Arylalkyl ketones, benzophenones, desoxybenzoins and chalcones inhibit TNF-α induced expression of ICAM-1: Structure-activity analysis

Article abstract of DOI:10.1002/ardp.201100279

The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in the pathogenesis of various inflammatory and autoimmune diseases. Small molecules that block these interactions have been targeted as potential therapeutic agents against acute and chronic inflammatory diseases. In an effort to identify potent intercellular cell adhesion molecule-1 (ICAM-1) inhibitors, a large number of arylalkyl ketones, benzophenones, desoxybenzoins and chalcones and their analogs (54 in total) have been synthesized and screened for their ICAM-1 inhibitory activity. The structure-activity relationship studies of these compounds identified three potent chalcone derivatives and also demonstrated the possible mechanism for their ICAM-1 inhibitory activities. The most active compound was found to be 79. A large number of arylalkyl ketones, benzophenones, desoxybenzoins and chalcones as well as their analogs (54 in total) were synthesized and screened for their ICAM-1 inhibitory activity. The structure-activity relationship studies of these compounds identified three potent chalcone derivatives and also demonstrated a possible mechanism of their ICAM-1 inhibitory activities. The most active compound was found to be 79. Copyright

Full text of DOI:10.1002/ardp.201100279

Arch. Pharm. Chem. Life Sci. 2011, 000, 1–10
1
Full Paper
Arylalkyl Ketones, Benzophenones, Desoxybenzoins and
Chalcones Inhibit TNF-a Induced Expression of ICAM-1:
Structure-Activity Analysis
Sarvesh Kumar1,2, Chandra Shekhar Reddy L3, Yogesh Kumar3, Amit Kumar3,
Brajendra K. Singh3,4, Vineet Kumar3,5, Shashwat Malhotra3, Mukesh K. Pandey3, Rajni Jain3,6
,
Rajesh Thimmulappa2, Sunil K. Sharma3, Ashok K. Prasad3, Shyam Biswal2, Erik Van der Eycken4,
Anthony L. DePass7, Sanjay V. Malhotra5, Balaram Ghosh1, and Virinder S. Parmar3
1 Laboratory of Immunogenetics, CSIR – Institute of Genomics and Integrative Biology,
Delhi University Campus, Delhi, India
2 Department of Environmental Health Sciences, Bloomberg School of Public Health,
Johns Hopkins University, Baltimore, MD, USA
3 Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi, India
4 Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Katholieke Universiteit Leuven,
Leuven, Belgium
5 Laboratory of Synthetic Chemistry, Development Therapeutics Program Support,
National Cancer Institute Frederick, SAIC-Frederick, Frederick, MD, USA
6 Department of Chemistry, Bharat Institute of Technology, Meerut, UP, India
7 Department of Biology, Long Island University, Brooklyn, NY, USA
The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion
molecules plays an important role in the pathogenesis of various inflammatory and autoimmune
diseases. Small molecules that block these interactions have been targeted as potential therapeutic
agents against acute and chronic inflammatory diseases. In an effort to identify potent
intercellular cell adhesion molecule-1 (ICAM-1) inhibitors, a large number of arylalkyl ketones,
benzophenones, desoxybenzoins and chalcones and their analogs (54 in total) have been
synthesized and screened for their ICAM-1 inhibitory activity. The structure-activity
relationship studies of these compounds identified three potent chalcone derivatives and also
demonstrated the possible mechanism for their ICAM-1 inhibitory activities. The most active
compound was found to be 79.
Keywords: Arylalkyl ketones / Benzophenones / Chalcones / Desoxybenzoins / Endothelial cells / ICAM-1
Received: August 3, 2011; Revised: October 17, 2011; Accepted: October 21, 2011
DOI 10.1002/ardp.201100279
Introduction
The recruitment of leukocytes from the blood into tissue is a
multistep process that requires a series of leukocyte-endo-
thelial adhesive interactions, involving several families of
adhesion molecules. They participate in inflammatory reac-
tions mainly by regulation of leukocyte migration, activation
Correspondence: Dr. Balaram Ghosh, Laboratory of Immunogenetics,
CSIR – Institute of Genomics and Integrative Biology, Delhi University, Mall
Road, Delhi 110 007, India.
E-mail: bghosh@igib.res.in
Fax: þ91-11-2766-7471
Additional correspondence: Prof. Virinder S. Parmar Bioorganic
Laboratory, Department of Chemistry, University of Delhi, Delhi-110 007,
India.
E-mail: virparmar@gmail.com
Fax: 91-11-2766-7206
Abbreviations: ICAM-1, intercellular adhesion molecule-1; VCAM-1,
vascular cell adhesion molecule-1; TNF-a, tumor necrosis factor a; NF-
kB, nuclear factor kB; ECs, endothelial cells; Nrf2, nuclear factor
erythroid-2 related factor 2.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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S. Kumar et al.
Arch. Pharm. Chem. Life Sci. 2011, 000, 1–10
and survival. Elevated expression of the cell adhesion mol-
ecules such as ICAM-1, VCAM-1, and E-selectin on the luminal
surface of vascular endothelial cells is a critical event in
inflammatory processes. Small molecules that block these
interactions have been targeted for potential therapeutic
treatments of acute and chronic inflammatory diseases.
Anti-adhesion therapy by using specific monoclonal anti-
bodies (mAbs) has been found to be beneficial for controlling
various diseases [1, 2]. However, due to endotoxin contami-
the biological activity. We have reported the cell adhesion
molecules inhibitory activity of the natural chalcone, isoli-
quiritigenin [15]. In this study, we are reporting the synthesis
and ICAM-1 inhibitory activities of four similar classes of
compounds (arylalkyl ketones, benzophenones, desoxyben-
zoins and chalcones and their analogs, 54 in total) to draw a
structure-activity relationship; a possible mechanism for this
activity is also proposed.
nation, unpredictable secondary antibody formation, cellu- Results and discussion
lar activation, and other complications like serum sickness
and anaphylaxis, the practical use of mAbs is limited.
However, inhibition of expression of ICAM-1, VCAM-1 and
E-selectin by various small molecules from natural and syn-
thetic sources such as curcumin, glucocorticoids, pentoxifyl-
line, etc. have been shown to downregulate the expression of
cell adhesion molecules and are effective in controlling var-
ious inflammatory diseases [3–5].
Arylalkyl ketones inhibit the TNF-a induced expression
of ICAM-1 on endothelial cells
The arylalkyl ketones 14–25 were synthesized by the Friedel–
Crafts acylation of the corresponding polyphenols 1–6 with
different aliphatic acids 7–13 (Scheme 1) and evaluated for
their effect on the inhibition of TNF-a induced expression of
ICAM-1 on endothelial cells. The % inhibition and IC50 values
of the screened ketones are summarized in Table 1. 1-(2,4,6-
Trihydroxyphenyl)-ethanone (21) was found to be the most
potent inhibitor of TNF-a induced expression of ICAM-1 with
IC50 of 178 mM and 70% of ICAM-1 inhibition, whereas its
dihydroxy analog 14 possesses IC50 of 328 mM and 70% of
ICAM-1 inhibition (Table 1). However, its analogs having
longer alkyl chains, i.e. n-butyl, iso-pentyl, hexyl, nonyl and
Arylalkyl ketones, benzophenones, desoxybenzoins and
chalcones are groups of compounds widely present in the
higher plants and have been synthesized in the laboratory
[6, 7]. They contain an aromatic ring and an alkyl moiety or
two aromatic rings separated by a 1–3 carbon chain (satu-
rated or unsaturated). This unique structural feature is
responsible for various activities of these molecules.
Chalcones have been reported to possess a wide variety of
biological properties including anti-inflammatory, analgesic
and antipyretic [8–10], antioxidant [11], antibacterial, anti-
fungal and antiprotozoal activities [12–14]. They are also
reported to be gastric protectant, anti-mutagenic and anti-
tumorogenic [10]. Substitution pattern on chalcone rings
plays a critical role in its biological properties. Various sub-
stituents on the chalcone rings either enhance or decrease
pentadecyl moieties, possess relatively lower
inhibition values (Table 1).
%
This clearly illustrates the significance of a greater number
of free phenolic hydroxyl groups on the benzene ring and the
length of the alkyl group present in the aryl-alkyl ketones.
When the number of free phenolic hydroxyl groups is higher,
the inhibition values are relatively higher, whereas a longer
alkyl chain lowers the inhibition values (Table 1). Moreover %
3
2
RO
OH
R2
ZnCl2 , 145 o
R2COOH
C
RO
OH
5
R1
6
4
1
R1
_
_
_
O
7 13
14 25
1
6
R2
R1
R1
R
R
R2
Acid
Comp.
Comp.
H
H
CH3
H
CH3
C2H5
H
7
8
9
10
11
14
15
16
17
18
1
2
3
4
5
C2H5
H
H
H
H
5-OH
4-OH
H
H
H
CH3
n-C4H9
iso-C5H11
n-C4H9
iso-C5H11
2,5-(OCH3)2
H
H
H
H
CH3
n-C6H13
n-C9H19
n-C6H13
n-C9H19
H
CH3
H
H
6-OH
5-OCH3
12
13
19
20
21
22
6
n-C15H31
n-C15H31
H
H
CH3
CH3
C2H5
5-OH
H
CH3
3,6-(OCH3)2
H
23
CH3
CH3
CH3
CH3
24
25
Scheme 1. Synthesis of different arylalkyl
ketones.
6-OCH3
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Arch. Pharm. Chem. Life Sci. 2011, 000, 1–10
TNF-a Induced Inhibition of ICAM-1 on Endothelial Cells
3
Table 1. Effect of arylalkyl ketones on the TNF-a induced expression of ICAM-1 on endothelial cells.
Compound
% Inhibition
Concentration mMꢀ
IC50 mM
1-(2,4-Dihydroxyphenyl)-ethanone (14)
70
40
35
40
30
25
10
70
55
50
55
40
460
421
308
240
224
151
114
237
219
221
300
356
328
–
–
–
–
1-(2,4-Dihydroxyphenyl)-propan-1-one (15)
1-(2,4-Dihydroxyphenyl)-pentan-1-one (16)
1-(2,4-Dihydroxyphenyl)-4-methylpentan-1-one (17)
1-(2,4-Dihydroxyphenyl)-heptan-1-one (18)
1-(2,4-Dihydroxyphenyl)-decan-1-one (19)
1-(2,4-Dihydroxyphenyl)-hexadecan-1-one (20)
1-(2,4,6-Trihydroxyphenyl)-ethanone (21)
1-(2,5-Dihydroxy-4-methoxyphenyl)-ethanone (22)
1-(2,4-Dihydroxy-3,6-dimethoxyphenyl)-propan-1-one (23)
1-(2-Hydroxy-4-methoxyphenyl)-ethanone (24)
1-(2-Hydroxy-4,6-dimethoxyphenyl)-ethanone (25)
–
–
178
197
221
282
–
ꢀ
The concentration levels of different compounds are based on their maximum tolerable concentration by the cells. The data
presented are representative of three independent experiments. Values shown are means ꢁ SD of quadruplicate wells.
inhibition of ICAM-1 expression was found to decrease as the
number of methoxy groups in the aromatic moiety increases.
Thus compound 21 lacking any methoxy group shows
the maximum inhibition value of 70% (Table 1); following
the trend, the compounds 22 and 24 (each showing 55%
inhibition and having one methoxy group) and the
compounds 23 and 25 (both having two methoxy groups
and two and one hydroxyl groups, respectively) show 50%
and 40% inhibition of ICAM-1 expression activity; the
same trend is followed in terms of the IC50 values of these
compounds (Table 1).
ICAM-1 expression, followed by the compounds 2,6-dihydrox-
yphenyl, phenylmethanone (40) and 2-carboxyphenyl,
2-hydroxy-4-methylphenylmethanone (42) (exhibiting 55%
ICAM-1 inhibition, IC50 326 mM and 50% ICAM-1 inhibition,
IC50 351 mM values, respectively). All of these three com-
pounds possess two polar groups, either two phenolic
hydroxyl groups or one hydroxyl and a carboxy group at
the conjugated positions to the carbonyl group. Remaining
compounds of this class viz. 38, 39 and 41 had insignificant
activity in lowering the ICAM-1 expression as they possess 1–4
methoxy groups. Thus, like arylalkyl ketones, benzophenones
possessing more free hydroxyl groups showed better activity
and compounds having more methoxy groups showed low
activity.
Benzophenones inhibit the TNF-a induced expression
of ICAM-1 on endothelial cells
Benzophenones 37–42 were synthesized by the Friedel-Crafts
acylation of various derivatives of benzene with different
benzoyl chloride analogs (Scheme 2) and evaluated for their
effect on the inhibition of TNF-a induced expression of
ICAM-1 (Table 2). 2,4-Dihydroxyphenyl, phenylmethanone
(37) was found to be the most active among the screened
benzophenones with IC50 of 256 mM and 85% inhibition of
Desoxybenzoins inhibit the TNF-a induced expression
of ICAM-1 on endothelial cells
The desoxybenzoins 55–64 having an additional methylene
group between the two aromatic rings, as compared to ben-
zophenones were synthesized (Scheme 3) and screened for
their effect on the TNF-a induced expression of ICAM-1.
i) AlCl3, ether, 90 oC,
_
ii) H2O-HCl, 70 oC,
30 min
4 5 h
Cl
+
R1
R1
R2
R2
O
O
_
_
32 36
_
26 31
37 42
Compd. R1
Compd. R2
Compd. R1
R2
H
26
27
28
29
30
31
2,4-(OH)2
2-OH, 5-OCH3
2,5 (OH)2, 4-OCH3
H
2-COOH, 6-NH2
2-COOH
32
33
34
35
36
2,4-(OH)2
H
37
38
39
40
41
42
1,3,5-(OCH3)3
1,5-(OH)2
1-OCH3, 3-CH3
1-OH, 3-CH3
2-OH, 5-OCH3
2,5-(OH)2, 4-OCH3
H
2-COOH, 6-NH2
2-COOH
2,4,6-(OCH3
H
2,6-(OH)2
)
3
2-OCH3, 4-CH3
Scheme 2. Synthesis of different benzo-
phenones.
2-OH, 4-CH3
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4
S. Kumar et al.
Arch. Pharm. Chem. Life Sci. 2011, 000, 1–10
Table 2. Effect of benzophenones on the TNF-a induced expression of ICAM-1 on endothelial cells.
Compound
% Inhibition
Concentration mMꢀ
IC50 mM
2,4-Dihydroxyphenyl, phenylmethanone (37)
85
45
35
55
35
50
326
251
327
373
350
351
256
–
–
326
–
351
2-Hydroxy-5-methoxyphenyl,2,4,6-trimethoxyphenylmethanone (38)
2,5-Dihydroxy-4-methoxyphenyl, phenylmethanone (39)
2,6-Dihydroxyphenyl, phenylmethanone (40)
2-Carboxy-6-aminophenyl,2-methoxy-4-methylphenylmethanone (41)
2-Carboxyphenyl,2-hydroxy-4-methylphenylmethanone (42)
ꢀ
The concentration levels of different compounds are based on their maximum tolerable concentration by the cells. The data
presented are representative of three independent experiments. Values shown are means ꢁ SD of quadruplicate wells.
R1O
OR
R1O
OR
O
COOH
BF3.Et2O
85 oC, 90 min
A
R2
R3
R2
B
_
43 48
_
49 54
_
55 64
R3
R2
Compd. R3
Compd.
R
R1
R3
R2
R1
Compd.
R
49
50
51
52
53
54
3,4-(OCH3)2
H
4-OCH3
4-OH
2,4-(OCH3)2
3,4 -OCH2O-
H
H
H
Ac
H
H
H
H
CH3
Ac
CH3
H
43
44
45
46
47
48
5-OH
5-CH3
2-OCH3
H
H
H
H
H
H
H
H
H
H
Ac
H
H
55
56
57
58
59
60
61
62
63
64
H
H
CH3
H
H
H
H
Ac
CH3
H
3,4-(OCH3)2
H
H
4-OCH3
H
4-OH
2,4-(OCH3)2
H
3,4 -OCH2O-
6-OH
6-CH3
3-OCH3
6-CH3
6-OH
6-OH
6-OH
H
H
H
Scheme 3. Synthesis of different desoxy-
benzoins.
4-OCH3
Table 3 summarizes the results of this screening; 1-(2-
hydroxy-4-methoxyphenyl)-2-(3,4-methylenedioxyphenyl)-
ethanone (63) was found to be the most active compound
(Table 3) with IC50 of 139 mM and 85% of ICAM-1 inhibition.
2-Phenyl-1-(2,4,6-trihydroxyphenyl)-ethanone (59) was also
comparable in its activity to that of 63 with IC50 of
184 mM and 80% of ICAM-1 inhibition. Again desoxybenzoins
having greater number of free phenolic hydroxyl groups in
the aromatic ring ‘A’ (conjugated to the carbonyl group) show
better ICAM-1 expression inhibition values, e.g. compounds
56, 59, 60, 62, 63 and 64, all have one to three free phenolic
hydroxyl groups at the conjugated positions to the carbonyl
group and showed inhibition values above 60% (Table 3). The
compounds 55, 57, 58 and 61, though containing two or three
free phenolic groups in the ring ‘A’, they also possess two
methoxy groups; like aryl alkyl ketones and benzophenones,
Table 3. Effect of desoxybenzoins on the TNF-a induced expression of ICAM-1 on endothelial cells.
Compound
% Inhibition
Concentration mMꢀ
IC50 mM
2-(3,4-Dimethoxyphenyl)-1-(2,4,6-trihydroxyphenyl)-ethanone (55)
1-(2,4-Dihydroxy-6-methylphenyl)-2-phenylethanone (56)
1-(2-Hydroxy-3,4-dimethoxyphenyl)-2-phenylethanone (57)
1-(2,4-Dihydroxy-6-methylphenyl)-2-(4-methoxyphenyl)-ethanone (58)
2-Phenyl-1-(2,4,6-trihydroxyphenyl)-ethanone (59)
2-(4-Hydroxyphenyl)-1-(2,4,6-trihydroxy-phenyl)-ethanone (60)
2-(2,4-Dimethoxyphenyl)-1-(2,4,6-trihydroxyphenyl)-ethanone (61)
1-(2,4-Diacetoxyphenyl)-2-phenylethanone (62)
50
60
50
30
80
60
40
65
85
65
328
371
367
367
245
384
295
256
209
271
328
330
367
–
184
326
–
224
139
232
1-(2-Hydroxy-4-methoxyphenyl)-2-(3,4-methylenedioxyphenyl)-ethanone (63)
1-(2,4-Dihydroxyphenyl)-2-(4-methoxyphenyl)-ethanone (64)
ꢀ
The concentration levels of different compounds are based on their maximum tolerable concentration by the cells. The data
presented are representative of three independent experiments. Values shown are means ꢁ SD of quadruplicate wells.
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Arch. Pharm. Chem. Life Sci. 2011, 000, 1–10
TNF-a Induced Inhibition of ICAM-1 on Endothelial Cells
5
CHO
R1
R
R2
R1
R
R1
R
O
R2
α
A
B
_
CH3
80 83
EtOH
+
β
-
Pd C H
, ,
2
ethyl acetate, 2 h
O
(
)
H
,
2
a
O
B
O
_
R2
reflux, 6 8 h
_
_
7
8
_
7
_
65
R
0
84
71
7
3
74 83
R1
Compd.
Compd.
NaBH4
MeOH, r. t.,
stirring
OH
OH
65
=
71
72
3
R2 CH3
=
H
H
3
O
H
H
H
OC
66
3
3
3
R2
R2
H
H
7
C
6
OC
H
H
68
69
=
7
H
OC
3
H
H
OC
7
OC
0
3
R1
R
R2
R1
R
R2
R1
R
R2
H
2SO4
,
-
Pd C
H
,
2
dioxane,
OH
ethyl acetate, 2 h
refluxing, 4 h
_
_
_
96 99
92 95
88 91
Compound
R
R1
R2
74
75
76
77
78
79
OH
OH
H
OH
CH3
H
OCH3
CH3
OH
OCH3
H
OH
H
CH3
OCH3
OCH3
H
H
OCH3
H
H
80, 84, 88, 92 and 96
81, 85, 89, 93 and 97
82, 86, 90, 94 and 98
83, 87, 91, 95 and 99
OCH3
H
H
H
H
OCH3
H
Scheme 4. Synthesis of different chalcones.
H
OCH3
desoxybenzoins carrying methoxy groups also showed lower
ICAM-1 expression inhibition values.
zoins (having two carbon atoms between the two aromatic
rings). For clear structure-activity relationship among chal-
cones, we have synthesized a series of ten chalcone deriva-
tives, viz. 74–83, via aldol condensation between various
benzaldehydes and different acetophenones in the presence
of barium hydroxide as catalyst and their analogs having
different structural features in the three-carbon moiety sep-
arating the two aromatic rings (Scheme 4). These derivatives
were evaluated for their ICAM-1 inhibitory activity; Table 4
summarizes the results of this activity. Interestingly, most of
the screened chalcones were active except for the compounds
76, 80 and 82 (Table 4). Three chalcones, viz. 75, 77and 79
(all having the unsubstitued C-3 phenyl moiety and the 2,4-
dioxygenated C-1 phenyl moiety), showed highest ICAM-1
inhibition (each exhibited 90% inhibition, Table 4).
The compound 62 contains two acetoxy groups in ring ‘A’,
as per earlier report [16], the acetoxy groups under test
conditions get deacetylated to furnish the corresponding
dihydroxy compound in situ having two free phenolic
hydroxy groups at the conjugated positions. Interestingly,
the most active compound of the series, i.e. 63, possesses the
methylenedioxyphenyl moiety, and we are synthesizing
more analogs possessing this moiety to establish the effect
of the methylenedioxy group and possible mechanism of
their action. The structure-activity analysis of arylalkyl
ketones, benzophenones and desoxybenzoins (possessing
one or two carbon atom chain between the aromatic rings,
thus lacking extended conjugation between the aromatic
rings) has revealed that compounds of all the three classes
possessing more free hydroxyl groups showed higher activity
and compounds having more methoxy groups showed lower
ICAM-1 expression inhibition activity.
However, the IC50 values of these three chalcones decrease
(hence ICAM-1 expression inhibition capacity increases) as we
protect one of the two hydroxyl groups in the C-1 phenyl
moiety in compound 77 (IC50 166 mM, Table 4) to get its
monoether, viz. this compound 75 (IC50 58 mM, Table 4),
and when we further look at the diether of 77, i.e. compound
79 (IC50 37 mM, Table 4), the activity still increases. Thus, SAR
studies on chalcones indicate that the most active com-
pounds of this series in inhibiting the ICAM-1 expression
should have the C-2, C-4 dioxygenation pattern in the C-1
phenyl ring (preferably both substituents as ether moieties)
and no substituent in the C-3 phenyl moiety. Interestingly it
Chalcones inhibit the TNF-a induced expression
of ICAM-1 on endothelial cells
When we introduced three carbons in between the two
aromatic rings (i.e. in chalcones), the ICAM-1 inhibitory
activity of these compounds was the highest as compared
to those of arylalkyl ketones and benzophenones (having one
carbon in between the two aromatic rings) and desoxyben-
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6
S. Kumar et al.
Arch. Pharm. Chem. Life Sci. 2011, 000, 1–10
Table 4. Effect of chalcones and their analogs/derivatives on the TNF-a induced expression of ICAM-1 on endothelial cells.
Compound
% Inhibition
Concentrationꢀ mM
IC50 mM
1-(2,4-Dihydroxyphenyl)-3-(4-methylphenyl) propenone (74)
1-(2-Hydroxy-4-methoxyphenyl)-3-phenylpropenone (75)
3-(4-Methoxyphenyl)-1-(4-methylphenyl) propenone (76)
1-(2,4-Dihydroxyphenyl)-3-phenylpropenone (77)
1-(4-Methylphenyl)-3-phenyl-propenone (78)
1-(2,4-Dimethoxyphenyl)-3-phenylpropenone (79)
1,3-Bis-(4-methoxyphenyl)-propenone (80)
1,3-Diphenylpropenone (81)
3-(4-Methoxyphenyl)-1-phenylpropenone (82)
1-(4-Methoxyphenyl)-3-phenylpropenone (83)
1,3-Bis-(4-methoxyphenyl)propanone (84)
1,3-Diphenylpropanone (85)
3-(4-Methoxyphenyl)-1-phenylpropanone (86)
1-(4-Methoxyphenyl)-3-phenylpropanone (87)
1,3-Bis-(4-methoxyphenyl)-propan-1-ol (88)
1,3-Diphenylpropan-1-ol (89)
3-(4-Methoxyphenyl)-1-phenylpropan-1-ol (90)
1-(4-Methoxyphenyl)-3-phenylpropan-1-ol (91)
1,3-Bis-(4-methoxyphenyl)propene (92)
1,3-Diphenylpropene (93)
60
90
40
90
85
90
8
70
34
70
5
55
10
15
10
20
12
15
31
40
35
40
15
35
15
18
39
78
39
291
44
58
29
58
–
166
35
37
–
81
–
188
–
–
–
–
–
–
–
–
–
149
96
124
293
332
195
374
166
146
329
247
247
353
308
401
312
195
254
220
214
–
–
–
–
–
–
–
3-(4-Methoxyphenyl)-1-phenylpropene (94)
1-(4-Methoxyphenyl)-3-phenylpropene (95)
1,3-Bis-(4-methoxyphenyl)propane (96)
1,3-Diphenylpropane (97)
3-(4-Methoxyphenyl)-1-phenylpropane (98)
1-(4-Methoxyphenyl)-3-phenylpropane (99)
ꢀ
The concentration levels of different compounds are based on their maximum tolerable concentration by the cells. The data
presented are representative of three independent experiments. Values shown are means ꢁ SD of quadruplicate wells.
is quite opposite to the effects of free phenolic hydroxyl
groups and ether moieties on the skeletons of arylalkyl
ketones, benzophenones and desoxybenzoins.
(Scheme 4) to obtain two groups of compounds: (i) having
the C–C double bond but lacking the carbonyl group (i.e.
compounds 92–95) and (ii) compounds lacking both the
carbonyl group and the C–C double bond (i.e. compounds
88–91 and 96–99). However, both the groups of compounds
lacking the carbonyl group, i.e. the hydroxy analogs, 1,3-
diphenylpropanols 88–91 (prepared by reducing the carbonyl
group of chalcones by NaBH4) and the compounds 92–95
(1,3-diphenylpropenes prepared by dehydration of 88–91),
have shown lower activity compared to the analogs containing
carbonyl group, i.e. compounds 84–87 (Table 4). Furthermore,
fully saturated analogs, i.e. the 1,3-diphenylpropanes 96–99,
obtained from 92–95 by reducing their double bond, lack both
To reveal the mechanism of action of chalcones and
identify the pharmacophore, we wanted to see the effect
of extended conjugation in chalcones due to the presence
of the three-carbon atom a,b-unsaturated carbonyl moiety in
chalcones by examining three different types of chalcone
derivatives: (i) those lacking the C–C double bond, (ii) those
lacking the carbonyl group and (iii) those lacking both
the C–C double bond and the carbonyl group.
In order to evaluate the significance of the C–C double
bond (unsaturation) and that of the carbonyl group present
in the chalcone skeleton, we have synthesized a large number
of analogs without the C-2, C-3 double bond, but still having
the C-1 carbonyl group (compounds 84–87) by reducing the
C–C double bond of 80–83 (Scheme 4).
–
the carbonyl group and C C bond and were found to be least
–
active (Table 4). This extensive study on different variants of
chalcones proves that the presence of both the C–C double
bond and the carbonyl group in the three-carbon moiety
separating the two aromatic rings is important and could be
responsible for the ICAM-1 expression lowering capacity of
chalcones.
Activity evaluation of these compounds affirmed that the
TNF-a induced ICAM-1 expression lowering activity of these
compounds sharply dropped down (Table 4). This clearly
signifies the importance of the C–C double bond in inhibiting
the TNF-a induced ICAM-1 expression. Further to establish the
importance of carbonyl group, we have carried out a series of
reduction/dehydration reactions on the compounds 84–87
It is interesting to mention here that in our separate yet
related study, we have synthesized a series of differently sub-
stituted chalcones and their analogs (54 compounds) having
groups like methoxy, trifluoromethyl, nitro, etc. [16]. Most of
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Arch. Pharm. Chem. Life Sci. 2011, 000, 1–10
TNF-a Induced Inhibition of ICAM-1 on Endothelial Cells
7
3'
3
A
6
e
M
O
F
3C
e
e
M
M
O
O
2
4
5
4'
5'
2'
B
6'
α
α
1
1'
β
β
O
O
Most active, Compound 79 from our present
study (Scheme 4, Table 4)
Most active, high solubility and non-toxic
Ref. No. 17, Kumar et al.
R2
R3
R1
A
B
α
R4
β
R5
O
H
=
e
C
,
R
R
R
R
R
M
O
F
N
O
H
C
,
3
,
,
,
,
,
,
Figure 1. Structures of the most active
1
2
3
4
5
3
2
compounds.
these chalcones have trifluoromethyl group in the ring B and
one to three methoxy groups at the different positions in the
ring A, and have determined their anti-inflammatory activi-
ties by a different test system, viz. modification results of
cysteine residue in Keap 1, an inhibitor of anti-inflammatory
transcription factor Nrf2, by a variety of inducers which can
act as Michael acceptors (like chalcones). The binding of
chalcones results in conformational changes that render
peutic modalities. In this context, compounds 75, 77 and
79 having comparatively lower IC50 values than the com-
monly used anti-inflammatory drugs such as diclofenac
(IC50 750 mM), N-acetylcysteine (IC50 100 mM), pyrrolidine
dithiocarbamate (IC50 1000 mM), etc. could be useful as lead
molecules towards developing anti-inflammatory drugs in
the future.
Keap 1 to dissociate from Nrf2, thereby activating Nrf2 Conclusion
and potentiating its antiinflammatory activity in epithelial
cells. Importantly, this study also showed the requirement of
a,b- unsaturated carbonyl moiety for the chalcones to exhibit
the antioxidant and anti-inflammatory activities [16]. We
have also observed that when methoxy group is present at
C-2 position in the ring A, they show greater activity which is
consistant with our present study (Figure 1). Most of the
chalcones having the C-2, C-4 dimethoxy substitution pattern
exhibit greater activity than others. The most active com-
pound of the present study is compound 79 (Scheme 4,
Table 4). Further, on comparison of the activities of chalcones
(Table 2, Figure 1, ref. 17) that contain two methoxy groups at
the C-2, C-4 positions show relatively higher activities, which
is the substitution pattern of the most active compound 79
of the present study (Figure 1).
In conclusion, we have synthesized a large number of differ-
ent analogs of naturally occurring arylalkyl ketones, benzo-
phenones, desoxybenzoins and chalcones and evaluated
their ICAM-1 expression inhibitory effect. Among all the four
different classes of compounds screened in the present inves-
tigation, chalcones (which have the three-carbon atom
a,b-enone chain between the two aromatic rings) show mod-
erate to very high ICAM-1 expression inhibitory activity. The
most active compound was found to be the chalcone 79.
Further modifications are under study in order to improve
the activity and find a lead/hit towards clinical anti-inflam-
matory agent which would be reported in due course.
Experimental section
Thus, in the present study, we have identified three chal-
cone derivatives, viz. compounds 75, 77 and 79, which inhib-
ited TNF-a induced ICAM-1 expression on human endothelial
cells with IC50 values of 58, 166, and 37 mM, respectively. As
expression of cell adhesion molecules including ICAM-1 plays
a crucial role in inflammatory diseases, inhibition of ICAM-1
has been suggested to be one of the most promising thera-
The organic solvents (acetone, ethyl acetate, methanol, chloro-
form, ethanol and petroleum ether) were dried and distilled
prior to their use. Analytical TLCs were performed on precoated
Merck silica gel 60 F254 plates; the spots were visualized under UV
light. Melting points were determined in a sulphuric acid
bath and are uncorrected. The IR spectra were recorded on a
Perkin-Elmer model 2000 FT-IR spectrophotometer. The 1H NMR
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8
S. Kumar et al.
Arch. Pharm. Chem. Life Sci. 2011, 000, 1–10
and 13C NMR spectra were recorded on a Bruker Avance instru-
ment at 300 MHz and 75.5 MHz, respectively using TMS as internal
standard. The HRMS were recorded on a TMS-AX 505 W instru-
ment. Anti-ICAM-1 antibody and TNF-a were purchased from
Pharmingen, USA; M199, L-glutamine, penicillin, streptomycin,
amphotericin, endothelial cell growth factor, trypsin, Pucks saline,
HEPES, DMSO, o-phenylenediamine dihydrochloride and anti-
mouse IgG-HRP were purchased from Sigma Chemical Co., USA.
Fetal calf serum was purchased from Biological Industries, Israel.
NADPH, ADP and trichloroacetic acid (TCA) were obtained from
Sisco Research Laboratory (Mumbai, India).
858C for 90 min. After completion of the reaction, the reaction
mixture was poured into NaOAc solution (10%) and allowed to
stand for 4 h. The product was filtered, washed with water and
dried in air. The crude compounds were purified by column
chromatography on silica gel using EtOAc/petroleum ether
(1:10) to yield desoxybenzoins 55–64. All these desoxybenzoins
were fully characterized from their spectral data and the com-
parison of the data with those reported in the literature [32–40].
Syntheisis of different chalcones and their analogues/
derivatives
General procedure for the synthesis of 1,3-
diarylpropenones (chalcones, 74–83): Claisen-Schmidt
condensation of acetophenones with aldehydes
Synthesis of aryl-alkyl ketones
Friedel-Crafts acylation
The heterogenous mixture of fused ZnCl2 (0.15 mol) and the
aliphatic acids (7–9, 0.15 mol) was heated slowly with stirring
till the solution became homogeneous. Appropriate phenol (1–6,
0.15 mol) was added and the reaction mixture was kept for about
2 h at 140–1458C. The reaction mixture was cooled, poured over
crushed ice containing hydrochloric acid (1:1). The solid that
separated out was filtered and washed separately with water and
sodium bicarbonate solution. The crude product was purified
using column chromatography over silica gel, elution was done
with a gradient solvent system of petroleum ether/ethyl acetate
to obtain the corresponding pure arylalkyl ketones 14–16 and
21–25 in 70–80% yields; these were characterized from their
spectral data and comparison of the data with those reported
in the literature [17–25].
The appropriately substituted acetophenone 65–70 (5 mmol) was
dissolved in ethanol (30 mL) and freshly fused Ba(OH)2 (2 g) was
added, followed by the addition of a solution of the correspond-
ing aldehyde 71–73 (5 mmol) in ethanol (5 mL). The reaction
mixture was refluxed for 6–7 h and progress of reaction was
monitored on TLC (petroleum ether/ethyl acetate, 4:1). After
completion of the reaction, the reaction mixture was poured
onto crushed ice and the pH of the solution was made acidic
using dilute hydrochloric acid. The solid obtained was filtered,
dried and recrystallized from ethanol to give 1,3-diarylprope-
nones (chalcones) 74–83 in 75–86% yields. The compounds 74–83
were known in the literature and were fully characterized from
their melting points, IR and NMR data and by comparison of the
data with the data reported in the literature [41–51].
Boron-trifluoride catalyzed condensation
Preparation of 1,3-diphenylpropanones 84–87
A mixture of the acid 10–13 (1 mol) and resorcinol 1 (0.25 mol)
was slowly saturated (2–3 h) with boron trifluoride at tempera-
ture ranging from 65–858C. The reaction mixture was treated
with water and the ketones 17–20 were obtained in good yields
after recrystallization from appropriate solvent. All the ketones
were characterized from their spectral data and the comparison
of the data with those reported in the literature [17–25].
A solution of 1,3-diphenylpropenone (chalcone) 80–83 (1 g, 3.5–
4.5 mmol) in 15 mL of dry ethyl acetate was placed in the
reaction bottle of atmospheric pressure hydrogenation appar-
atus and to that was added 0.1 g of palladium-charcoal (10%).
The air was displaced with hydrogen and the mixture was shaken
for 1 h. The progress of the reaction was monitored by TLC
(petroleum ether/ethyl acetate, 4:1). After completion of the
reaction, the palladium-charcoal was filtered and ethyl acetate
was removed under vaccum. The solid obtained was purified by
column chromatography to obtain the 1,3-diphenylpropanones
84–87 in 80–85% yields. The spectral data of all products were
identical with those of compounds mentioned in the literature
[52, 53].
Synthesis of benzophenones
The synthesis of benzophenones was achieved under anhydrous
conditions at room temperature by the Friedel-Crafts acylation of
hydroxy/methoxy benzene derivatives 32–36 with the appropri-
ately substituted benzoyl chloride 26–31 in the presence of
aluminium chloride in ether. The hydroxy/methoxy benzene
derivatives 32–36 (1 mmol), benzoyl chloride (0.5 mmol,
0.07 g) and anhydrous aluminium chloride (0.7 mmol,
0.094 g) were mixed and heated at 908C for 4–5 h. The progress
of the reaction was followed by TLC. The dark brown mixture was
poured onto crushed ice containing conc. HCl (10 mL) and the
resulting mixture was stirred at 708C for 30 min. After cooling,
the organic layer was separated, washed with water and dried
over Na2SO4. The solvent was removed by distillation and the
products 37–42 were recrystallized from a mixture of chloroform
and petroleum ether. All the benzophenones were characterized
from their spectral data and the comparison of the data with
those reported in the literature [26–31].
Preparation of 1,3-diphenylpropan-1-ols 88–91
Powdered NaBH4 (0.25 g) was added to a stirred solution of 1,3-
diphenylpropanones 84–87 (1 g) in MeOH (50 mL) and the reac-
tion mixture was stirred at room temperature for 5 min. After
completion of reaction, MeOH was removed in vacuo. The oily
residue was washed with NaHCO3 and water, and the mixture
was extracted with ethyl acetate. The organic layer was dried
over Na2SO4 and concentrated to dryness to get compounds 88–
91 as oils in 95–97% yields, the spectral data of all the products
were found to be identical with those of the corresponding
compounds mentioned in the literature [54–57].
Synthesis of 1,3-diphenylpropenes 92–95
Synthesis of desoxybenzoins
A mixture of the appropriate phenol 43–48 (1 mmol), phenyl
acetic acid 49–54 (1 mmol) and BF3.Et2O (5.1 mmol) was stirred at
To a solution of 1,3-diphenylpropan-1-ol 88–91 (1 g) in dioxane
(30 mL), 5–7 drops of concentrated H2SO4 were added. The reac-
tion mixture was refluxed for 4–5 h and the progress of reaction
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Arch. Pharm. Chem. Life Sci. 2011, 000, 1–10
TNF-a Induced Inhibition of ICAM-1 on Endothelial Cells
9
was monitored by TLC in pure petroleum ether. After completion
of reaction, the reaction mixture was poured over ice-cold water
with vigorous stirring. The reaction mixture was extracted with
petroleum ether and the combined organic layer was dried over
Na2SO4 and concentrated to dryness to get the compounds 92–95
as oils in 85–90% yields, the spectral data of all the products were
compared and found identical with those of the corresponding
compounds mentioned in the literature [58–61].
incubated with peroxidase-conjugated goat anti-mouse secon-
dary Abs. After washings cells were exposed to the peroxidase
substrate (o-phenylenediamine dihydrochloride 40 mg/100 mL
in citrate phosphate buffer, pH 4.5). Reaction was stopped by
the addition of 2 N sulphuric acid and absorbance at 490 nm was
measured using a microplate reader (Spectramax 190, Molecular
Devices, USA). The percentage inhibition was calculated as
[DCꢂDD/DC]ꢃ100. Where, DC is delta control; optical density
of TNF-a stimulated cells – unstimulated cells and DD is delta
drug; optical density of drug treated and TNF-a stimulated cells –
drug unstimulated cells.
Synthesis of 1,3-diphenylpropanes 96–99
A solution of 1,3-diphenylpropene 92–95 (1 g, 3.5–4.5 mmol) in
15 mL of dry ethyl acetate was placed in the reaction bottle of
atmospheric pressure hydrogenation apparatus and to that was
added 0.1 g of palladium-charcoal (10%). The air was displaced
with hydrogen and the mixture was shaken for 1 h. The progress
of the reaction was monitored by TLC (petroleum ether/ethyl
acetate 4:1). After completion of the reaction, the palladium-
charcoal was filtered and ethyl acetate was removed under
vacuum. The solid obtained was purified by column chromatog-
raphy to obtain 1,3-diphenylpropanones 96–99 in 85–90% yields.
The spectral data of all the products were identical with
those of the corresponding compounds reported in the literature
[62–65].
Determination of IC50
The percentage inhibitions of each compound at its various log
concentrations were measured and plotted graphically from
three independent experiemnts. From the graph plotted, the
concentration at which a compound showed 50% inhibition
was taken as its IC50 value.
Statistical analysis
Results are given as means ꢁ SD. Independent two-tailed
Student’s t test was performed. Differences were considered
statistically significant for p < 0.05. The statistical analysis
was performed using Microcal Origin software (ver 3.0;
Microcal Software Inc, Northampton, MA, and Cell Quest
Software, Becton–Dickinson, USA).
Cells and cell culture
Primary endothelial cells were isolated from human umbilical
cord using mild trypsinization [3]. The cells were grown in M-199
medium supplemented with 15% heat inactivated fetal calf
serum, 2 mM L-glutamine, 100 units/mL penicillin, 100 mg/mL
streptomycin, 0.25 mg/mL amphotericin B, endothelial cell
growth factor (50 mg/mL). At confluence, the cells were subcul-
tured using 0.0 5% trypsin-0.01 M EDTA solution and were used
between passages three to four.
Authors acknowledge the help of St. Stephen’s Hospital, Delhi for providing
the umbilical cord. This work was partly funded by the Council of Scientific
and Industrial Research, India grant NWP0033 (to BG); the NIH
grants HL081205, HL095420 (SCCOR), NIEHS-P50ES01590, GM079239,
P50ES015903, P01 ES018176 and ES03819 (to SB); the University of
Leuven (IDO06/006) & the F.W.O. (Fund for Scientific Research–Flanders,
Belgium) grant (to EVDE); the University of Delhi grant under the
Strengthening R&D Doctoral Research Programme and the Department
of Scientific & Industrial Research (DSIR, New Delhi) to VSP, SKS and AKP.
Cell viability assay
The cytotoxicity of different compounds was analyzed by using
Trypan blue exclusion test and it was further confirmed by
colorimetric MTT (methylthiazolydiphenyl-tetrazolium bro-
mide) assay as described by us earlier [15]. Briefly, endothelial
cells were treated with DMSO or these derivatives for 24 h. Four
hours before the end of incubation, medium was removed and
100 mL of MTT (5 mg/mL in serum free medium) was added to
each well. The MTT was removed after 4 h, cells were washed
out with PBS, and 100 mL DMSO was added to each well to
dissolve water insoluble MTT-formazan crystals. Absorbance
was recorded at 570 nm in an ELISA reader (BIO RAD, Model
680, USA). All experiments were performed at least 3 times in
triplicate wells. Maxium tolerable dose at which the cells were
more than 95% viable was used for testing the compounds.
The authors have declared no conflict of interest.
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