Resveratrol derivatives (4a-4ee) were synthesized according
to methods described in previous papers11 (Scheme 1 - 4).
Compounds 4a-4f were directly synthesized from resveratrol (1),
and amide derivatives (4g-4h) were obtained by amide coupling
reactions of the corresponding amines and carboxylic acids
HO
R''
AcO
COCl
a
+
R''
OH
OAc
4ff: R''=tBu
4gg: R''=cHex
9a: R''=tBu for 4ff
9b: R''=cHex for 4gg
7b
OH
(Scheme 1).
Compounds 4i-4n were obtained from the
Br
MeO
B(OH)2
b
HO
corresponding Wittig reagents (5) and benzaldehydes (6)
(Scheme 2). Compound 4n was similarly prepared by a Wittig-
Horner reaction. Synthesis of compounds 3b and 4o-4ee is
shown in Scheme 3. Coupling of acid chlorides (7) with
substituted styrenes (8) was carried out using a palladium-
catalyzed decarbonylative Heck reaction with continuous
demethylation with BBr3 or deacetylation with aqueous solution
of NaOH to give 4o-4ee. Compounds 4ff-4gg were also prepared
by the palladium-catalyzed decarbonylative Heck coupling, and
biphenyl derivative 4hh was obtained by a palladium-catalyzed
Suzuki coupling (Scheme 4).
+
4hh
OMe
OMe
OH
Scheme 4. Synthesis of compounds 4ff-4hh.
Reagents and conditions: (a) (i) Pd(OAc)2, N-ethylmorpholine, (ii) 1N
NaOH, (b) (i) Pd(PPh3)4, Na2CO3, (ii) BBr3
We evaluated compounds for their inhibitory activity of the
TRPA1 receptor by the increase in concentration of free Ca2+ in
HEK293 cells expressing the hTRPA1 receptor after stimulation
with AITC using the Calcium KitⅡ- Fluo4 (Table 1).
Desensitization of receptors is a fundamental approach for
reducing TRPA1 channel activation. Therefore, the effects of
pretreatment with the compounds in TRPA1-expressing HEK293
cells on calcium influx, an agonistic effect, were also examined
(Table 1). As shown in Table 1, all compounds almost equally
stimulated TRPA1 channel (relative activity: 0.3-0.7) and among
of those that had inhibitory activity, they might be desensitizers
such as resveratrol against AITC. In this study, all compounds,
including resveratrol (1), the previously reported resveratrol
derivative (3a), and 4a-4ii, were assessed first at 30 M (Table 1
and 2). Compound 3a10 showed 1.1 times more potent inhibitory
activity than resveratrol. Inhibitory activities were reduced by
acetylation or alkylations of the phenolic hydroxyl groups (4a-
4e). Modification of the hydroxyl group of ring B of 1 (4p-4o,
4m-4q, 4w-4bb) also decreased the activities. Among them,
compound 4x, bearing a hydroxyl group at the 3 position, showed
R'
a
R
1(Resveratrol)
4a: R=3,5-di-AcO R'=4-AcO
4b: R=3,5-di-MeO, R'=4-MeO
4c: R=3,5-di-EtO, R'=4-EtO
4d: R=3,5-di-nPrO, R'=4-nPrO
4e: R=3,5-di-MOMO, R'=4-MOMO
b
OH
HO
4f
OH
R''
O
MOMO
COOH
+
c
HO
X
N
H
H2
N
OMOM
4g: R''=OH
4h: R''=OMe
OH
X=OMOM for 4g
=OMe for 4h
Scheme 1. Synthesis of compounds 4a - 4h.
Reagents and conditions: (a) Ac2O, Py for 4a, MeI, K2CO3 for 4b, EtBr,
KI, K2CO3 for 4c, nPrI, K2CO3 for 4d, and MeOCH2-Cl (MOM-Cl), DIPEA
for 4e, (b) H2/Pd-C, (c) (i) EDC hydrochloride, DMAP, (ii) 4 N HCl/AcOEt.
relatively potent inhibitory activity.
Replacement of the
X-
hydroxyl group of 1 on ring B with a chlorine atom maintained
activity (4q), which indicated the hydroxyl group was not vital
for the inhibition. Replacement of the hydroxyl groups with
chlorine atoms was therefore carried out on ring A as well (4i-
4k). Compounds 4i and 4j, bearing 3,5-dichloro atoms on ring
A, exhibited relatively potent inhibitory activity as expected.
Addition of a hydroxyl group on ring B (4ee), methylation of the
hydroxyl group of 3a, and removal of a hydroxyl group of ring A
of 1 decreased inhibitory activities. The compound bearing 3,4-
dihydroxy groups on ring A (4y) had diminished inhibitory
activity. Replacement of the 3,5-dihydroxyphenyl of 1 with 3,5,-
dibromo-4-hydroxyphenyl (4z) resulted in 1.4 times increased the
inhibitory activity, while replacement of the 4-hydroxyphenyl
with a 3,5-dibromophenyl moiety (4aa) did not affect the
activity. Replacement of the 2-hydroxy group of 3a with a 4-
hydroxy
R'
a
PPh3
R
R
CHO
5
4i: R=3,5-di-Cl, R'=4-Cl
4j: R=3,5-di-Cl, R'=H
4k: R=H, R'=4-Cl
6
R'
4l: R=H, R'=3,5-di-MeOH
Br-
b
c
MOMO
HO
PPh3
CHO
4m
OMe
OMe
MeO
OMOM
b
PO(OEt)2
MOMO
HO
CHO
OH
4n
OMOM
Scheme 2. Synthesis of compounds 4i - 4n..
Reagents and conditions: (a) n-BuLi (X=Br) for 4i, n-BuLi (X=Cl) for 4j,
n-BuLi (X=Br) for 4k, n-BuLi (X=Cl) for 4l, (b) n-BuLi, (c) 4 N HCl/AcOEt.
COCl
R'
a
R
+
R'
R
3b: R=H, R'=2-MeO
4o: R=3,5-di-HO, R'=4-MeO
4p: R=3,5-di-HO, R'=H
4q: R=3,5-di-HO, R'=4-Cl
4r: R=3,5-di-HO, R'=4-EtO
4s: R=3,5-di-HO, R'=4-nPrO
4t: R=3,5-di-HO, R'=4-nHexO
4u: R=3,5-di-HO, R'=4-nHexCH2O
4v: R=3,5-di-HO, R'=4-BzlO
4w: R=3,5-di-HO, R'=2-HO
4x: R=3,5-di-HO, R'=3-HO
7a: R=H for 3b
8a: R'=4-MeO for 4o
7b: R=3,5-di-AcO for 4o-x, 4bb-4ee
8b: R'=H for 4p
7c: R=3,4-di-MeO for 4y
8c: R'=4-Cl for 4q
7d: R'=3,5-di-Br-4-MeO for 4z, 4aa
8d: R'=4-EtO for 4r
8e: R'=4-nPrO for 4s
8f: R'=4-nHexO for 4t
8g: R'=4-cHexCH2O for 4u
8h: R'=4-BzlO for 4v
8i: R'=2-MeO for 4w, 3b
8j: R'=3-MeO for 4x
8k: R'=4-AcO for 4y, 4z
8l: R'=3,5-di-MeO for 4aa
8m: R'=3,4-OCH2O- for 4bb
8n: R'=3,4-di-MeO for 4cc, 4dd
8o: R'=3,4,5-tri-MeO for 4ee
4y: R=3,4-di-HO, R'=4-HO
4z: R=3,5-di-Br, 4-HO, R'=4-HO
4aa: R=3,5-di-Br, 4-HO, R'=3,5-di-HO
4bb: R=3,5-di-HO, R'=3,4-OCH2O-
4cc: R=3,5-di-HO, R'=3,4-di-MeO
4dd: R=3,5-di-HO, R'=3,4-di-HO
4ee: R=3,5-di-HO, R'=3,4,5-tri-HO
Scheme 3. Synthesis of compounds 4o - 4ee.
Reagents and conditions: (a) (i) Pd(OAc)2, N-ethylmorpholine, (ii) 1N
NaOH for 4o-4v and 4bb-4cc, BBr3 for 4w-4aa, and 4dd-4ee.