Development of Novel 1,2,3,4-Tetrahydroquinoline Scaffolds as Potent NF-κB Inhibitors and Cytotoxic Agents

Article abstract of DOI:10.1021/acsmedchemlett.6b00004

1,2,3,4-Tetrahydroquinolines have been identified as the most potent inhibitors of LPS-induced NF-κB transcriptional activity. To discover new molecules of this class with excellent activities, we designed and synthesized a series of novel derivatives of 1,2,3,4-tetrahydroquinolines (4a-g, 5a-h, 6a-h, and 7a-h) and bioevaluated their in vitro activity against human cancer cell lines (NCI-H23, ACHN, MDA-MB-231, PC-3, NUGC-3, and HCT 15). Among all synthesized scaffolds, 6g exhibited the most potent inhibition (53 times that of a reference compound) of LPS-induced NF-κB transcriptional activity and the most potent cytotoxicity against all evaluated human cancer cell lines.

Full text of DOI:10.1021/acsmedchemlett.6b00004

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Letter
Development of Novel 1,2,3,4-Tetrahydroquinoline
Scaffolds as Potent NF-#B Inhibitors and Cytotoxic Agents
Hyeju Jo, Minho Choi, Arepalli Sateesh Kumar, Yeongeun Jung, Sangeun Kim, Jieun Yun, Jong Soon Kang,
Youngsoo Kim, Sang-bae Han, Jae-Kyung Jung, Jungsook Cho, Kiho Lee, Jae-Hwan Kwak, and Heesoon Lee
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00004 • Publication Date (Web): 16 Feb 2016
Downloaded from http://pubs.acs.org on February 18, 2016
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Development of Novel 1,2,3,4-Tetrahydroquinoline Scaffolds as
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Potent NF-κB Inhibitors and Cytotoxic Agents
†
†
†
†
†
‡
Hyeju Jo , Minho Choi , Arepalli Sateesh Kumar , Yeongeun Jung , Sangeun Kim , Jieun Yun , Jongꢀ
‡
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Soon Kang , Youngsoo Kim , Sangꢀbae Han , JaeꢀKyung Jung , Jungsook Cho , Kiho Lee , JaeꢀHwan
†
§
Kwak , Heesoon Lee *
†
Department of Pharmacy, Chungbuk National University, Chungbuk 362ꢀ763, Republic of Korea
‡
Korea Research Institute of Bioscience and Biotechnology, Ochang, 363ꢀ883, Republic of Korea
▽
College of Pharmacy, Korea University, Sejong 339ꢀ700, Republic of Korea
║
College of Pharmacy, Dongguk University, Goyang 410ꢀ773, Republic of Korea
§
College of Pharmacy, Kyungsung University, Busan 608ꢀ736, Republic of Korea
KEYWORDS: 1,2,3,4-Tetrahydroquinolines, NF-κB inactivation, In vitro cytotoxicity, human cancer cell lines.
ABSTRACT: 1,2,3,4ꢀTetrahydroquinolines have been identified as the most potent inhibitors of LPSꢀinduced NFꢀκB transcripꢀ
tional activity. To discover new molecules of this class with excellent activities, we designed and synthesized a series of novel deꢀ
rivatives of 1,2,3,4ꢀtetrahydroquinolines (4aꢀg, 5aꢀh, 6aꢀh, and 7aꢀh) and bioꢀevaluated their in vitro activity against human cancer
cell lines (NCIꢀH23, ACHN, MDAꢀMBꢀ231, PCꢀ3, NUGCꢀ3, and HCT 15). Among all synthesized scaffolds, 6g exhibited the
most potent inhibition (53 times that of a reference compound) of LPSꢀinduced NFꢀκB transcriptional activity and the most potent
cytotoxicity against all evaluated human cancer cell lines.
NFꢀκB is a lymphoidꢀspecific protein that binds to the enꢀ
hancer of kappa light chain in the nucleus of B cells; NFꢀκB
was discovered by Sen and Baltimore. NFꢀκB is involved in
derivatives of 1,2,3,4ꢀtetrahydroquinolineꢀ2ꢀcarboxylic acid
Nꢀ(substituted)phenyl amide and tested them as potential NFꢀ
κB inhibitors and also evaluated their cytotoxicities against six
human cancer cell lines (NCIꢀH23, ACHN, MDAꢀMBꢀ231,
1
the regulation of many immune and inflammatory responses,
2
,3
9ꢀ
cellular growth and apoptosis. At present, NFꢀκB and its
signalling is one of the most exciting and extensively studied
research fields since NFꢀκB dysregulation is associated with
many diseases such as cancer, AIDS, asthma, arthritis, diabeꢀ
PCꢀ3, NUGCꢀ3 and HCTꢀ15). Based on our previous reports,
1
1
we wish to maintain amide functionality to the core motifs
and the effect of the synthesized molecules on NFꢀκB tranꢀ
scriptional activity was measured by using a reported proceꢀ
4
ꢀ6
19
tes, and inflammatory bowel disease. Several natural and
synthetic compounds, including some drugs, have been tested
for their potential to inhibit NFꢀĸB, but very few of them are
dure. In vitro cytotoxicity assay was performed using the
number of cells measured indirectly by the sulforhodamine B
method according to the National Cancer Institute (USA) proꢀ
7
,8
20
suitable for anticancer therapy . Therefore, it has been sugꢀ
gested that the development of novel NFꢀκB inhibitors with
antitumor and antiꢀinflammatory activities is most important.
Our group has been involved in the development of novel poꢀ
tocol.
We commenced our synthesis from commercially available
quinolineꢀ2ꢀcarboxylic acid, which underwent amidation reacꢀ
tion with various substituted aromatic amines in the presence
of the coupling reagent 1,1'ꢀcarbonyldiimidazole (CDI) in
tetrahydrofuran at room temperature. This reaction afforded
the 3aꢀg series of Nꢀ(substituted)quinolineꢀ2ꢀcarboxamides in
good yields (Scheme 1). The 3aꢀg derivatives were also conꢀ
9
ꢀ11
tent NFꢀκB inhibitors with anticancer activity.
Besides, quinolines and tetrahydroquinolines are important
ubiquitous structural motifs in biologically active natural
1
2ꢀ
products and pharmacologically relevant therapeutic agents.
1
6
17
However, Khan et al. demonstrated that tetrahydroquinoꢀ
verted to 4aꢀg by Pd/C hydrogenation reaction (H balloon) in
2
ethanol solvent at room temperature. To obtain the 5aꢀh, 6aꢀh
and 7aꢀh series, we performed acylation reaction in the presꢀ
ence of triethylamine in anhydrous tetrahydrofuran (Scheme
2). All newly synthesized derivatives (3aꢀg, 4aꢀg, 5aꢀh, 6aꢀh
and 7aꢀh) were confirmed by H and C NMR and mass specꢀ
tra. In evaluation studies of inhibition of LPSꢀinduced NFꢀĸB
transcriptional activity, we compared all synthesized derivaꢀ
tives (4aꢀg, 5aꢀh, 6aꢀh, and 7aꢀh)
lines can be used as NFꢀκB inhibitors as well as anti HIV
agents and anti Parkinson's diseases etc. María José Abad et
al. were also tested quinolineꢀbased compounds as modulaꢀ
18
1
13
tors of HIV transcription through NFꢀκB and Sp1 inhibition.
These distinct inhibitory activities have encouraged us to preꢀ
pare such core motifs to test our hypothesis that their derivaꢀ
tives would act as most potent NFꢀκB inhibitors and have antiꢀ
cancer activity. We designed and synthesized different novel
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a
Scheme 1. Synthesis of 3aꢀg and 4aꢀg series of scaffolds
R , R and R , which resulted in 4aꢀg analogues. Subsequently
2 3 4
R =R =R =R =H (4a, IC : 60 ꢁM) was prepared to study the
1
2
3
4
50
R
1
effect of the core 1,2,3,4ꢀtetrahydroquinolineꢀ2ꢀcarboxamide
motif. We also examined the electronic influence of different
groups at R , R , R and R , including electronꢀdeficient (ꢀ
H
2
N
R
2
R
1
a
H
OH
N
R2
N
N
R
3
O
O
1
2
3
4
R
4
R
3
CF3) and electronꢀrich groups (ꢀOCH3 and –OH). Next, we
introduced various acyl and aroyl groups at the 1ꢀposition of
tetrahydroquinolineꢀ2ꢀcarboxamides, which resulted in 5aꢀh,
1
R
4
2
3a-g
R
1
=R
=OH; R
=OH; R
2
=R
3
=R
=R
=R
; R =R
=R =R
=R =R
=R
4
=H, 3a, 80%
=H, 3b, 57%
=H, 3c, 30%
4
R
1
2
3
=R
=R
4
6
aꢀh and 7aꢀh analogues. Sizes of different aliphatic chains (ꢀ
0
1
2
3
4
5
6
7
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0
1
2
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6
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0
1
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4
5
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7
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9
0
R
3
1
2
R
3
=OCH
3
1
2
=R
=H, 3e, 49%
=H, 3f, 67%
=H, 3g, 46%
4
=H, 3d, 63%
R) and substituents at the aromatic ring were then examined.
The inhibitory effects of these compounds (4aꢀg, 5aꢀh, 6aꢀh
and 7aꢀh) depended on the nature of the substitution at the Rꢀ
position and the substituents (R , R , R and R ) on the Nꢀ
R
1
=CF
=CF
3
3
; R
; R
2
3
4
R
3
1
2
4
R
2
=R
4
=CF
3
; R
1
3
1
2
3
4
R
1
phenyl ring of tetrahydroquinolineꢀ2ꢀcarboxamides. For inꢀ
stance, with R = an alkyl group (methyl, ethyl, propyl or octyl),
we did not notice any significant inhibitory effects, but with R
= phenyl. The following compounds exhibited excellent inhibꢀ
itory effects on LPSꢀinduced NFꢀĸB transcriptional activity
H
R
1
4
N
R
R
2
3
b
H
N
N
R
R
2
3
N
H
O
O
R
4
3
a-g
4a-g
R
R
1
=R
=OH; R
=OH; R
2
=R
3
=R
=R
=R
; R =R
=R =R
=R =R
; R =R
4
=H, 4a, 49%
=H, 4b, 36%
=H, 4c, 23%
4
(
Figure 2): 5e (IC : 1.4±0.071 μM, about 26 and 37 times
50
R
1
2
3
=R
4
R
3
1
2
=R
more potent than PDTC and KLꢀ1156, respectively), 6f (IC :
5
0
R
3
=OCH
3
1
2
=R
=H, 4e, 40%
=H, 4f, 10%
=H, 4g, 35%
4
=H, 4d, 73%
R
1
=CF
=CF
3
3
; R
; R
2
3
4
0
0
.90±0.071 μM, about 41 and 58 times more potent), 6g (IC :
50
R
3
1
2
4
R
2
=R
4
=CF
3
1
3
.70±0.071 μM, about 53 and 75 times) and 6h (IC : 2.7±0.42
5
0
a
Reagents and conditions: (a) CDI, anhydrous THF, RT, 1 h.
b) Pd/C, H balloon, EtOH, RT, 24 h.
μM, about 13 and 19 times). We also tested other substitutions
(
2
at the Rꢀposition and different substituents at the R , R , R
3
1
2
with the reference compound pyrrolidine dithiocarbamate
PDTC), which acts as an antioxidant and is a potent inhibitor
and also with the lead compound KLꢀ
156, which is an inhibitor of NFꢀĸB translocation to the nuꢀ
and R positions of the 1,2,3,4ꢀtetrahydroquinoline core motif
4
(
(Table 1). To explain the trend toward NFꢀĸB inhibition interꢀ
estingly, the electronꢀwithdrawing group –CF at the R posiꢀ
21ꢀ25
of NFꢀĸB activation,
3
1
1
tion resulted in outstanding inhibitory effects on LPSꢀinduced
NFꢀĸB transcriptional activity in comparison with any elecꢀ
tronꢀreleasing group (for example, –OH). We also noticed that
26
cleus in LPSꢀstimulated RAW 264.7 macrophages.
nd
rd
Scheme 2. Synthesis of 5aꢀh, 6aꢀh and 7aꢀh series of scafꢀ
–
I and +M effect groups (such as –Cl) at the 2 and 3 posiꢀ
b
folds
tions of the aryl group of R in combination with –CF at the R
3
1
position also showed excellent inhibition of NFꢀĸB transcripꢀ
tional activity (6g, IC : 0.70±0.071 ꢁM; 6f, IC : 0.90±0.071
50
50
ꢁM). Overall, most of the synthesized compounds (4d, 4e, 4g,
f, 5h, 6d, 7aꢀc and 7e–h) were more potent inhibitors of NFꢀ
5
ĸB transcriptional activity than PDTC and KLꢀ1156 (Figure 2).
We next studied the in vitro cytotoxicity of the synthesized
compounds and initially evaluated quinolineꢀ2ꢀcarboxamide
derivatives (3aꢀg) with the human lung cancer cell line (NCIꢀ
H23) and doxorubicin (ADR) as a reference compound.
b
Reagents and conditions: (c) Triethylamine, anhydrous THF,
o
0
C, 5ꢀ10 min, RT, 30ꢀ60 min.
Initially, we screened the 4aꢀg derivatives; they exhibited
marginal inhibitory effects on NFꢀĸB transcriptional activity
(Table 1). After having the tetrahydroquinoline core motif was
less potent, we next turned our attention mainly to the substiꢀ
tutions of R, R , R , R and R , which resulted in 24 derivaꢀ
1
2
3
4
tives (5aꢀh, 6aꢀh, and 7aꢀh; Table 1). Among them, 5e, (IC50:
1
0
.4±0.71 ꢁM), 6f, (IC : 0.90±0.071 ꢁM), 6g, (IC :
50 50
.70±0.071 ꢁM) and 6h, (IC : 2.7±0.42 ꢁM) exhibited outꢀ
standing inhibitory effects (Figure 1) on LPSꢀ induced NFꢀĸB
transcriptional activity in comparison with remaining derivaꢀ
tives (Table 1). After having the initial experimental results,
structure–activity relationship development was initiated for
5
0
the
tetrahydroquinoline
scaffold.
The
1,2,3,4ꢀ
tetrahydroquinolineꢀ2ꢀcarboxamide motif was modified at two
key positions interpreted as R and substitutions were perꢀ
formed at the aromatic system (R , R , R and R ). In the first
1
2
3
4
set of compounds, we performed different substitutions at R1,
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Table 1. Inhibitory effect on LPSꢀinduced NFꢀκB transcriptional activity for 1,2,3,4ꢀtetrahydroquinolines.
0
1
2
3
4
5
6
7
8
9
0
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0
Substituents (R group)
c
% inhibition
at 100 ꢁM
IC50
No.
(ꢁM)
R
1
R
2
R
3
R
4
PDTC
37.2
53±15
60±10
83±9.9
65±0.71
34±12
26±5.0
68±16
26±1.4
KLꢀ1156
72
85
4
4
a
H
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
b
57
4
c
OH
OCH
H
64
4
d
H
3
>100
>100
79
4
e
CF
3
4
f
H
H
CF
3
4g
CF
3
H
CF
3
>100
c
c
Substituents
% inhibition
at 100 ꢁM
IC50
% inhibition
at 100 ꢁM
c
% inhibition
at 100 ꢁM
IC50
No.
No.
IC50 (ꢁM)
No.
(R group)
(ꢁM)
(ꢁM)
3
4
5
6
2
3
1
3
ꢀ
5
5
a
methyl
ethyl
19
31
41
22
ꢀ
ꢀ
ꢀ
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
85
91
88
58
66
23±0.0
20±0.71
20±0.71
51±21
ꢀ
b
95±0.71
27±0.71
ꢀ
5
c
propyl
octyl
5
d
ꢀ
>
100
1.4±0.071
44
5
e
phenyl
29±0.71
8
2
0.90±0.071
0.70±0.071
2.7±0.42
5f
2ꢀchlorophenyl
3ꢀchlorophenyl
4ꢀchlorophenyl
78
58
82
20±0.71
78±2.1
20±2.8
6f
6g
6h
7f
7g
7h
90
68
92
23±0.0
27±0.71
20±2.1
90
5
5
g
9
2
h
c
IC50 values are means of the concentration ( μ M) exhibiting 50% inhibition of LPSꢀinduced NFꢀ κ B transcriptional activity.
Figure 1. Efficacy of 4aꢀg, 5aꢀh, 6aꢀh and 7aꢀh analogues in Inhibition of NFꢀκB transcriptional activities
Table 2. Cytotoxicity of 3aꢀg series against lung cancer (NCIꢀH23) cell lines
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NO.
R
1
R
2
R
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R
4
GI50 (ꢁM)
ADR
0.101±0.00602
108±8.74
87.5±9.77
102±11.4
7.65±1.93
>90
3
a
H
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3b
3
c
OH
OCH
H
3
d
H
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0
1
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4
5
6
7
8
9
0
3
e
CF
3
3
f
H
H
CF
3
>90
3g
CF
3
H
CF
3
1.44±0.463
d
GI50 values are taken as a mean from three experiments and
correspond to the agent’s concentration causing a 50% decrease
in net cell growth.
As shown in Table 2, electronꢀwithdrawing substituents such
as –CF at the R and R positions of the phenyl ring (3g;
GI : 1.44±0.463 ꢁM) resulted in most potent cytotoxicity.
The series 4aꢀg, 5aꢀh, 6aꢀh and 7aꢀh were also evaluated for
in vitro cytotoxicity against six human cancer cells: NCIꢀ
H23, ACHN (renal), MDAꢀMBꢀ231 (breast), PCꢀ3 (prostate),
NUGCꢀ3 (gastric) and HCT15 (colon) (Figure 3). Any subꢀ
stitution on the phenyl ring was not beneficial and only 4b
3
2
4
50
(
GI : 2.23±0.455 ꢁM) exhibited better cytotoxic activities
50
against all tested cell lines than other analogues of the 4aꢀg
series (Figure 3). To further confirm that the tetrahydroquinꢀ
oline motif is beneficial for cytotoxicity, we executed acylaꢀ
tion reaction with triethyl amine in tetrahydrofuran with 4b,
e and 4g; introduction of electronꢀrich or electronꢀ
withdrawing substituents at the R position afforded 5aꢀh,
aꢀh and 7aꢀh analogues. As expected, these analogues had
improved cytotoxicity against all tested cell lines (Figure 2),
suggesting that substitutions at the R position and the first
position of the tetrahydroquinoline motif are most important
4
1
6
1
(
(
3
Table 3). Compound 5e exhibited the highest cytotoxicity
Figure 3) against all evaluated cell lines (NCIꢀH23, GI :
5
0
.49±0.999 ꢁM; NUGCꢀ3, GI : 3.78±0.618 ꢁM; HCT 15,
GI : 3.83±0.994 ꢁM). The importance of an electronꢀ
withdrawing group was also confirmed by 6g and 6h derivaꢀ
tives, which have –CF and –Cl on both phenyl rings and
exhibited outstanding cytotoxicity (6g, GI : 0.292±0.111 –
0.797±0.173 ꢁM; 6h, GI : 0.307±0.0.0941 – 0.839±0.0610
ꢁM) against all tested cell lines (Figure 2, Table 3). The –
CF3 group at the R and R positions of the phenyl ring in 7g
50
50
3
5
0
5
0
2
4
also resulted in potent cytotoxicity against all tested cell
lines (0.420–1.19 ꢁM; Table 3). Compound 7h also exhibitꢀ
ed potent cytotoxicity against lung (NCIꢀH23, (GI :
5
0
0
ꢁ
.889±0.102 ꢁM) and gastric (NUGCꢀ3, GI : 1.66±0.406
M) cancer cell lines and moderate cytotoxicity against the
other four cell lines (Table 3).
In summary, we identified a new class of 1,2,3,4ꢀ
tetrahydroquinolines as the most potent NFꢀκB
50
Figure 2. In vitro efficacy of 4aꢀg, 5aꢀh, 6aꢀh and 7aꢀh anaꢀ
logues in inhibiting growth of human cancer cell lines.
inhibitors and potent cytotoxic agents against human cancer
cell lines.
Table 3. Cytotoxicity against NCIꢀH23, ACHN, MDAꢀMBꢀ231, PCꢀ3 NUGCꢀ3 and HCTꢀ15 Cancer cell lines
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d
.
GI50 (ꢁM)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
No.
ADR
R
R
1
R
2
R
3
R
4
NCIꢀH23
0.0726±0.00940
97.1±15.3
2.23±0.455
>100
ACHN
0.0995±0.00848
72.9±11.4
3.99±1.33
>100
MDAꢀMBꢀ231
0.112±0.0132
108±17.8
PCꢀ3
NUGCꢀ3
0.125±0.0104
59.0±9.88
2.68±0.824
>100
HCT 15
0.0854±0.00329
109±15.0
Ref
H
0.0923±0.0103
110±15.6
4.31±1.34
>100
4a
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4b
OH
H
5.26±1.77
>100
5.61±1.31
>100
4c
OH
OCH
H
4d
H
3
55.7±9.80
56.8±11.4
25.8±4.12
8.41±1.01
38.0±11.7
57.6±11.7
25.0±8.17
8.19±3.78
51.4±11.2
45.5±13.1
24.2±5.10
8.27±2.74
56.9±17.6
53.3±9.65
20.3±7.35
8.12±5.09
51.9±11.0
39.3±8.58
18.6±5.76
8.76±1.36
50.2±8.10
40.4±4.68
17.6±3.45
8.70±3.02
4e
CF
3
4f
H
H
CF
3
4g
CF
3
H
CF
3
d
GI50 (ꢁM)
No.
5a
R
R
1
R
2
R
3
R
4
NCIꢀH23
65.7±8.84
>90
ACHN
MDAꢀMBꢀ231
PCꢀ3
NUGCꢀ3
49.7±10.9
>90
HCT 15
54.5±7.60
>90
methyl
ethyl
OH
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
H
H
50.7±6.32
>90
89.6±9.29
>90
70.7±14.6
>90
5b
5c
propyl
octyl
43.1±6.24
55.8±8.08
50.6±11.2
65.0±6.13
38.0±3.55
54.3±10.0
72.5±9.36
45.2±7.03
35.4±7.10
31.1±5.10
58.3±9.89
5d
38.4±6.27
3
.78±0.618
3.83±0.994
5e
phenyl
OH
H
H
H
3.49±0.999
4.26±1.21
4.21±0.892
5.69±1.21
5f
2ꢀchlorophenyl
3ꢀchlorophenyl
4ꢀchlorophenyl
OH
OH
OH
H
H
H
H
H
H
H
H
H
46.9±2.99
11.6±2.75
19.2±3.77
44.2±9.55
17.2±3.54
19.6±5.06
47.4±5.04
10.6±1.60
19.6±3.54
60.0±14.3
23.3±4.39
25.1±4.62
36.8±6.41
11.0±2.34
13.4±2.20
44.9±8.04
23.1±5.28
20.2±2.97
5
5
g
h
d
GI50 (ꢁM)
No.
6a
R
R
1
R
2
R
3
R
4
NCIꢀH23
>80
ACHN
>80
MDAꢀMBꢀ231
PCꢀ3
NUGCꢀ3
HCT 15
>80
methyl
ethyl
CF
CF
CF
CF
3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
>80
>80
>80
>80
>70
>80
>80
6b
3
>80
>80
>80
6c
propyl
3
>70
>70
>70
>70
>70
6
d
octyl
3
4.22±1.26
6.34±2.52
2.15±0.680
8.33±3.09
3.35±0.482
4.32±1.04
6.18±1.30
7.70±1.11
6
e
phenyl
CF
3
3
8.09±1.68
3.90±0.946
0.526±0.178
5.29±0.846
2.53±0.625
5.56±0.990
5.14±1.02
8.12±1.44
2.73±0.554
0.754±0.129
6.50±1.14
4.22±0.303
0.797±0.173
6
f
2ꢀchlorophenyl
CF
0
.292±0.111
0.288±0.0992
0.729±0.131
6
g
3ꢀchlorophenyl
4ꢀchlorophenyl
CF
3
3
H
H
H
H
H
H
0.307±0.0941
0.824±0.0708
0.533±0.0824
0.786±0.0996
0.551±0.126
0.839±0.0610
6h
CF
d
.
GI50 (ꢁM)
No.
7a
7b
7c
7d
7e
7f
R
methyl
R
1
R
2
R
3
R
4
NCIꢀH23
>70
ACHN
MDAꢀMBꢀ231
PCꢀ3
>70
NUGCꢀ3
HCT 15
>70
H
H
H
H
H
H
CF
3
3
H
CF
CF
CF
CF
CF
CF
CF
3
>70
>70
>70
ethyl
CF
H
H
H
H
H
3
7.82±1.62
15.0±2.67
3.23±0.397
2.13±0.638
2.08±0.482
7.72±2.40
13.9±4.03
4.52±1.13
2.92±0.640
7.28±0.965
15.2±2.44
7.53±1.69
2.43±0.632
8.54±1.99
18.6±2.87
7.43±1.89
3.50±0.630
7.22±1.35
14.4±3.49
2.23±0.579
1.68±0.238
7.62±0.902
21.9±3.11
4.97±1.09
3.54±1.20
propyl
CF
3
3
octyl
CF
CF
CF
3
3
3
3
phenyl
3
2ꢀchlorophenyl
3
4.70±0.733
5.25±1.08
8.04±2.55
1.93±0.404
4.05±0.820
0
.420±0.0607
0.813±0.271
1.19±0.313
1.05±0.254
0.560±0.189
0.625±0.0674
7g
3ꢀchlorophenyl
4ꢀchlorophenyl
H
H
CF
3
3
H
H
3
0.889±0.102
2.57±0.981
2.00±0.683
4.23±1.67
1.66±0.406
2.22±0.216
7
h
CF
CF
3
d
GI50 values are taken as a mean from three experiments and correspond to the agent’s concentration causing a 50% decrease in net cell
growth
The first round of screening starting from the initial lead scafꢀ
fold 4a led to the discovery of 6f, 6g and 6h analogues. These
new lead analogues inhibited LPSꢀinduced NFꢀκB transcripꢀ
tional activity 41, 53 and 13 times more potently, respectively,
than the reference compound PDTC. Analogues 6f, 6g and 6h
have also shown the most potent in vitro cytotoxicity against
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all evaluated human cancer cell lines. Thus, 6f, 6g, 6h and
related analogues provide new chemical tools for development
of pathwayꢀselective NFꢀκB inhibitors with anticancer activity.
Work on the enhancement of potency and pharmacological
profiles of these probe molecules are underway.
tethered niclosamide derivatives as potent and orally
bioavailable anticancer agents. ACS Med. Chem. Lett. 2013, 4,
80ꢀ185.
Choi, M.; Hwang, Y. S.; Kumar, A. S.; Jo, H.; Jeong, Y.; Oh,
Y.; Lee, J.; Yun, J.; Kim, Y.; Han, S. B.; Jung, J. K.; Cho,
J.; Lee, H. Design and synthesis of 3,4ꢀdihydroꢀ2Hꢀ
benzo[h]chromene derivatives as potential NFꢀκB inhibitors.
Bioorg. Med. Chem. Lett. 2014, 24, 2404ꢀ2407.
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9
1
.
0. Choi, M.; Jo, H.; Park, H. J.; Sateesh Kumar, A.; Lee, J.; Yun,
J.; Kim, Y.; Han, S. B.; Jung, J. K.; Cho, J.; Lee, K.; Kwak, J.
H.; Lee, H. Design, synthesis, and biological evaluation of
benzofuranꢀ and 2,3ꢀdihydrobenzofuranꢀ2ꢀcarboxylic acid Nꢀ
(substituted)phenylamide derivatives as anticancer agents and
inhibitors of NFꢀκB. Bioorg. Med. Chem. Lett. 2015, 25,
2545ꢀ2549.
1. Kwak, J. H.; Kim, Y.; Park, H.; Jang, J. Y.; Lee, K. K.; Yi,
W.; Kwak, J. A.; Park, S. G.; Kim, H.; Lee, K.; Kang, J. S.;
Han, S. B.; Hwang, B. Y.; Hong, J. T.; Jung, J. K.; Kim, Y.;
Cho, J.; Lee, H. Structureꢀactivity relationship of indolineꢀ2ꢀ
carboxylic acid Nꢀ(substituted)phenylamide derivatives.
Bioorg. Med. Chem. Lett. 2010, 20, 4620ꢀ4623.
ASSOCIATED CONTENT
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Supporting Information. Synthetic Procedures, characterization
of final products, biological assay protocols and data and pharmaꢀ
cology profiles. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
Corresponding Author
*
Tel.: +82 43 261 2811; fax: +82 43 268 2732.
Eꢀmail addresses: medchem@chungbuk.ac.kr (H. Lee).
12. Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C. Advances
in the chemistry of tetrahydroquinolines. Chem. Rev. 2011,
1
11, 7157ꢀ7259.
ACKNOWLEDGMENT
1
1
3. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Recent progress in
the synthesis of 1,2,3,4ꢀtetrahydroquinolines. Tetrahedron
1996, 52, 15031
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (NRFꢀ
4. Asolkar, K. N.; Schröder, D.; Heckman, R.; Lang, S.;
WagnerꢀDöbler, I.; Laatsch, H. Helquinoline,
a new
2
013R1A1A2009381), and Medical Research Center Program
tetrahydroquinoline antibiotic from Janibacter limosus Hel 1.
J. Antibiot. 2004, 57, 17ꢀ23.
(2008ꢀ0062275).
15. Pitta, M. G. R.; Pitta, M. G. R.; Rêgo, M. J. B. M.; Galdino, S.
L. The evolution of drugs on schistosoma treatment: Looking
to the past to improve the future. Mini-Rev. Med. Chem. 2013,
ABBREVIATIONS
LPS, Lipopolysaccharide; NFꢀκB, nuclear factor kappaꢀlightꢀ
chainꢀenhancer of activated B cells.
1
3, 493ꢀ508.
1
1
1
6. Leeson, P. D.; Carling, R. W.; Moore, K. W.; Moseley, A. M.;
Smith, J. D.; Stevenson, G.; Chan, T.; Baker, R.; Foster, A.
C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R.; Hoogsteen,
K. 4ꢀAmidoꢀ2ꢀcarboxytetrahydroquinolines. Structureꢀactivity
relationships for antagonism at the glycine site of the NMDA
receptor. J. Med. Chem. 1992, 35, 1954ꢀ1968.
7. Khan, P. M., R. G. Correa, D. B. Divlianska, S. Peddibhotla,
E. H. Sessions, G. Magnuson, B. Brown, E. Suyama, H. Yuan,
A. MangravitaꢀNovo, M. Vicchiarelli, Y. Su, S. Vasile, L. H.
Smith, P. W. Diaz, J. C. Reed, and G. P. Roth. 2011.
Identification of inhibitors of NOD1ꢀinduced nuclear factorꢀ
κB activation. ACS Med. Chem. Lett. 2011, 2, 780ꢀ785.
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TOC Graphics
6
g
Inhibition of NF-κBactivity
IC50 (μM)
0
.70±0.071
GI50 (μM)
Human CancerCell lines
NCI-H23
0.292±0.0111
0.526±0.178
0.288±0.0992
ACHN
MDA-MB-231
PC-3
0.729±0.131
0.754±0.129
0.797±0.173
NUGC-3
HCT 15
7
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