Synthesis and biological evaluation of [6]-gingerol analogues as transient receptor potential channel TRPV1 and TRPA1 modulators

Article abstract of DOI:10.1016/j.bmcl.2011.12.113

In order to explore the structural determinants for the TRPV1 and TRPA1 agonist properties of gingerols, aseries of nineteen analogues (1b-5) of racemic [6]-gingerol (1a) was synthesized and tested on TRPV1 and TRPA1 channels. The exploration of the structure-activity relationships, by modulating the three pharmacophoric regions of [6]-gingerol, led to the identification of some selective TRPV1 agonists/desensitizers of TRPV1 channels (3a, 3f, and 4) and of some full TRPA1 antagonists (2c, 2d, 3b, and 3d). 2011 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.bmcl.2011.12.113

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1674–1677
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of [6]-gingerol analogues as transient
receptor potential channel TRPV1 and TRPA1 modulators
Enrico Morera a, , Luciano De Petrocellis b, , Ludovica Morera a, Aniello Schiano Moriello b,
⇑
⇑
Marianna Nalli a, Vincenzo Di Marzo c, Giorgio Ortar a
a Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, piazzale Aldo Moro 5, 00185 Roma, Italy
b Endocannabinoid Research Group, Istituto di Cibernetica, Consiglio Nazionale delle Ricerche, via Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy
c Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, via Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to explore the structural determinants for the TRPV1 and TRPA1 agonist properties of gingerols, a
series of nineteen analogues (1b–5) of racemic [6]-gingerol (1a) was synthesized and tested on TRPV1
and TRPA1 channels. The exploration of the structure–activity relationships, by modulating the three
pharmacophoric regions of [6]-gingerol, led to the identification of some selective TRPV1 agonists/desen-
sitizers of TRPV1 channels (3a, 3f, and 4) and of some full TRPA1 antagonists (2c, 2d, 3b, and 3d).
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 December 2011
Revised 22 December 2011
Accepted 23 December 2011
Available online 31 December 2011
Keywords:
TRP channels
TRPV1
TRPA1
Gingerol analogues
Shogaol analogues
Ginger (Zingiber officinale Roscoe), one of the world’s favourite
spices in culinary preparations, is also widely used in traditional or-
iental herbal medicineto treat various kinds of diseases such as asth-
ma, catarrh, muscle ache, rheumatism, nervous diseases, headache,
bacterial and fungal infections, diabetes, and other ailments.1 Recent
research confirmed the pharmacological potential of ginger, in par-
ticular its antioxidant, anticancer, antimicrobial, and anti-inflam-
matory properties.2 The main active and pungent constituents of
this plant, identified in the nonvolatile oleoresin fraction of pro-
cessed ginger, are gingerols and shogaols (Fig. 1). Molecular targets
involved in their therapeutic properties encompass matrix metallo-
proteinases MMP-2 and MMP-9,3 nuclear-factor-kB (NF-kB),4 cyclo-
oxygenase (COX) and lipooxygenase (LOX),5 and peroxisome
pathophysiology of many illnesses like pain, cancer, and bladder,
skin, and respiratory disorders.10
The best known of the exogenous chemical stimuli for TRPV1,
capsaicin (Fig. 2), that is, the pungent component of hot chilli pep-
pers, shares the vanillyl moiety with gingerols and shoagols.9e,10d,i
In the case of TRPA1 agonists, in addition to several exogenous
electrophiles that activate the channel through covalent binding
to critical cysteine residues at the intra-cellular domain, there is
a number of TRPA1 agonists that specifically bind to and activate
the channel via non-covalent ligand–receptor interactions.10b Sev-
eral phenolic derivatives (Fig. 2) belong to this latter group and, on
the basis of SAR analyses, an increase of potency correlated with
high logP values and an enhancement of steric hindrance of
branched alkyl substituents in the ortho position of the phenolic
hydroxyl group was observed.11
proliferator-activated receptor (PPARc
).6 In addition, gingerols and
shogaols have been reported to activate the transient receptor po-
tential channels, TRPV17 and TRPA1,8 which belong respectively to
the TRPV (vanilloid) and TRPA (ankyrin) subfamilies of the large
transient receptor potential (TRP) cation channel family.9 TRPV1
and TRPA1 channels display a wide diversity of activation and
regulation by temperature, flavours, mechanical and osmotic input,
and noxious chemical stimuli and play a fundamental role in the
Despite remarkable interest for the major gingerol, [6]-gingerol,
which is deemed of prime importance for the pharmacological
O
OH
O
O
O
n
n
HO
HO
n = 4, (+)-(S)-[6]-Gingerol
n = 6, (+)-(S)-[8]-Gingerol
n = 8, (+)-(S)-[10]-Gingerol
n = 4, [6]-Shogaol
n = 6, [8]-Shogaol
n = 8, [10]-Shogaol
⇑
Corresponding authors. Tel.: +39 6 49913893; fax: +39 6 49693268 (E.M.); tel.:
+39 081 8675173 (L.D.P.).
E-mail addresses: enrico.morera@uniroma1.it (E. Morera), l.depetrocellis@cib.-
na.cnr.it (L. De Petrocellis).
Figure 1. Structures of gingerols and shogaols.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.113

E. Morera et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1674–1677
1675
O
O
the TRPV1 agonist piperine, the major pungent compound from
pepper (Piper nigrum L.).15 In the second place, since it was re-
ported that the potency of gingerols as TRPV1 agonists increased
with increasing lipophilicity of the side chain,7b,13 we explored
the effect on activity of the introduction of phenylalkyl side chains
of different length. Finally, with the aim of evaluating the influence
of the hydroxyl group in the b-hydroxy ketone polar linker, we
synthesized [6]-shogaol (4), and its analogue 5.
O
O
O
N
N
H
HO
Capsaicin
Piperine
OH
O
OH
OH
OH
The synthesis of racemic gingerol (1a) and of gingerol analogues
1b–3 was performed by a regioselective aldol condensation be-
tween appropriate 4-aryl-2-butanones 6 and appropriate alde-
hydes 7.16 In the case of aryl moieties carrying a hydroxyl group,
the phenolic functionalities were protected as trimethysilyl ethers
before the deprotonation step,17 and the protecting group was re-
moved at the end of the coupling reaction by a brief treatment with
tetrabutylammonium fluoride (TBAF) (Scheme 1). An acid cata-
lyzed dehydration was exploited for the synthesis of shogaol 4
and its analogue 5.18 The twenty compounds synthesized here
were tested for their ability to induce intracellular Ca2+ elevation
in HEK293 cells stably transfected with either the human TRPV1
or the rat TRPA1 cDNAs (Table 1).19 Control experiments were car-
ried out using non-transfected HEK293 cells.
Carvacrol
Eugenol
Thymol
Propofol
OH
O
OH
H
O
H
O
C5H11
HO
Δ9-Tetrahydrocannabinol
6-Gingerol
Figure 2. Structures of TRPV1 agonists capsaicin and piperine and of some phenolic
modulators of TRPA1.
activities of ginger,12 little is known on its structure–activity rela-
tionships, in particular with respect to the activity on TRPV1 and
TRPA1 channels.7a,13 Conceivably, the dual action of [6]-gingerol
at TRPV1 and TRPA1 channels seems well related to its structural
analogy with capsaicin and its phenolic nature, respectively. The
[6]-gingerol structure could be ideally divided into three regions,
as described for capsaicin by Walpole et al.14 that is, the aromatic
region, the b-hydroxy ketone polar region, and the hydrophobic
side chain (Fig. 3). To investigate the possibility to identify new po-
tent and selective modulators of TRPV1 and TRPA1 channels
through structure modifications of [6]-gingerol, we synthesized a
series of racemic gingerol (1a) analogues (compounds 1b–5), by
modifying the three aforementioned regions. Firstly, we assessed
the importance of the phenolic hydroxyl group of gingerol and
its steric requirements, by selecting, inter alia, aromatic moieties
that are either correlated to thymol and propofol, two alkyl phe-
nols active on TRPA1, or lacking the hydroxyl functionality, like
The biological assays underlined the importance of a phenolic
hydroxyl group for the activity at TRPV1 channels. In particular,
the substitution of a methylenedioxy group for the vanillyl moi-
ety reduced or abolished the activity (compare compounds 1a,
2a, and 3a with 1b, 2b, and 3b, respectively). An analogous re-
sult had been previously observed with capsaicin, whereas the
opening of the methylenedioxy group of piperine proved to be
detrimental to its activity at hTRPV1.20 Among the phenol deriv-
atives, compounds 1e, 2e, 3a, and 3f were more potent than [6]-
gingerol (1a) at activating TRPV1 channels, while 1c, 2c, and 3c
were inactive, thus highlighting the negative impact on TRPV1
activity of high steric hindrance around the phenolic hydroxylic
group. With regard to the hydrophobic side chain, the potency
increased with lipophilicity, with the 6-phenylhexyl derivatives
3a and 3f being the most potent and selective TRPV1 activators
(EC50 = 0.11 0.02
lM and EC50 = 0.5 0.2 lM, respectively). An
opposite trend was observed for TRPA1 activation, where the
aromatic
region
polar link
OH
hydrophobic
tail
O
O
HO
6-Gingerol
O
OH
R =
Ar
R
O
O
O
Ar =
HO
HO
HO
HO
a
b
c
d
e
f
Figure 3. General structure of gingerol analogues synthesized.
O
O
O
OH
R
R
a,b
c
X
X
X
1-3
4,5
6
Scheme 1. Synthesis of compounds 1–5. Reagents and conditions: (a) LDA, THF, N2, À78 °C, 30 min, then RCH2CHO (7), THF, À78 °C, 2 h. (b) TBAF, H2O, 0 °C, 30 min (in case of
Me3Si-protected phenol derivatives). (c) p-TsOH, C6H6, reflux, 3 h.

1676
E. Morera et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1674–1677
Table 1
Results of TRPV1 and TRPA1 assays of racemic gingerol (1a), shogaol (4), gingerol (1b–3), and shogaol (5) analoguesa
O
OH
O
OH
O
O
O
4
6
n
X
X
4
HO
HO
2: n = 1; 3: n = 6
4
1
5
Compd
X
TRPV1b
(efficacy)
TRPV1 (EC50
,
TRPV1c (IC50
,
TRPA1d
(efficacy)
TRPA1 (EC50
,
TRPA1e (IC50
M)
,
lM)
lM)
lM)
l
1a (Racemic [6]-gingerol) 3-OMe, 4-OH
51.4 1.7
<10
<10
<10
23.6 0.1
<10
3.3 0.5
ND
ND
ND
1.2 0.1
ND
5.0 0.2
>100
>50
>50
10.5 0.2
4.8 0.1
11.4 0.1
<10
63.6 3.3
<10
114.3 1.5
78.2 1.1
10.4 0.03
ND
2.1 0.9
ND
8.4 0.4
1.1 0.1
>100
>100
2.8 0.3
56.1 0.4
22.6 2.4
3. 9 0.6
1b
1c
1d
1e
1f
3,4-OCH2O
3,5-bis i-Pr, 4-OH
H
4-OH
2-Me, 4-OH, 5-i-
Pr
2a
2b
2c
2d
2e
2f
3-OMe, 4-OH
3,4-OCH2O
3,5-bis i-Pr, 4-OH
H
4-OH
2-Me, 4-OH, 5-i-
Pr
56.9 1.6
<10
<10
<10
10.8 0.1
<10
14.3 2.6
ND
ND
ND
1.0 0.1
ND
13.2 0.8
>50
>50
>50
33.5 5.8
35.3 2.3
<10
16.5 1.0
<10
17.5 1.0
130.9 2.9
51.3 0.1
ND
ND
ND
ND
10.7 0.1
3.5 0.1
97.85 0.02
14.4 0.6
3.3 0.3
4.5 0.7
35.1 3.4
39.7 1.5
3a
3b
3c
3d
3e
3f
3-OMe, 4-OH
3,4-OCH2O
3,5-bis i-Pr, 4-OH
H
4-OH
2-Me, 4-OH, 5-i-
Pr
60.0 1.4
<10
<10
<10
43.0 0.3
33.5 0.8
0.11 0.02
ND
ND
ND
14.6 0.1
0.5 0.2
0.11 0.02
>10
>10
>10
9.4 0.1
1.3 0.3
<10
<10
<10
<10
<10
163.2 7.3
ND
ND
ND
ND
ND
22.1 4.5
38.2 4.5
2.8 0.6
11.1 2.0
3.6 0.9
15.8 1.6
14.3 1.0
4 ([6]-Shogaol)
5
Capsaicin
Allyl isothiocyanate
(AITC)
79.2 0.9
19.7 0.5
78.6 2.4
0.32 0.02
0.10 0.01
0.0039 0.0004
0.29 0.02
1.2 0.2
91.1 2.5
89.2 5.1
16.0 2.3
2.2 0.8
16.7 0.4
2.3 0.4
100
41.8 3.8b
2.5 0.7
a
b
c
Data are means SEM of N = 3 determinations.
As percent of ionomycin (4 M).
Determined against the effect of capsaicin (0.1
l
l
M).
d
e
As percent of allyl isothiocyanate (100
lM).
Determined against the effect of allyl isothiocyanate (100
lM). ND, not determined when efficacy is lower than 10%.
highest activity was exhibited by analogues featuring n-hexyl
(1c, 1e, 1f) or benzyl (2e, 2f) side chains. With respect to the
aryl substitution, again the phenolic functionality was a struc-
tural requirement for efficient activation of TRPA1 but, in con-
trast with TRPV1, branched alkyl substituents at the ortho
position of the phenolic hydroxyl group were beneficial for the
activity, thus rendering 1c and 1f the most potent and selective
TRPA1 modulators. Compounds 3a, 3f, and 4, which act as potent
and selective TRPV1 agonists/desensitizers, and compounds 2c,
2d, 3b, and 3d, which behave as novel selective TRPA1 antagonists,
deserve a special mention as they might find potential therapeutic
applications against pain, inflammation, and migraine.
Supplementary data
TRPA1 activators (EC50 = 2.1 0.9
Data obtained with shogaol (4) and its analogue 5, which were
shown to potently activate both TRPV1 (EC50 = 0.32 0.02
and EC50 = 0.10 0.01 M, respectively) and TRPA1 channels
(EC50 = 16.0 2.3 M and EC50 = 2.2 0.8 M, respectively), high-
lM and 1.1 0.1, respectively).
Supplementary data (detailed experimental procedures and
characterization data for all products and further details of bio-
chemical assays) associated with this article can be found, in the
online version, at doi:10.1016/j.bmcl.2011.12.113.
lM
l
l
l
lighted the marginal importance of the b-hydroxylic group for
the activity.
Five-min preincubation of TRPV1–HEK293 cells with com-
pounds 1a, 1f, 3a, 3f, 4, and 5, before stimulation with capsaicin in-
References and notes
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TRPA1 response to this agonist with IC50 values <5 lM for com-
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the identification of some novel potent and selective TRPV1 or

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19. Cells transfected with either human TRPV1 or rat TRPA1 were loaded with the
fluorescent probe 4 lM Fluo-4-AM in EMEM, then were washed twice in
Tyrode’s buffer and transferred to the quartz cuvette of a spectrofluorimeter.
Intracellular Ca2+ concentration ([Ca2+]i) was determined before and after the
addition of various concentrations of test compounds by measuring cell
fluorescence (kEX = 488 nm, kEM = 516 nm). Potency was expressed as the
concentration of test substances exerting a half-maximal agonist effect (i.e.
half-maximal increases in [Ca2+]i) (EC50). The efficacy of TRPV1 agonists was
determined by normalizing their effect to the maximum Ca2+ influx effect on
[Ca2+
]
observed with application of 4
l
M ionomycin, while the effects of
TRPA1 agonists are expressed as a percentage of the effect obtained with
100 M allyl isothiocyanate. For both TRPV1 and TRPA1 agonism, the values of
the effect on [Ca2+
in wild type HEK293 (i.e., not transfected with any TRP
i
l
]
i
construct) were taken as baselines and subtracted from the values obtained
from transfected cells. Antagonist/desensitizing behaviour was evaluated
against capsaicin (0.1 lM) for TRPV1 and AITC (100 lM) for TRPA1.
of
compounds
1–3.
A
solution
of
4-(3-methoxy-4-
20. Correa, E. A.; Högestätt, E. D.; Sterner, O.; Echeverri, F.; Zygmunt, P. M. Bioorg.
Med. Chem. 2010, 18, 3299.
trimethylsilyloxyphenyl)butan-2-one (266 mg, 1.0 mmol) in 1.0 mL of dry
THF was added dropwise, over 30 min, to a stirred 1.0 M solution of lithium