Synthesis of 2-methoxybenzamide derivatives and evaluation of their hedgehog signaling pathway inhibition

Article abstract of DOI:10.1039/d1ra00732g

Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened (Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway to target the Smo receptor is a practical approach for development of anticancer agents. We report herein the design and synthesis of a series of 2-methoxybenzamide derivatives as Hh signaling pathway inhibitors. The pharmacological data demonstrated that compound 21 possessed potent Hh pathway inhibition with a nanomolar IC50 value, and it prevented Shh-induced Smo from entering the primary cilium. Furthermore, mutant Smo was effectively suppressed via compound 21. The in vitro antiproliferative activity of compound 21 against a drug-resistant cell line gave encouraging results. This journal is

Full text of DOI:10.1039/d1ra00732g

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Synthesis of 2-methoxybenzamide derivatives and
evaluation of their hedgehog signaling pathway
inhibition†
Cite this: RSC Adv., 2021, 11, 22820
*
Chiyu Sun,
Dajun Zhang, Tian Luan, Youbing Wang, Wenhu Zhang, Lin Lin,
Meihua Jiang, Ziqian Hao and Ying Wang
Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened
(Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway
to target the Smo receptor is a practical approach for development of anticancer agents. We report
herein the design and synthesis of a series of 2-methoxybenzamide derivatives as Hh signaling pathway
inhibitors. The pharmacological data demonstrated that compound 21 possessed potent Hh pathway
inhibition with a nanomolar IC50 value, and it prevented Shh-induced Smo from entering the primary
cilium. Furthermore, mutant Smo was effectively suppressed via compound 21. The in vitro
antiproliferative activity of compound 21 against a drug-resistant cell line gave encouraging results.
Received 27th January 2021
Accepted 22nd June 2021
DOI: 10.1039/d1ra00732g
rsc.li/rsc-advances
murine Smo mutant.28,29 The bottlenecks of Hh pathway
inhibitors have prompted an extensive search for novel che-
Introduction
motype inhibitor.
The hedgehog (Hh) signaling pathway is one of the pivotal
targets for cancer therapy, and it is fundamental in regulating
embryonic development and maintaining homeostasis of adult
tissues.1–4 Upon secretion of Hh ligands, the transmembrane
protein patched (Ptch) abrogates its inhibition of smoothened
(Smo) receptor.5–8 Smo trafficking into the primary cilium (PC)
transmits the signal to the downstream cascade.9–11 The glioma
(Gli) transcription factors translocate into the nucleus and
activate the target genes.12–14 Abnormal activation of the Hh
pathway is able to facilitate tumorigenesis and metastasis,
inducing multiple solid tumors and non-solid tumors such as
basal cell carcinoma (BCC), medulloblastoma (MB), pancreatic
carcinoma, colorectal carcinoma and leukaemia.15–20 Hence, the
inhibition of the Hh signaling pathway is deemed as a prom-
ising option for antitumor therapy.
There have been two highly efficacious Hh pathway inhibi-
tors, vismodegib (1) and sonidegib (2) (Fig. 1), launched for
treating BCC nowadays.21–23 However, it was reported that 30
percent of patients who had taken 1 suffered from several
adverse reactions such as muscle cramps, hair loss, taste
disorders, weight loss, and fatigue.24,25 Besides, acquired drug
resistance is a major drawback with this class of drugs. The best
studied instance was that Smo mutation (D473H) interfered
with the binding of the drug to Smo.26,27 Similarly, Smo D477G
in the mouse MB allogra model was deemed as a comparable
In recent years, several benzimidazole derivatives, such as
glasdegib, SANT-2(3), have exhibited potent Hh pathway inhi-
bition, all of which target Smo receptor.30–32 Compound 3 is
a known Smo inhibitor with submicromolar IC50 in the Shh
light II test.33 Combination of glasdegib and low-dose of arabi-
noside are currently for the treatment of leukemia.34 Alterna-
tively, aryl amide groups in some Hh antagonists were deemed
as the pharmacophores responsible for high affinity with Smo
receptor, for instance, taladegib, XL139 and MDB5.35–37 In our
effort on the discovery of novel chemotype Hh inhibitors
(Fig. 2), aryl amide group was introduced into compound 3 to
replace the metabolically labile triethoxy groups. The resulting
compound 4 (IC50 of 0.25 mM) displayed similar potency to
compound 3 in Gli-luciferase (Gli-luc) reporter assay. With the
addition of methoxy, the formation of a new hydrogen bond (H-
bond) acceptor was in compound 10 (IC50 of 0.17 mM). To
enhance the molecular exibility, the replacement of benz-
imidazole with phenyl imidazole fragment offered compound
17 with higher potency (IC50 of 0.12 mM) in the light of the ring-
opening strategy. Followed by Smo crystal structures analysis
(PDB ID: 5L7I),38 compounds 3, 4, 10 and 17 were docked into
School of Pharmacy, Shenyang Medical College, Shenyang 110034, China. E-mail:
scy_dream@126.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra00732g
Fig. 1 Structure of hedgehog pathway inhibitors.
22820 | RSC Adv., 2021, 11, 22820–22825
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Fig. 2 Design of 2-methoxybenzamide derivatives.
Fig. 3 (A) Overlay of compounds 3 (yellow), 4 (green), 10 (blue) and 17 (violet) in binding pocket of Smo. (B) Docking conformation of compound
3 at the binding site. (C) Docking conformation of compound 17 at the binding site. Hydrogen bonds are represented by the dashed green lines.
Surrounding amino acid are shown in grey stick format and labelled.
Scheme 1 Reagents and conditions: (a) (1) SOCl2, toluene, 80 ꢁC, 3 h; (2) methyl 4-amino-2-methoxybenzoate, TEA, DMF, rt, overnight, yield
85%; (b) NaOH, aqueous alcohol, 40 ꢁC, 5 h, yield 83–92%; (c) 3-(1H-benzo[d]imidazol-2-yl)-4-chloroaniline, HATU, DIPEA, DCM, rt, 24 h, yield
71–86%; the specific position of R group directed at Table 1.
the binding pocket of Smo receptor using AutoDock vina.39 The
Result and discussion
Chemistry
calculated binding energy of their best poses was ꢀ9.4, ꢀ10.9,
ꢀ12.5, ꢀ12.7 kcal molꢀ1, respectively, and their binding
orientations superimposed well with one another (Fig. 3A).
Comparing the interaction patterns between compounds 3 and
17 (Fig. 3B and C), the introduction of aryl amide group and
methoxy afforded two extra H-bonds with Tyr394 and Arg400.
Herein, the novel compounds with 2-methoxybenzamide skel-
eton were developed and their Hh pathway inhibition were
evaluated.
Compounds 10–23 were prepared according to the routes out-
lined in Schemes 1 and 2. Substituted acids reuxed in SOCl2
for 3 h to generate acyl chlorides, which were condensed with
methyl 4-amino-2-methoxybenzoate in the presence of triethyl-
amine in dimethyl formamide at room temperature overnight
to obtain the intermediate 5a–g. Then, the esters were hydro-
lyzed to the carboxylic acid 6a–g, before their amidation with 3-
(1H-benzo[d]imidazol-2-yl)-4-chloroaniline33 afforded the target
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Scheme 2 Reagents and conditions: (a) CH3ONa, CH3OH, ꢀ20 ꢁC, 2 h; NH4Cl, 40 ꢁC, 3 h, yield 46%; (b) 2-bromoacetophenone, NaHCO3, THF,
reflux, 40 ꢁC, 24 h, yield 65%; (c) SnCl2$2H2O, ethanol, HCl, 80 ꢁC, reflux, 8 h, yield 86%; (d) 5a–g, HATU, DIPEA, DCM, rt, 24 h, yield 76–84%; the
specific position of R group directed at Table 1.
Table 1 Hh signaling pathway inhibition of designed compounds
Compd.
R
X
Yield (%)
Gli-luc reporter IC50a (mM)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3b
2-Cl
2,4-Cl2
3-F
CH
CH
CH
CH
N
75
71
83
85
80
73
86
79
76
84
82
81
77
83
0.17 ꢂ 0.06
0.53 ꢂ 0.05
0.79 ꢂ 0.14
0.34 ꢂ 0.07
0.05 ꢂ 0.02
0.86 ꢂ 0.09
0.08 ꢂ 0.02
0.12 ꢂ 0.06
0.26 ꢂ 0.08
0.31 ꢂ 0.09
0.25 ꢂ 0.04
0.03 ꢂ 0.01
0.15 ꢂ 0.08
0.07 ꢂ 0.02
0.18 ꢂ 0.03
0.02 ꢂ 0.01
4-F
2-Cl
6-Cl
—
2-Cl
2,4-Cl2
3-F
N
N
CH
CH
CH
CH
N
4-F
2-Cl
6-Cl
—
N
N
1c
a
Results expressed as the mean ꢂ standard deviation of three separate IC50 determinations. For each determination, concentration-inhibition
b
curves were acquired in triplicate and then averaged to afford a single IC50 curve with a 95% condence interval. Used as a lead compound.
c
Used as a positive control.
compounds 10–16. In the presence of sodium alkoxide, 2-
chloro-5-nitrobenzonitrile and ammonium chloride combined
chemically to produce amidine hydrochloride 7 in a yield of
45%. Next, the cyclization of 7 and 2-bromoacetophenone gave
imidazole intermediate 8, which converted to amino compound
9 by adding stannous chloride in acidic ethanol solution. The
condensation of 9 with 6a–g generated the target compounds
17–23.
Biological evaluation
As shown in Table 1, the targeted compounds contained the
following three parts: A, B and a connector. Part A involved
imidazole group, and part B contained aryl amide. 2-Methox-
ybenzamide scaffold was the connector.
Using compound 1 as positive control and compound 3 as
the lead compound, the Hh pathway inhibition of compounds
22822 | RSC Adv., 2021, 11, 22820–22825
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Fig. 6 Cell viability of Daoy cells incubated with the indicated doses of
vismodegib and compound 21 for 48 h. Data represent mean ꢂ SD of
experiments performed in triplicate.
activity in this class, which was even 6-fold higher as compared
to compound 3. Also, the Hh pathway inhibition of compound
21 was comparable to that of compound 1.
Fig. 4 Benzamide analogs inhibit Hh pathway through regulating
Smo. Error bars represent standard deviation of three parallel groups.
To explore the mode of action of the representative
compound 21 in Hh signaling pathway, its effect on Smo ciliary
translocation was measured. As presented in Fig. 4, Smo local-
ization in the primary cilia enhanced signicantly as the
NIH3T3 cells expressing Smo were treated with Shh, an agonist
of Hh pathway. In compound 21 group, there was a sharp drop
in Smo ciliary translocation, and this result was similar to that
of vismodegib group, indicating that the target of compound 21
was Smo receptor. It was reported that drug-resistant mutation
in Smo reduced the Hh pathway inhibition of vismodegib by
a large of margin.40 To further test the potency of compound 21
on Smo mutation, wild-type (WT) or mutant D477G was over-
expressed in the NIH3T3-Gli-Luc reporter cell line. Compliant
with previous reports, mutant D477G was refractory to vismo-
degib (Fig. 5A). In contrast, the Hh pathway inhibitory activity of
compound 21 slightly decreased in mutant D477G (Fig. 5B). The
2.4-fold shi in IC50 suggested that mutant D477G did not
markedly inuence its interaction with Smo (IC50 ¼ 39 nM for
WT, IC50 ¼ 96 nM for mutant).
10–23 have been evaluated in Gli luciferase reporter assay. The
results were expressed as IC50 values. At the outset, the rela-
tionship between part A and its Hh inhibitory activity was dis-
cussed. Encouragingly, the activity of phenyl imidazole
analogues were higher than that of benzimidazole counterparts
(11 vs. 18, 12 vs. 19 and 13 vs. 20), suggesting that ring-opening
structural modication was effective. Further analysis revealed
that different Hh pathway inhibition was observed as various R
groups were introduced into the aromatic ring (part B). Mono-
chlorine substituent 17 exhibited decent activity (IC50 ¼ 0.12
mM), however, dichloride 18 lost potency by 2.2-fold (IC50 ¼ 0.26
mM). Although uoro analogs such as 19 and 20 (IC50 ¼ 0.31 mM
and 0.25 mM) were effective in suppressing Hh signaling
pathway, their IC50 values were larger than that of compound
17. We then enhanced the hydrophilicity of part B by replacing
phenyl with pyridine, and it was satisfying that the potency of
pyridyl derivative 21 (IC50 ¼ 0.03 mM) was higher as compared to
that of phenyl derivative 17. When chlorine located at 20-posi-
tion of nicotinamide group, its anti-Hh activity improved (21 vs.
23 and 14 vs. 16). Diminished activity was observed as the
chlorine transferred to the 60-position of the nicotinamide
group (22 vs. 23). Overall, compound 21 yielded the most potent
Due to the failure of vismodegib to kill MB cells in patient,41
it was anticipated that compound 21 obtained a positive
respond in vitro. Then, we carried out the antiproliferative assay
Fig. 5 The inhibition of drug-resistant Smo mutant for compound 21. The inhibition of Gli-Luc reporter activity by vismodegib (A) and compound
21 (B) in NIH3T3-Gli-Luc cells overexpressing wild-type Smo or Smo D477G. Error data point represents the mean ꢂ SD of three determinations.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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Fig. 7 (A) Docking conformation of compound 1 (orange) at the binding site. (B) Docking conformation of compound 21 (pink) at the binding site.
Hydrogen bonds are represented by the dashed green lines. Surrounding amino acid are shown in grey stick format and labelled.
on Daoy cell line which was a proper MB model with consecu- and Technology Fund Project of Shenyang Medical College
tive Hh signaling activation. To our delight, compared with (20201004 and 20205041).
vismodegib, compound 21 demonstrated stronger anti-
proliferation against Daoy cells (Fig. 6). And the cell viabilities
of compound 21 were 72% and 43% at concentrations of 1 mM
Notes and references
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In this report, novel series of Hh signaling pathway antagonists
with 2-methoxybenzamide skeleton were explored by structural
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