Inflammatory bowel disease (IBD), which classified mainly
as ulcerative colitis and Crohn’s disease, is characterized by
chronic relapsing inflammatory condition of the gastrointestinal
cells. The result suggested that pyridinium salts of indanone
derivatives has enhanced anti-inflammatory activity (Table 1)
due to its water solubility, and thus, improved cellular uptake.
Therefore, in the present work we designed and synthesized the
pyridine-linked hydroxylated indanones 5a-l, and O-alkylated
indanones 8a-c and 11a-c to increase the inhibition of TNF-α-
induced monocyte adhesion by modifying the pyridine ring and
indanone moiety of compound 1. This work represents the first
effort made to assess the effects of pyridinium-linked indanones
that target TNF-α with an aim to develop novel and potent agents
for the treatment of IBD.
1
, 2
tract. The pro-inflammatory cytokine, tumor necrosis factor-α
TNF-α), is a major player in IBD and enhances inflammatory
reactions by inducing various cytokines and adhesion molecules
(
2, 3
that recruit leukocytes to the site of inflammation.
TNF-α
blockers like infliximab and adalimumab provide effective
treatment for Crohn’s disease, and golimumab is effective against
4
, 5
ulcerative colitis.
Due to their greater efficacies than orally
available drugs, such as, salicylates, immunosuppressants and
corticosteroids, those biologics have become main stay therapies
to overcome IBD. However, in a substantial number of patients,
treatment failure or development of resistance to TNF-α blockers
6
has been reported. Moreover, biologics are expensive, must be
administered by intravenous infusion, and have side effects, such
as, to increase the risk of cancer development when administered
7
, 8
long term.
In addition to TNF-α, levels of IL-1β in colon
tissues of IBD have also been correlated with the presence of
9
, 10
active lesions.
IL-1β can function as a modulator of both
innate and adaptive immune cells by promoting Th17 responses
by CD4+ T cells, and act synergistically with IL-23 signals.
Blocking IL-1β has been reported to ameliorate chronic
1
1
inflammation of intestine, and synergism between IL-1β and
TNF-α enhanced the synthesis of IL-8, a potent chemoattractant
for neutrophils and inducer of various other adhesion molecules
like ICAM-1. The production of these inflammation-associated
molecules is regulated by a common transcription factor, nuclear
Figure 1. The design strategy used in the present study: (i) pyridine-
linked hydroxylated indanones, and (ii) pyridinium-linked O-alkylated
indanones.
1
2-15
factor κB (NF-κB).
Activation of NF-ĸB induces SNAIL
which functions as a transcription repressor of E-cadherin that
serves as an epithelial marker and as a structural component in
junction proteins. Furthermore, pro-inflammatory cytokines
induced by disruption and loss of epithelial barrier are commonly
observed in the intestines of IBD patients, and the mucosa
disruption allows the invasion of commensal bacteria and further
Scheme 1 shows the general synthesis of pyridinium
chloride salts (5a-l) from corresponding pyridine-linked
hydroxylated indanones 4a-l. A series of pyridine containing
hydroxylated indanone derivatives, 4a-l (see Supplementary Data
for analytical information), were prepared by aldol condensation
by treating hydroxy-indanone (3a-d) with 2-, 3-, or 4-pyridine
1
6-18
aggravates inflammatory processes.
carboxaldehyde in the presence of 5% aqueous NaOH in
Several drug discovery researchers have described indanone
as a privileged structure. Indanone and hydroxylated indanones
are known to exhibit various biological activities including anti-
3, 20, 28
ethanol.
Target compounds 5a-l were formed in yields
ranging from 47.2–98.8% by treating 4a-l with aqueous 1M HCl
in acetone. Compound 2 was obtained by treating compound 1
with aqueous 1M HCl, and was used as the parent compound of
this series. As mentioned above, modification of the pyridine and
indanone rings of compound 2, allowed us to explore structure-
activity relationships.
1
9, 20
inflammatory, and anti-cancer activities.
importance of indanone moiety, our group previously reported 2-
benzylidene indanone derivatives containing phenol,
Considering the
chlorophenyl, fluorophenyl, pyridyl, and various substituted aryl
3
moieties as potential therapeutics for IBD.
We prepared compounds 8a-c and 11a-c from the most
active compounds 5b and 5d, as determined by introduction of
alkyl groups at the hydroxyl functionality of the indanone rings
for expansion of SAR study. The syntheses of pyridinium-linked
O-alkylated indanones 8a-c and 11a-c were carried out in three
steps as shown in Scheme 2. At first, 6a-c and 9a-c were
prepared via methylation, ethylation or isopropylation of 4- or 6-
Pyridine ring present in several natural and synthetic
compounds is considered an important moiety to have diverse
2
1
therapeutic activities such as anti-cancer,
and anti-
In the drug discovery and development
process, various salt forms have been utilized to address the poor
2
2, 23
inflammatory.
2
4, 25
water-solubilities of compounds.
In particular, it is reported
that pyridinium salt formation enhance the physicochemical and
2
2
6, 27
hydroxy- indanone by an alkyl iodide (R –I) in the presence of
biological properties of several compounds.
In a previous
potassium carbonate (K CO ) in dry tetrahydrofuran (THF) under
2
3
study, among pyridine-linked indanones, we demonstrated that
compound with 4’-pyridine ring (represented by compound 1,
Fig. 1) most inhibited (52.1% at 10 µM) TNF-α-induced
monocyte adhesion to human colonic epithelial cells which was
o
refluxing at 50-70 C for 24-48 h. In the second step, 6a-c and
a-c were condensed with 4-pyridine carboxaldehyde in the
9
presence of 5% aqueous NaOH in ethanol to afford 7a-c and 10a-
c (see Supplementary Data for analytical information). The
resulting intermediates 7a-c and 10a-c were dissolved in acetone
and treated with aqueous 1M HCl solution to obtain the
corresponding HCl salts 8a-c and 11a-c, respectively.
3
highly potent than reference compound (5-aminosalicylate).
Accordingly, we sought to determine whether modification of
compound 1 to its pyridinium chloride salt would improve
inhibitory activity. We prepared the pyridinium chloride salt
(compound 2) by treating compound 1 with using aqueous 1M
HCl. As expected, compound 2 exhibited significantly greater
inhibitory activity (74.1% at 10 µM) than compound 1 on the
TNF-α-induced monocyte adhesion to human colonic epithelial