J. Kim et al. / European Journal of Medicinal Chemistry 48 (2012) 36e44
41
of the most potent derivatives, ameliorated TNBS-induced colitis
of rats, which was more effective than 5-ASA, a conventional anti-
IBD drug.
Inhibitory activity of SA against NFkB could be enhanced by
chemical modification such as 5-substitution or/and amidation.
needs to be confirmed by testing more derivatives in elaborated
conditions where the pharmacokinetic factors are well-controlled.
5-CSPA elicited a substantial anti-inflammatory activity against
TNBS-induced colitis of rats as shown in the data demonstrating
the improvement of colonic damage score and attenuation of MPO
activity. The therapeutic activity of 5-CSPA seems to be relevant to
This is shown by the data demonstrating that the potencies of 5-
CSA and salicylamide (SAM) for inhibiting NF
k
B was greater than
inhibition of NF
inflamed tissue is supported by showing that 5-CSPA substantially
suppressed the expression of pro-inflammatory NF B target gene
products such as COX-2 and CINC-3, which is in line with the
in vitro results of the NF B luciferase assay and iNOS expression.
This hypothesis on a molecular mechanism of therapeutic action is
consistent with the recent findings that NF B inhibition is a prom-
ising therapeutic target for treatment of IBD [4,15]. The data
showing that 5-CSPA (300 M) was more effective at ameliorating
kB in the inflamed tissue. NFkB inhibition in the
SA and simultaneous modification to produce 5-CSAM further
increased the inhibitory potency, which suggests that the structural
effect of each modification is additive. Although substitution of 2,4
difluorophenylgroup at 5 position of SA, namely diflunisal, afforded
an equivalent inhibitory effect to that of chlorine, the modification
was not adopted as a lead for further modification because its
solubility became too low on modification of the carboxylic group
of diflunisal. N-modification of 5-CSAM was found to further
k
k
k
m
increase the potency for NF
tution, was taken by previous papers demonstrating that the bio-
logical activities (including NF B inhibition) of caffeic acid (3,4
k
B inhibition. The direction, N-substi-
the rat colitis than 5-ASA (30 mM) imply that 5-CSPA is much more
potent than 5-ASA. Although molecular mechanisms of 5-ASA
underlying anti-IBD activity are still controversial [16], previous
k
dihydroxycinnamic acid) are enhanced by esterification with alkyl
or arylalkyl alcohols [12,14]. It seems that N-monosubstituted
derivatives elicit greater potency than N-disubstituted derivatives.
However, it is not certain whether the difference is derived from
pharmacokinetic or pharmacodynamic factors. This observation
papers provide a number of evidence that NFkB inhibition is crucial
for its therapeutic activity [6,9]. Therefore, their difference in
therapeutic effectiveness may come from that in the inhibitory
potency on NFkB. Recently, peroxisome proliferator-activated
receptor-r (PPAR-r), which is involved in the regulation of colon
Table 3
Physical data of N-substituted CSAM derivatives.
Compd. no.
1
Mp (ꢁC)
IR (Nujol,
1H NMR (DMSO-d6, ppm)
M.S. m/z
[M þ H]þ
eC]O, cmꢂ1
)
E.A (calculated/found)
183e185
1640
1583
1635
2.80 (s, 3H, CH3), 6.83 (d, J ¼ 8.8 Hz, 1H, H-3), 7.29 (dd, J ¼ 8.7, 2.7 Hz, 1H, H-4), 7.82
(d, J ¼ 3.0 Hz, 1H, H-6)
196
210
256
C, 51.77; H, 4.34; N, 7.55/C, 51.53; H, 4.31; N, 7.57
2
3
166e168
2.78e2.92 (br d, 6H, N(CH3)2), 6.86 (d, J ¼ 8.8 Hz, 1H, H-3), 7.10 (d, J ¼ 2.6, 1H, H-6), 7.23
(dd, J ¼ 8.8, 2.7 Hz, 1H, H-4)
C, 54.15; H, 5.05; N, 7.02/C, 54.23; H, 5.07; N, 7.05
65
0.84 (t, J ¼ 7.1 Hz, 3H, CH3), 1.22e1.31 (m, 6H, CH2CH2(CH2)3CH3, 1.51 (p, J ¼ 7 Hz, 2H,
CH2CH2(CH2)3CH3, 3.25 (q, J ¼ 5.9 Hz, 2H, NCH2CH2(CH2)3CH3), 6.91
(d, J ¼ 9.0 Hz, 1H, H-3), 7.41 (dd, J ¼ 8.8, 2.7 Hz, 1H, H-4), 7.93 (d, J ¼ 2.7, 1H, H-6)
C, 61.05; H, 7.09; N, 5.48/C, 61.16; H, 7.04; N, 5.44
4
5
6
7
218e221
187e188
164e165
200e202
1570
1574
1576
1572
3.16e3.58 (br m, 8H, morpholine), 6.86 (d, J ¼ 8.8 Hz, 1H, H-3), 7.15 (d, J ¼ 2.7 Hz, 1H, H-6),
253
241
255
317
7.24 (dd, J ¼ 8.7, 2.5 Hz, 1H, H-4)
C, 54.67; H, 5.00; N, 5.80/C, 54.74; H, 5.03; N, 5.76
3.05e3.98 (br m, 8H, piperazine), 6.84 (d, J ¼ 8.6 Hz, 1H, H-3), 7.09 (d, J ¼ 2.7 Hz, 1H, H-6),
7.18 (dd, J ¼ 8.8. 2.7 Hz, 1H, H-4)
C, 54.89; H, 5.44; N, 11.64/C, 54.81; H, 5.47; N, 11.59
2.16 (s, 3H, N(CH3)), 2.28 (br m, 4H, N(CH2)2), 3.33 (br t, 4H, OCN(CH2)2), 6.85
(d, J ¼ 8.8 Hz, 1H, H-3), 7.1 (d, J ¼ 2.7 Hz, 1H, H-6), 7.2 (dd, J ¼ 8.6, 2.9 Hz, 1H, H-4)
C, 56.58; H, 5.94; N, 11.00/C, 56.77; H, 5.98; N, 11.05
3.13 (br m, 4H, N(CH2)2), 3.32 (br m, 4H, OCN(CH2)2), 6.89 (d, J ¼ 8.8 Hz, 1H, H-3), 7.18
(d, J ¼ 2.7 Hz, 1H, H-6), 7.27 (dd, J ¼ 8.5, 2.7 Hz, 1H, H-4),6.79 (t, J ¼ 7.3 Hz,
1H, H-40), 6.93 (d, J ¼ 8.1 Hz, 2H, H-20,60), 7.21 (t, J ¼ 8.3 Hz, 2H, H-30,50)
C, 64.46; H, 5.41; N, 8.84/C, 64.71; H, 5.38; N, 8.89
8
192e194
146e147
120e121
1565
1638
1639
1.46e1.56 (m, 6H, (CH2)3, 3.13e3.53 (br d, 4H, N(CH2)2), 6.85 (d, J ¼ 8.7 Hz, 1H, H-3),
7.09 (d, J ¼ 2.7 Hz, 1H, H-6), 7.21 (dd, J ¼ 8.8, 2.7 Hz, 1H, H-4)
C, 60.13; H, 5.89; N, 5.84/C, 60.31; H, 5.85; N, 5.83
4.50 (d, J ¼ 5.9 Hz, 2H, NCH2), 6.94 (d, J ¼ 8.8 Hz, 1H, H-3), 7.4 (dd, J ¼ 8.8, 2.4 Hz, 1H,
H-4), 7.98 (d, J ¼ 2.7 Hz, 1H, H-6), 7.25 (m, 1H, H-40), 7.32 (m, 4H, H-20, 30, 50, 60)
C, 64.25; H, 4.62; N, 5.35/C, 64.41; H, 4.64; N, 5.32
2.84 (t, J ¼ 7.1 Hz, 2H, NCH2CH2), 3.51 (m, 2H, NCH2CH2), 6.92 (d, J ¼ 8.8 Hz, 1H, H-3),
7.4 (dd, J ¼ 8.8, 2.7 Hz, 1H, H-4), 7.9 (d, J ¼ 2.4 Hz, 3H, 6-H), 7.19 (t, J ¼ 8.5, 1H, H-40),
7.22e7.30 (m, 4H, H-20, 30, 50, 60)
251
272
286
9
10
C, 65.34; H, 5.12; N, 5.08/C, 65.42; H, 5.09; N, 5.05
11
12
99e100
1638
1638
1.83 (p, J ¼ 7.3 Hz, 2H, NCH2CH2CH2), 2.62 (t, J ¼ 7.9 Hz, 2H, NCH2CH2CH2), 3.30
(q, J ¼ 6.8 Hz, 2H, NCH2CH2CH2), 6.92 (d, 8.8 Hz, 1H, H-3), 7.41 (dd, J ¼ 8.8, 2.7 Hz, 1H, H-4),
7.9 (d, J ¼ 2.4 Hz, 1H, H-6), 7.15 (t, J ¼ 7.4 Hz, 1H, H-40), 7.20e7.28 (m, 4H, H-20, 30, 50, 60)
C, 66.32; H, 5.57; N, 4.83/C, 66.60; H, 5.55; N, 4.85
290
292
176e178
2.71 (t, J ¼ 7.3 Hz, 2H, NCH2CH2), 3.44 (q, J ¼ 6.4 Hz, 2H, NCH2CH2), 6.91 (d, 8.8 Hz, 1H, H-3),
7.41 (dd, J ¼ 8.8, 2.7 Hz, 1H, H-4), 7.89 (d, J ¼ 2.5 Hz, 1H, H-6), 6.67 (d, J ¼ 8.5 Hz, 2H,
H-20, 60), 7.01 (d, J ¼ 8.6 Hz, 2H, H-30, 50)
C, 61.76; H, 4.84; N, 4.80/C, 61.77; H, 4.81; N, 4.79
CSAM: 5-chlorosalicylamide.