New 3,4-seco-diterpene and coumarin derivative from the leaves of Trigonostemon flavidus Gagnep

Article abstract of DOI:10.1080/14786419.2020.1851225

Two new compounds named trigoflavidus A (1) and trigoflavidus B (2), and eight known compounds, trigoflavidone (3), heterophypene (4), howpene C (5), 3,4-seco-sonderianol (6), trigonochinene C (7), fraxidin (8), isofraxidin (9), and isofraxetin (10) were isolated from the leaves of Trigonostemon flavidus Gagnep. by various chromatographic methods. Their chemical structures were elucidated via UV, IR, HR-ESI-MS and NMR spectroscopic methods and divided into two groups including six 3,4-seco-diterpenes (1, 3-7) and four coumarins (2, 8-10). Absolute configurations at stereocenters of compound 1 were confirmed by comparison of its CD spectra with those of the TD-DFT calculations. At a concentration of 30 μM, compounds 1–10 exhibited weak cytotoxic activity toward LU1, HepG2, MCF7, and SKMel2 human cell lines (cell viability all over 50%).

Full text of DOI:10.1080/14786419.2020.1851225

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
New 3,4-seco-diterpene and coumarin derivative
from the leaves of Trigonostemon flavidus Gagnep
Ninh Khac Ban , Tran My Linh , Nguyen Chi Mai , Bui Huu Tai , Nguyen Xuan
Nhiem , Nguyen Huy Hoang & Phan Van Kiem
To cite this article: Ninh Khac Ban , Tran My Linh , Nguyen Chi Mai , Bui Huu Tai , Nguyen Xuan
Nhiem , Nguyen Huy Hoang & Phan Van Kiem (2020): New 3,4-seco-diterpene and coumarin
derivative from the leaves of Trigonostemonꢀflavidus Gagnep, Natural Product Research, DOI:
10.1080/14786419.2020.1851225
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1851225
New 3,4-seco-diterpene and coumarin derivative from the
leaves of Trigonostemon flavidus Gagnep
Ninh Khac Bana,b, Tran My Linha, Nguyen Chi Maia, Bui Huu Taia,b
,
Nguyen Xuan Nhiema,b, Nguyen Huy Hoanga and Phan Van Kiema,b
aInstitute of Marine Biochemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Viet
b
Nam; Graduate University of Science and Technology, Vietnam Academy of Science and Technology
(VAST), Hanoi, Viet Nam
ABSTRACT
ARTICLE HISTORY
Received 15 September 2020
Accepted 9 November 2020
Two new compounds named trigoflavidus A (1) and trigoflavidus
B (2), and eight known compounds, trigoflavidone (3), heterophy-
pene (4), howpene C (5), 3,4-seco-sonderianol (6), trigonochinene
C (7), fraxidin (8), isofraxidin (9), and isofraxetin (10) were isolated
from the leaves of Trigonostemon flavidus Gagnep. by various
chromatographic methods. Their chemical structures were eluci-
dated via UV, IR, HR-ESI-MS and NMR spectroscopic methods and
divided into two groups including six 3,4-seco-diterpenes (1, 3-7)
and four coumarins (2, 8-10). Absolute configurations at stereo-
centers of compound 1 were confirmed by comparison of its CD
spectra with those of the TD-DFT calculations. At a concentration
of 30 mM, compounds 1–10 exhibited weak cytotoxic activity
toward LU1, HepG2, MCF7, and SKMel2 human cell lines (cell via-
bility all over 50%).
KEYWORDS
Trigonostemon flavidus;
trigoflavidus A; trigoflavidus
B; secoditerpene; coumarin;
cytotoxicity
CONTACT Phan Van Kiem
phankiem@yahoo.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1851225.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
N. K. BAN ET AL.
1. Introduction
The genus Trigonostemon Blume consists approximately 85 species in the family
Euphorbiaceae, which are mainly distributed in tropical and subtropical regions of the
Asia with 22 species being endemic to Vietnam (Chen et al. 2011; Tagane et al. 2017).
Terpenoids, especially diterpenoids, triterpenoids, alkaloids, steroids, flavonoids,
lignans, coumarins, and phenolics have been reported from this genus and regarded
as the major constituents, displaying diverse biological effects such as insecticidal,
antifeedant, antimicrobial, cytotoxic, antitumor, and anti-HIV-1 activities (Chen et al.
2011; Xu and Yue 2014; Xi et al. 2019; Ban et al. 2020). Previous phytochemical investi-
gation on Trigonostemon flavidus Gagnep. (known as Trigonostemon heterophyllus
Merrill) (Li and Gilbert 2008) growing in China resulted in the isolation of diterpenoids
(Dong et al. 2011; Tang, He, et al. 2012; Tang, Zhang, et al. 2012). However, up to
now, there has not been any research on the chemical constituents as well as bio-
logical activity of this plant growing in Vietnam. As a part of our ongoing research on
genus Trigonostemon (Ban et al. 2020), this paper reports the isolation, structural eluci-
dation of six diterpenes and four coumarins including two new ones isolated from the
methanol extract of the T. flavidus leaves and their cytotoxic activity toward some can-
cer cell lines.
2. Results and discussion
Compound 1 was obtained as colorless amorphous powder. Its molecular formula was
established as C21H28O3 by the HR-ESI-MS quasi-molecular ion peaks at m/z 351.1940
[M þ Na]þ (Calcd. for [C21H28O3Na]þ, 351.1931), m/z 329.2119 [M þ H]þ (Calcd. for
[C21H29O3]þ, 329.2111) indicating 8 degrees of unsaturation. The infrared (IR) spectrum
of 1 exhibited the presence of carbonyl (1714 cmꢀ1) and C-O-C (1076 cmꢀ1) groups in
the molecule. The proton nuclear magnetic resonance spectroscopy (1H NMR) of 1
indicated signals corresponding to three singlet methyl groups at dH 1.05, 1.76, and
1.79 (each 3H, s), one methoxy group at dH 3.65 (3H, s), one olefinic proton at dH 5.19
(1H, broad singlet). The 13C NMR spectrum of compound 1 contained signals corre-
sponding to 21 carbon atoms. Of these, signals at dC 209.8 and 174.0 indicated the
presence of a ketone and a carboxylate group, respectively. Three double bonds were
identified by six olefinic carbon signals at dC 114.3 (CH2), 119.9 (CH), 139.5 (C), 141.2
(C), 145.8 (C ꢁ 2), three methyl groups were at dC 23.0, 24.1, and 24.5, and a methoxy
1
group was at dC 51.6. In the H-1H COSY spectrum of 1, cross peaks between protons
H-1 (dH 1.72, 1.88) and H-2 (dH 1.87, 2.25), H-6 (dH 1.70, 1.82) and H-5 (dH 2.19)/H-7 (dH
2.14, 2.31), and between H-13 (dH 5.19) and H-12 (dH 2.47, 2.63) were observed indicat-
ing the fragments of its molecule. The above evidence suggested that compound 1
was a methoxylated diterpene (Tang, He, et al. 2012; Tang, Zhang, et al. 2012). A
comparison of the NMR data of compound 1 with the corresponding data of trigoflavi-
dones A-E, isolated from T. flavidus pointed out that this compound is a 3,4-seco-diter-
penoid (Tang, He, et al. 2012; Tang, Zhang, et al. 2012). However, the NMR data of the
C ring of 1 differed from the corresponding of trigoflavidones A-E. These partial
assignments together with HR-ESI-MS results required five degree of unsaturation, and
therefore the molecule should possess three cyclic patterns. It means that ring C was

NATURAL PRODUCT RESEARCH
3
Figure 1. Chemical structures of compounds 1–10 and 1a.
suggested to become bicyclic patterns as compound 1a, a Norrish type 1 photode-
graded product (Maslovskaya et al. 2011) and suggeted structure of compound 1 was
shown in Figure 1. A detailed structural elucidation of compound 1 was further per-
formed using data from HSQC and HMBC experiments. HMBC correlations from H-20
(dH 1.05) to C-1 (dC 32.1), C-5 (dC 46.1), C-9 (dC 139.5), C-10 (dC 39.8), from H-19 (dC
1.76) to C-4 (dC 145.8), C-5, C-18 (dC 114.3), from H-18 (dC 4.67/4.94) to C-5, and C-19
(dC 23.0), and from methoxy proton at dH 3.65 to C-3 (dC 174.0) confirmed the 3,4-
seco-diterpenoid structure similar to trigoflavidones A-E (Tang, He, et al. 2012; Tang,
Zhang, et al. 2012). The bicyclic structure of 1 was further confirmed by HMBC correla-
tions from H-7 (dH 2.14/2.31) to C-8 (dC 145.8), C-9 (dC 139.5), from H-15 (dH 2.50) to C-
16 (dC 209.8), C-9, C-13 (dC 119.9), C-14 (dH 141.2), C-17 (dC 24.1), from H-17 (dH 1.79)
to C-13, C-14, C-15, and from H-11 (dH 2.74) to C-8, C-13, C15, C-16. As for the stereo-
chemistry, the relative configuration of 1 was determined by NOESY experiment. The
NOEs cross peaks from H3-19 (dH 1.76) to H3-20 (dH 1.05), H-20 to H-11 (dH 2.74) and
Ha-12 (dH 2.47), and from H-17 (dH 1.79) to H-13 (dH 5.19) and H-15 (dH 2.50) indicated
Me-20 a-axially oriented, H-5 b-axially oriented, and H-20, H-11, H-12, H-13, H-15, and
H-17 were on the same side as compound 1a (Maslovskaya et al. 2011). Finally, the
absolute configurations of 1 was determined by ECD spectra. Two enantiomers of 1,
(5 R,10R,11S,15R) and (5S,10S,11R,15S), were submitted to TD-DFT calculation their ECD
spectra using Gaussian 16 program. Comparison calculated ECD spectra to experimen-
tal ECD spectrum of 1 indicated absolute configurations of 1 to be 5 R,10R,11S,15R
(Figure 3). Consequently, the chemical structure of compound 1 was fully established
(Figure 1). This is a new 3,4-seco-diterpenoid and named as trigoflavidus A.
Compound 2 was obtained as colorless amorphous powder. The HR-ESI-MS analysis
of 2 revealed a quasi-molecular ion peaks at m/z 355.1023 [M þ H]þ (Calcd. for
[C16H19O9]þ, 355.1024), m/z 389.0634 [M þ 35Cl]- (Calcd. for [C16H18O935Cl]-, 389.0645),
and m/z 391.0618 [M þ 37Cl]- (Calcd. for [C16H18O937Cl]-, 391.0681), indicating a
molecular formula of C16H18O9. The IR spectrum of 2 exhibited the presence of
hydroxyl (3401 cmꢀ1), carbonyl (1711 cmꢀ1) and C-O-C (1073 cmꢀ1) groups in the mol-
1
ecule. The H-NMR spectrum of 2 exhibited four olefinic proton signals including two
singlets at dH 7.22 and 7.19, and two doublets at dH 7.92 and 6.32 (J ¼ 9.5 Hz), one

4
N. K. BAN ET AL.
methoxy group at dH (3.92), one anomeric proton at dH 5.40 (d, J ¼ 8.0 Hz), and six
oxygenated methine protons at dH 3.65-4.19. The 13C-NMR spectrum of 2 indicated
the presence of nine carbon atoms at dC 105.1, 110.8, 114.4, 145.7, 148.3, 150.7, and
163.6, assigning for a coumarin molecule, one methoxy group at dC 57.1, and one
sugar at dC 100.3, 76.0, 73.0, 71.9, 68.5, and 62.7. The assignments of protons belong-
ing to carbons were taken by HSQC spectrum. The above data suggested that com-
pound 2 was a coumarin glycoside having a methoxy group. The NMR data of 2 were
similar to the corresponding data of scopolin (7-O-b-D-glucopyranosyl-scopoletin)
(Kuroyanagi et al. 1986) except for the sugar data, suggesting that compound 2 was a
scopoletin glycosyl derivative. For the sugar moiety, a set of carbon chemical shifts of
2 (from C-10 to C-60: dC 100.3, 71.9, 73.0, 68.5, 76.0, 62.7) were found to very similar to
the corresponding data of the allose unit of charantoside A (Nhiem et al. 2010). Detail
1
analysis of the proton and carbon chemical shifts as well as the H-1H coupling con-
stants of the sugar unit of 1 matched perfectly with those of the allose sugar (Nhiem
et al. 2010). Proton appeared at dH 4.19 as a triplet with a small coupling constant
(J ¼ 3.0 Hz) confirming that this proton was in equatorial orientation. In addition,
HMBC correlations from proton at dH 4.19 to C-10 (dC 100.3), C-20 (dC 71.9), C-40 (dC
68.5), C-50 (dC 76.0) were observed indicating that this signal corresponds to the pro-
ton H-30 of the allose unit. The sugar linkage must be in the b-form as judged from
coupling constant (J ¼ 8.0 Hz) of the anomeric proton signal at dH 5.40. The HMBC cor-
relation from H-10 (dH 5.40) to C-7 (dC 152.1) indicated the allose sugar linked to C-7 of
the aglycone. Finally, monosaccharide in the sugar residue was confirmed to be D-allose
by hydrolysis (Nhiem et al. 2010). Consequently, compound 2 was determined to be 7-
O-b-D-allopyranosyl-scopoletin, a new compound and named as trigoflavidus B.
The other compounds isolated from Trigonostemon flavidus Gagnep. were identified
as trigoflavidone (3) (Tang, He, et al. 2012), heterophypene (4) (Xi et al. 2019), how-
pene C (5) (Ma et al. 2017), 3,4-seco-sonderianol (6) (Craveiro and Silveira 1982), trigo-
nochinene C (7) (Yin et al. 2008), fraxidin (8) (Hu et al. 2011), isofraxidin (9)
(Tsukamoto et al. 1985), and isofraxetin (10) (Majnooni et al. 2020) by comparisons of
their NMR data with those data reported in the literature.
Compounds 3-7 were previously isolated from genus Trigonostemon growing in
China, however compounds 8-10 were first reported from this genus and compounds
3-10 were first found from T. flavidus growing in Vietnam.
The cytotoxic effect of compounds 1–10 was evaluated on four human cancer cell
lines including LU1 (lung cancer), HepG2 (liver cancer), MCF7 (breast cancer) and SKMel2
(skin cancer). Each compound was first examined cytotoxic activity at concentration of
30 mM using sulforhodamine B assay (Monks et al. 1991). Because compounds 1–10 exhib-
ited weak cytotoxic activities with cell viability percentages all higher than 50%
(Supplementary data), they were not subjected for further evaluation on cytotoxic study.
3. Experimental
3.1. General
Optical rotation was measured on a Jasco P2000 polarimeter. CD spectrum was
obtained on a Chirascan spectrometer. IR spectra were recorded on a Spectrum Two

NATURAL PRODUCT RESEARCH
5
FT-IR spectrometer. HR-ESI-MS spectra were acquired on an Agilent 6530 Accurate
Mass Q-TOF LC/MS. NMR spectra were recorded on a Bruker 500 MHz spectrometer.
Preparative HPLC were run on an Agilent 1100 system including quaternary pump,
autosampler, DAD detector, and preparative HPLC column YMC J’sphere ODS-H80
(4 mm, 20 ꢁ 250 mm). Isocratic mobile phase with the flow rate of 3 mL/min was used
in pre-HPLC. The compounds were monitored at wavelengths of 205, 230, 254 and
280 nm. Flash column chromatography was performed using silica gel, reversed phase
C-18, and diainon HP-20 resins as the adsorbent. Thin layer chromatography was car-
ried out on pre-coated silica gel 60 F254 and RP-18 F254S plates. The spots were
detected by spraying with aqueous solution of H2SO4 5% followed by heating with a
heat gun.
3.2. Plant material
The leaves of Trigonostemon flavidus Gagnep. were collected at Melinh District, Vinh
Phuc Province, Vietnam in September 2019 and taxonomically identified by Dr Do Van
Hai at the Institute of Ecology and Biological Resources, VAST. Voucher specimen
(TNSV-ML-02-NKB) was deposited at the Institute of Marine Biochemistry, VAST.
3.3. Extraction and isolation
Dried powdered leaves of T. flavidus (5 kg) was ultrasonically extract with methanol at
room temperature for three times (each, 10 L of methanol in 2 h). The solvent was
then removed in vacuo to give methanol extract. This extract (250 g) was suspended
in distilled water (3 L) and successively partitioned with n-hexane, dichloromethane,
and ethyl acetate to give four soluble fractions including n-hexane fraction (10 g),
dichloromethane fraction (70 g), ethyl acetate fraction (5 g), and water layer.
Dichloromethane and ethyl acetate fractions were combined and separated on a silica
gel column, eluting with gradient solvent system of n-hexane/acetone (0-100%
acetone) to give four fractions DE1- DE4. Fraction DE1 (16 g) was loaded on a silica gel
column and eluted with n-hexane/ethyl acetate (8/1, v/v) to give five fractions DE1A-
DE1E. Fraction DE1C was firstly chromatographed on a reversed phase C18 (RP18) col-
umn, eluting with acetone/water (4/1, v/v) and then purified by pre-HPLC using ACN
in water (88% in volume) to give compound 5 (27 mg, tR 45.0 min). Fraction DE1D was
separated on a RP18 column, eluting with methanol/water (9/2, v/v) to give five frac-
tions DE1D1- DE1D5. Fraction DE1D2 was purified by pre-HPLC using ACN in water
(75% in volume) to give compound 7 (6.5 mg, tR 35.4 min). Fraction DE1D5 was puri-
fied by pre-HPLC using ACN in water (80% in volume) to give compound 1 (7.5 mg, tR
62.2 min). Fraction DE1C was purified on a RP18 column, eluting with methanol/water
(9/2, v/v) to obtain compounds 3 (27 mg), 4 (51 mg), and 6 (38 mg). Fraction DE3 (9 g)
was separated on a silica gel column, eluting with dichloromethane/methanol (40/1, v/
v) to give five fractions DE3A-DE3E. Fraction DE3A was continuously chromatographed
on a RP18 column, eluting with methanol/water (2/1, v/v) to give four fractions
DE3A1-DE3A4. Fraction DE3A1 was purified by pre-HPLC using ACN in water (25% in
volume) to give compound 9 (12 mg, tR 43.2 min). Fraction DE3A3 was purified by

6
N. K. BAN ET AL.
pre-HPLC using ACN in water (45% in volume) to give compound 10 (12 mg, tR
33.6 min). Fraction DE3C was first separated on a RP18 column, eluting with methanol/
water (1/1, v/v) and then purified by pre-HPLC using ACN in water (35% in volume) to
give compound 8 (6 mg, tR 46.5 min). Water layer was poured on a diaion (HP-20) col-
umn, washed with water, and then eluted with methanol/water (1/1 and 1/0, v/v, step
wise) to give two fractions W1 and W2. Fraction W1 was first chromatographed on a
RP18 column, eluting with methanol/water (2/3, v/v) and then purified by pre-HPLC
using ACN in water (18% in volume) to give compound 2 (7 mg, tR 31.4 min).
25
3.3.1. Trigoflavidus A (1): Colorless amorphous powder, ½aꢂD : ꢀ 37.8ꢃ (c 0.1, MeOH);
UV (MeOH) kmax 235 nm; IR (KBr): ꢀmax 2,92,71,71,41,076 cmꢀ1; HR-ESI-MS m/z 351.1940
[M þ Na]þ (Calcd. for [C21H28O3Na]þ, 351.1931), m/z 329.2119 [M þ H]þ (Calcd. for
[C21H29O3]þ, 329.2111). CD (MeOD) mdeg(k): ꢀ14.8(221), ꢀ15.2(290)
;
1H-NMR (CDCl3,
500 MHz), d (ppm): 1.72 (1H, m, Ha-1), 1.88 (1H, m, Hb-1), 1.87 (1H, m, Ha-2), 2.25 (1H,
m, Hb-2), 2.19 (1H, dd, J ¼ 12.0, 3.0 Hz, H-5), 1.70 (1H, m, Ha-6), 1.82 (1H, m, Hb-6), 2.14
(1H, m, Ha-7), 2.31 (1H, m, Hb-7), 2.47 (1H, d, J ¼ 5.0 Hz, H-11), 2.47 (1H, m, Ha-12), 2.63
(1H, m, Hb-12), 5.19 (1H, brs, H-13), 2.50 (1H, s, H-15), 1.79 (3H, s, H-17), 4.67 (1H, s, Ha-
18), 4.94 (1H, s, Hb-18), 1.76 (3H, s, H-19), 1.05 (3H, s, H-20), 3.65 (3H, s, OCH3).
13C-NMR (CDCl3, 125 MHz), d (ppm): 32.1 (C-1), 29.2 (C-2), 174.0 (C-3), 145.8 (C-4), 46.1
(C-5), 24.7 (C-6), 25.5 (C-7), 145.8 (C-8), 139.5 (C-9), 39.8 (C-10), 47.1 (C-11), 32.7 (C-12),
119.9 (C-13), 141.2 (C-14), 55.8 (C-15), 209.8 (C-16), 24.1 (C-17), 114.3 (C-18), 23.0 (C-
19), 24.5 (C-20), 51.6 (OCH3).
3.3.2. Trigoflavidus B (2)
25
Colorless amorphous powder, ½aꢂD : þ 58.2ꢃ (c 0.1, MeOH); UV (MeOH) kmax
2,04,235 nm; IR (KBr): ꢀmax 3,40,12,93,41,71,11,070 cmꢀ1; HR-ESI-MS m/z 355.1023
[M þ H]þ (Calcd. for [C16H19O9]þ, 355.1024), m/z 389.0634 [Mþ Cl]- (Calcd. for
35
[C16H18O935Cl]-, 389.0645), m/z 391.0618 [Mþ Cl]- (Calcd. for [C16H18O937Cl]-,
37
1
391.0681). H-NMR (CD3OD, 500 MHz), d (ppm): 6.32 (1H, d, J ¼ 9.5 Hz, H-3), 7.92 (1H, d,
J ¼ 9.5 Hz, H-4), 7.22, (1H, s, H-5), 7.19 (1H, s, H-8), 3.92 (3H, s, OCH3), All: 5.40 (1H, d,
J ¼ 8.0 Hz, H-10), 3.71 (1H, dd, J ¼ 8.0, 3.0 Hz, H-20), 4.19 (1H, dd, J ¼ 3.0, 3.0 Hz, H-30),
3.65 (1H, dd, J ¼ 9.0, 3.0 Hz, H-40), 3.93 (1H, m, H-50), 3.70 (1H, dd, J ¼ 12.0, 5.0 Hz, Ha-
60), 3.91 (1H, dd, J ¼ 12.0, 2.5 Hz, Hb-60). 13C-NMR (CD3OD, 125 MHz), d (ppm): 163.6 (C-
2), 114.4 (C-3), 145.7 (C-4), 110.8 (C-5), 148.3 (C-6), 152.1 (C-7), 105.1 (C-8), 150.7 (C-9),
114.5 (C-10), 57.1 (OCH3), All: 100.3 (C-10), 71.9 C-20), 73.0 (C-30), 68.5 (C-40), 76.0 (C-50),
62.7 (C-60).
4. Conclusions
Six 3,4-seco-diterpenes and four coumarin derivatives were isolated from the leaves of
T. flavidus. Among them one 3,4-seco-diterpene, trigoflavidus A (1), and one coumarin
derivative, trigoflavidus B (2), are previously undescribed. Their chemical structures
were identified by extensive analysis of HR-ESI-MS and NMR spectral data.
Additionally, absolute configuration of compound 1 was determined by comparison
its experimental ECD spectrum with those of TD-DFT calculations ECD spectra.
Compounds 1-10 showed weak cytotoxic effect on LU1, HepG2, MCF7, and SKMel2

NATURAL PRODUCT RESEARCH
7
human cell lines. At concentration of 30 mM, cell viability percentages were all higher
than 50% in the presence of compounds 1-10.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This research is funded by Vietnam National Foundation for Science and Technology
Development (NAFOSTED) under grant number 104.01-2018.300. The authors would like to
thank Dr Do Van Hai at the Institute of Ecology and Biological Resources, VAST, for identification
the scientific name of the plant.
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