Isolation and structure–activity relationship studies of jacaranones: Anti-inflammatory quinoids from the Cuban endemic plant Jacaranda arborea (Bignoniaceae)

Article abstract of DOI:10.1016/j.tetlet.2020.152005

The Cuban endemic plant Jacaranda arborea (Bignoniaceae) has been traditionally used in folk medicine as an acaricide and for acne treatment. Two known quinoids, methyl (1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl)acetate (jacaranone) (1) and its ethyl ester 2 were isolated from this species as anti-inflammatory substances. Compound 1 prominently inhibited the production of TNF-α in both LPS-treated macrophages and mice, with low toxicity. Structure-activity relationship studies revealed that the high electrophilicity of 1 as a Michael acceptor played an important role in these effects. Unlike in previous studies, such as those on antitumor, anti-oxidant, and anti-malarial activities, ester derivatives of 1 retained their potent anti-inflammatory activity. Our results suggest that jacaranones may target specific biomacromolecule(s) at lower concentrations than hitherto expected to exhibit potent activities.

Full text of DOI:10.1016/j.tetlet.2020.152005

Journal Pre-proofs
Isolation and structure-activity relationship studies of jacaranones: anti-in‐
flammatory quinoids from the Cuban endemic plant Jacaranda arborea
(Bignoniaceae)
Minako Hirukawa, Menghua Zhang, Lazaro M. Echenique–Diaz, Koji
Mizota, Satoshi D. Ohdachi, Gerardo Begué –Quiala, Jorge L. Delgado–
Labañino, Jorgelino Gámez–Díez, José Alvarez–Lemus, Leandro Galano
Machado, Miguel Suárez Nú ñez, Takahiro Shibata, Hideo Kigoshi, Masaki
Kita
PII:
S0040-4039(20)30448-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152005
TETL 152005
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Tetrahedron Letters
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Revised Date:
Accepted Date:
16 March 2020
28 April 2020
1 May 2020
Please cite this article as: Hirukawa, M., Zhang, M., Echenique–Diaz, L.M., Mizota, K., Ohdachi, S.D., Begué –
Quiala, G., Delgado–Labañino, J.L., Gámez–Díez, J., Alvarez–Lemus, J., Machado, L.G., Nú ñez, M.S., Shibata,
T., Kigoshi, H., Kita, M., Isolation and structure-activity relationship studies of jacaranones: anti-inflammatory
quinoids from the Cuban endemic plant Jacaranda arborea (Bignoniaceae), Tetrahedron Letters (2020), doi:
https://doi.org/10.1016/j.tetlet.2020.152005
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Isolation and structure-activity relationship studies
of jacaranones: anti-inflammatory quinoids from
the Cuban endemic plant Jacaranda arborea
(Bignoniaceae)
Leave this area blank for abstract info.
Minako Hirukawa,a Menghua Zhang,b,c Lazaro M. Echenique–Diaz,d Koji Mizota,d Satoshi D. Ohdachi,e
Gerardo Begué–Quiala,f Jorge L. Delgado–Labañino,f Jorgelino Gámez–Díez,f José Alvarez–Lemus,g Leandro
Galano Machado,h Miguel Suárez Núñez,h Takahiro Shibata,a Hideo Kigoshi,b and Masaki Kita *,a
aGraduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
c
bGraduate School of Pure and Applied Sciences, and School of Integrative and Global Majors (SIGMA),
University of Tsukuba, Tsukuba 305-8571, Japan.
dEnvironmental Education Center, Miyagi University of Education, Sendai 980-0845, Japan.
eInstitute of Low Temperature Science, Hokkaido University, Sapporo 060-0819, Japan.
fUnidad Presupuestada Parque Nacional Alejandro de Humboldt, CITMA, Guantanamo 95200, Cuba.
gCentro de Inspección y Control Ambiental, Environment Agency, Havana 11300, Cuba.
hEmpresa Nacional para la Protección de la Flora y la Fauna, Baracoa 97310, Cuba.

3
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Isolation and structure-activity relationship studies of jacaranones: anti-
inflammatory quinoids from the Cuban endemic plant Jacaranda arborea
(Bignoniaceae)
Minako Hirukawaa, Menghua Zhangb,c, Lazaro M. Echenique–Diazd, Koji Mizotad, Satoshi D. Ohdachie,
Gerardo Begué–Quialaf, Jorge L. Delgado–Labañinof, Jorgelino Gámez–Díezf, José Alvarez–Lemusg,
Leandro Galano Machadoh, Miguel Suárez Núñezh, Takahiro Shibataa, Hideo Kigoshib, and Masaki
Kitaa,*
a Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
b Graduate School of Pure and Applied Sciences, and c School of Integrative and Global Majors (SIGMA), University of Tsukuba, Tsukuba 305-8571, Japan
d Environmental Education Center, Miyagi University of Education, Sendai 980-0845, Japan
e Institute of Low Temperature Science, Hokkaido University, Sapporo 060-0819, Japan
f Unidad Presupuestada Parque Nacional Alejandro de Humboldt, CITMA, Guantanamo 95200, Cuba
g Centro de Inspección y Control Ambiental, Environment Agency, Havana 11300, Cuba
h Empresa Nacional para la Protección de la Flora y la Fauna, Baracoa 97310, Cuba
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The Cuban endemic plant Jacaranda arborea (Bignoniaceae) has been traditionally used in
folk medicine as an acaricide and for acne treatment. Two known quinoids, methyl (1-
hydroxy-4-oxocyclohexa-2,5-dien-1-yl)acetate (jacaranone) (1) and its ethyl ester 2 were
isolated from this species as anti-inflammatory substances. Compound 1 prominently
inhibited the production of TNF- in both LPS-treated macrophages and mice, with low
toxicity. Structure-activity relationship studies revealed that the high electrophilicity of 1 as a
Michael acceptor played an important role in these effects. Unlike in previous studies, such
as those on antitumor, anti-oxidant, and anti-malarial activities, ester derivatives of 1 retained
their potent anti-inflammatory activity. Our results suggest that jacaranones may target
specific biomacromolecule(s) at lower concentrations than hitherto expected to exhibit potent
activities.
Available online
Keywords:
Jacaranone
Quinoid
Anti-inflammatory activity
Structure-activity relationship studies
2020 Elsevier Ltd. All rights reserved.
The Caribbean islands are rich in biodiversity, having a large
number of endemic species [1]. Several Cuban plants have
been traditionally used by locals as folk medicines for the
treatment and prevention of diseases related to chronic
inflammation,
ethnopharmacological
while
there
and
have
phytochemical
been
few
studies.
Figure 1. Structures of jacaranone (1) and its derivatives isolated from
Jacaranda arborea.
Inflammation is a cellular and vascular response that occurs
immediately after tissue damage and is observed in several
diseases, such as asthma, chronic peptic ulcer, tuberculosis,
rheumatoid arthritis, and periodontitis [2]. In our continuing
search for anti-inflammatory substances from tropical
organisms [3], we examined the screening and activity-guided
separation of the Cuban endemic plants. This work has led to
the isolation of two structurally simple quinoids, methyl (1-
The plant specimens were collected at the conservation
zone of Alejandro de Humboldt National Park or Yumuri
Canyon in Cuba. Among the 27 plant species (22 families)
tested, four (Jacaranda arborea, Mikania cordifolia, Bauhinia
cumanensis, and Cojoba arborea) prominently inhibited nitric
oxide (NO) production in lipopolysaccharide (LPS)-stimulated
murine RAW264.7 macrophage cells at 100 µg/mL, with low
cytotoxicity (Table S1). Two other species (Metopium venosun
and Lysiloma latisigua) also strongly inhibited NO production,
but were cytotoxic (<20% cell viability). J. arborea was the
most active from the viewpoint of anti-inflammatory activity.
hydroxy-4-oxocyclohexa-2,5-dien-1-yl)acetate
(jacaranone)
(1) and its ethyl ester analog 2, as potent anti-inflammatory
substances (Fig. 1). We describe herein the isolation and
structure–activity relationship (SAR) studies of jacaranones.

4
Tetrahedron Letters
The genus Jacaranda includes 49 species of flowering
ketone moiety and tether any detecting groups for further
chemical probe studies, oxime 6 was prepared (94%) by
condensation with hydroxylamine hydrochloride. To establish
the significance of the -dienone moiety of 1,
tetrahydrojacaranone (7) was synthesized (79%) by the
catalytic hydrogenation of 1 with a palladium catalyst [31]. In
addition, a known acetate 8 (99%) [7a,16] and 5-hexynoate 9
(92%) were prepared by condensation with acetic anhydride or
5-hexynoic acid, respectively.
plants that are native to Central and South America and the
Caribbean region [4], and several phytochemical studies have
been performed [5]. Among them, J. arborea is a Cuban
endemic species, and on the International Union for
Conservation of Nature and Natural Resources (IUCN) red list
of threatened ones [6]. In the La Melba region of Humboldt
National Park, the aerial part of this species has been used as
an acaricide and for acne treatment (a personal communication
from one of the authors, J.L.D.). To the best of our knowledge,
however, no chemical, biological, or pharmaceutical studies
on J. arborea have been reported, which motivated us to
investigate the active substances.
Guided by an anti-inflammatory assay, the aqueous EtOH
extract of the leaf of J. arborea was partitioned with EtOAc
and H2O, and the organic layer was further separated with n-
hexane / CH2Cl2 / 60% aq. MeOH. The CH2Cl2 layer (active at
10 µg/mL) was separated by repeated SiO2 and ODS column
chromatography and reversed-phase HPLC to afford three
known compounds, jacaranone (1) (4.1 × 10–1 %), jacaranone
ethyl ester (2) (1.3
×
10–2 %), and methyl (4-
hydroxyphenyl)acetate (3) (8.3 × 10–3 %). Both 1 and 2
exhibited potent anti-inflammatory activity (EC50 = 0.99 and
1.0 µM, respectively), while 3 did not, even at 500 µM. Due to
its high content, compound 1 might account for most of the
activity in the crude extracts.
Jacaranone (1) was originally isolated from J. caucana in
1976 [7]. Compounds 1 and 2 are widely contained in the
genera Jacaranda (at least eight species) [5] and Senecio
(Asteraceae, at least 16 species) [8]. Also, 1 has been
identified in many terrestrial plants including the genera
Bethencourtia [9], Emilia [10], Pseudogynoxys [11], Cineraria
[12], Packera [13], Pentacalia [14], and Jacobaea [15]
(Asteraceae), Ajuga (Lamiaceae) [16], and Ternstroemia
(Pentaphylacaceae) [17], as well as the marine seaweed
Delesseria sp. (Delesseriaceae) [18]. Among these, methyl (p-
hydroxyphenyl)acetate (3) has also been isolated from several
Bignoniaceae and Asteraceae plants in association with 1
[13,19]. Jacaranones exhibit a wide range of biological
activities, including antitumor [7], antifeedant [9],
antioxidative [17], antiplatelet [19], antiproliferative [14b,20],
antibacterial [21], antifungal [22], insecticidal [23], and
antimalarial / antitrypanosomal / antileishmanial activities
[14a,24]. Also, 1 induces larval settlement and metamorphosis
against the king scallop Pecten maximus [18]. However, there
have been no reports on the anti-inflammatory activity of
Scheme 1. Synthesis of jacaranone (1) and its derivatives.
Jacaranones 1 and 2 both have high electrophilicity as
Michael acceptors, and their water, MeOH, or EtOH adducts
have been isolated from Senecio sp. [32] To reduce this
reactivity of 1, selective 1,2-reduction of the -dienone was
examined. A modified Luche reduction [33] using NaBH4 in
combination with CaCl2 [34] gave the desired cyclohexadiene-
1,4-diol 10 (15%, single stereoisomer), along with an
overreduction product, cyclohexene-1,4-diol 11 (47%, 1.6:1
diastereomer mixture) (Entry 1). Meanwhile, the use of CeCl3
at room temperature solely afforded phenol 3 (56%) via the
dehydrative aromatization of 10 (Entry 2). It has been shown
that the Zn-mediated reduction of p-quinols in aq. AcOH
quantitatively gave phenols [35]. As a result, this side reaction
was partially suppressed at –70 °C, and the yield of 10 was
improved to 27% (Entry 3).
jacaranones.
Among
the
jacaranone
derivatives,
jacaglabrosides, which are glucosidic esters bearing two
jacaranone molecules, were isolated from J. glabra and
showed antiprotozoal activity [25]. Several structurally-related
anti-inflammatory quinoids have also been reported, such as
melodamide A [26], eutigosides [27] and PMX464 [28], but
their activities are much less potent than that of 1.
To establish their biological activities, 1 and its derivatives
were synthesized. According to the literature [21,29,30], aldol
reaction of 1,4-benzoquinone (4) with the lithium enolate of
methyl acetate gave 1, along with cis-diol 5 (Scheme 1).
Synthetic 1 was found to be identical to natural 1 on the basis
of TLC, HPLC analysis and NMR spectroscopy, as well as
anti-inflammatory activity. Next, to reduce the reactivity of the
With the seven synthetic jacaranone derivatives in hand, we
performed an anti-inflammatory assay (Table 1). Bis-aldol
adduct 5 and oxime 6 were approximately 180 and 26 times

5
less potent than 1. Saturated ketone 7 and diols 10 and 11 were
not effective at least up to 500 µM. These results suggested
that the high electrophilicity of the -dienone in jacaranones
was important for their activities. Meanwhile, esters 8 and 9
potently inhibited NO production (EC50 = 1.7 and 0.65 µM),
comparable to 1. Notably, the selective index values (IC50
/
EC50) of 8 and 9 were both higher than those of jacaranones.
As a result, the anti-inflammatory activity of 9 was the most
potent among the compounds tested [36].
Table 1. NO production inhibitory effects by jacaranone and its
derivatives in murine macrophage RAW264.7 cells.a
a
RAW264.7 cells (104 cells) were treated with LPS (50 ng/mL) and
samples for 24 h. Average of two reproducible runs is shown. NO
production inhibitory effects and cytotoxicity are expressed as EC50 and
IC50 values, respectively.
Figure 2. In vitro and in vivo anti-inflammatory activity of jacaranone (1).
(a, b) NO-production inhibitory assay. RAW264.7 cells [104 cells in (a)
and 105 cells in (b)] were treated with LPS [50 ng/mL in (a) and 500
ng/mL in (b)] for 24 h. IC50 values in (a) and (b) were 25 and >55 µM,
respectively. (c) TNF- concentration in the culture medium of
RAW264.7 cells treated with LPS as in (a). (d) IL-6 concentration in the
culture medium of RAW264.7 cells treated with LPS as in (b). (e, f)
Cytokine concentrations in serum collected from mice treated with LPS
(2.5 mg/kg, i.p.). Data are means ± SD (n = 4) in (a) and (b), (n = 2) in (c)
and (d), and (n = 3) in (e) and (f), respectively. *p < 0.01 versus control
(LPS +).
As expected by the synthetic route, retro-aldol reaction of 1
could afford 1,4-benzoquinone (4). Compound 4 undergoes
reduction under mild conditions to give p-hydroquinone (12).
The redox system of quinones is reversible and common in
biological systems, such as ubiquinones in the mitochondrial
electron transport chain [37]. Several antioxidants containing
phenol groups, such as coumaric acids (phenolic acids) and
rutin (flavonoids), show anti-inflammatory activities [38]. In
fact, the anti-inflammatory activities of 4 and 12 were
comparable to those of jacaranones (EC50 = 6.8, 1.8 µM)
(Table 1). To clarify the source of the activity of 1, the
stability of 1 under physiological conditions was examined. As
a result, 1 was stable in Ca2+ and Mg2+-free phosphate buffered
saline [PBS(–)] at 37 °C for at least 24 h, and neither 4 nor 12
was generated under these conditions (Fig. S1). In addition,
due to the higher selective index values of 1 and 2 than those
of 4 and 12, the anti-inflammatory activities of jacaranones
might not be derived from degraded quinones or quinols, but
rather from their own structures.
As mentioned above, many papers have described the
biological activities of jacaranones, such as antitumor, anti-
oxidative, and anti-malarial activities. To the best of our
knowledge, however, this paper is the first to show that
jacaranone (1) has potent in vitro and in vivo anti-
inflammatory activities. In previous SAR studies, acetate 8 did
not exhibit the antitumor activity seen for 1 [7a], and the
tertiary alcohol-protected jacaranone derivatives gave negative
results [16]. Herein, we demonstrated that 5-hexynoate analog
9 exhibited more potent anti-inflammatory activity than
natural jacaranones, with low cytotoxicity. Protection of the
tertiary alcohol in 1 might increase its stability, lipophilicity,
and cellular permeability, which might contribute to the anti-
inflammatory activity of the ester derivatives.
Finally, the in vitro and in vivo anti-inflammatory activities
of jacaranone (1) were investigated (Fig. 2). Compound 1
prominently inhibited the production of two proinflammatory
cytokines, tumor necrosis factor alpha (TNF-) and
Interleukin 6 (IL-6), in LPS-treated RAW264.7 cells (EC50
=
7.7 and 3.3 µM, respectively). Furthermore, treatment with 1
(50 mg/kg, i.p.) significantly reduced the serum concentration
of TNF- in LPS-treated mice (2.5 mg/kg, i.p.), while the
same treatment increased that of IL-6.
It has been shown that jacaranone (1) induces apoptosis in
murine melanoma cells at 20–50 µM, and improves the
survival of melanoma-bearing mice [14b]. This apoptotic

6
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Acknowledgments
We thank Mr. Osamu Takahashi for his cooperation on the
field experiments and sample collection of Cuban plants, Ms.
Toshiko Takenaka for the preparation of plant extracts, and
Ms. Saeka Nishio for her support on animal experiments. This
work is supported in part by JSPS grants (16H05655), JSPS
A3 Foresight Program, The Toyota Foundation, and the Naito
Foundation.
Supplementary data
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Footnote * Corresponding author. tel./fax: +81 52 789 4284 (M.K.); e-
mail address: mkita@agr.nagoya-u.ac.jp (M.K.).

8
Tetrahedron Letters
Highlights
• Activity screening of Cuban endemic plants
used as traditional medicines
• Discovery of an anti-inflammatory quinoid
from a Cuban endemic plant
• Structure-activity relationship studies and
stability analysis
• Monitoring of inflammatory cytokines in vitro
and in vivo
• Relationship of anti-inflammatory activity and
electrophilicity as a Michael acceptor