Discovery of N-(2-(Benzylamino)-2-oxoethyl)benzamide analogs as a novel scaffold of pancreatic β-cell protective agents against endoplasmic reticulum stress

Article abstract of DOI:10.1111/cbdd.13650

Endoplasmic reticulum (ER) stress-induced pancreatic β-cell dysfunction and death play important roles in the development of diabetes. The 1,2,3-triazole derivative 1 is one of only a few structures that have thus far been identified that protect β cells against ER stress. However, this compound has narrow activity range and limited aqueous solubility. To overcome these, we designed and synthesized a new scaffold in which the triazole pharmacophore was substituted with a glycine-like amino acid. Structure–activity relationship studies on this scaffold identified a N-(2-(Benzylamino)-2-oxoethyl)benzamide analog WO5m that possesses β-cell protective activity against ER stress with much improved potency (maximal activity at 100% with EC₅₀ at 0.1?±?0.01?μm) and water solubility. Identification of this novel β-cell protective scaffold thus provides a new promising modality for the treatment of diabetes.

Full text of DOI:10.1111/cbdd.13650

DR WEIDONG WANG (Orcid ID : 0000-0003-3619-0953)
Article type : Research Letter
Title:
Discovery of N-(2-(Benzylamino)-2-oxoethyl)benzamide analogs as a Novel Scaffold of
Pancreatic β-cell Protective Agents against ER Stress
Running title:
Benzamide analogs Protects β-cells against ER Stress
Venkateswararao Eedaa, Oana Herlea-Panaa, Hui-Ying Limb* and Weidong Wanga*
a Department of Medicine, Division of Endocrinology, Harold Hamm Diabetes Center, The
University of Oklahoma Health Science Center, b Department of Physiology, The University of
Oklahoma Health Science Center, 941 Stanton L. Young Boulevard, Oklahoma City, Oklahoma
73104, United States
This article has been accepted for publication and undergone full peer review but has not been through the
copyediting, typesetting, pagination and proofreading process, which may lead to differences between this
version and the Version of Record. Please cite this article as doi: 10.1111/CBDD.13650
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Key words: ER stress, Pancreatic  cell survival, Diabetes, UPR, Aqueous solubility
* Corresponding Authors:
Weidong Wang
Weidong-wang@ouhsc.edu
Hui-Ying Lim
Hui-Ying-Lim@ouhsc.edu
Acknowledgments: This work was supported by Oklahoma Center for the Advancement of
Science and Technology and National Institutes of Health (DK108887, DK116017) to W.W..
The authors claim no conflict of interest. Data available on request from the authors.
Abstract:
Endoplasmic reticulum (ER) stress-induced Pancreatic β-cell dysfunction and death plays
important roles in the development of diabetes. The 1,2,3-triazole derivative 1 is one of only a
few structures that have thus far been identified that protect β cells against ER stress. However, this
compound has narrow activity range and limited aqueous solubility. To overcome these, we
designed and synthesized a new scaffold in which the triazole pharmacophore was substituted
with a glycine-like amino acid. Structure-activity relationship studies on this scaffold identified a
N-(2-(Benzylamino)-2-oxoethyl)benzamide analog WO5m that possesses β-cell protective
activity against ER stress with much improved potency (maximal activity at 100% with EC50 at
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0.1  0.01 µM) and water solubility. Identification of this novel β-cell-protective scaffold thus
provides a new promising modality for the treatment of diabetes.
Key words: ER stress, beta cell death, diabetes, beta cell survival, benzamide, anti-diabetic drug,
hyperglycemia.
Graphical Abstract
1. Introduction:
The endoplasmic reticulum (ER) has key roles in synthesis, folding and maturation of secreted
transmembrane proteins.1-2 Upon translation, secretory, luminal and membrane proteins are
translocated into the lumen of the ER where they are covalently modified and attain their proper
folding.3 A balance between the ER protein loading and its folding capacity must be established
to maintain the proper function of the ER. However, pathophysiological stimuli can disrupt this
ER homeostasis, resulting in an accumulation of unfolded or misfolded proteins in the ER, a
condition known as ER stress. ER stress triggers an evolutionarily conserved signaling cascade
called the unfolded protein response (UPR). This process is mediated by three ER membrane-
spanning proteins, inositol-requiring protein 1 (IRE1), PKR-like ER kinase (PERK), and
activating transcription factor 6 (ATF6), which act as unfolded protein sensors.4-7 In unstressed
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cells, these sensors are maintained in an inactive state through interaction with the protein
chaperone binding immunoglobulin protein (BiP). Under ER stress, unfolded and misfolded
proteins accumulate in the ER and bind to and sequester BiP, thereby releasing and activating the
8
sensors . As an initial adaptive response, IRE1, PERK, and ATF6 each activates a series of
events aimed at restoring ER homeostasis by altering the translation, folding, and post-
translational modification of secreted and membrane proteins.1 Under chronic or severe ER
stress, however, the UPR often fails to adequately resolve ER stress and instead activates the
expression of ER stress-specific pro-apoptotic genes such as the transcription factor C/EBP-
homologous protein (CHOP), eventually leading to cell death.
Type 2 Diabetes (T2D), a chronic condition of hyperglycemia, is a pervasive threat to health and
a burden on the healthcare system in the United States. T2D usually develops in obese and
insulin-resistant subjects with the onset of insulin-producing β cell dysfunction and death.9
Increasing evidence indicates that ER stress is a major mechanism underlying the progressive
decline in β cell function and mass in T2D patients.10-11 ER stress has also been implicated in
T1D and monogenic diabetes.12-13 These findings illustrate the therapeutic potential for novel
drugs that block ER stress-induced  cell dysfunction and death for the treatment of diabetes.
14-15
Recent reports of chemical chaperons such as 4-phenyl butyrate (PBA)
and
14-17
tauroursodeoxycholic acid (TUDCA)
(see Figure 1) have shown effect on ER stress
modulation and antidiabetic activity in T2D animal models. However, because of their low
efficacy, large dose is needed for any therapeutic treatment, which makes it unlikely that these
agents can be used for the treatment for human patients due to the increased toxicity.18-19
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Figure 1. Known β-cell protecting agents against ER stress.
Recently, our group has discovered a novel small molecule, 1-(3-chloro-2-methylphenyl)-N-(2,5-
20
dimethylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (1)
that protects  cell function
and survival against ER stress with maximal activity at 97% and an EC50 value of about 6 µM.
However, the 1,2,3-triazole analog exhibited  cell protective activity at around 5~10 µM and
aqueous insolubility, which becomes a hindrance for further drug development. In this study, we
used 1 as a starting point to synthesize a series of novel peptide mimics and obtained several new
analogs with better potency in a wider range of concentration and with improved aqueous
solubility.
2. Results and discussion
Synthesis of N-(2-(Benzylamino)-2-oxoethyl)benzamide 5a-q analogs were outlined in Scheme
1 and substituents are listed in Table 1. Commercially available substituted benzoic acids 2 were
coupled with corresponding substituted ethyl glycinates 3 in the presence of EDC/HOBt in
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dimethylformamide to yield benzoylglycine ester, which was hydrolyzed with an aqueous
solution of LiOH in ethanol at 5−10 °C afforded key intermediate benzoylglycine 4. For
preparation of 5a-q analogs, benzoylglycines 4 were reacted with various substituted benzyl
amine in dichloromethane using HATU at 0-rt yielded N-(2-(Benzylamino)-2-
oxoethyl)benzamide 5 analogs in excellent yields. All these synthesized compounds were listed
in Table 1 and characterized by physical and spectral analysis data that confirmed their assigned
structures.
Scheme 1. Synthesis of compounds 5a-q. Reagents & Conditions: a) HOBt, EDC, DIPEA, DMF
at 0 oC-rt; b) LiOH/EtOH, 0 oC-rt; c) HATU, DIPEA/DCM
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Table 1. Effects of compounds 5a-q and 1 on CHOP-Luc reporter and β cell viability against
(tunicamycin) Tm
Compound
ID
R1
R2
R3
Max
Activity
(%)a
EC50
(µM)b
1c
3-Cl,2-Me
3-Cl,2-Me
3-Cl,2-Me
3-Cl,2-Me
3-Cl,2-Me
3-Cl,2-Me
3-Cl,2-Me
3-Cl,2-Me
3-Cl,2-Me
3-Cl,2-Me
H
-
2,5-di Me
2,5-di Me
2-Pyridine
Indazole
4-OMe
97
6  1
18  4
38  9
-
5a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
45
16
5b
5c
Cytotoxic
55
5d
32  7
40  12
34  8
13  1
10  2
32  7
43  11
45  8
41  6
0.1  0.01
65  8
29  6
5e
4-SO2NH2
Tyramine
4-CF3
52
5f
41
5g
88
5h
3-OMe,4-OH
3-CF3
100
46
5i
5j
4-CF3
35
5k
4-Et
4-CF3
42
5l
4-F
4-CF3
12
5m (WO5m)
3-OH
4-CF3
100
30
5n
5o
3-OH
3-OMe,4-OH
4-CF3
3-OMe,4-
43
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OH
5p
5q
3-Cl,2-Me
3-Cl,2-Me
Me
4-CF3
4-CF3
34
63  4
Tyrosine
Cytotoxic
-
aMaximum activity value is reported as % rescue from Tm (0.15 μg/mL) -induced reduction of
cell viability, as measured by intracellular ATP levels; the values for Tm treatment alone and
b
control (DMSO, without Tm) treatment are designated as 0% and 100%, respectively. EC50
values (the concentrations that reach half-maximal activity) for INS-1 cell viability are calculated
with GraphPad Prism from the data of ten 2-fold serial titration points in all tables. All
c
experiments were performed in triplicate. Compound 1 contains the 1,2,3-triazole group, as
shown in Figure 1.
We have previously described that compound 1 possesses the structural motif of triazole amide
(Figure 1) for effective β-cell protective activity against ER stress (see Table 1).20 However, 1
showed less-desired potency within a narrow range of doses,20 and poor aqueous solubility (see
Figure 2). Since 1,2,3-triazole is a scaffold frequently present in various structures with multiple
bioactivities, such as antimicrobial, antiviral, and antitumor effects, we reasoned that the triazole
ring could be the reason for these less-desirable properties. We therefore designed and
synthesized novel analogs (5a–q, Table 1) of 1 by replacing 1,2,3-triazole with amide bond
isosteres and studied the effect of resultant analogs on β-cell protection against ER stress. The
newly synthesized compounds were tested for the viability of rat INS-1 β-cells in the presence of
tunicamycin (Tm), a potent ER stress inducer that inhibits N-linked glycosylation of proteins.
The maximum activities and the concentrations that reach half-maximal activity (EC50) of the
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compounds were evaluated by the degree of increase in viability of INS-1 cells co-treated with
the compounds in the presence of Tm compared with Tm treatment alone.
First, we wanted to determine whether replacing the 1,2,3-triazole group with the amino acid
glycine-like group still maintains the β-cell protective activity. We synthesized 5a by replacing
the 1,2,3-triazole group with the glycine-like group while maintaining other moieties intact and
observed that 5a exhibited moderate activity (maximum activity = 45%, EC50 = 18.6  4 µM).
With this encouraging result, we explored the effect of substituents on the moieties on β-cell
protection. We started investigating the effect of modifying the right ring (R3) on the 5a scaffold.
We found that the glycine derivatives with modifications as 2-pyridine (5b) or indazole (5c) are
not or minimally active (maximal activity at 16 and 0%, respectively), while derivatives with
modifications as 4-OMe (5d), 4-SO2NH2 (5e), or Tyramine (5f) are moderately active with
maximal activity from 41 to 55%, suggesting that the introduction of new hydrogen bonding
groups and the extension of length in-between amide and B-ring may are not beneficial for the
activity. However, excitingly, substitutions with 4-CF3 (5g) or 4-OH, 3-OMe (5h) yielded very
active compounds with maximal activity at 88 and 100%, although the EC50s of both derivatives
are still less desired (13  1 and 10  2 µM, respectively). Next, as 5g showed significant β-cell
protective activity (see Table 1), to establish the suitable position of the -CF3 group in the phenyl
ring of 5g, we synthesized 5h with the -CF3 group at position 3 and observed that 5h (with 3-
CF3) was less potent than 5g (with 4-CF3) (5h with maximum activity = 46%, EC50 = 32 7 µM
vs. 5g with maximum activity = 88%, EC50 = 13  1 µM). These results indicate that the CF3
substitution at position 4 on phenyl ring (5g) is more favorable than at position 3 (5h) for β-cell
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protective activity. We therefore kept the 4-CF3 substitution on the right ring for further
structure-activity relationship (SAR) studies.
We next sought to determine the suitable substituents on the left ring (R1) on β-cell protection
against ER stress. The compounds synthesized with various substituents at the left ring (5j –n)
are listed in Table 1. While substituting the 3-Cl,2-Me (5g) on the phenyl ring R1 with hydrogen
(5j), 4-ethyl (5k), or 4-F (5l) substantially reduced their respective activities (maximal activity:
88% (5g) vs. 35% (5j), 42% (5k), or 12% (5l), and EC50 (µM): 13  1 (5g) vs. 43  11 (5j), 45 
8 (5k), or 41  6 (5l)), substitution with 3-hydroxy group (5m (WO5m)) remarkably enhanced
the activity with the maximum activity at 100% and EC50 = 0.1  0.01 µM. These results suggest
that the hydrogen bond donating group at meta position of R1 is critical for the β-cell protective
activity. As we have shown that compound 5h with the 3-OMe,4-OH substituent at R3 in a
scaffold containing a 3-Cl,2-Me moieties at R1 exhibited the excellent β-cell protective activity,
and that the 3-OH substituent (WO5m) at R1 yielded an activity superior to that of 3-Cl,2-Me
moieties (5g) in a scaffold with 4-CF3 at R3, we wondered whether an analog containing 3-OH at
R1 and 3-OMe,4-OH at R3 (5n) and a second analog containing 3-OMe,4-OH at R1 with 4-CF3 at
R3 (5o) are equally active. However, as shown in Table 1, these analogs exhibited a significantly
compromised activity. To further explore the SAR, we studied the effect of substituent at R2
position, compounds 5p (R2 = Me) and 5q (R2 = Tyrosine) are significantly less or not active.
These results indicated that the bulkier substitution at R2 position is not well tolerated.
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-
-
+
-
+
+
Tm
WO5m (µM)
10
20
Cleaved PARP
Cleaved caspase-3
α-Tubulin
Figure 2. Compound WO5m protects INS-1 β cells against Tm-induced apoptosis. INS-1
cells were treated with or without Tm (0.3 μg/mL) in the presence of WO5m at indicated
concentrations or DMSO for 24 h. Cleaved caspase-3 and PARP were determined by Western
blotting. α-Tubulin was used as a loading control. The data shown are representative of 3
independent experiments.
Based on above SAR results we selected the most potent compound WO5m for further
investigation. We next investigated whether WO5m treatment inhibited ER stress-induced β-cell
death. We used cleaved caspase-3 and cleaved PARP for this purpose. Under chronic ER stress,
caspase 3 and PARP are activated by undergoing proteolytic cleavage to trigger apoptotic cell
death. Tm treatment for 24 h significantly induced both cleaved caspase-3 and cleaved PARP
protein levels in INS-1 cells (Figure 2). However, WO5m co-treatment eliminated the Tm-
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induced cleavage of both caspase-3 and PARP (Figure 2). These results demonstrated that
WO5m protects β-cells against ER stressor Tm-induced cell death.
A
B
1.2
1
1.2
1
0.8
0.6
0.4
0.2
0
0.8
0.6
0.4
0.2
0
BFA
TG
WO5m (µM)
-
+
0
+
+
5
+
+
-
+
0
+
+
5
+
+
0
2.5
10
15
WO5m (µM)
0
2.5
10
15
Figure 3. Compound WO5m protects INS-1 β cells against other ER stress inducers. INS-1
cells were treated with or without TG (18 nM) (A) or with or without BFA (0.2 μg/mL) (B) in
the presence of WO5m at indicated concentrations (μM) or DMSO for 72 h. The cell viability
was determined by CellTiter-Glo. The values for control (DMSO, without Tm) treatment were
normalized as 1. The results in all panels are the means of 3 replicate wells and are representative
of 3 independent experiments.
We further investigated whether the protective effect of WO5m on  cells is specific to Tm-
induced stress. We used two other ER stressors thapsigargin (TG), which disrupts intraluminal
Ca2+ homeostasis in the ER and causes accumulation of unfolded proteins by inhibiting
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sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA), and brefeldin A (BFA), which
inhibits a key guanine nucleotide exchange factor essential for the transport of proteins from the
ER to the Golgi, to treat INS-1 cells.21 As expected, both stressors induced significant reduction
in cell viability; however, compound WO5m significantly reversed the reduction in viability in
INS-1 cells treated with TG or BFA (Figure 3). All these results indicate that compound WO5m
protects β cell survival against ER stress induced by all stressors tested.
Turbidimetric assay
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
5a
WO5m
5f
1
Water
0
50
100
150
200
250
300
350
400
Concentration (µM)
Figure 4. Aqueous solubility of newly synthesized compounds. Aqueous solubility was
assessed as the degree of turbidity of compounds at indicated concentrations in aqueous
solutions, detected by absorbance at 620 nm. The experiments were performed in triplicate, with
the results as the means ± SD of triplicate wells.
Finally, as a major drawback of compound 1 is its poor water solubility, we investigated whether
the newly synthesized compounds obtain the improvement in aqueous solubility. In the SAR
studies, we hypothesized that substituting the 1,2,3-triazole moiety with the amino acid glycine-
like group likely improves the water solubility of the newly synthesized compounds. Using a
thermodynamic turbidimetric assay we evaluated the aqueous solubility of the newly synthesized
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compounds. As shown in Figure 4, as expected, several compounds including 5g, 5h, and
WO5m exhibited improved water solubility compare to 1. In contrast to compound 1 that did not
show any water solubility (i.e., near 0 µm concentration), WO5m exhibited complete solubility
at the concentration of approximately 50 µm in H2O (Figure 4). 5a and 5f exhibited ever higher
water solubility than WO5m, with ~75 and ~200 50 µm in H2O, respectively.
3. Conclusion
In this study, we have discovered a series of N-(2-(Benzylamino)-2-oxoethyl)benzamide
derivatives capable of protecting pancreatic β cells from ER stress-induced death. Although we
initiated the SAR studies using compound 1, a 1,2,3-triazole-4-carboxamide derivative, as the
starting scaffold, we identified a novel scaffold that possesses potent β-cell protective activity. In
particular, compound WO5m exhibited a maximal β-cell protective activity at 100% with EC50
at 0.1  0.01 µM. Furthermore, this class of compounds also possesses far better water solubility
than the original 1,2,3-triazole derivatives, a property critical for further drug development. In
summary, we have discovered a novel scaffold of β cell-protective compounds against ER stress
with excellent potency and aqueous solubility.
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