Three New Terpenoid Indole Alkaloids from Catharanthus roseus

754
Original Papers
Three New Terpenoid Indole Alkaloids
from Catharanthus roseus
Authors Lei Wang 1,2 , Yu Zhang 1 , Hong-Ping He 1 , Qiang Zhang 1 , Shi-Fei Li 1,2 , Xiao-Jiang Hao 1
Affiliations
Key words
l " Catharanthus roseus (L.)
G. Don
l " Apocynaceae
l " terpenoid indole alkaloids
l " vidolicine
l " normacusine B N‑oxide
l " lochnerine N‑oxide
l " cytotoxic activity
received Sept. 15, 2010
revised October 21, 2010
accepted October 26, 2010
Bibliography
DOI http://dx.doi.org/
10.1055/s-0030-1250569
Published online November 23,
2010
Planta Med 2011; 77: 754–758
© Georg Thieme Verlag KG
Stuttgart · New York ·
ISSN 0032‑0943
Correspondence
Prof. Xiao-Jiang Hao
State Key Laboratory
of Phytochemistry and
Plant Resources in West China
Kunming Institute of Botany,
the Chinese Academy
of Sciences
Kunming 650204
Peopleʼs Republic of China
Phone: + 86 8715 2232 63
Fax: +868715223070
haoxj@mail.kib.ac.cn
1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany,
The Chinese Academy of Sciences, Kunming, P.R. China
2 Graduate School of Chinese Academy of Sciences, Beijing, P.R. China
Abstract
!
Three new terpenoid indole alkaloids, vidolicine
(1), normacusine B N-oxide (2), and lochnerine
N-oxide (3), together with seven known ones (4–
10), were isolated from whole plants of Catharanthus
roseus. Their structures were elucidated by
spectroscopic methods (NMR, MS, UV, and IR). Cy-
Introduction
!
Catharanthus roseus (L.) G. Don (Apocynaceae) is a
well-known medicinal plant, mainly distributed
in tropical and subtropical regions of China. Terpenoid
indole alkaloids, the main constituents of
this plant, are used to treat diverse cancers in chemotherapy,
as in the case of the remarkable antitumor
alkaloids vincristine and vinblastine [1].
Some other bioactive compounds were also isolated
from this plant, such as ajmalicine (which
exhibited a potent antitumor activity) and serpentine
(which exhibited a potent acetylcholinesterase
inhibitory activity) [2–4]. In our continuing
research for bioactive terpenoid indole alkaloids
from medicinal plants [5–8], three new terpenoid
indole alkaloids (1–3, l " Fig. 1), together with seven
known ones (4–10) were isolated from the
methanol extract of whole plants of C. roseus. This
paper deals with the isolation and structure elucidation
of the new compounds as well as the cytotoxic
activities of compounds 1–10.
Materials and Methods
!
General
Column chromatography: silica gel (200–300
mesh; Qingdao Marine Chemical, Inc.); Sephadex
LH-20 (Amersham Biosciences); reverse-phase C-
18 silica gel (40–63 µm; Merck). UV spectra were
obtained on a Shimadzu UV 2401 PC spectrome-
Wang L et al. Three New Terpenoid … Planta Med 2011; 77: 754–758
totoxic activities of these isolates (1–10) were
evaluated, but only compound 8 was active
against HL-60, SMMC-7721, and A549 cell lines.
Supporting information available online at
http://www.thieme-connect.de/ejournals/toc/
plantamedica
ter (Shimadzu); IR spectra were obtained on a
Bruker Tensor 27 spectrometer (Bruker Optics
Inc.) with KBr pellets; MS were recorded on a VG
Autospec-3000 or API QSTAR PULSAR LC‑Q‑TOF
spectrometer (VG); NMR spectra were recorded
on a Bruker AM-400 (400 MHz/100 MHz) or
DRX-500 (500 MHz/125 MHz) spectrometer
(Bruker BioSpin AG) with chemical shifts in δ relative
to TMS as the internal reference. TLC was
carried out on plates precoated with silica gel
(10–40 µm; Qingdao Marine Chemical, Inc.) with
Dragendorffʼs reagent as the chromogenic agent.
Plant material
Whole plants of C. roseus were collected in April
2009 from Qionghai City, Hainan Province, P. R.
China, and identified by Prof. Xun Gong (Kunming
Institute of Botany, Chinese Academy of Sciences).
A voucher specimen (No. H20090705-1) is preserved
at the State Key Laboratory of Phytochemistry
and Plant Resources in West China, Kunming
Institute of Botany, Chinese Academy of Sciences,
P.R. China.
Extraction and isolation
The air-dried whole plants of C. roseus (28 kg)
were powdered and extracted with methanol
(3 × 100 L) under reflux. The methanol was evaporated
under reduced pressure to a concentrate.
The extract was suspended in water, and acidified
with 2% HCl to pH 3. After being defatted by petroleum
ether, the acid liquor was added on an

ion exchange resin column until the effluent was positive to
Dragendorffʼs reagent. The resin was washed with water until it
was neutral, then basified with 10% aq. NH3 soln. for 4 h, and finally
extracted with AcOEt and MeOH, successively. The AcOEt
fraction was concentrated to afford a residue of crude alkaloids
(300 g).
The AcOEt extract was subjected to silica gel column chromatography
(∅ 10 × 90 cm) eluting with CHCl3/CH3OH (99 : 1 → 1:1) to
give 5 fractions (A–E). Fraction A (42 g) was repeatedly applied to
column chromatography over reverse-phase C-18 silica gel (∅
3.0 × 40, 50 g) with MeOH/H2O from 1:9 to 9:1 (each 2 L), Sephadex
LH-20 (∅ 1.0 × 120 cm, CHCl3/MeOH, 1: 1, 500 mL), and then
silica gel (petroleum ether-Me2CO from 10:1 to 3:1, 2.4 L) to give
compounds 1 (11 mg), 4 (12 mg), 7 (5 mg), 8 (92 mg), and 9
(13 mg). Compounds 2 (7 mg) and 3 (8 mg) were obtained from
fraction B (35 g) by column chromatography (∅ 10 × 150 cm,
CHCl3/CH3OH, 20 : 1, 2 L). Fraction C was also applied to repeated
column chromatography (∅ 3.0 × 40 cm, reverse-phase C-18 silica
gel, 50 g, MeOH/H2O, from 1: 10 to 10 : 1; then ∅ 2.0 × 30 cm,
silica gel, 40 g, CH3Cl/MeOH, 10: 1; ∅ 1.0 × 120 cm, Sephadex
LH-20, MeOH, 300 mL) to yield 5 (300 mg) and 6 (40 mg).
Isolates
Vidolicine (1): white amorphous powder (Me2CO): m.p. 140–
142 °C [α] D 23 : − 8.4 (c 0.16, MeOH); UV (MeOH): λmax (log ε)=326
(4.1), 296 (4.0), 222 (4.2), 204 (4.3); IR (KBr): νmax = 3441, 2924,
2853, 1630, 1115, 600 cm −1 ; 1 H- and 13 C‑NMR data, see l " Table 1;
EI‑MS: m/z = 352 [M] + , 323, 228, 214, 168, 154, 69; HR‑EI‑MS: m/
z = 352.1807 [M] + (calcd. for C21H24 N2O3: 352.1787).
Normacusine B N-oxide (2): white amorphous powder (MeOH):
m.p. 270–271 °C; [α] D 21 : − 1.6 (c 0.10, MeOH); UV (MeOH): λmax
(log ε) = 273 (3.3), 223 (4.0), 203 (3.9); IR (KBr): νmax = 3425,
2924, 2853, 1641, 1452, 1384, 1033, 744, 594 cm −1 ; 1 H- and
13 C‑NMR data, see l " Table 2; ESI‑MS: m/z = 311 [M + H] + ;
HR‑EI‑MS: m/z = 310.1685 [M] + (calcd. for C19H22 N2O2: 310.1681).
Lochnerine N-oxide (3): white amorphous powder (MeOH):
m.p. 233–235 °C; [α] D 23 : + 22.8 (c 0.14, MeOH); UV (MeOH): λmax
(log ε) = 276 (3.8), 224 (4.3), 205 (4.4); IR (KBr): νmax = 3396,
3211, 2938, 1628, 1596, 1482, 1457, 1384, 1327, 1215, 1168,
Table 1 1 H‑NMR (400 MHz) and 13 C‑NMR (100 MHz) data of compound 1.
No. 1 a
δH δC 2 – 166.8 (s)
3 2.95 (1H, d, J = 3.1) 60.9 (d)
5 2.88 (1H, m)
2.52 (1H, m)
50.6 (t)
6 1.91 (1H, m)
1.78 (1H, m)
44.9 (t)
7 – 55.0 (s)
8 – 137.0 (s)
9 7.16 (1H, d, J = 7.6) 121.8 (d)
10 6.86 (1H, ddd, J = 7.6, 7.6, 1.0) 120.6 (d)
11 7.12 (1H, ddd, J = 7.6, 7.6, 1.0) 127.7 (d)
12 6.80 (1H, d, J = 7.6) 109.3 (d)
13 – 143.3 (s)
14 1.89 (1H, m) 38.2 (d)
15 2.99 (1H, s) 61.2 (d)
16 – 95.1 (s)
17 2.61 (1H, d)
2.35 (1H, t, J = 11.9)
21.5 (t)
18 1.00 (3H, t, J = 7.5) 8.7 (q)
19 1.64 (2H, m) 29.5 (t)
20 – 62.0 (s)
21 3.35 (1H, d, J = 12.3)
2.90 (1H, m)
52.9 (t)
COOCH3 3.78 (3H, s) 51.1 (q)
COOCH3 – 168.4 (s)
a δ in ppm and J in Hz
Original Papers
Fig. 1 Chemical structures of compounds 1–10.
1144, 1032, 797, 656, 543 cm −1 ; 1 H- and 13 C‑NMR data, see l " Table
2; ESI‑MS: m/z = 341 [M+H] + ;HR‑EI‑MS: m/z = 340.1788 [M] +
(calcd. for C20H24 N2O3: 340.1787).
Cytotoxicity assay
The cytotoxicity of compounds 1–10 against HL–60, SMMC–
7721, A–549, MCF–7, and SW480 human tumor cell lines was determined
by the MTT method (see details in Supporting Information)
[9]. Briefly, cell lines were plated in 96-well plates (10 000–
Wang L et al. Three New Terpenoid … Planta Med 2011; 77: 754–758
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756
Original Papers
Table 2 1 H‑NMR (500 MHz) and 13 C‑NMR (125 MHz) data of compounds 2–3.
No. 2a 3a δH δC δH δC 2 – 134.6 (s) – 135.3 (s)
3 4.53 (1H, d, 67.7 (d) 4.50 (1H, d, 67.7 (d)
J = 10.1)
J = 10.2)
5 3.19 (1H, t, 70.4 (d) 3.18 (1H, t, 70.4 (d)
J = 6.5)
J = 6.4)
6 3.47 (1H, m) 24.9 (t) 3.44 (1H, m) 25.0 (t)
2.84 (1H, d,
2.88 (1H, d,
J = 15.7)
J = 15.5)
7 – 102.9 (s) – 102.7 (s)
8 – 128.1 (s) – 128.1 (s)
9 7.46 (1H, d, 118.9 (d) 6.97 (1H, d, 101.1 (d)
J = 7.8)
J = 2.0)
10 7.02 (1H, m) 120.3 (d) – 155.4 (s)
11 7.09 (1H, m) 122.6 (d) 6.75 (1H, dd,
J = 2.0, 8.8)
112.6 (d)
12 7.32 (1H, d, 112.2 (d) 7.21 (1H, d, 112.9 (d)
J = 7.8)
J = 8.8)
13 – 138.5 (s) – 133.6 (s)
14 2.50 (1H, t, 34.7 (t) 2.47 (1H, t, 34.7 (t)
J = 12.0)
J = 11.2)
2.07 (1H, ddd,
2.05 (1H, dd,
J = 1.5, 4.0,
13.0)
J = 2.6, 13.0)
15 2.96 (1H, t, 27.7 (d) 2.96 (1H, t, 27.7 (d)
J = 2.5)
J = 1.5)
16 2.17 (1H, dd, 45.9 (d) 2.17 (1H, dd, 45.9 (d)
J = 7.5, 14.5)
J = 7.5, 14.5)
17 4.35 (1H, d, 71.7 (t) 4.34 (1H, d, 71.7 (t)
J = 15.8)
J = 15.7)
3.96 (1H, d,
3.95 (1H, d,
J = 15.7)
J = 15.7)
18 1.68 (3H, d, 13.0 (q) 1.67 (3H, d, 13.0 (q)
J = 6.7)
J = 6.7)
19 5.54 (1H, q, 120.7 (d) 5.54 (1H, q, 120.7 (d)
J = 6.7)
J = 6.73)
20 – 132.2 (s) – 132.2 (s)
CH2OH 3.51 (2H, m) 64.0 (t) 3.65 (2H, m) 64.0 (t)
OCH3 – – 3.81 (3H, s) 56.2 (q)
a δ in ppm and J in Hz
20000 cells/well) 12 h before treatment and continuously exposed
to different concentrations of compounds (0.064, 0.32,
1.6, 8, and 40 µM), and the plates were incubated at 37°C for
48 h. After that, 20 µL test solution of MTT was put into each well,
and the plates were incubated for an additional 4 h. Then, formazan
produced was dissolved by the addition of 100 µL/well of detergent
reagent, Trevogen, followed by a further incubation at
37°C overnight in the dark. The optical density (OD) was measured
at 595 nm using a BioTeck microplate reader against a
blank prepared from cell-free cultures. Cell growth inhibition
curve was graphed using the concentration as the horizontal axis
and the survival rate as the vertical axis. IC50 value of each compound
was calculated by the Reed and Muenchʼs method [10].
Supporting information
A detailed description of the structures as well as physicochemical
and spectral data for compounds 4–10, along with detailed
protocols for in vitro cytotoxicity assay are available as Supporting
Information.
Wang L et al. Three New Terpenoid … Planta Med 2011; 77: 754–758
Results and Discussion
!
Compound 1 was obtained as a white amorphous powder and
was positive to Dragendorffʼs reagent. Its molecular formula was
determined as C21H24N2O3 based on HR‑EI‑MS (m/z = 352.1807
[M] + ), indicating eleven degrees of unsaturation. The UV (222
and 326 nm) and IR (3441 and 1630 cm −1 ) data indicated the
presence of β-anilinoacrylate chromophore [11]. The 1 H‑NMR
spectrum displayed 4 aromatic protons [7.16 (d, J = 7.6), 7.12
(ddd, J = 7.6, 7.6, 1.0), 6.86 (ddd, J = 7.6, 7.6, 1.0), 6.80 (d, J = 7.6)],
together with a broad singlet at δ H = 8.89 ppm, indicating the
presence of an N-1 unsubstituted indole moiety [12]. The proton
signals [δH = 1.00 (3H, t, J = 7.5), 1.64 (2H, m)] indicated the presence
of an ethyl group. The 13 C‑NMR and DEPT spectra showed 21
carbon atoms including one benzene ring, 2 methyl groups, 5
methylene groups, 3 methine groups, 4 quaternary carbons, and
1 carbonyl. These features were similar to those of pandoline [13]
except that the C-15 signal (δ C = 61.2) shifted downfield suggesting
that C-15 was oxygenated. In consideration of its molecular
formula (C21H24 N2O3) and by comparison with the 13 C‑NMR
spectrum of lochnericine (8) [14], C-15 and C-20 should be connected
to an oxygen atom to form an epoxide. The presence of
the key HMBC correlations of H-21 (δ H = 3.35)/C‑19 (δC = 29.5)
and H-18 (δH = 1.00)/C-20 (δC = 62.0) indicated that the ethyl
group was linked to C-20 (l " Fig. 2 A).
By comparison of the NMR data with those of lochnericine (8), H-3
was assigned to be α-oriented, and C-7 was in R*-configuration. In
the ROESY spectrum, the presence of a cross-peak of H-6β/H-15
indicated that H-15 was β-oriented. Because of the high tension
of the three-membered ring, H-15 and the ethyl group should
be cofacial. The cross-peak of H-18/H-14 indicated that the ethyl
group and H-14 should also be cofacial, which showed that H-14
was β-oriented (l " Fig. 2 B). Thus, the structure of compound 1
was determined as shown in l " Fig. 1.
Compound 2, a white amorphous powder, was also positive to
Dragendorffʼs reagent. The HR‑EI‑MS (m/z = 310.1685 [M] + )
showed the molecular formula C19H22 N2O2 with ten degrees of
unsaturation. In 1 H‑NMR spectrum, the presence of a three-proton
triplet [δH = 1.68 (3H, t, J = 6.7)] and a one proton quartet
[δH = 5.54 (H, q, J = 6.7)], indicated the presence of a methylmethylene
group. Four aromatic proton signals [δ = 7.46 (1H, d,
J = 7.8), 7.32 (1H, d, J = 7.8), 7.09 (1H, m), 7.02 (1H, m)] and eight
carbon signals [δ = 138.5 (s, C-13), 134.6 (s, C-2), 128.1 (s, C-8),
122.6 (d, C-11), 120.3 (d, C-10), 118.9 (d, C-9), 112.2 (d, C-12),
102.9 (s, C-7)] indicated an unsubstituted indole ring. Besides
the indole ring signals, alkaloid 2 possessed 1 methyl, 4 methyl-
Fig. 2 A 1 H− 1 H COSY(→) and key HMBC (H→C, arrow) correlations of
compound 1; B key ROESY (arrow) correlations of 1.

enes, 6 methines, and 1 quaternary carbon. The 1 H- and 13 C‑NMR
signals of 2 were close to those of normacusine B [14]. The key
HMBC correlations indicated that C-3, C-5, and C-17 were all
linked to N-4 (l " Fig. 3). Comparing the 13 C‑NMR spectrum with
that of normacusine B [15], the downfield chemical shifts of C-3
(δ = 67.7), C-5 (δ = 70.4), and C-17 (δ = 71.7) were found, indicating
that 2 was an imine N-oxide. Thus, 2 was defined as normacusine
B N-oxide (l " Fig. 1).
Compound 3 was obtained as a white amorphous powder and
positive to Dragendorffʼs reagent. Its molecular formula was determined
as C 20H24 N2O3 from the HR‑EI‑MS (m/z = 340.1788
[M] + ), and its NMR spectra indicated ten degrees of unsaturation.
The 1 H- and 13 C‑NMR figures were very close to those of compound
2 except that there were only 3 aromatic proton signals
[δ = 6.75 (1H, dd, J = 2.0, 8.8), 6.97 (1H, d, J = 2.0), 7.21 (1H, d,
J = 8.8)], revealing that 3 had a 1,2,4-trisubstituted benzene. The
proton and carbon signals at δH 3.81 and δC 56.2 indicated an aromatic
methoxy group, which should be linked to C-10 by comparison
with the 13 C‑NMR spectra of lochnerine (10) [16] and confirmed
by the key HMBC correlation of H‑OCH3 (δH = 3.81)/C-10
(δC = 155.4) (l " Fig. 3). Accordingly, the structure of compound 3
was determined as lochnerine N-oxide (l " Fig. 1).
Original Papers
Fig. 3 1 H− 1 H COSY(→) and key HMBC (H →C, arrow) correlations of compounds
2–3.
The seven known compounds were identified as deacetylvindoline
(4), vindorosine (5), vindolinine (6), vincoline (7), lochnericine
(8), cathovaline (9), and lochnerine (10) by comparison of
their spectroscopic data with literature values.
Vidolicine (1) seemed biogenetically related to pandoline [13], a
known ibogamine-type alkaloid isolated from the plant Ervatamia
orientalis [17], which also belongs to the Apocynaceae family.
The possible biogenetic pathway was proposed as shown in
l " Fig. 4. Compound 1 could be generated from geissoschizine
through rearrangement and its N-oxidation, followed by Polo-
Fig. 4 Possiblebiogeneticpathwayofcompound1.
Fig. 5 Possible pathway of N-oxide decomposition.
Wang L et al. Three New Terpenoid … Planta Med 2011; 77: 754–758
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Original Papers
novski-type reaction and then condensation to form pseudotabersonine
[18]. The oxidation occurred to the double bond between
C-15 and C-20 yield vidolicine (1).
Compounds 2 and 3 were N-oxides, which are very common decomposition
products of the corresponding tertiary alkaloids.
Perivine could be one of the possible tertiary alkaloids, which
had been isolated from this plant before [19]. The possible pathway
of N-oxide decomposition was proposed as shown in
l " Fig. 5.
The cytotoxicity against HL–60, SMMC–7721, A–549, MCF–7, and
SW480 human tumor cell lines of all the alkaloids above were
evaluated, and only compound 8 showed moderate cytotoxicities
against HL–60, SMMC–7721, and A–549, with IC50 values of 11.0,
22.8, and 29.5 µM, respectively.
Acknowledgements
!
The authors are grateful to the staffs of the analytical group at the
State Key Laboratory of Phytochemistry and Plant Resources in
the West China, Kunming Institute of Botany, and Chinese Academy
of Sciences for measuring spectral data. This work was financially
supported by grants from the Ministry of Science and Technology
(2009CB940900 and 2009CB522300) and National Natural
Science Foundation of China (30830114).
Wang L et al. Three New Terpenoid … Planta Med 2011; 77: 754–758
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