A new cardenolide glycoside from the roots of Streptocaulon juventas (lour.) merr. (Asclepiadaceae)

Article abstract of DOI:10.1080/14786419.2019.1641806

From remaining aqueous fraction of the roots of Streptocaulon juventas, one new cardiac glycoside named periplogenin 3-O-β-gentiobioside (1) together with six known ones (2–7) were isolated. Their relative structures were elucidated based on NMR spectroscopic analysis. Compound 1 showed moderate cytotoxicity against non-small cell lung carcinoma NCI-H460 and ovarian cancer HeLa cells. Moreover, compounds 2 and 3 exhibited remarkable cytotoxicity against NCI-H460 cell with the IC₅₀ values of 0.34 and 0.068 μM, respectively.

Full text of DOI:10.1080/14786419.2019.1641806

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
A new cardenolide glycoside from the
roots of Streptocaulon juventas (lour.) merr.
(Asclepiadaceae)
Xuan-Hao Bui, Phu Hoang Dang, Tuan Trong Vo, Nhi Y Thi Nguyen, Minh-Duc
Nguyen & Quan Le Tran
To cite this article: Xuan-Hao Bui, Phu Hoang Dang, Tuan Trong Vo, Nhi Y Thi Nguyen,
Minh-Duc Nguyen & Quan Le Tran (2019): A new cardenolide glycoside from the roots of
Streptocaulonꢀjuventas (lour.) merr. (Asclepiadaceae), Natural Product Research, DOI:
10.1080/14786419.2019.1641806
To link to this article: https://doi.org/10.1080/14786419.2019.1641806
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1641806
SHORT COMMUNICATION
A new cardenolide glycoside from the roots of
Streptocaulon juventas (lour.) merr. (Asclepiadaceae)
Xuan-Hao Buia, Phu Hoang Dangb , Tuan Trong Voc, Nhi Y Thi Nguyenb,
Minh-Duc Nguyend and Quan Le Tranb
b
aFaculty of Chemistry, Ho Chi Minh City University of Pedagogy, Ho Chi Minh City, Vietnam; Faculty
c
of Chemistry, VNUHCM–University of Science, Ho Chi Minh City, Vietnam; Faculty of Traditional
d
Medicine, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam; Faculty of Pharmacy,
Ton Duc Thang University, Ho Chi Minh City, Vietnam
ABSTRACT
ARTICLE HISTORY
Received 16 March 2019
Accepted 30 June 2019
From remaining aqueous fraction of the roots of Streptocaulon
juventas, one new cardiac glycoside named periplogenin 3-O-
b-gentiobioside (1) together with six known ones (2–7) were iso-
lated. Their relative structures were elucidated based on NMR
spectroscopic analysis. Compound 1 showed moderate cytotox-
icity against non-small cell lung carcinoma NCI-H460 and ovarian
cancer HeLa cells. Moreover, compounds 2 and 3 exhibited
remarkable cytotoxicity against NCI-H460 cell with the IC50 values
of 0.34 and 0.068lM, respectively.
KEYWORDS
Streptocaulon juventas;
Asclepiadaceae; cardiac
diglycoside; cytotoxicity
1. Introduction
Streptocaulon juventas (Lour.) Merr. (Asclepiadaceae) is mainly found in Indochina. In
Vietnam, S. juventas is called “Ha thu o trang”, and its roots are used as a tonic for
various conditions such as anemia, chronic malaria, rheumatism, menstrual disorders,
neurasthenia, and dyspepsia (Vo 1999). The phytochemical investigation of S. juventas
has led to the isolation of various cardenolides, hemiterpenes, and phenylpropanoids
(Ueda et al. 2003a). Cardenolides are the active components of S. juventas, that have
CONTACT Xuan-Hao Bui
buixuanhao@yahoo.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1641806.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
X.-H. BUI ET AL.
Figure 1. Structure of compounds 1–7
long been used as cardiotonic drugs (Morsy 2017). Additionally, cardenolides induce
apoptosis in human tumor cells with no significant toxicity on normal cells (Ueda
et al. 2003b, Xue et al. 2015).
Cardiac glycosides from S. juventas showed potent cytotoxicity against human lung
A549 adenocarcinoma and non-small lung cancer NCI-H460 cells (Xue et al. 2014).
Therefore, further investigation on the remaining aqueous extract of S. juventas was
carried out, that resulted in the isolation of a new cardiac glycoside, periplogenin 3-O-
b-gentiobioside (1), along with six known ones (2–7). Details regarding the isolation,
structural elucidation, and cytotoxicity of 1–7 are reported herein.
2. Results and discussion
The powdered roots of S. juventas were heated at reflux in MeOH. The MeOH-soluble
extract was successively partitioned to yield CHCl3-soluble and remaining aqueous
fractions. Further separation and purification of the remaining aqueous fraction led to
the isolation of seven compounds: periplogenin 3-O-b-gentiobioside (1), periplogenin
(2) (Ueda et al. 2003a), periplogenin 3-O-b-D-glucopyranoside (3) (Kawaguchi et al.
1988), corchorusoside C (4) (Nakamura et al. 1998), periplocin (5) (Sakuma et al. 1971),
periplogenin 3-O-[O-b-D-glucopyranosyl-(1➔ 4)-O-b-D-digitalopyranoside] (6) (Ueda
et al. 2003a), and periplogenin 3-O-[O-b-D-glucopyranosyl-(1➔ 4)-2-O-acetyl-b-D-digi-
talopyranoside] (7) (Myint Khine et al. 2004) (Figure 1).
Compound 1, periplogenin 3-O-b-gentiobioside, showed a quasi-molecular ion peak
1
at m/z 713.3389 [M ꢀ H]ꢀ (calcd for C35H53O15, 713.3384) in the HRESIMS. The H NMR
spectrum showed the presence of two methyl singlets [dH 0.97 (s, Me-18) and 1.00 (s,

NATURAL PRODUCT RESEARCH
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Table 1. Cytotoxicity of the isolated compounds (at concentration of 100 mg mLꢀ1) against NCI-
H460, HeLa, and MCF-7 cells.
Growth Inhibition (%)
Compounds
NCI-H460
HeLa
MCF-7
1
2
3
4
5
6
71.87 2.31
89.66 0.50
89.25 0.30
87.33 2.45
87.54 1.02
87.99 1.85
77.90 2.30a
60.16 0.48
73.75 3.70
84.02 2.10
69.54 5.52
80.60 1.58
73.69 4.41
49.57 1.25b
47.72 5.77
69.56 2.60
72.86 7.40
83.88 3.15
74.60 5.70
80.83 3.53
47.00 1.86a
Camptothecin
aat concentration of 0.01 mg mLꢀ1
.
bat concentration of 1 mg mLꢀ1
.
Me-19)], an a,b-unsaturated-c-lactone moiety [dH 6.12 (brs, H-22), 5.03 (d, J ¼ 18.0 Hz,
H-21a), 5.28 (d, J ¼ 18.0 Hz, H-21b)], one oxymethine proton [dH 4.52 (m, H-3)], and one
methine proton [dH 2.80 (dd, J ¼ 8.5 and 5.0 Hz, H-17)]. Additionally, two anomeric pro-
tons [dH 4.92 (d, J ¼ 7.5 Hz, H-10) and 5.02 (d, J ¼ 8.0 Hz, H-100)] and two oxymethylene
groups [dH 4.79 (d, J ¼ 11.0 Hz, H-60a), 4.25 (m, H-60b), 4.45 (d, J ¼ 10.5 Hz, H-600a), 4.27
(m, H-600b)] were indicated the presence of two b-glucopyranose moieties. The 13C and
DEPT NMR spectra showed resonances for one ester carbonyl carbon (dC 174.6), one
pair of olefinic carbons (dC 176.0, 117.6), two acetal carbons (dC 101.6, 105.3), three
oxymethylene carbons (dC 73.8, 70.2, 62.8), nine oxymethine carbons (dC 78.6, 2 ꢁ 78.4,
77.4, 75.2, 75.0, 74.4, 2 ꢁ 71.7), two oxygenated tertiary carbons (dC 84.7, 73.2), three
methine carbons (dC 51.3, 40.9, 39.2), nine methylene carbons (dC 40.0, 36.2, 34.1, 33.2,
27.3, 26.6, 26.1, 24.5, 22.0), two quaternary carbons (dC 50.0, 41.2), and two methyl car-
bons (dC 17.2, 16.1) (Table S1). These signals were consistent with those reported for a
periplogenin diglycoside comprising a 17b-lactone unit (Gil et al. 1995) and two b-glu-
1
copyranose moieties (Agrawal 1992). Based on the paired J coupling responses in the
0
0
00
00
HMBC spectrum (Figure S7), the measured JC-1 /H-1 and JC-1 /H-1 values of 157.6 and
157.4 Hz, respectively, were consistent with the anomeric axial bond of b-gentiobiose
octaacetate (JC/H ¼ 162.0 Hz in CDCl3) (Tvaroska and Taravel 1995), which is a disac-
charide composed of two units of D-glucose joined with a b(1➔6) linkage (Reynolds
and Evans 1938). The D-configurations of two glucosyl moieties were attempted to
define based on the acid-catalyzed hydrolysis and the specific rotations of resulting
sugars (Xue et al. 2013). Due to the small isolated amount of 1, few resulting sugars
were obtained to measure the optical rotations. On the other hand, compound 1
25
showed ½aꢂD value of ꢀ36.2 (c 0.05, MeOH), in comparison with those of digitoxigenin
25
3-O-b-D- and 3-O-b-L-glucopyranosides (½aꢂD ; ꢀ6.30 and þ16.33 (c 0.3, MeOH),
respectively) (Rathore et al. 1985), to deduce the D-configuration of two glucose moi-
1
eties. The steroidal tetracyclic skeleton was verified by using the H–1H COSY correla-
tions between H-1/H-2/H-3/H-4, H-6/H-7/H-8/H-9/H-11/H-12, H-15/H-16/H-17 and
HMBC correlations between Me-18/C-12/C-14/C-17, Me-19/C-1/C-5/C-9 (Figure S1). The
a,b-unsaturated-c-lactone ring at C-17 was indicated based on HMBC correlations
between H-17/C-20/C-21. The 10,3- and 100,60-glycosidic linkages were indicated based
on the HMBC correlations between H-10/C-3, H-100/C-60, and H-60/C-100. The 13C NMR
chemical shift of Me-19 (dC 17.2) in 1 closely resembled with those of periplogenin
(5b-OH cardenolide) glycosides (Robien et al. 1987). In 5a-cardenolides, C-9 has its

4
X.-H. BUI ET AL.
signal at dC 45.2–53.9 ppm (Robien et al. 1987) whereas in 1 at upfield region dC 39.
2 ppm; therefore the cis A/B ring fusion for 1 was established. It was confirmed based
on the NOESY correlations between H-1/Me-19 and H-2/H-9. The NOESY correlations
between Me-19/H-8/Me-18 indicated the relative configuration of rings B/C and C/D
were trans- and cis-fused, respectively (Figure S1). Based on the 13C NMR chemical
shift of C-4 (dC 36.9 in periplogenin and dC 41.3 in 3-epi-periplogenin) (Peter and Max
1980), it was supported the presence of C-3 b-substituted of 1 (dC-4 36.9 in 1).
Moreover, the presence of two b-D-glucopyranose moieties was affirmed based on the
NOESY spectrum. Thus, the relative structure of periplogenin 3-O-b-gentiobioside (1)
was assigned as shown.
All isolated compounds, except for 7 due to the meager amount isolated, were
tested for their cytotoxicity against non-small cell lung carcinoma NCI-H460, ovarian
cancer HeLa, and breast cancer MCF-7 cells (Table 1). These compounds at a concen-
tration of 100 lg mLꢀ1 showed more than 70% cytotoxicity against NCI-H460 cell line.
At the same concentration, all isolated compounds produced more than 60% and 45%
cytotoxic effect against HeLa and MCF-7 cells, respectively. In this regard, compound 1
showed moderate cytotoxicity (71.87% and 60.16% growth inhibition) against NCI-
H460 and HeLa cells, respectively. Compounds 2 and 3 exhibited remarkable cytotox-
icity (approx. 90% growth inhibition) against NCI-H460 non-small cell lung cancer cells.
Thus, their cytotoxicities at various concentrations were evaluated to obtain the IC50
values of 0.34 and 0.068 lM, respectively. Camptothecin was used as a positive control,
with an IC50 value of 0.0086 lM.
3. Experimental
3.1. General experimental procedures
€
€
Optical rotations were measured on an A. Kruss Optronic polarimeter P3000 (Kruss
Optronic GmbH, Hamburg, Germany). Optical density values were determined with a
96-well microtiter plate reader (Synergy HT, Biotek Instruments). The IR spectra were
measured with a Shimadzu IR-408 infrared spectrometer (Shimadzu Pte., Ltd.). The
NMR spectra were recorded on a Bruker Avance III 500 spectrometer (Bruker BioSpin
AG, Bangkok) with pyridine-d5 as a solvent, and the chemical shifts are expressed as d
values. HRESIMS data were acquired on Bruker micrOTOF QII (Bruker Singapore Pte.,
Ltd.) mass spectrometer. Column chromatography was carried out using silica gel 60,
R
V
0.06–0.2 mm (Scharlau, Barcelona) and LiChroprep RP-18, 40 ꢀ 63 mm (Merck KGaA,
Darmstadt). Analytical and preparative TLCs were carried out on precoated Kieselgel
60 F254 or RP18 plates (Merck KGaA, Darmstadt).
3.2. Plant material
The roots of Streptocaulon juventas (Lour.) Merr. was collected at An Phu Commune,
Tinh Bien District, An Giang Province, Vietnam, in October 2007 and was identified by
MSc. Viet Hoang, Department of Ecology and Evolutionary Biology, Faculty of Biology
and Biotechnology, VNUHCM–University of Science. A voucher specimen (DOC2007-

NATURAL PRODUCT RESEARCH
5
HTOT) has been deposited at the Department of Organic Chemistry, Faculty of
Chemistry, VNUHCM–University of Science.
3.3. Extraction and isolation
The powdered roots of S. juventas (8 kg) were refluxed with MeOH (30 L, 3 h ꢁ 3) to
obtain the MeOH-soluble extract (850 g). This extract was suspended in H2O and suc-
cessively partitioned with CHCl3 (2.5 L) to give the CHCl3-soluble (191 g) and remaining
aqueous (about 720 g, not dry completely) fractions. The aqueous fraction was sub-
jected to a Diaion HP-20 column chromatography and eluted with H2O–MeOH (v/v,
100:0, 75:25, 50:50, 25:75, 0:100) mixtures, to obtain 5 fractions (Fr.1 ꢀ 5). Fraction Fr.3
(29.6 g) was separated over a silica gel column with H2O–MeOH–CHCl3 (v/v, 0.1:1:9 ➔
1:4:6) mixtures, to give 5 subfractions (Fr.3.1 ꢀ 3.5). Subfraction Fr.3.3 (9.9 g) was chro-
matographed over a silica gel column with H2O–MeOH–CHCl3 (v/v, 0.2:2:8 ➔ 1:5:10)
mixtures and purified by RP-18 silica gel with H2O–MeOH–MeCN (4:1:1), to afford 4
(5.5 mg) and 5 (6.5 mg). Subfraction Fr.3.4 (1.1 g) was passed over a silica gel column
eluted with H2O–MeOH–CHCl3 (v/v, 0.2:2:8 ➔ 1:5:10) mixtures and purified by pre-
parative RP-18 TLC with H2O–MeCN (2:1), to afford 1 (3.8 mg). Fraction Fr.4 (44.6 g)
was loaded onto a silica gel column and eluted with H2O–MeOH–CHCl3 (v/v, 0.2:2:8
➔ 1:6:14) mixtures, to yield 5 subfractions (Fr.4.1 ꢀ 4.5). Subfraction Fr.4.1 (10.3 g) was
subjected to silica gel column chromatography eluted with H2O–MeOH–CHCl3 (v/v,
0.1:1:9 ➔ 0.2:2:8) mixtures and further separated by RP-18 silica gel with H2O–MeCN
(3:2), to afford 2 (15 mg). Subfraction Fr.4.2 (14.2 g) was chromatographed over a silica
gel column with H2O–MeOH–CHCl3 (v/v, 0.1:1:9 ➔ 1:6:14) mixtures and followed by a
RP-18 silica gel column with H2O–MeOH–MeCN (3:2:1), to obtain 3 (6.5 mg).
Subfractions Fr.4.3 (5.6 g) and Fr.4.4 (1.6 g) were subjected to silica gel column chroma-
tography eluted with (v/v, 0.2:2:8 ➔ 1:5:10) mixtures and further purified by prepara-
tive RP-18 TLC with H2O–MeCN (2:1) and H2O–MeOH–MeCN (4:1:1), to afford 6 (5 mg)
and 7 (2 mg), respectively.
3.3.1. Periplogenin 3-O-b-gentiobioside (1)
25
White amorphous solid; IR (KBr) ꢀmax 3445, 1741, 1623 cmꢀ1; ½aꢂD ꢀ36.2 (c 0.05,
1
MeOH); H (500 MHz, C5D5N) and 13C NMR (125 MHz, C5D5N), see Table S1; HRESIMS
m/z 713.3389 [M ꢀ H]ꢀ (calcd for C35H53O15, 713.3384).
3.4. Acid-Catalyzed hydrolysis of 1
An aliquot (2 mg) of compound 1 in 1 N HCl (1,4-dioxane–H2O, 1:1; 1.5 mL) was heated
at 90 ꢃC for 24 h. The resulting mixture was diluted with 5 mL of water. The aqueous
solution was extracted with EtOAc (3 ꢁ 3 mL), and the aqueous phase was neutralized
with 1 N KOH. After removal of solvent, 0.3 mg of glucose was obtained. TLC identifica-
tion was performed using CHCl3–CH3OH–H2O (60:30:5), in comparison with that of an
authentic sample of glucose. Due to the small amount of resulting sugar, its optical
rotation could not be determined.

6
X.-H. BUI ET AL.
3.5. Cell lines and cell culture
NCI-H460 (HTB-177), MCF-7 (HTB-22), and HeLa (CCL-2) cells were purchased from the
American Type Culture Collection (Manassas, Rockville). Cells were cultured at 37 ꢃC
and 5% CO2 in Eagle’s Minimal Essential Medium (EMEM) supplemented with 10% (v/
v) FBS (Sigma-Aldrich), 2 mM L-glutamine (Sigma-Aldrich), 20 mM HEPES (Sigma-
Aldrich), 0.025 lg mLꢀ1 amphotericin B (Sigma-Aldrich), 100 IU mLꢀ1 penicillin G
(Sigma-Aldrich), and 100 lg mLꢀ1 streptomycin (Sigma-Aldrich).
3.6. Sulforhodamine B (SRB) cytotoxicity assay
The assay was performed as previously described with some modifications (Vistica
et al. 1990). Cells were seeded at a density of 10,000 cells/well (MCF-7, HeLa) or 7,500
cells/well (NCI-H460) in 96-well plates. Cells were cultured for 24 h before being incu-
bated with isolated compounds at different concentrations for 48 h. Treated cells were
fixed with cold 50% (w/v) trichloroacetic acid (Merck KGaA) for 1–3 h, washed, and
stained with 0.2% (w/v) SRB (Sigma-Aldrich) for 20 min. After five washes with 1%
acetic acid (Merck KGaA), the protein-bound dye was solubilized in 10 mM Tris base
solution (Promega). Optical density values were determined at the wavelengths of
492 nm and 620 nm. The percentage of growth inhibition (Inh %) was calculated
according to the formula: Inh % ¼ (1 ꢀ [ODt/ODc] ꢁ 100) %, in which ODt and ODc
are the optical density value of the test sample and the control sample, respectively.
Data were represented as means standard error (n ꢄ 3). The IC50 values was deter-
mined by using Prism software with multivariate nonlinear regression and R2 > 0.9.
Camptothecin (Merck KGaA) was used as a positive control.
4. Conclusions
Chemical investigation of the roots of Streptocaulon juventas, led to the isolation of
seven cardenolide glycosides (1–7), including a new compound, periplogenin 3-O-
b-gentiobioside (1). Compounds 1–6 showed potent cytotoxicity against non-small cell
lung carcinoma NCI-H460 cell. Moreover, these compounds exhibited moderate
growth inhibition against HeLa and MCF-7 cells. Thus, this promising S. juventas may
be useful as a potential anti-tumor candidate.
Supplementary material
NMR and MS spectra for the new compound 1.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Phu Hoang Dang
http://orcid.org/0000-0002-4989-9315

NATURAL PRODUCT RESEARCH
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