New vasorelaxant indole alkaloids, taberniacins A and B, from Tabernaemontana divaricata

Article abstract of DOI:10.1007/s11418-019-01293-9

Taberniacins A (1) and B (2), new indole alkaloids, were isolated from the stems of Tabernaemontana divaricata (Apocynaceae). Structure elucidation of 1 and 2 was based on spectroscopic methods and total synthesis. Each alkaloid showed vasorelaxant activity against phenylephrine-induced contraction of isolated rat aorta.

Full text of DOI:10.1007/s11418-019-01293-9

Journal of Natural Medicines
https://doi.org/10.1007/s11418-019-01293-9
NOTE
New vasorelaxant indole alkaloids, taberniacins A and B,
from Tabernaemontana divaricata
1
1
1
1
1
1
Yusuke Hirasawa · Xin Dai · Jun Deguchi · Shota Hatano · Tadahiro Sasaki · Ruri Ohtsuka ·
1
1
1
Alfarius Eko Nugroho · Toshio Kaneda · Hiroshi Morita
Received: 9 January 2019 / Accepted: 20 February 2019
©
The Japanese Society of Pharmacognosy 2019
Abstract
Taberniacins A (1) and B (2), new indole alkaloids, were isolated from the stems of Tabernaemontana divaricata (Apoc-
ynaceae). Structure elucidation of 1 and 2 was based on spectroscopic methods and total synthesis. Each alkaloid showed
vasorelaxant activity against phenylephrine-induced contraction of isolated rat aorta.
Keywords Indole alkaloid · Taberniacin A · Taberniacin B · Tabernaemontana divaricata · Vasorelaxant
Introduction
Results and discussion
Tabernaemontana divaricata (L.) R.Br. ex Roem. & Schult.,
belonging to the family Apocynaceae, is widely distributed
in the tropical and subtropical areas of Asia and Australia
Taberniacin A (1), a yellow amorphous solid, has the
molecular formula C H N O by HRESITOFMS [m/z
1
7
14
4
+
291.1269 (M + H) , Δ + 2.3 mmu] compatible with 13°
[
1]. It is mainly known as a garden tree, but in China and
of unsaturation. IR spectrum suggested the presence of
−
1
−1
Thailand it is traditionally used for the treatment of fever
and pain [1, 2]. T. divaricata is known for the production of
a wide variety of indole alkaloids [3–10]. According to van
Beek et al.[11], these alkaloids are classiꢀed into 11 classes:
Vincosan, Corynanthean, Vallesiachotaman, Strychnan,
Aspidospermatan, Plumeran, Eburan, Ibogan, Tacaman,
Bis-indole and miscellaneous. Recently, we isolated a new
type of tetrakis-indole alkaloid as alasmontamine A from T.
elegans [12], and new yohimbine-related alkaloids from T.
corymbosa [13]. In our search for structurally and biogeneti-
cally interesting natural products [14–18], we have isolated
two new indoles, taberniacins A (1) and B (2) (Fig. 1).
In this paper we would like to describe the structures
of taberniacins A (1) and B (2) proposed on the basis of
their spectral data and total synthesis, and their vasorelax-
ant activity.
NH (3334 cm ) and amide carbonyl (1672 cm ) groups.
1
3
The C NMR (Table 1) spectrum of 1 disclosed seven-
teen carbon signals due to one amide carbonyl (δ 168.8),
C
2
seven sp quaternary carbons (δ 157.9, 149.6, 138.1,
C
2
133.0, 127.1, 125.1 and 119.2), seven sp methines (δ
C
151.5, 135.4, 129.9, 125.4, 120.6, 120.2, and 112.8), two
3
1
13
sp methylenes (δ 48.6 and 19.4). H and C NMR sig-
C
nals for 1 were assigned by detail analysis of the HSQC
1
1
spectrum. The H– H COSY spectrum revealed the con-
nectivity of C-5–C-6 and C-9 to C-12 (Fig. 2). HMBC
correlations of H -5 (δ 4.05) to C-3 (δ 157.9) and C-7
2
H
C
(δ 119.2), and H -6 (δ 3.04) to C-2 (δ 127.1) and C-8
C
2
H
C
(δ 125.1), and H-9 (δ 7.65) to C-7, C-8, and C-13 (δ
C
H
C
138.1), and H-11 (δ 7.33) to C-13, and H-12 (δ 7.45) to
H
H
C-8 indicated the presence of a 3,4-dihydro-β-carboline
skeleton. The signals at δ 9.11 and δ 9.06 appeared as
H
H
broadened singlets, while the signal δ 8.50 appeared as
H
a triplet (J = 2.4 Hz) were attributed to H-15, H-17 and
H-19, respectively, which associated with a 3,5-disubsti-
tuted pyridine system. The presence of primary amide was
deduced from the HMBC correlations of H-17 (δ 9.11)
*
Hiroshi Morita
H
moritah@hoshi.ac.jp
to C-18 (δ 129.9) and H-19 (δ 9.06) to C-20 (δ 168.8)
C
H
C
and mass spectrum. The connectivity of 3,4-dihydro-β-
1
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara
carboline and nicotinamide was conꢀrmed by the HMBC
2
-4-41 Shinagawa-ku, Tokyo 142-8501, Japan
Vol.:(0
1
123456789)
3

Journal of Natural Medicines
Fig. 1 Structures of isolated compounds (1 and 2) from Tabernae-
montana divaricata
Fig. 3 Selected 2D NMR correlations for taberniacin B (2)
Table 1 1H (400 MHz) and 13C (100 MHz) NMR Data of 1 and 2 in
Taberniacin B (2) was obtained as a white powder. The
CDCl /CD OD
3
3
HRESITOFMS revealed a pseudo-molecular ion peak at
+
1
2
[m/z 289.1102 (M + H) , Δ + 1.3 mmu], compatible with
the molecular formula C H N O and 14° of unsaturation.
1
7
12
4
δH
δC
δH
δC
The molecular formula of taberniacin B (2) was less than
1
13
2
3
5
6
7
8
9
1
1
1
1
1
1
1
1
1
2
127.1
157.9
134.9
138.6
139.0
115.7
131.6
121.7
122.2
that of taberniacin A (1) by 2 mass units. H and C NMR
data (Table 1) of taberniacin B (2) indicated that a double
bond took the place of a single bond between C-5 and C-6
of taberniacin A (1). The structure of taberniacin B (2) was
ꢀnally established by 2D NMR correlations (Fig. 3) and tab-
erniacin B (2) was indicated the dehydrogenated derivative
of taberniacin A (1).
4.05 (2H, m)
3.04 (2H, t, 8.4)
48.6 8.48 (1H, d, 5.2)
19.4 8.12 (1H, d, 5.2)
119.2
125.1
7.65 (1H, d, 7.8)
120.2 8.21 (1H, d, 7.8)
0
1
2
3
4
5
7
8
9
0
7.17 (1H, dd, 7.8, 7.8) 120.6 7.32 (1H, dd, 7.8, 7.8) 120.8
7.33 (1H, dd, 7.8, 7.8) 125.4 7.60 (1H, dd, 7.8, 7.8) 129.6
In previous papers, we have reported vasorelaxant activi-
ties of β-carboline alkaloids [21, 22]. Taberniacins A (1) and
B (2) were also expected to show strong vasoleraxant activ-
ity. Thus, to evaluate their biological activity and conꢀrm
the proposed structures, we synthesized 1 and 2. We have
attempted the preparation of β-carboline skeleton and pri-
mary amide moiety with the combination of Bischler–Napi-
eralski procedure [23] and hydrolysis of a cyano group.
Tryptamine was reacted with acid chloride of 5-bromo-
7.45 (1H, d, 7.8)
112.8 7.63 (1H, d, 7.8)
138.1
133.0
135.4 8.78 (1H, t, 2.1)
129.9 9.13 (1H, d, 1.8)
149.6
151.5 9.29 (1H, d, 1.8)
168.8
112.7
142.4
134.9
136.1
130.6
148.5
152.2
169.5
8.50 (1H, t, 2.4)
9.11 (1H, brs)
9.06 (1H, brs)
3
3
3
-pyridinecarboxylic acid to aꢁord the corresponding amide
in 62% yield. For preparation of aromatic nitrile 4 from
, we initially investigated two methods, a Rosemund–von
Braun reaction [24] and a Cu-catalyzed cyanation [25],
which gave only recovery of starting materials or decompo-
sition. In the other procedures for the synthesis of nitriles,
application of the Weissman protocol [26] (K [Fe(CN) ]/
4
6
Pd(OAc) /Na CO ) in N,N-dimethylacetamide (DMAc)
2
2
3
gave the best result, 80% yield of 4. Bischler–Napieralski
cyclization of amide 4 in the presence of POCl resulted
3
in the formation of the desired 3,4-dihydro-β-carboline 5.
Subsequent transformation of nitriles into primary amides
in mild conditions using the urea-hydrogen peroxide adduct
Fig. 2 Selected 2D NMR correlations for taberniacin A (1)
(
UHP) [27] gave 1 in good yield (Fig. 4).
correlations of H-19 to C-3 and C-14 (δ 133.0). There-
Direct conversion of 1 into 2 by dehydrogenation with
C
fore, taberniacin A could be assigned as 1. While a related
alkaloid, naucledine, which possessing methyl nicotinate,
was isolated from Nauclea diderrichii and synthesized by
Mclean et al. [19, 20], this is the ꢀrst report for the isola-
tion of a β-carboline alkaloid attaching nicotinamide.
2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) ended
in a low yield of 2 with the recovery of 1. We next chose
to synthesize β-carboline 6, which could be then converted
to amide easily, from 3,4-dihydro-β-carboline 5 by dehy-
drogenation with DDQ. This attempt generated the desired
1
3

Journal of Natural Medicines
Fig. 4 Total synthesis of taberniacin A (1)
Fig. 5 Total synthesis of taberniacin B (2)
β-carboline 6 in good yield. The primary amide was formed
by the same hydrolysis method in 69% yield to aꢁord taber-
niacin B (2) (Fig. 5). The spectroscopic data and retention
time of the synthetic compounds 1 and 2 were identical to
those of the natural products.
Vasorelaxant activities of synthesized taberniacins A (1)
and B (2) were evaluated. After a maximal response was
−
7
achieved when applying phenylephrine (PE, 3×10 M) to
thoracic aortic rings with endothelium, we added taberni-
acins A (1) and B (2). Both alkaloids showed a moderate
vasorelaxant activity on isolated rat aorta in a concentration-
dependent manner, as shown in Fig. 6. The IC values of
5
0
taberniacins A (1) and B (2) were 2.86 μM and 580 nM,
respectively. The mode of action of both alkaloids on vas-
orelaxant activity is under investigation.
Fig. 6 Relaxation eꢁect of taberniacins A (1) and B (2) on rat aortic
rings precontracted with phenylephrine 3×10−
7
M
Experimental section
spectra were recorded on a Bruker AV 400 spectrometer,
and chemical shifts were referenced to the residual solvent
peaks (δ 7.26 and δ 77.0 for CDCl ) and TMS for CDCl /
General Experimental Procedures Optical rotations were
measured on a JASCO DIP-1000 polarimeter. UV spectra
were recorded on a Shimadzu UVmini-1240 spectrophotom-
eter and IR spectra on a JASCO FT/IR-4100 spectrophotom-
eter and PerkinElmer FT-IR spectrometer, spectrum RX 1.
High-resolution ESI MS were obtained on a LTQ Orbitrap
XL (Thermo Scientiꢀc) and LC MS were obtained on a
H
C
3
3
CD OD. Standard pulse sequences were employed for the
3
2D NMR experiments.
Material The stems of T. divaricata were collected at
Okinawa, Japan, in 2015. The botanical identiꢀcation was
made by Dr. Yusuke Hirasawa, Faculty of Pharmaceuti-
cal Sciences, Hoshi University. The voucher specimen
1
Shimadzu LCMS- IT- TOF (Shimadzu). H and 2D NMR
1
3

Journal of Natural Medicines
(
Herbarium No. HO ) was deposited at the Herbarium of
δ 8.72 (d, 1H, J = 2.0 Hz), 8.66 (d, 1H, J = 2.0 Hz), 8.18
(brs, 1H), 8.15 (t, 1H, J=2.0 Hz), 7.62 (d, 1H, J=8.0 Hz),
7.39 (d, 1H, J=8.0 Hz), 7.23 (dd, 1H, J=7.2, 7.2 Hz), 7.14
(dd, 1H, J=7.2, 7.2 Hz), 7.07 (d, 1H, J=1.6 Hz), 6.29 (brs,
3
the Faculty of Pharmaceutical Sciences, Hoshi University,
Tokyo, Japan.
Vasodilation Assay The vasorelaxant activities of alka-
loids 1 and 2 were tested using the same procedure as
reported previously by Mukhtar et al. [28]. The animal
experimental studies were conducted in accordance with
the Guiding Principles for the Care and Use of Laboratory
Animals, Hoshi University and under the supervision of the
Committee on Animal Research of Hoshi University, which
is accredited by the Ministry of Education, Science, Sports
Culture, and Technology of Japan.
1
3
1H), 3.80 (q, 2H, J=6.4 Hz), 3.11 (t, 2H, J=6.4 Hz); C-
NMR (CDCl ) δ 164.3, 152.9, 145.8, 137.8, 136.5, 131.7,
3
127.3, 122.3, 122.2, 120.9, 119.5, 118.5, 112.5, 111.5, 40.7,
25.1; HRESIMS m/z 368.0179 [calcd. for C H BrN NaO
1
6
14
3
+
(M+Na) , 368.0198].
N‑(2‑(1H‑indol‑3‑yl)ethyl)‑5‑cyanonicotinamide (4) A round
ꢂask was charged with the aryl bromide 3 (3.5 mmol, 1.2 g),
DMAc (6 mL), K [Fe(CN) ] (3.9 mmol, 1.65 g), Na CO
Extraction and Isolation Dried stems of T. divaricata
4
6
2
3
(
2.5 kg) were defatted with hexane, and the plant material
(17.5 mmol, 1.9 g), and Pd(OAc) (0.5 mol%, 30 mg). The
2
was dried and then soaked in 25% NH OH for 2 h. They
ꢂask was ꢀlled with nitrogen and heated to 120 °C for 14 h.
4
were then soaked and macerated with CHCl twice over a
The reaction mixture was cooled to room temperature and
3
period of 3 days. The supernatant obtained was concentrated
to give crude alkaloids (3.5 g). The crude alkaloids (3.0 g)
were subjected to a SiO column (CHCl /MeOH, 1:0→0:1).
diluted with 20 mL of CHCl . The resulting slurry was ꢀl-
3
tered through Celite and the ꢀltrate washed with water and
brine, dried (Na SO ), concentrated, and puriꢀed by column
2
3
2
4
Further puriꢀcation of the 7th and 8th fractions was done
chromatography on SiO . Elution with CHCl /MeOH (20:1,
2 3
by a preparative thin layer chromatography (CHCl /MeOH,
v/v) gave 4 (810 mg, 80%) as a yellow solid; IR (Zn–Se)
−1 1
3
8
5:15, saturated with NH OH) to get a mixture of taber-
ν
3308, 2237, 1652 cm ; H-NMR (CDCl ) δ 8.97 (d,
max 3
4
niacins A (1) and B (2). This mixture was further puri-
1H, J = 2.0 Hz), 8.89 (d, 1H, J = 2.0 Hz), 8.24 (brs, 1H),
8.23 (t, 1H, J = 2.0 Hz), 7.60 (d, 1H, J = 7.6 Hz), 7.39 (d,
1H, J = 8.0 Hz), 7.22 (ddd, 1H, J = 7.2, 7.2, 1.2 Hz), 7.13
(ddd, 1H, J=7.2, 7.2, 0.8 Hz), 7.08 (d, 1H, J=2.0 Hz), 6.48
(brs, 1H), 3.81 (q, 2H, J=6.4 Hz), 3.12 (t, 2H, J=6.4 Hz);
ꢀ
ed by ODS HPLC (CAPCELL PAK C18 MG-II, 5 μm,
1
2
0×250 mm; eluent, 40% MeOH/0.1% TFA aq.; ꢂow rate,
.0 mL/min; UV detection at 254 nm) to aꢁord taberniacins
A (1, 0.5 mg, 0.000025%) and B (2, 0.5 mg, 0.000025%).
Taberniacin A (1): yellow amorphous solid, IR (Zn–Se)
1
3
C-NMR (CDCl ) δ 163.4, 153.9, 150.1, 138.4, 136.4,
3
−
1
νmax 3334, 1672 cm ; UV (MeOH) λ (log ε) 201 (4.21),
130.3, 127.2, 122.4, 122.3, 119.6, 118.5, 115.9, 112.5,
max
+
3
27 (3.54) nm; ESIMS (pos.) m/z 291 (M + H) ; HRE-
111.5, 109.9, 40.8, 25.0; HRESIMS m/z 313.1070 [calcd.
+
+
SITOFMS m/z 291.1269 [(M+H) ; calcd. for C H N O,
for C H N NaO (M+Na) , 313.1065].
1
7
15
4
17 14
4
2
91.1246].
Taberniacin B (2): white powder, IR (Zn–Se) ν 3322,
5‑(4,9‑dihydro‑3H‑pyrido[3,4‑b]indol‑1‑yl)nicotinoni‑
trile (5) To a solution of amide 4 (2.8 mmol, 800 mg) in
max
−
1
1
4
678 cm ; UV (MeOH) λ
(log ε) 219 (4.42), 240 (sh,
max
.21), 290 (4.03), 362 (3.64) nm; ESIMS (pos.) m/z 289
1,4-dioxane (5 mL) at 0 °C, we added POCl (8.6 mmol,
3
+
+
(
M+H) ; HRESITOFMS m/z 289.1102 [(M+H) ; calcd.
800 μL) dropwise. The mixture was reꢂuxed for 2 h followed
by cooling to room temperature. The reaction was quenched
for C H N O, 289.1089].
1
7
13
4
with saturated aqueous NaHCO solution (25 mL) and parti-
3
N‑(2‑(1H‑indol‑3‑yl)ethyl)‑5‑bromonicotinamide (3) To a
solution of 5-bromonicotinic acid (6.0 mmol, 1.2 g) in tolu-
ene (10 mL), we added thionyl chloride (10 mL) at room
temperature. The mixture was reꢂuxed for 2 h and concen-
trated under vacuum to give crude acyl chloride (1.3 g),
which, without further puriꢀcation, was used in the next
reaction. To a solution of tryptamine (6.0 mmol, 1.0 g) and
N,N-dimethyl-4-aminopyridine (DMAP, 1.2 mmol, 146 mg)
in pyridine (10 mL), we added the acyl chloride at 0 °C.
After stirring at room temperature for 4 h, the reaction mix-
tioned with CHCl . The combined organic layers were dried
3
(Na SO ), concentrated, and puriꢀed by column chroma-
2
4
tography on NH–SiO . Elution with CHCl /MeOH (20:1,
2
3
v/v) gave 5 (330 mg, 44%) as a red solid; IR (Zn–Se) ν
max
−
1 1
2236 cm ; H-NMR (CDCl ) δ 9.23 (d, 1H, J= 2.0 Hz),
3
9.00 (d, 1H, J=2.0 Hz), 8.42 (t, 1H, J=2.0 Hz), 8.06 (brs,
1H), 7.67 (d, 1H, J=7.6 Hz), 7.43 (d, 1H, J=8.4 Hz), 7.36
(ddd, 1H, J=8.4, 8.4, 1.2 Hz), 7.23 (ddd, 1H, J =8.0, 8.0,
1.2 Hz), 4.10 (dd, 2H, J=8.8, 8.4 Hz), 3.01 (dd, 2H, J=8.8,
1
3
8.4 Hz); C-NMR (CDCl ) δ 155.1, 152.8, 152.0, 138.8,
3
ture was diluted with CHCl and successively washed with
137.2, 133.7, 126.5, 125.6, 125.4, 121.0, 120.3, 119.6,
3
water and brine, dried (Na SO ), concentrated, and puri-
116.0, 112.3, 110.3, 49.2, 19.2; HRESIMS m/z 273.1113
2
4
+
ꢀ
ed by column chromatography on NH–SiO . Elution with
[calcd. for C H N (M+H) , 273.1140].
2
17 13
4
CHCl /MeOH (20:1, v/v) gave 3 (1.26 g, 62%) as a yellow
3
−1 1
crystal; IR (Zn–Se) ν 3272, 1644 cm ; H-NMR (CDCl )
max
3
1
3

Journal of Natural Medicines
1
‑(pyridin‑3‑yl)‑4,9‑dihydro‑3H‑pyrido[3,4‑b]indole (1) (Tab‑
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erniacin A) To a solution of nitrile 5 (0.037 mmol, 10 mg) in
acetone–water (1:1, 2 mL) at room temperature, we added
UHP (0.15 mmol, 13.8 mg) and anhydrous K CO (1 mg).
6
.
Kam TS, Anuradha S (1995) Alkaloids from Tabernaemontana
divaricata. Phytochemistry 40:313–316
2
3
The mixture was stirred for 1 h and acetone was removed
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andbisindole alkaloids from Tabernaemontana divaricata. Org
Biomol Chem 1:1292–1297
under vacuum. H O was added to the residue and the pre-
2
cipitate was ꢀltered oꢁ. The product was puriꢀed by washing
8
.
Kam TS, Choo YM, Komiyama K (2004) Biologically active
iboganand vallesamine derivatives from Tabernaemontana
divaricata. Chem Biodivers 1:646–656
with H O and CHCl to aꢁord 1 (6.9 mg, 65%) as a yellow
2
3
amorphous solid; All spectroscopic data corresponded to
9
.
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1
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5
‑(9H‑pyrido[3,4‑b]indol‑1‑yl)nicotinonitrile (6) To a solu-
tion of amide 5 (0.037 mmol, 10 mg) in CHCl :EtOH (1:1,
3
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2
1
mL) at room temperature, we added DDQ (0.074 mmol,
6.7 mg). The mixture was stirred for 12 h and concen-
trated and puriꢀed by column chromatography on ODS.
Elution with MeOH/H O (6:4, v/v) gave 6 (6 mg, 60%) as
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2
−
1 1
a red amorphous solid; IR (Zn–Se) ν
2361 cm ; H-
max
NMR (CDCl ) δ 9.50 (d, 1H, J = 2.4 Hz), 8.97 (d, 1H,
3
J = 2.0 Hz), 8.81 (brs, 1H), 8.67 (t, 1H, J = 2.0 Hz), 8.62
13. Nugroho AE, Moue M, Sasaki T, Shirota O, Hadi AHA, Morita
H (2018) Yohimbine-related alkaloids from Tabernaemontana
corymbosa. Nat Prod Commun 13:347–350
(
d, 1H, J = 5.2 Hz), 8.19 (d, 1H, J= 8.0 Hz), 8.05 (d, 1H,
J=5.2 Hz), 7.61 (ddd, 1H, J=8.4, 7.2, 1.2 Hz), 7.58 (brd,
1
1
4. Nugroho AE, Hashimoto A, Wong CP, Yokoe H, Tsubuki M,
Kaneda T, Hadi AHA, Morita H (2018) Ceramicines M-P from
Chisocheton ceramicus: isolation and structure-activity relation-
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1
3
1
H, J = 8.0 Hz), 7.37 (ddd, 1H, J = 8.0, 6.8, 1.2 Hz); C-
NMR (CDCl ) δ 153.8, 152.3, 144.2, 141.3, 136.8, 135.3,
3
1
1
33.9, 133.0, 131.5, 129.8, 123.3, 122.2, 121.9, 117.2,
5. Nugroho AE, Inoue D, Wong CP, Hirasawa Y, Kaneda T, Shi-
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14.1, 113.5, 111.8; HRESIMS m/z 271.0948 [calcd. for
+
C H N (M+H) , 271.0984].
1
7
11
4
1
‑(pyridin‑3‑yl)‑9H‑pyrido[3,4‑b]indole (2) (Taberniacin
16. Kaneda T, Matsumoto M, Sotozono Y, Nugroho AE, Hirasawa
Y, Hadi AHA, Morita H (2019) Cycloartane-triterpenoid, (23R,
B) Nitrile 6 (0.019 mmol, 5 mg) was converted to 2 (3.7 mg,
2
4E)-23-acetoxy-mangiferonic acid inhibited proliferation and
6
9%) as a white powder using the same procedure as taber-
migration in B16-F10 melanoma via MITF downregulation
caused by inhibition of both β-catenin and c-Raf-MEK1-ERK
signaling axis. J Nat Med 73:47–58
niacin A (1). All spectroscopic data corresponded to those
of natural product 2.
1
1
1
7. Kaneda T, Nakajima Y, Koshikawa S, Nugroho AE, Morita H
(
2019) Cyclolinopeptide F, a cyclic peptide from ꢂaxseed inhib-
ited RANKL-induced osteoclastogenesis via downergulation of
RANK expression. J Nat Med. https://doi.org/10.1007/s1141
Acknowledgements This work was supported by Grants in-Aid for
Scientiꢀc Research from JSPS, Japan.
8
-019-01292-w
8. Prema, Wong CP, Awouafack MD, Nugroho AE, Win YY, Win
NN, Ngwe H, Morita H, Morita H (2019) Two new quassinoids
and other constituents from the Picrasma javanica wood and
their biological activities. J Nat Med. https://doi.org/10.1007/
s11418-018-01279-z
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