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. 2017 Jul 28;8(9):931–935. doi: 10.1021/acsmedchemlett.7b00100

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

Simone Gräßle †, Steven Susanto †, Sonja Sievers §, Emel Tavsan †, Martin Nieger ∥, Nicole Jung †,‡,*, Stefan Bräse †,‡,*
PMCID: PMC5601384  PMID: 28947939

Abstract

graphic file with name ml-2017-00100x_0009.jpg

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 class that exhibits Hedgehog signaling activity in a low micromolar range. The scope of the 2-mercaptobenzoimidazole 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.

Keywords: Hedgehog signaling, cancer, small molecules, 2-mercaptobenzoimidazoles

The Hedgehog (Hh) signaling pathway acts as a key mediator of many fundamental processes, such as cell fate specification, proliferation, and patterning, as well as tissue morphogenesis and homeostasis.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 absence 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 cancers of the skin (basal cell carcinoma) and the brain (medulloblastoma) where activating mutations of Hh signaling components have been found.4 Furthermore, there are emerging roles for Hh signaling also in other cancer types such as breast, ovarian, and prostate cancer, while the particular contribution and effect of Hh signaling on different cancer types is still unclear.5−7 Synthetic small molecule 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 developing resistance against currently available drugs.20,21 Searching for new structures with potential to inhibit Hh signaling, an in-house library of 940 compounds22 has been screened resulting in the identification of 2-mercaptobenzoimidazoles as new lead structures. 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 reported as a promising compound class toward 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-mercaptobenzoimidazoles with respect to the Hh signaling pathway has been reported before.

Figure 1.

Figure 1

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Known inhibitors of the Hedgehog pathway.8−9,10,1,12,13,14

Figure 2.

Figure 2

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Structures of selected drugs including a 2-mercaptobenzoimidazole core (4, 5),23−26 the potent BF3-inhibitor 6,28 and a selected library member 7 [R1 = (CH2)3CO2Et].29

Recently, we were able to present a solid supported strategy for the synthesis of diverse S,N-dialkylated 2-mercaptobenzoimidazoles by immobilization and derivatization of mercaptobenzoimidazole 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 investigated toward 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 reduction of the Hh signaling; only the results of the derivative 7 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 mercaptobenzoimidazoles was synthesized.30 Therefore, a literature-known procedure without functionalization of the NH-group was successfully used.28 The library consisted of five main types of compounds (10 to 14) (Tables 1–3), which differ in the type or position of the heteroatoms N, O, and S and the length of the bridging linker unit (Scheme 1). All compounds were tested toward their activity in the Hedgehog signaling pathway and have been evaluated in comparison to the Hh inhibitor Vismodegib (1), being a benchmark drug for the inhibition of Hh signaling with an IC50 of approximately 0.1 μM in the herein described osteogenesis assay (Table 1).

Table 1. O-Aryl-Type C2-Based Mercaptobenzoimidazoles 10a–10q.

graphic file with name ml-2017-00100x_0006.jpg

  R1 R2 R3 R4 R5 Hh IC50 [μM]a VIA IC50 [μM]b,c
10a Me H H H Me 1.76 ± 0.07 inact
10b H Me H H H 2.08 ± 0.15 inact
10c H H H H H 2.22 ± 0.09 inact
10d H H OH H H 2.23 ± 0.41 7.12
10e F H H H H 2.32 ± 0.13 inact
10f H Me Cl H H 2.57 ± 0.02 inact
10g OMe H H H H 2.61 ± 0.08 inact
10h Me Me H H Me 2.90 ± 0.50 inact
10i Me H H H H 4.26 ± 0.86 inact
10j H NO2 H H H 4.47 ± 0.18 inact
10k H -(CH)4-   H H 4.49 ± 0.44 inact
10l Me H H Me H 6.41 ± 1.41 inact
10m H H H iPr H 9.17 ± 1.23 inact
10n H H Ph H H inact inact
10o iPr H H H H >10 inact
10p NO2 H Me H H inact inact
10q H H H CO2Me H inact inact
1           0.14 ± 0.1 inact
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a

Hh inhibiting activity was determined using mesodermal stem cells C3H/10T1/2 in the osteogenesis assay.

b

VIA = viability, inact = inactive; cell viability was determined using Cell Titer Glo assay.

c

Compounds were scored inactive if the viability of the cells was higher than 80% (compared to the DMSO control).

Table 3. S- and O-Aryl-Type C3-Based Mercaptobenzoimidazoles 13 and 14.

graphic file with name ml-2017-00100x_0008.jpg

  Z R1 R2 R3 R4 R5 Hh IC50 [μM]a VIA IC50 [μM]b,c
13 S H H Cl H H 2.85 ± 0.1 inact
14a O Me H H H Me 5.60 ± 0.31 inact
14b O H H Me H H 6.29 ± 1.26 inact
14c O H Me H H H inact inact
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a

Hh inhibiting activity was determined using mesodermal stem cells C3H/10T1/2 in the osteogenesis assay.

b

VIA = viability, inact = inactive; cell viability was determined using Cell Titer Glo assay.

c

Compounds were scored inactive if the viability of the cells was higher than 80% (compared to the DMSO control).

Scheme 1. General Scheme for the Synthesis of Compounds 10–14 and Crystal Structures for Selected Examples (10c, 11b).

Scheme 1

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(A) Two different conformers of 10c. (B) Asymmetric unit of 11b, showing the two crystallographic independent molecules (displacement parameters are drawn at 50% probability level).

For investigating signal transduction through the Hh pathway, mouse embryonic mesodermal fibroblast C3H/10T1/2 cells were used in the osteogenesis assay. These multipotent mesenchymal progenitor cells can differentiate into osteoblasts upon treatment with the SMO agonist Purmorphamine.31,32 During differentiation, osteoblast specific genes such as alkaline 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-(aryloxyalkylthio)-1H-benzoimidazoles 10–14 revealed a significantly higher inhibition of the Hh pathway for almost all compounds in comparison to the initially identified S,N-dialkylated 2-mercaptobenzoimidazole 7b. Especially, several derivatives of the series of 2-((2-aryloxyethyl)thio)-1H-benzoimidazoles 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 depends on the substitution pattern of the phenolic ring system. While the 2,6-dimethylphenoxy derivative 10a and the 3-methylphenoxy derivative 10b gave the best results in the screening of the 2-mercaptobenzoimidazole library, a 3-fold decrease of the inhibition was detected for very similar compounds 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 signal (Figure 3 shows the dose-dependent inhibition of the Hh signal). While all compounds 10 rely on the same core structure, compounds of type 11–14 were examined to elucidate the 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-mercaptobenzoimidazole 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 compounds 12a,b (Table 2) caused loss of activity.

Figure 3.

Figure 3

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Dose–response curve of the most promising compound 10a. Half-logarithmic plot of Hh activity against compound concentration.

Table 2. S-Aryl-Type C2-Based Mercaptobenzoimidazoles 11a–c and 12a,b.

graphic file with name ml-2017-00100x_0007.jpg

  X Y Z R1 R2 R3 R4 R5 Hh IC50 [μM]a VIA IC50 [μM]b,c
11a NH S S H Me H H H 3.06 ± 0.18 inact
11b NH S S H OMe H H H 5.63 ± 0.73 inact
11c NH S S Cl Cl Cl H H 5.71 ± 0.91 inact
12a S NH O Me H H Me Me >10 inact
12b S NH O H H H H Me inact inact
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a

Hh inhibiting activity was determined using mesodermal stem cells C3H/10T1/2 in the osteogenesis assay.

b

VIA = viability, inact = inactive; cell viability was determined using Cell Titer Glo assay.

c

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 benzoimidazoles 10, a small set of propylthio-substituted benzoimidazoles (13, 14a–14c) (Table 3) has been investigated to determine the effect of the aliphatic linker part on the inhibition of Hh signaling. It was found that the inhibition of the Hh signaling can also be achieved with compounds bearing a propyl linker part. Activity in a low micromolar range could be detected for compound 13 (Table 3), which has been synthesized with a thiophenolic moiety, while other derivatives bearing a phenolic building block (like compounds 14a–14c) (Table 3) showed weaker inhibition values in comparison to the originally investigated 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 alkaline phosphatase could also be excluded (Supporting Information). A summary of the structure–activity relationship for 2-(aryloxyalkylthio)-1H-benzoimidazoles as Hh inhibitors is presented in Figure 4.

Figure 4.

Figure 4

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Structure–activity relationship for 2-(aryloxyalkylthio)-1H-benzoimidazoles as Hh inhibitors.

To validate the biological activity of the mercaptobenzoimidazoles, a selection of compounds was tested for their Hh inhibition 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 specifically induced by treatment of the cells with the Hh agonist Purmorphamine; while treatment with inhibitors leads to a reduction in the luminescent signal. The activity against Hh signaling of the most important compounds was confirmed using this orthogonal assay system. Just as already seen in the osteogenesis results, compound 10a was found to be the most active compound, while, e.g., compound 10q was inactive (Table 4). Again, compound 10d was the only compound that affected the viability of the Shh-LIGHT 2 cells.

Table 4. Results of the Shh-LIGHT 2 Assay.

  Shh light IC50 [μM]a VIA IC50 [μM]b,c   Shh light IC50 [μM]a,c VIA IC50 [μM]b,c
10a 3.16 ± 0.12 inact 10k 7.29 ± 2.15 inact
10b 5.11 ± 1.05 inact 10q inact inact
10c 8.92 ± 1.51 inact 11a 3.48 ± 0.12 inact
10d 8.12 ± 2.31 7.70 11b 3.55 ± 0.23 inact
10f 7.89 ± 2.19 inact 13 >10 inact
10i 6.93 ± 2.22 inact 14a 4.12 ± 0.54 inact
10j 6.49 ± 2.50 inact 1 0.98 ± 0.04 inact
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a

Hh inhibiting activity was validated in a subset of compounds using Shh-LIGHT 2 assay.

b

VIA = viability, inact = inactive; cell viability was determined using Cell Titer Glo assay.

c

Compounds were scored inactive if the remaining activity or viability after compound treatment was higher than 80% (compared to the DMSO control).

While several small molecules targeting the Hh signaling pathway are well-known drugs in clinical use, the arising resistance toward 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. Although all of the tested compounds were found to have lower activities in the osteogenesis assay in comparison to the established Hh inhibitor Vismodegib currently in clinical use, they serve as beneficial starting points for novel modes of Hh inhibition to overcome resistance. The scope of the 2-mercaptobenzoimidazole 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 promising results will be used for further modifications of the 2-mercaptobenzoimidazole core structure aiming for the enhancement of the compound activities into a nanomolar range in the future.

Acknowledgments

This work was supported by the Helmholtz program Biointerfaces in Technology and Medicine (BIFTM) and the Landesgraduiertenförderung Baden-Württemberg (scholarship for S.S.). We thank Alexandre Felten for his contribution to the syntheses and Antje Neeb and Andrew Cato of the Institute of Toxicology and Genetics at the KIT for fruitful discussions. We acknowledge support by Deutsche Forschungsgemeinschaft and the core facility Molecule Archive.

Glossary

ABBREVIATIONS

Hh

Hedgehog

ALK

alkaline phosphatase

SMO

smoothened

Ptch1

patched

BF3

binding function 3

VIA

viability

IC

inhibitory concentration

inact

inactive

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.7b00100.

  • Syntheses of the 2-mercaptobenzoimidazoles 10–14 and their precursor 9 as well as the analytical data, copies of the spectra of all synthesized compounds, and crystallographic data of 10c and 11b, and biological methods (PDF)

The authors declare no competing financial interest.

Notes

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 Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Supplementary Material

ml7b00100_si_001.pdf (4MB, pdf)

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Associated Data

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Supplementary Materials

ml7b00100_si_001.pdf (4MB, pdf)

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