Protective effects of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols against 4-hydroxynonenal-induced cell death in adult retinal pigment epithelial-19 cells

Article abstract of DOI:10.1016/j.bmcl.2017.11.046

Dysfunction or progressive degeneration of retinal pigment epithelium (RPE) contributes in the initial pathogenesis of age-related macular degeneration (AMD) causing irreversible vision loss, which makes RPE the prime target of the disease. The present study aimed to identify compounds to protect 4-hydroxynonenal (4-HNE)-induced RPE cell death by inhibiting NADPH oxidase 4 (NOX4) activity, not just as free radical scavengers, using ARPE-19, a human adult retinal pigment epithelial cell line, as a RPE representative. Novel thirty-two 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ol derivatives 17 were synthesized and tested. We found that there was a strong correlation between level of protective effect of compounds 17 against 4-HNE-induced APRE-19 cell death and that of inhibitory activity against 4-HNE-induced superoxide production, and that most of the compounds 17 showed minimal DPPH radical scavenging activity. Compound 17–28 showed the best protective activity against 4-HNE-induced superoxide production (79.5% inhibition) and cell death (85.1% recovery) at 10 μM concentration, which was better than that of VAS2870, a NOX2/4 inhibitor. In addition, compound 17–28 blocked 4-HNE-induced apoptosis of ARPE-19 cells in a concentration-dependent manner. The results indicate that compound 17–28 may be a lead compound to develop AMD therapeutics.

Full text of DOI:10.1016/j.bmcl.2017.11.046

Bioorganic & Medicinal Chemistry Letters 28 (2018) 107–112
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Protective effects of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols
against 4-hydroxynonenal-induced cell death in adult retinal pigment
epithelial-19 cells
Dawon Bae a,c, Jaya Gautam a,c, Hyeonjin Jang a, Suhrid Banskota a, Sang Yeul Lee b, Min-Ji Jeong a,
A-Sol Kim a, Hong Chul Kim b, Iyn-Hyang Lee a, Tae-gyu Nam b, , Jung-Ae Kim a, , Byeong-Seon Jeong a,
⇑
⇑
⇑
a College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
b Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Dysfunction or progressive degeneration of retinal pigment epithelium (RPE) contributes in the initial
pathogenesis of age-related macular degeneration (AMD) causing irreversible vision loss, which makes
RPE the prime target of the disease. The present study aimed to identify compounds to protect 4-hydrox-
ynonenal (4-HNE)-induced RPE cell death by inhibiting NADPH oxidase 4 (NOX4) activity, not just as free
radical scavengers, using ARPE-19, a human adult retinal pigment epithelial cell line, as a RPE represen-
tative. Novel thirty-two 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ol derivatives 17 were synthesized
and tested. We found that there was a strong correlation between level of protective effect of compounds
17 against 4-HNE-induced APRE-19 cell death and that of inhibitory activity against 4-HNE-induced
superoxide production, and that most of the compounds 17 showed minimal DPPH radical scavenging
activity. Compound 17–28 showed the best protective activity against 4-HNE-induced superoxide pro-
Received 12 October 2017
Revised 21 November 2017
Accepted 27 November 2017
Available online 28 November 2017
Keywords:
Retinal pigment epithelium
Apoptosis
NADPH oxidase 4
6-Ureido/thioureido-2,4,5-
trimethylpyridin-3-ol
4-Hydroxynonenal
duction (79.5% inhibition) and cell death (85.1% recovery) at 10 lM concentration, which was better than
that of VAS2870, a NOX2/4 inhibitor. In addition, compound 17–28 blocked 4-HNE-induced apoptosis of
ARPE-19 cells in a concentration-dependent manner. The results indicate that compound 17–28 may be a
lead compound to develop AMD therapeutics.
Ó 2017 Elsevier Ltd. All rights reserved.
Retinal pigment epithelium (RPE), located at the outermost
layer of the retina, plays critical roles in the maintenance of the
underlying photoreceptors by transporting nutrients from the vas-
cular choroid, formation of the blood-retinal barrier, absorption of
scattered light, and phagocytosis of shed photoreceptor outer seg-
ments.1 Dysfunction or progressive degeneration of RPE con-
tributes to the initial pathogenesis of age-related macular
degeneration (AMD) which is one of the major causes of irre-
versible vision loss.2
The retina is particularly vulnerable to oxidative damage
because it has high metabolic activity under high level of oxygen
consumption and polyunsaturated fatty acids.3,4 During degrada-
tion of outer segments of photoreceptor, RPE generates reactive
oxygen species (ROS), and thus oxidative stress. In association with
clinical studies that increased serum levels of antioxidant nutrients
may reduce the risk for AMD,5,6 oxidative stress of RPE has been
the prime target of AMD.7 There are literatures that small mole-
cules protect RPE cells against oxidative stress. For example, mela-
tonin protected RPE from H2O2-induced oxidative stress probably
as radical scavenger8 and as
a
signaling molecule.9,10 Some
polyphenol antioxidants such as quercetin11,12 and resveratrol13,14
afforded protective effects on RPE cells against oxidative stress.
However, radical scavenging antioxidant mechanism is a non-
specific and somewhat broad concept for drug development.
4-Hydroxynonenal (4-HNE) is produced in the RPE as a lipid
peroxidation product. In a previous study, high level of 4-HNE is
demonstrated to generate superoxide anion which leads to the
apoptotic degeneration of RPE through activation of NADPH oxi-
dase 4 (NOX4).15 4-HNE-induced superoxide production is time-
dependently increased and maintained up to 24 h, which is accom-
plished through further induction of NOX4 expression. The present
study aimed to identify compounds to protect 4-HNE-induced RPE
cell death by inhibiting NOX4 activity, not just as free radical scav-
engers using a human adult retinal pigment epithelial cell line-19
(ARPE-19).
⇑
Corresponding authors.
E-mail addresses: tnam@hanyang.ac.kr (T.-g. Nam), jakim@yu.ac.kr (J.-A. Kim),
jeongb@ynu.ac.kr (B.-S. Jeong).
c
Equally contributed as the first author.
https://doi.org/10.1016/j.bmcl.2017.11.046
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.

108
D. Bae et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 107–112
We have investigated 2,4,5-trimethylpyridin-3-ol scaffold as a
scavenging activity. Some 6-aminopyridin-3-ol analogues have
been known for their excellent radical scavenging activity due to
the electron-donating effect of the substituents on C(6)-position
of pyridin-3-ol ring. Because we would like to identify compounds
to inhibit NOX4 thereby to protect RPE against superoxide, we
designed and synthesized novel 6-ureido- and 6-thioureido- ana-
logues that are not generally considered to have strong electron-
donating substituents on C(6)-position.
General scheme for the preparation of novel 6-ureido- and 6-
thioureido-2,4,5-trimethylpyridin-3-ols is described in Scheme 1.
Commercially available isocyanates (15, Z = O) or isothiocyanates
(15, Z = S) containing various substituents (R) were coupled with
versatile key structure for drug discovery. We reported several
papers on the design and synthesis of a series of derivatives of
2,4,5-trimethylpyridin-3-ol with various amino or amido func-
tional groups on C(6)-position of pyridin-3-ol ring. Biological and
pharmacological studies have also been performed to evaluate
their activities in angiogenesis, cancer, inflammatory bowel dis-
ease, and autoimmune disease.16–21 Here, we would like to report
the synthesis of novel 6-ureido- and 6-thioureido-2,4,5-trimethyl-
pyridin-3-ols, compounds 17 in Scheme 1. The compounds pro-
tected RPE cells against 4-HNE-induced cell death through the
inhibition of NOX4 enzyme without exerting significant radical
Cl
OH
HO
Cl
HO
OH
a
N
N
HCl
HCl
2
1
b
BnO
BnO
HO
HO
TBDPSO
k
g
c
N
N
N
Br
Br
N
Br
8
3
4
13
h
d
l
BnO
BnO
TBDPSO
N
N
NH2
N
N
N CPh2
O
9
7a
5
14
i
e
m
j
f
BnO
BnO
TBDPSO
O
N
N
N
N
CPh2
N
NH2
10
6
7b
O
PO
HO
PO
n
o
Z
Z
+
NH2
R
N C Z
R
N
R
N
N
H
N
N
H
N
N
H
H
7
15
Z = O, S
16-01 ~ 16-32
17-01 ~ 17-32
7a
7b
: P = Bn
: P = TBDPS
Scheme 1. General synthetic scheme for 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols (17). Reagents and conditions: (a) SOCl2, DMF, reflux, 30 min., 93%; (b) Zn, AcOH,
reflux, 3 h, 92%; (c) DBDMH, THF, r.t., 3 h, 80%; (d) PhCH2Cl, K2CO3, DMF, 12 h, 97%; (e) benzophenone imine, Pd2(dba)3, BINAP, NaOtBu, toluene, reflux, 12 h, 83%; (f) HCl,
MeOH-THF, r.t., 12 h, 83%; (g) PhCH2Cl, K2CO3, DMF, r.t., 12 h, 71%; (h) m-CPBA, CH2Cl2, r.t., 1 h, 94%; (i) p-TsCl, i-Pr2NEt, phthalimide, CH2Cl2, r.t., 12 h, 70%; (j) H2NNH2, THF-
EtOH, r.t., 1 h, 90%; (k) TBDPSCl, imidazole, DMF, r.t., 24 h, 87%; (l) benzophenone imine, Pd2(dba)3, BINAP, NaOtBu, toluene, reflux, 5 h, 89%; (m) HCl, MeOH-THF, r.t., 24 h,
93%; (n)# 15 (isocyanates or isothiocyanates), solvent (CH2Cl2, EtOH, or CH3CN); (o)# For debenzylation, H2, Pd/C, MeOH (with or without CH2Cl2), r.t. or BCl3, CH2Cl2, r.t. For
desilylation, n-Bu4NF, THF, r.t. #See the supplementary data for details.

D. Bae et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 107–112
109
two key intermediates (7a or 7b) to give urea or thiourea com-
pounds (16–01 ꢀ 16–32), respectively. Thirty-two compounds
(17–01 ꢀ 17–32) for biological evaluation were obtained by depro-
tection of the protective groups (Bn, TBDPS). Sixteen ureas (17–01
ꢀ 17–16) and sixteen thioureas (17–17 ꢀ 17–32) were prepared
for this study. The benzyl-protected key intermediate (7a) was
obtained by two synthetic approaches developed by us as shown
in Scheme 1. In brief, 2,4,5-trimethylpyridin-3-ol (3) was obtained
protection with TBDPS group, palladium-catalyzed amination with
benzophenone imine, and acidic methanolysis of the imine group.
Fig. 1 shows structure of all thirty-two final compounds; sixteen
ureido derivatives and sixteen thioureido ones.
Treatment of ARPE-19 cells with 4-HNE (10 lM) for 24 h signif-
icantly suppressed cell viability, which accompanied with superox-
ide production. To assess if the protective activity of the
compounds (17, 10 lM) against 4-HNE-induced cell death was
by
a
two-step sequence from pyridoxine hydrochloride (1).
mediated through inhibition of NOX activity, not through radical
scavenging activity, we measured DPPH radical scavenging activ-
ity, inhibition on 4-HNE-induced ROS production, and protective
activity against cell death in a sequential manner. These inhibitory
activities of 17 were compared to those of VAS2870,22 a NOX2/4
Introduction of amino group at C(6)-position was done either via
palladium-catalyzed amination of bromo compound (5) or via pyr-
idine-N-oxide compound (9). Another key intermediate (7b) was
prepared from 6-bromo-compound (4) by the following sequence;
HO
N
G
17
CF3
O
O
O
O
N
H
N
N
H
N
H
N
H
N
H
N
H
N
H
H
17-01
17-02
17-03
17-04
Cl
Br
F
O
O
O
O
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
17-05
17-06
17-07
17-08
NO2
OMe
OCF3
O
O
O
O
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
17-09
17-11
17-12
17-10
O
O
O
O
O
O
O
S
C3H7
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
17-13
17-14
17-15
17-16
Cl
Br
S
S
S
S
S
S
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
17-17
17-18
17-19
17-20
Cl
Cl
CF3
NO2
S
S
N
H
N
H
N
H
N
H
N
H
N
H
CF3
N
H
N
H
17-21
17-22
17-23
17-24
OMe
S
S
S
S
S
S
O
C2H5
C4H9
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
17-25
17-26
17-27
17-28
S
S
C6H13
C8H17
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
17-32
17-29
17-30
17-31
Fig. 1. Structures of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols.

110
D. Bae et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 107–112
inhibitor. In addition, DPPH radical scavenging activity of 17 was
compared to vitamins (vitamin C and E), well-known free radical
scavenging antioxidants, to assess whether 4-HNE-induced cell
death was associated with radical scavenging activity or not.
As shown in Table 1, it is not difficult to notice at a glance there
is a strong correlation between the level of protective effect of
compounds 17 against APRE-19 cell-death from 4-HNE-treatment
and that of inhibitory activity against 4-HNE-induced superoxide
production. For the statistical analysis of the correlation, a linear
regression model was set. The simple linear regression equation
with y (recovery of cell viability) as the response variable and x
(inhibition of 4-HNE-induced superoxide production) as the
explanatory variable wasy = 1.03 x + 3.62 (R2 = 0.9598)
For every one-unit increase in x, the y increased by 1.03 on aver-
age. In other words, increasing x by 10% is associated with an
increase in the y of 10.3% (p < .0001). That is, these series com-
pounds could improve the rate of cell viability recovery by pre-
venting 4-HNE-induced superoxide production. This relationship
is graphically displayed in Fig. 2.
However, no significant correlation between DPPH radical scav-
enging activity and 4-HNE-induced cell death was observed in 17
as well as VAS2870 and vitamins. Although vitamin C and E,
well-known antioxidants, showed about 10% activity in DPPH rad-
ical scavenging, their inhibitory activity against 4-HNE-induced
superoxide production was only 4%. The effect of VAS2870 was
opposite to vitamins, showing strong inhibitory activity (78%)
against 4-HNE-induced superoxide production, but quite low inhi-
bitory activity against DPPH radical generation. Similar to
VAS2870, DPPH radical scavenging effect of most of compounds
17 was not significant and even lower than vitamin C and E. How-
ever, most of compounds 17 showed significant and stronger inhi-
bitory activity against 4-HNE-induced superoxide production than
vitamins. Such inhibitory activity of compounds 17 corresponded
to the protective activity against 4-HNE-induced cell death. These
results demonstrate that protective activity of compounds 17
against 4-HNE-induced cell death was not due to free radical scav-
enging activity but due to suppression of NOX-derived superoxide
generation.
Interestingly, it was found that thioureido-derivatives generally
showed better activity than ureido-analogues in protection of
ARPE-19 cells from 4-HNE-induced cell death as well as in inhibi-
tion of superoxide production. Twelve urea compounds turned out
to be almost ineffective in these assay systems, and the other four
derivatives (17–03, 17–07, 17–11, and 17–15) showed low to mod-
erate activity. In contrast, only three among the sixteen thioureido
derivatives were found not to possess protective activity. Nine
compounds (17–29, 17–25, 17–21, 17–23, 17–20, 17–22, 17–27,
17–30, and 17–18) showed low to moderate protective effects,
whereas 17–32 and 17–26 increased level of cell viability to
Table 1
Protective activity of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols (17) against
DPPH radical production, 4-HNE-induced superoxide production, and cell death.
Compound
(10 M)
Recovery of
cell viability
(%)
Inhibition of 4-HNE-
induced superoxide
production (%)
DPPH radical
scavenging
activity (%)
l
17–01
17–02
17–03
17–04
17–05
17–06
17–07
17–08
17–09
17–10
17–11
17–12
17–13
17–14
17–15
17–16
17–17
17–18
17–19
17–20
17–21
17–22
17–23
17–24
17–25
17–26
17–27
17–28
17–29
17–30
17–31
17–32
8.9 9.0
5.3 3.7
7.1 6.9
5.8 5.2
3.4 1.1
5.9 3.6
4.2 2.1
3.3 2.9
7.4 5.6
6.2 4.5
4.0 5.8
5.2 1.0
7.4 6.5
6.1 5.9
6.3 4.5
6.0 4.2
6.7 4.9
5.7 6.0
5.5 6.3
5.6 3.5
6.9 4.6
6.5 6.2
7.4 5.8
6.6 3.6
6.7 5.0
7.6 4.2
5.5 3.4
4.7 3.9
4.9 2.9
13.3 0.7
5.9 3.0
16.5 1.1
14.6 0.8
5.5 3.3
7.1 2.9
6.2 6.8
44.2 7.0*
À5.1 7.8
12.8 7.4
6.2 10.5
43.6 7.6*
7.3 12.4
13.9 2.5
10.8 9.1
58.4 16.0*
7.3 9.9
41.3 6.8*
À1.3 3.9
8.9 9.9
6.9 5.6
30.8 6.5*
0.9 3.4
8.3 2.2*
5.8 3.3
51.1 5.5*
2.4 6.7
10.5 4.2
1.5 11.4
32.5 12.9*
12.5 5.7
8.9 13.5*
54.0 12.8*
12.8 13.3
33.5 10.2*
24.9 5.8*
40.4 11.9*
29.6 8.5*
77.7 7.6*
23.2 4.6*
63.1 10.1*
44.9 2.6*
85.1 6.1*
22.8 3.8*
45.9 2.9*
14.7 5.8
62.2 14.1*
4.6 4.8
8.8 13.2
28.6 4.2*
9.4 8.0
2.3 7.3
41.3 0.8*
13.0 3.0*
22.8 11.4*
19.0 6.3*
30.5 7.5*
20.1 2.8*
71.8 4.9*
17.7 5.5*
68.7 5.8*
36.7 2.8*
79.5 5.2*
17.9 3.0*
40.7 3.6*
13.9 4.2*
61.9 6.7*
VAS2870a
Vitamin C
Vitamin E
79.4 2.9*
8.2 18.3
9.8 15.0
78.7 3.4*
3.4 3.9
3.9 0.5
6.9 4.4
10.2 1.1
10.2 0.9
a
Structure of VAS 2870.
N
O
S
N
N
N
N
N
VAS2870
*
P < .05 compared to vehicle-treated control group. Data are presented as Mean
Fig. 2. The regression of recovery of cell viability (y) on inhibition of 4-HNE-
induced superoxide production (x). Analyses were conducted using SAS procedures
(SAS version 9.4, SAS Institute, Cary, NC, USA) and significance was defined at the level p
< .05. The regression model explains 96% of the variability of the y values around its
mean (R2 = 0.9598).
S.E.M. of three independent experiments. Statistics were analyzed using Student’s
t-test or one-way ANOVA followed by the Student-Newman-Keuls comparison
method for calculation of differences between groups (GraphPad Prism 5.0 soft-
ware, San Diego, CA, USA).

D. Bae et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 107–112
111
62.2% and 63.1%, respectively. It seems that thioureido sub-group
contains more active compounds than ureido sub-group. The most
active analogues turned out 4-nitrophenyl (17–24) and n-butyl
(17–28) with thiourea scaffold. Among active ones with >30%
recovery of cell viability, compounds having electron-withdrawing
substituents in G group in the general structure 17 in Fig. 1 are
found both in ureido- and thioureido sub-groups. However, active
compounds with electron-donating alkyl substituents in G group
are only found in thioureido sub-group. For example, electron-
withdrawing 4-trifluorophenyl substituent lead to quite strong
activity in both ureido- and thioureido sub-groups (17–03 vs.
17–22). However, other electron-withdrawing substituents rather
lead to preferential activities between ureido- and thioureido
sub-groups. 4-Chlorophenyl analogues showed 3.4-fold more
activity with ureido scaffold (17–07 vs. 17–19) while 4-bro-
mophenyl (17–08 vs. 17–20), 4-nitrophenyl (17–09 vs. 17–24),
and benzoyl (17–14 vs. 17–26) analogues showed 4.6-, 5.6-, and
42-fold higher activities, respectively, with thiourea scaffold. On
the other hand, thioureido analogues with alkyl substituents
(17–27, 17–28, 17–30, and 17–32) generally showed strong activ-
ities (45 ꢀ 85%) while ureido analogues with alkyl substituents
(17–02, 17–04, and 17–16) showed marginal activities (À5.1 ꢀ
12.5%). Protective activity of 4-nitrophenyl-thiourea derivative
(17–24) against cell death of ARPE-19 cells is very close to the
effect of VAS2870, a positive control, although the level of inhibi-
tion of 4-HNE-induced superoxide production was slightly lower
than that of VAS2870. The highest level of protective effect as well
as inhibition of superoxide production was observed with n-butyl
analogue of thiourea compound 17–28. The level of its activity in
each assay was 85.1% and 79.5%, respectively, which is similar or
superior to that of VAS2870. As shown in Fig. 3, compounds
17–24 and 17–28 showed protective activity in a concentration-
dependent manner.
Fig. 4. Anti-apoptotic effect of 17–28. (A) Dot plots from flow cytometry analysis of
annexin-V and propidium iodide (PI) staining of apoptotic ARPE-19 cells treated
with NOX2/4 inhibitor (VAS2870) and 17–28. (B) Bar graph showing % of apoptotic
cells (sum of annexin-V positive and annexin-V/PI double positive cells).
Fig. 3. Comparison on the protective effects of NOX2/4 inhibitor (VAS2870), two 6-
thioureido-2,4,5-trimethylpyridin-3-ols (17–24 and 17–28) against 4-HNE-induced
cell death.

112
D. Bae et al. / Bioorganic & Medicinal Chemistry Letters 28 (2018) 107–112
We measured anti-apoptotic activity of the best compounds
References
17–28. 4-HNE induced apoptosis of ARPE-19 cells, which was
detected with FITC Annexin V and PI (Fig. 4A). The increase in num-
ber of cells that are Annexin V positive (+) and PI negative (À)
(early apoptosis) as well as Annexin V and PI double (+) (end stage
apoptosis) were significantly and dose-dependently inhibited by
compound 17–28, which was better than that of VAS2870 (Fig.
4B).
In summary, 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ol
derivatives showed a strong correlation between level of protective
effect against 4-HNE-induced APRE-19 cell death and that of inhi-
bitory activity against 4-HNE-induced superoxide production. The
compound 17–28 showing best protective activity may be a lead
compound to develop AMD therapeutics.
1. Bok DJ. Cell Sci Suppl. 1993;17:189.
2. Bhutto I, Lutty G. Mol Aspects Med. 2012;33:295.
3. Vingerling JR, Hofman A, Grobbee DE, de Jong PT. Arch Ophthalmol.
1996;114:1193.
4. Ethen CM, Reilly C, Feng X, Olsen TW, Ferrington DA. Invest Ophthalmol Vis Sci.
2007;48:3469.
5. Snodderly DM. Am J Clin Nutr. 1995;62:1448S.
6. AREDS report. Arch Ophthalmol. 2001;119:1439.
7. Beatty S, Koh HH, Henson D, Boulton M. Surv Ophthalmol. 2000;45:115.
8. Liang F-Q, Green L, Wang C, Alssadi R, Godley BF. Exp Eye Res. 2004;78:1069.
9. Rosen RB, Hu DN, Chen M, McCormick SA, Walsh J, Roberts JE. Mol Vis.
2012;18:1640.
10. Zareba M, Raciti MW, Henry MM, Sarna T, Bruke JM. Free Radical Biol Med.
2006;40:87.
11. Kook D, Wolf AH, Yu AL, et al. Invest Ophthalmol Vis Sci. 2008;49:1712.
12. Hytti M, Piippo N, Salminen A, Honkakoski P, Kaarniranta K, Kauppinen A. Exp
Eye Res. 2015;132:208.
13. Sheu SJ, Liu NC, Chen JL. J Ocul Pharmacol Ther. 2010;26:231.
14. Pintea A, Rugina˘ D, Pop R, Bunea A, Socaciu C, Diehl HA. J Ocul Pharmacol Ther.
2011;27:315.
Acknowledgments
This work was supported by the Yeungnam University Research
Grant.
15. Gautam et al., under revision.
16. Kim D-G, Kang Y, Lee H, et al. Eur J Med Chem. 2014;78:126.
17. Lee H, Banskota S, Kim D-G, et al. Bioorg Med Chem Lett. 2014;24:3131.
18. Banskota S, Gautam J, Regmi SC, et al. PLoS One. 2016;11:e0148133.
19. Banskota S, Kang H-E, Kim D-G, et al. Bioorg Med Chem Lett. 2016;26:4587.
20. Gautam J, Banskota S, Regmi SC, et al. Mol Cancer. 2016;15:75.
21. Kang Y, Timilshina M, Nam T-G, Jeong B-S, Chang J-H. Biol Res. 2017;50:8.
22. Wingler K, Altenhoefer SA, Kleikers PW, Radermacher KA, Kleinschnitz C,
Schmidt HH. Cell Mol Life Sci. 2012;69:3159.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2017.11.046.