for almost all
compounds in comparison to the initially identified S,N-dial-
kylated 2-mercaptobenzoimidazole 7b. Especially several de-
rivatives of the series of 2-((2-aryloxyethyl)thio)-1H-benzo-
imidazoles 10a-q were found to inhibit Hh signaling in the low
micromolar range (Table 1). The activity of the individual
compounds within the targeted substance class strongly de-
pends on the substitution pattern of the phenolic ring system.
While the 2,6-dimethylphenoxy derivative 10a and the 3-
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Table 3 S- and O-aryl-type C3-based mercaptobenzoimidaz-
oles 13 and 14.
6
7
8
9
10
11
12
13
14
15
16
17
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Figure 3. Dose-response curve of the most promising com-
pound 10a. Half-logarithmic plot of Hh activity against com-
pound concentration.
Hh IC50
[µM] a
VIA
IC50
Z
R1
R2
R3
R4
R5
[µM] b,c
inact
13
S
H
Me
H
H
H
H
Cl
H
Me
H
H
H
H
H
H
Me
H
2.85±0.1
5.60±0.31
6.29±1.26
inact
14a
14b
14c
O
O
O
inact
inact
inact
Table 2 S-aryl-type C2-based mercaptobenzoimidazoles
H
Me
H
11a-c and 12a,b
.
aHh inhibiting activity was determined using mesodermal stem cells
C3H/10T1/2 in the osteogenesis assay; b VIA = viability, inact = inac-
tive; cell viability was determined using Cell Titer Glo assay; Com-
pounds were scored inactive if the viability of the cells was higher
than 80% (compared to the DMSO control).
c
Hh IC50 VIA IC50
R5
X
Y
Z
R1
R2
R3
R4
[µM]a
[µM] b,c
11a
11b
11c
12a
12b
NH
NH
NH
S
S
S
S
NH
NH
S
S
S
O
O
H
H
Cl
Me
H
Me
OMe
Cl
H
H
H
H
Cl
H
H
H
H
H
Me
H
H
H
H
Me
Me
3.06±0.18
5.63±0.73
5.71±0.91
> 10
inact
inact
inact
inact
inact
S
inact
aHh inhibiting activity was determined using mesodermal
stem cells C3H/10T1/2 in the osteogenesis assay; b VIA = vi-
ability, inact = inactive; cell viability was determined using
c
Cell Titer Glo assay; Compounds were scored inactive if the
viability of the cells was higher than 80% (compared to the
DMSO control).
In addition to the synthesis of ethylthio-substituted benzoim-
idazoles 10, a small set of propylthio-substituted benzoimid-
azoles (13, 14a–14c) (Table 3) has been investigated to deter-
mine the effect of the aliphatic linker part on the inhibition of
Hh signaling. It was found that the inhibition of the Hh signal-
ing can also be achieved with compounds bearing a propyl
linker part. Activity in a low µM range could be detected for
compound 13 (Table 3), which has been synthesized with a
thiophenolic moiety while other derivatives bearing a phenolic
Figure 4 Structure activity relationship for 2-(aryloxy-
alkylthio)-1H-benzoimidazoles as Hh inhibitors.
building block (like compounds 14a–14c) (Table 3) showed
To validate the biological activity of the mercaptobenzoimid-
azoles, a selection of compounds were tested for their Hh in-
hibition in the Shh-LIGHT 2 assay. The Shh-LIGHT 2 cells
carry a firefly luciferase reporter under the control of a GLI-
dependent promoter. Luciferase gene activity can be specifi-
cally induced by treatment of the cells with the Hh agonist
Purmorphamine; while treatment with inhibitors leads to a re-
duction in the luminescent signal. The activity against Hh sig-
naling of all tested compounds was confirmed using this or-
thogonal assay system. Just as already seen in the osteogenesis
results, compound 10a was found to be the most active com-
pound, while e.g. compound 10n was inactive (Table 4).
Again, compound 10d was the only compound that affected
the viability of the Shh-LIGHT 2 cells.
weaker inhibition values in comparison to the originally inves-
tigated ethylthio-substituted benzoimidazoles (e.g. compound
10a in direct comparison to compound 14a). Except from one
example (10d), none of the compounds affected the viability
of the cells (see Figure 4). In addition, an inhibition of the al-
kaline phosphatase could also be excluded (supplementary
info). A summary of the structure activity relationship for 2-
(aryloxyalkylthio)-1H-benzoimidazoles as Hh inhibitors is
presented in Figure 4.
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ACKNOWLEDGMENT
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This work was supported by the Helmholtz program Biointerfaces
in Technology and Medicine (BIFTM) and the
Landesgraduiertenförderung Baden-Württemberg (scholarship for
S. Susanto). We thank Alexandre Felten for his contribution to the
syntheses and Antje Neeb and Andrew Cato of the Institute of Tox-
icology and Genetics at the KIT for fruitful discussions. We
acknowledge support by Deutsche Forschungsgemeinschaft and
the core facility Molecule Archive.
Table 4 Results of the Shh-LIGHT 2 assay.
VIA
IC50
[µM]b,c
VIA IC50
[µM]b,c
Shh light
IC50 [µM]a
Shh light
IC50 [µM]a,c
10a
10b
10c
10d
10f
10i
3.16±0.12
5.11±1.05
8.92±1.51
8.12±2.31
7.89±2.19
6.93±2.22
6.49±2.50
inact
inact
inact
7.70
inact
inact
inact
10k
10q
11a
11b
13
7.29±2.15
inact
3.48±0.12
3.55±0.23
> 10
inact
inact
inact
inact
inact
inact
inact
9
ABBREVIATIONS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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41
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44
45
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47
48
49
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Hh, Hedgehog; ALK, alkaline phosphatase; SMO, Smoothened;
Ptch1, Patched; BF3, binding function 3; VIA, viability; IC, inhib-
itory concentration, inact, inactive.
14a
1
4.12±0.54
0.98±0.04
10j
aHh inhibiting activity was validated in a subset of compounds using
Shh-LIGHT 2 assay; b VIA = viability, inact = inactive, - = not tested;
cell viability was determined using Cell Titer Glo assay; cCompounds
were scored inactive if the remaining activity or viability after com-
pound treatment was higher than 80% (compared to the DMSO con-
trol).
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While several small molecules targeting the Hh signaling
pathway are well-known drugs in clinical use, the arising re-
sistance towards those established compounds enforces the
identification of new compound classes with inhibitory effect
for the development of new lead structures. We discovered S-
alkylated 2-mercaptobenzoimidazoles as a new compound
class that exhibits activity in the low micromolar range. Alt-
hough all of the tested compounds were found to have lower
activities in the osteogenesis assay in comparison to the estab-
lished Hh inhibitor Vismodegib being currently in clinical use,
they serve as beneficial starting points for novel modes of Hh
inhibition to overcome resistance. The scope of the 2-mercap-
tobenzoimidazole motif been investigated by the synthesis of
further derivatives, showing that the elongation of the linker
unit and the exchange of particular substitution patterns are
tolerable without a noteworthy loss of activity. These promis-
ing results will be used for further modifications of the 2-mer-
captobenzoimidazole core structure aiming for the enhance-
ment of the compound activities into a nanomolar range in fu-
ture.
ASSOCIATED CONTENT
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Treatment of Adults With Recurrent, Locally Advanced Basal Cell
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(13) Burness, C. B.; Sonidegib: First Global Approval. Drugs 2015,
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Supporting Information
Supporting Information covers the syntheses of the 2-mercap-
tobenzoimidazoles 10–14 and their precursors 9 as well as the
analytical data, copies of the spectra of all synthesized com-
pounds, and crystallographic data of 10c and 11b. In addition,
the Supporting Information contains the description of the bio-
logical methods. It is available free of charge on the ACS Pub-
lications website. CCDC 1561471 (10c), and CCDC 1561472
(11b) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
(14) Lauressergues, E.; Heusler, P.; Lestienne, F.; Troulier,
D.; Rauly-Lestienne, I; Tourette, A.; Ailhaud, M.-C.; Cathala, C.;
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Dumoulin, A.; De Vries, L.; Cussac, D. Pharmacological evalua-
tion of a series of smoothened antagonists in signaling pathways
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bridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
AUTHOR INFORMATION
Corresponding Author
* nicole.jung@kit.edu; braese@kit.edu
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