Design and synthesis of 3,4-dihydro-2H-benzo[h]chromene derivatives as potential NF-κB inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.04.053

A novel class of NF-κB inhibitors were designed and synthesized based on KL-1156 (6-hydroxy-7-methoxychroman-2-carboxylic acid phenyl amide) which is unambiguously considered to be a promising inhibitor for the translocation step of NF-κB. Especially in this study we focused on the modifying the chroman moiety of KL-1156 into four parts for exploring the SAR studies linked with physical properties of substituents resulted the development of novel 1a-k, 2a-f, 3a-d and 4a-d derivatives of 3,4-dihydro-2H-benzo[h]chromene. From the SAR studies we were very delightfully identified that several new N-aryl-3,4-dihydro-2H-benzo[h]chromene-2-carboxamide derivatives (1a-k) exhibited good inhibitory activity and anti-proliferative activity than parent lead compound KL-1156, among them 1i exhibited outstanding inhibitory effect on LPS-induced NF-κB transcriptional activity and anti-proliferative activity on NCI-H23 lung cancer cell lines than KL-1156.

Full text of DOI:10.1016/j.bmcl.2014.04.053

Accepted Manuscript
Design and Synthesis of 3,4-Dihydro-2H-benzo[h]chromene Derivatives as Po-
tential NF-ĸB Inhibitors
Minho Choi, Young-Sik Hwang, Arepalli Sateesh Kumar, Hyeju Jo, Yeongeun
Jeong, Yunju Oh, Joonkwang Lee, Jieun Yun, Youngsoo Kim, Sang-bae Han,
Jae-Kyung Jung, Jungsook Cho, Heesoon Lee
PII:
S0960-894X(14)00401-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.04.053
BMCL 21546
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 March 2014
11 April 2014
12 April 2014
Please cite this article as: 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 3,4-Dihydro-2H-benzo[h]chromene Derivatives as
Potential NF-ĸB Inhibitors, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/
j.bmcl.2014.04.053
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Bioorganic & Medicinal Chemistry Letters
journal hom epage: www.elsevier.com
Design and Synthesis of 3,4-Dihydro-2H-benzo[h]chromene Derivatives as
Potential NF-ĸB Inhibitors
Minho Choi a, Young-Sik Hwang a, Arepalli Sateesh Kumar a, Hyeju Jo a, Yeongeun Jeong a, Yunju Oh a,
Joonkwang Leea, Jieun Yunb, Youngsoo Kim a, Sang-bae Han a, Jae-Kyung Jung a, Jungsook Cho c and
Heesoon Lee a ∗
aDepartment of Pharmacy, Chungbuk National University, Chungbuk 361-763, Republic of Korea.
bKorea Research Institute of Bioscience and Biotechnology, Ochang, 363-883, Republic of Korea.
cCollege of Pharmacy, Dongguk University, Goyang 410-773, Republic of Korea.
ARTICLE INFO
ABSTRACT
A novel class of NF-κB inhibitors were designed and synthesized based on KL-1156 (6-
Hydroxy-7-methoxychroman-2-carboxylic acid phenyl amide) which is unambiguously
considered to be a promising inhibitor for the translocation step of NF-κB. Especially in this
study we focused on the modifying the chroman moiety of KL-1156 into four parts for exploring
the SAR studies linked with physical properties of substituents resulted the development of
novel 1a-k, 2a-f, 3a-d and 4a-d derivatives of 3,4-dihydro-2H-benzo[h]chromene. From the
SAR studies we were very delightfully identified that several new N-aryl-3,4-dihydro-2H-
benzo[h]chromene-2-carboxamide derivatives (1a-k) exhibited good inhibitory activity and anti-
proliferative activity than parent lead compound KL-1156, among them 1i exhibited outstanding
inhibitory effect on LPS-induced NF-κB transcriptional activity and anti-proliferative activity on
NCI-H23 lung cancer cell lines than KL-1156.
Article history:
Received
Revised
Accepted
Available online
Keywords:
NF-κB inhibitors
Cytotoxic activity
N-aryl-3,4-dihydro-2H-benzo[h]chromene-2-
carboxamide derivatives
2014 Elsevier Ltd. All rights reserved.
In 1986 Baltimore et al., discovered NF-κB as a factor in
the nucleus of B cells that binds to the enhancer of the kappa
light chain of immunoglobulin and it also has been
characterized as a lymphoid specific protein.1 Since then an
intensive research have been dedicated to the study of NF-
κB signaling, approximately more than 25,000 publications
have been reported so far. NF-κB is also found in almost all
animal cell types and is involved in cellular responses to
stimuli such as stress cytokines, oxidized LDL, ultraviolet
irradiation, free radical, and viral or bacterial antigens.2-6 NF-
κB is constitutively active in most tumor cell lines, whether
derived from solid tumors or hematopoietic tumors. It is
infrequently established to be constitutively active in normal
cells except for proliferating T cells, thymocytes, B cells,
monocytes, and astrocytes.7 Constitutively active NF-κB has
been identified not only in human cell lines but also in tumor
tissues derived from patients with multiple myeloma, chronic
myelogenous leukemia, acute lymphocyte leukemia, and acute
myelogenous leukemia, breast and prostate cancers.8-11
multiplicity of chroman derivatives having inhibitory activity
of NF-κB13–16 based on compound KL-1156 (6-hydroxy-7-
methoxychroman-2-carboxylic acid phenyl amide) (Figure 1),
an inhibitor of translocation to the nucleus in LPS-stimulated
macrophage RAW 264.7 cells.13 In the investigation studies of
inhibitors of NF-κB, we had been recognized that the parent
lead compound KL-1156 having phenolic -OH group and short
alkyl groups of the chroman moiety have no significant effect
for enhancement of inhibitory activity of NF-κB. Therefore we
synthesized
a series of indoline-2-carboxylic acid N-
(substituted) phenylamide derivatives and they were also
evaluated for cytotoxicity against various cancer cell lines.17
Consequently, it has been suggested and very useful that
inhibitors of NF-κB function both as anti-inflammatory agents
and as antitumor agents.12 Over the years, having interest on
developing the novel inhibitors of NF-κB, our group reported a
Figure 1. Representative examples of chroman (Benzopyran) scaffolds
containing biologically active molecules.
———
∗ Corresponding author. Tel.: +82-43-261-32; fax: +82-43-268-27; e-mail: medchem@chungbuk.ac.kr (H. Lee)

Scheme 1. General methods to prepare 1 series. Reagents and conditions: (a) diethyloxalate, NaOEt, EtOH, reflux, 3 h (b) EtOH,
HCl (c) H2, 10% Pd/C, EtOH, 24 h (d) KOH, isopropylalcohol/H2O, reflux, 3h (after 4 steps yield 50%) (e) CDI, THF, 12 h, 52-
75%
Furthermore, chroman (benzopyran) scaffold also frequently
found in various biologically active molecules as shown in
Figure 1. Hence these scaffolds are also traditionally valuable
and to establish a systematic SAR of pyranyl moiety in
chroman scaffolds, expansion of aromatic core of chroman to
benzo[h]chromene could be considered. Furthermore we have
introduced amide, carboxamide, aryl and alkyl amine
functionalities to the core structure of benzo[h]chromene
which could provide high-water solubility and exert beneficial
pharmacokinetic effects. Thus, as part of our ongoing efforts
to develop novel NF-κB inhibitory agents, herein we reported
the synthesis of various amide, amine derivatives of 3,4-
dihydro-2H-benzo[h]chromene and their structure-activity
relationship (SAR).
evaluation of inhibitory studies some of these derivatives have
low solubility so that to overcome the obstacle we modified the
amide functionality to amine functionality without disturbing
the core structure of 3,4-dihydro-2H-benzo[h]chromene as
depicted in Scheme 2. To introduce the amine functionality to
the core of 3,4-dihydro-2H-benzo[h]chromene we initiated our
synthetic plan from acid 8 which is on reduction with lithium
aluminum hydride (LiAlH4) in tetrahydrofuran (THF) afforded
99% of alcohol 10 which is good precursor for the synthesis of
aryl amine and alkyl amine derivatives of 3,4-dihydro-2H-
benzo[h]chromene as shown in scheme 2. Alcohol 10 on
treatment
(DDQ) and triphenylphosphine (PPh3) in acetonitrile at reflux
temperature obtained six N-((3,4-dihydro-2H-
with
3-dichloro-5,6-dicyano-1,4-benzoquinone
benzo[h]chromen-2-yl)methyl)-2-methylaniline derivatives 2a-
f as depicted in scheme 2. We have also synthesized various
3,4-dihydro-2H-benzo[h]chromene derivatives 3a-d and 4a-d
from the precursor 10 which is at first involved in tosylation
reaction with TsCl/DMAP/Et3N in DCM at 0°C provided 76%
of tosylated product which is also converted to azide
functionality in 97% yield by treatment with NaN3/DMF at 60°
C. Further the azide compound involved in Staudinger
reaction18 with triphenylphosphine (PPh3) in tetrahydrofuran
(THF) obtained 88% of 11 as shown in Scheme 2. We have
derived four methyl amide derivatives 3a-d and four alkyl
amine derivatives 4a-d from 11 as depicted in Scheme 2.
As shown in Scheme 1, we commenced our synthesis with
commercially available
5 which involved in tandem
cyclization with diethyl oxalate, sodium ethoxide and ethanol
in acidic medium provided 6. The reduction of 6 with Pd/C
obtained 7. Hydrolysis of ester 7 which is on treatment with
KOH in aqueous isopropyl alcohol was accomplished to acid 8
in 50% overall yield. After obtaining acid 8, we furnished
amidation reaction with various substituted anilines 9 using
coupling reagent such as 1,1'-carbonyldiimidazole (CDI) in
tetrahydrofuran (THF) afforded eleven compounds of N-aryl-
3,4-dihydro-2H-benzo[h]chromene-2-carboxamide derivatives
(1a-k). After synthesis of these derivatives we noticed that in
Scheme 2. General methods to prepare 2,3 & 4 series. Reagent and condition: (f) LAH, THF, reflux, 3 h, 99% (g) DDQ, PPh3,
MeCN, reflux, 12 h, 9-22% (h) DMAP, Et3N, TsCl, CH2Cl2, 0 °C to rt, 3 h, 76% (i) NaN3, DMF, 60 °C, 97% (j) TPP, H2O, THF,
rt, 88% (k) Et3N, THF, 0 °C to rt, 30 min, 34-91%, (l) LAH, THF, 3 h, 32-42%

Table 1. Inhibitory effect on LPS-induced NF-ĸB transcriptional activity for 3,4-dihydro-2H-benzo[h]chromene derivatives.
a
a
Substituents (R group)
Substituents (R group)
% inhibition
at 100 μM
IC50
(μM)
% inhibition
at 100 μM
IC50
(μM)
NO.
NO.
R1
Ref
Ref
H
R2
R3
R4
R1
R2
H
R3
H
R4
H
PDTC
37.2
40.1
43.5
12.3
5.0
2a
2b
2c
2d
2e
2f
H
49
88
-
KL-1156
H
H
OCH3
Cl
H
44.5
26.5
-
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
62
91
H
H
H
94
OH
H
H
Cl
H
H
H
36
H
OH
OCH3
Cl
H
>100
>100
>100
87
H
CF3
H
H
42
-
H
H
H
12.9
5.8
H
CF3
CF3
96
56.3
48.6
-
H
H
H
3a
3b
3c
3d
4a
4b
4c
4d
phenyl
methyl
isopropyl
isobutyl
phenyl
methyl
isopropyl
isobutyl
>100
35
H
Cl
Cl
Cl
H
H
H
27.9
-
1g
1h
1i
H
Cl
H
40
31
-
H
H
Cl
H
52
96.7
2.4
77
56.3
14.6
-
CF3
H
H
>100
>100
66
>100
39
1j
H
CF3
H
H
12.9
63.8
1k
H
CF3
CF3
>100
>100
27.1
25.9
a IC50 values are taken as a mean from three experiments and exhibiting 50% inhibition of LPS-induced NF-κB transcriptional activity.
As shown in Table 1, a total twenty five compounds of 3,4-
dihydro-2H-benzo[h]chromene derivatives were evaluated for
inhibitory effect on LPS-induced NF-κB transcriptional
activity19 and also compared to parent lead compound KL-
1156 and reference compound pyrrolidine dithiocarbamate
(PDTC), which acts as an antioxidant and potent inhibitor of
NF-κB activation.20 Among all evaluated twenty five
compounds when compared to KL-1156 (IC50: 40.1 µM) and
PDTC (IC50: 37.2 µM); 1b (IC50: 12.3 µM), 1c (IC50: 5.0 µM),
1d (IC50: 12.9 µM), 1e (IC50: 5.8 µM), 1f (IC50: 27.9 µM), 1i
(IC50: 2.4 µM), 1j (IC50: 12.9 µM), 2c (IC50: 26.5 µM), 4a
(IC50: 14.6 µM), 4c (IC50: 27.1 µM) and 4d (IC50: 25.9 µM),
exhibited more good potent activity. In particular N-(2-
(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[h]chromene-
2-carboxamide 1i (IC50: 2.4 µM) exhibited excellent inhibitory
µM), 4c (IC50: 27.1 µM) and 4d (IC50: 25.9 µM) respectively
exhibited better activity than parent lead compound KL-1156
and reference PDTC as depicted in Table 1.
Table 2. In vitro anti-proliferative activity against NCI-H23
cancer cell lines21
aGI50
aGI50
aGI50
(μM)
(μM)
(μM)
No.
No.
No.
NCI-H23
0.178
9.316
>30
NCI-H23
>30
NCI-H23
14.62
11.38
>30
ADR
1h
1i
2f
3a
3b
3c
3d
4a
4b
4c
4d
KL-1156
0.521
3.482
11.18
25.78
12.77
29.76
17.17
>30
1a
1b
1c
1d
1e
1f
1j
>30
1k
2a
2b
2c
2d
2e
>30
activity
among
all
synthesized
3,4-dihydro-2H-
11.28
3.977
2.794
>30
>30
benzo[h]chromene derivatives (1a-k) and it was found to be
about 16 and 15 times more potent than parent lead and
reference compounds KL-1156 and PDTC respectively. Not
only above compounds but also 1c (IC50: 5.0 µM) and 1e (IC50:
5.8 µM) also exhibited better inhibitory activities than KL-
1156 and PDTC as shown in Table 1. From Table 1, we
concluded that 1a-k derivatives exhibited outstanding
inhibitory activities than 2a-f , 3a-d and 4a-d derivatives when
evaluated in LPS-stimulated macrophage RAW 264.7 cells.
10.43
>30
11.72
11.3
1g
23.47
a
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.
To explore the structure-activity relationship of N-
phenyl)-3,4-dihydro-2H-benzo[h]chromene-2-
For finding the correlation between the inhibitory activities of
NF-κB and anti-proliferative activities (cytotoxicity) a total
twenty-five compounds were also evaluated for anti-
proliferative activity against NCI-H23 human lung cancer cell
line (Table 2). The results of anti-proliferative activity in NCI-
H23 cell line was not directly proportional to NF-κB inhibitory
activities. However, compounds exhibiting good inhibitory
activities of NF-κB also exhibited better anti-proliferative
activities in NCI-H23 cell line. Among them interestingly 1i
exhibited the outstanding NF-κB inhibitory activity as well as
excellent anti-proliferative activity than other compounds
against NCI-H23 cell line and which is also found to have
comparable anti-proliferative activity of doxorubicin (ADR)
(GI50: 0.178 μM). From the Table 2, we concluded that the 1a-
k derivatives exhibited more potent activities and maintained a
(substituted
carboxamide derivatives (1a-k) toward NF-ĸB inhibition, we
substituted different groups at planar phenyl ring and also been
observed that the substitutions at ortho (R1 substitution) and
para (R3 substitution) positions of phenyl ring exhibited good
inhibitory activities than compared to meta (R4 substitution) in
evaluation of LPS-stimulated macrophage RAW 264.7 as
shown in Table 1. For instance ortho and para substitution
analogs 1b, 1i, 1d, 1e, 1j exhibited good inhibitory activities
than meta substitution analogs 1f, 1h, 1k. But in the case of
4a-d derivatives we could not find any structure-activity
relationship (SAR) since they have also exhibited better
inhibitory activity of NF-ĸB. Among them bulky substitutions
benzyl, isobutyl, isopropyl containing analogs 4a (IC50: 14.6

15. Kwak, J. H.; Won, S. W.; Kim, T. J.; Roh, E.; Kang, H. Y.;
Lee, H. W.; Jung, J. K.; Hwang, B. Y.; Kim, Y.; Cho, J.; Lee,
H. Arch. Pharm. Res. 2008, 31, 133–141.
good correlation between their NF-κB inhibition and anti-
proliferative activities than 2a-f, 3a-d and 4a-d derivatives in
NCI-H23 lung cancer cell line.
16. Kwak, J. H.; Won, S. W.; Kim, T. J.; Yi, W.; Choi, E. H.; Kim,
S. C.; Park, H.; Roh, E.; Jung, J. K.; Hwang, B. Y.; Hong, J. T.;
Kim, Y.; Cho, J.; Lee, H. Arch. Pharm. Res. 2009, 32, 167–
175.
In conclusion, a total twenty-five compounds of 3,4-
dihydro-2H-benzo[h]chromene have been synthesized and
evaluated their inhibitory effects on LPS-induced NF-κB
transcriptional activity. Among them 1a-k derivatives
exhibited good inhibitory activities than 2a-f, 3a-k and 4a-g
series. Structure-activity relationship of 1a-k analogs appears
to be essential for its NF-κB transcriptional activities and slight
substitution variation at ortho position (R1) like 1i22 (IC50: 2.4
µM) surprisingly exhibited excellent inhibitory activity on
LPS-induced NF-κB transcriptional activity than parent lead
compound KL-1156 and reference compound PDTC and it is
also exhibiting good anti-proliferative activity than KL-1156.
This might indicate that 3,4-dihydro-2H-benzo[h]chromene
core could be the lead scaffold for investigating new anticancer
agent through inactivation of NF-κB.
17. 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.;
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G.; Bertozzi, C. R. J. Am. Chem. Soc, 2005, 127, 2686–2695.
19. Measurement of NF-κB transcriptional activity: RAW 264.7
macrophages were stably transfected with NF-κB-SEAP-NPT
plasmid and then treated with 1 µg/mL LPS plus sample for 16
h. Aliquots of the cell-free media were heated at 65℃ for 5
min, and then reacted with SEAP assay buffer (500 µM 4-
methylumbelliferyl phosphate, 2 M diethanolamine, and 1 mM
MgCl2) in the dark at room temperature for 1 h. As a reporter,
SEAP activity was measured as relative fluorescence units
(RFU) with emission 449 nm and excitation 360 nm.
20. (a) Nurmi, A.; Vartiainen, N.; Pihlaja, R.; Goldsteins, G.;
Yrjaenheikki, J.; Koistinaho, J. J. Neurochem. 2004, 91, 755–
765. (b) Hayakawa, M.; Miyashita, H.; Sakamoto, I.; Kitagawa,
M.; Tanaka, H.; Yasuda, H.; Karin, M.; Kikugawa, K. EMBO J.
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Sternsdorf, T.; Liese, J.; Belohradsky, B.; Weber, C.; Wedel,
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6986–6993. (e) Schreck, R.; Meier, B.; Mannel, D. N.; Droge,
W.; Baeuerle, P. A. J. Exp. Med. 1992, 175, 1181–1194.
21. In vitro anti-proliferative activity (cytotoxicity) assay was
performed using the number of cells was measured indirectly
using the sulforhodamine B (SRB) method according to the
NCI (USA) protocol (see ref. 13a). Briefly, the cells were
plated into a 96 well plate at a density of 2 × 103 cells per well.
On the next day (day 0), the compounds of interest dissolved in
DMSO/media were added in quadruplicate. The final
concentration of each compound ranged from 1 nM - 10 µM
and the final concentration of DMSO was < 0.1%. Seventy-two
hours later, the cells were fixed with 10% trichloroacetic acid
(TCA) overnight at 4℃. The TCA-treated cells were washed
extensively with distilled water and dried in air. A SRB
solution (0.4% in 1% acetic acid) was then added to the well at
room temperature for one hour. The bound dye was dissolved
in 10 mM Tris after washing the wells with 1% acetic acid. The
absorbances were measured at 690 nm using a micro plate
reader. The absorbance of the day 0 sample was subtracted
from the absorbance of the day 3 sample.
Acknowledgments
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 (NRF-2013R1A1A2009381), Medical Research
Center Program (2008-0062275) and the research grant of
Chungbuk National University in 2012.
Supplementary data
Supplementary data (general preparation procedures and
analytical data) associated with this article can be found in
online version at http://dx.doi.org/
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22. N-(2-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[h]chromene-2-
carboxamide (1i): IR (neat): 3307, 2946, 1661, 1320, 1023, 652
cm-1. 1H NMR (CDCl3, 400 MHz): δ 9.10 (s, 1H, NH), 8.42 (d,
J = 8.3 Hz, 1H, Ar-H), 8.23 (d, J = 8.3 Hz, 1H, Ar-H), 7.79 (d,
J = 7.4 Hz, 1H, Ar-H), 7.65 - 7.47 (m, 5H, Ar-H), 7.26 (t, J =
7.6 Hz, 1H, Ar-H), 7.19 (d, J = 8.4 Hz, 1H, Ar-H), 4.85 (dd, J
=9.9 Hz, 2.9 Hz, 1H, OCHCH2CH2), 3.14 - 2.93 (m, 2H,
OCHCH2CH2), 2.67 - 2.60 (m, 1H, OCHCH2CH2), 2.31 - 2.21
(m, 1H, OCHCH2CH2). 13C NMR (CDCl3, 100 MHz): δ 169.6,
146.9, 138.4, 133.4, 132.7, 132.4, 128.0, 127.5, 126.2, 126.1,
124.6, 124.4, 121.5, 120.2, 119.8, 119.8, 118.1, 116.4, 75.8,
24.9, 24.0. HRMS Calcd. For C21H16F3NO m/z 371.11 found
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Design and Synthesis of 3,4-Dihydro-2H-
benzo[h]chromene Derivatives as Potential
NF-κB Inhibitors
Leave this area blank for abstract info.
Minho Choi a, Young-Sik Hwang a, Arepalli Sateesh Kumar a, Hyeju Joa, Yeongyun Jeong a, Yunju Oh a,
Joonkwang Leea, Jieun Yunb, Youngsoo Kima, Sang-bae Hana, Jae-Kyung Junga, Jungsook Cho c and Heesoon
Lee a ∗