Bioactive iridoids and a new lignan from Allamanda cathartica and Himatanthus fallax from the suriname rainforest

Article abstract of DOI:10.1021/np970253e

Bioassay-guided fractionation of the EtOAc extract of both Allamanda cathartica and Himatanthus fallax (Apocynaceae) using the Sc-7 yeast strain resulted in the isolation of the, weakly cytotoxic isoplumericin and plumericin. In addition, the new lignan 7(R)-methoxy-8-epi-matairesinol and three known compounds, plumieride, matairesinol, and pinoresinol, were isolated from H. fallax.

Full text of DOI:10.1021/np970253e

1294
J . Nat. Prod. 1997, 60, 1294-1297
Notes
Bioa ctive Ir id oid s a n d a New Lign a n fr om Alla m a n d a ca th a r tica a n d
Him a ta n th u s fa lla x fr om th e Su r in a m e Ra in for est1
Maged S. Abdel-Kader,† J an Wisse,‡ Randy Evans,§ Hendrik van der Werff,§ and David G. I. Kingston*,†
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0212,
Bedrijf Geneesmiddelen Voorziening Suriname, Commissaris Roblesweg, Geyersluit, Suriname, and Missouri Botanical
Garden, P.O. Box 299, St. Louis, Missouri 63166-0299
Received May 16, 1997X
Bioassay-guided fractionation of the EtOAc extract of both Allamanda cathartica and
Himatanthus fallax (Apocynaceae) using the Sc-7 yeast strain resulted in the isolation of the
weakly cytotoxic isoplumericin and plumericin. In addition, the new lignan 7(R)-methoxy-8-
epi-matairesinol and three known compounds, plumieride, matairesinol, and pinoresinol, were
isolated from H. fallax.
Ta ble 1. 13C-NMR Data (δ values) for Compounds 1 and 2a
As previously described,2 we have embarked on a
program to discover and develop potential therapeutic
agents from the Surinamese rainforest and, in the
process, to provide economic arguments for the preser-
vation of this valuable resource. Plant collections under
this program are being made independently by Conser-
vation International, Suriname, and by the Missouri
Botanical Garden, with the former collecting on an
ethnobotanical basis and the latter on a phytochemical
basis. Plant extracts are prepared at Bedrijf Ge-
neesmiddelen Voorziening Suriname (BGVS). Work at
Virginia Polytechnic Institute and State University
(VPI&SU) is centered around the discovery of potential
anticancer agents, and the Sc-7 strain of Saccharomyces
cerevisiae (yeast) is used as a primary assay tool in this
work. This strain shows growth inhibition by cytotoxic
agents,3 and activities are expressed as IC12 values,
which are the dosages needed to produce an inhibition
zone of 12 mm under defined conditions.2
carbon
compound 1
compound 2
1
3
4
5
6
7
8
9
101.7
152.6
108.9
38.2
141.1
126.1
104.9
53.7
102.3
152.7
109.4
38.4
141.1
126.4
104.6
53.7
10
83.8
80.3
11
12
13
14
COOCH3
COOCH3
125.7
167.4b
148.2
14.8
127.4
168.2b
145.3
16.1
166.7b
51.6
166.7b
51.7
a
Obtained in CDCl3. Assignments made by a combination of
DEPT and HETCOR data and comparison with the spectrum of
plumenoside.10 b The signals in each column may be interchanged.
As a part of our collaborative work, the plants
Allamanda cathartica L. and Himatanthus fallax (Muell.
Arg.) Plumel (Apocynaceae) were collected from the
central region of Suriname as part of the phytochemical
collection strategy by Missouri Botanical Garden. An
EtOAc extract of A. cathartica had an IC12 value of 690
µg/mL, and a similar extract of H. fallax had an IC12
value of about 3320 µg/mL against the Sc-7 yeast strain,
and fractionation studies were initiated.
Previous work on A. cathartica has included the
isolation of the iridoid lactones plumericin and isoplum-
ericin4 and of plumieride coumarate and plumieride
coumarate glucoside.5 Plumericin and isoplumericin
have also been isolated from Allamanda doniana,6 while
the occurrence of iridoids in various Allamanda sp. has
been surveyed.7 Studies on Himatanthus sp. have
included the isolation of plumericin and isoplumericin,
from H. phagedaenica,8 and H. obovatus.6
Fractionation of A. cathartica involved liquid-liquid
partition, in which the bioactivity went successively into
the aqueous MeOH phase of a hexane-80% aqueous
MeOH partition and into the CHCl3 phase of a CHCl3-
60% aqueous MeOH partition. Purification on a Sepha-
dex LH-20 column yielded the active material in a
CH2Cl2-hexane (4:1) fraction, and final purification by
vacuum liquid chromatography (VLC) over Si gel with
Me2CO-hexane as eluent, by column chromatography
over Si gel, and by preparative TLC gave the two active
products 1 (7 mg) and 2 (60 mg), with IC12 values of 42
and 74 µg/mL, respectively.
The structures of the two compounds were elucidated
as isoplumericin (1) and plumericin (2) on the basis of
their spectroscopic data, and specifically by comparison
of their 1H-NMR data with those in the literature.9
Complete assignments for the 13C-NMR spectra of both
compounds (Table 1) were made for the first time,
utilizing DEPT and HETCOR experiments as well as
comparison with the 13C-NMR data of plumenoside.10
As noted above, both compounds have previously been
isolated from A. cathartica.4
* To whom correspondence should be addressed. Phone: (540) 231-
6570. FAX: (540) 231-7702. E-mail: dkingston@vt.edu.
† Virginia Polytechnic Institute and State University.
‡ Bedrijf Geneesmiddelen Voorziening Suriname.
§ Missouri Botanical Garden.
X Abstract published in Advance ACS Abstracts, November 15, 1997.
Fractionation of H. fallax followed lines similar to that
S0163-3864(97)00253-X CCC: $14.00
© 1997 American Chemical Society and American Society of Pharmacognosy

Notes
J ournal of Natural Products, 1997, Vol. 60, No. 12 1295
Ta ble 2. 1H- and 13C-NMR Data (δ values) for Compound 6a
13C-NMR assignments (Table 2) were made on the basis
of 1H-1H decoupling in different solvents, TOCSY,
DEPT, and HETCOR experiments. The oxygenated CH
group (δH 5.23 ppm, δC 82.3 ppm) was assigned to
position 7 based on the coupling of its proton with H-8
(3.08 ppm, dd, J ) 7.2, 8.7 Hz) rather than with H-8′
(2.91 ppm, m). The C-7 substituent was assigned as a
methoxyl group (δH 3.67, δC 51.8) rather than a hydroxyl
group, based on the fact that the chemical shift of H-7
was essentially unchanged after acetylation of 6 to form
its diacetate 7. This assignment was further supported
by correlations of the C-7 OMe group with the two H-7′
protons and with H-8′ in a NOESY experiment. The
chemical shifts of the aryl carbons supported a 4,4′-
dihydroxy-3,3′-dimethoxy substitution.14 The NOE cor-
relations of the two resolved aryl protons at δ 6.66 and
6.67 with H-7′â and H-7′R assign them to the 2′ and 6′
positions, respectively.
b
c
position
δH
δC
1
2
3
4
5
6
7
8
9
1′
2′
3′
4′
5′
6′
7′
133.4 (0)d
108.3 (1)
145.2 (0)e
146.5 (0)f
114.4 (1)
118.7 (1)
82.3 (1)
6.85 (m)
6.85 (m)
6.85 (m)
5.23 (d, J ) 7.2)
3.08 (dd, J ) 7.2, 8.7)
55.9 (1)
172.5 (0)
131.3 (0)d
111.2 (1)
144.1 (0)e
146.4 (0)f
114.3 (1)
121.2 (1)
34.5 (2)
6.66(m)
6.85 (m)
6.67 (m)
2.55 (dd, J ) 10.6, 13.7, â)
2.76 (dd, J ) 5.3, 13.7, R)
2.91 (m)
3.79 (dd, J ) 6.7, 8.7, â)
4.08 (dd, J ) 6.4, 8.7, R)
3.67
8′
9′
44.2 (1)
72.9 (2)
The CD spectrum of 6 was similar to those of the rare
cis-fused-type lignans.15 To determine the stereochem-
istry at position 7 compound 6 was allowed to epimerize
in 3% methanolic KOH solution.16 The resulting epimer
8 had a CD spectrum similar to those of the more
common trans-fused lignans, particularly those with the
7-position oxygenated as in podorhizol (9).16,17 The C-7
methoxyl group was assigned the R-configuration based
on comparison of the J 7,8 value of 8 (7.9 Hz) with those
of epipodorhizol (10) with a 7R-OH group (7.7-7.9 Hz)
and its 7â-OH isomer podorhizol (9) (1.6-2.9 Hz) (Chart
1).18-20
7 OCH3
3,3′ OCH3
4,4′ OH
51.8 (3)
55.8 (3), 55.9 (3)
3.87, 3.88
5.52, 5.60
a
b
Obtained in CDCl3. J in Hz. c Carbon type as determined by
DEPT spectra: 0 ) quaternary, 1 ) methine, 2 ) methylene, 3 )
methyl. d,e,f Signals for carbons with similar shifts may be inter-
changed.
of A. cathartica, and yielded six products. Two were
identified again as the compounds 1 and 2, and three
inactive known compounds were identified as plum-
ieride (3), pinoresinol (4), and matairesinol (5) based on
comparison of their mps, [R]D, UV, and 1H- and 13C-
NMR spectra with those in the literature.10-13 The last
compound was identified as the new lignan 6, 7(R)-
methoxy-8-epi-matairesinol, on the basis of the evidence
outlined below.
Isoplumericin and plumericin are known to have
antifungal, algicidal, and barnicidal activities,5,6,21 and,
in addition, plumericin possesses antimicrobial activ-
ity.22 In a cytotoxicity assay with the Madison lung
carcinoma (M109) cell line, compounds 1 and 2 showed
IC50 values of 25 and 100 µg/mL, respectively, suggest-
ing that these compounds are not potent enough to be
considered as development candidates.
The HREIMS of 6 showed an M+ at m/z 388.152,
consistent with the molecular formula C21H24O7. Its
13C-NMR spectrum (Table 2) indicated the presence of
three OMe groups, a lactone carbonyl (δc 172.5 ppm),
and 12 aromatic carbon resonances, six of which were
fully substituted. The remaining carbons (1 CH2, 1
CH2O, 2 CH, and 1 OCH) supported the assignment of
The group of rare spirolactone-containing iridoids
exemplified by plumericin and isoplumericin seems to
be restricted in its occurrence to the family Apocyn-
aceae, and mainly to the two genera Allamanda and
1
6 as a diaryl butyrolactone-type lignan.13 The H- and
Ch a r t 1

1296 J ournal of Natural Products, 1997, Vol. 60, No. 12
Notes
Plumeria,7 although plumericin has also been reported
from Nerium indicum.23 Although lignans are known
to occur in the Apocynaceae,24 this is the first isolation
of lignan derivatives from a Himatanthus species.
CHCl3) to obtain isoplumericin (1, 1.2 mg) and plum-
ericin (2, 2.6 mg).
Fractions eluted with 50% Me2CO in hexane (110 mg)
were subjected to preparative TLC (Si gel, 20% Me2CO
in CHCl3) to afford 6 (12 mg, Rf 0.65). The more polar
band (15 mg, Rf 0.5) provided pinoresinol (4, 6 mg) and
matairesinol (5, 5 mg) after HPLC separation (C18 Si
gel, MeOH-H2O, 1: 1).
Fractions eluted from Sephadex LH-20 with CH2Cl2-
Me2CO, 3:2 (0.5 g), were chromatographed by VLC (Si
gel, hexane-Me2CO-MeOH mixtures), and fractions
eluted with Me2CO (250 mg) were further purified by
preparative TLC (Si gel, CHCl3-MeOH 85:15) to afford
plumieride (3, 150 mg).
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. The CD spec-
trum was recorded on a J ASCO J 720 spectropolarim-
eter. NMR spectra were recorded in CDCl3 on a Varian
1
Unity 400 NMR instrument at 399.951 MHz for H and
100.578 MHz for 13C, using standard Varian pulse
sequence programs. LRMS were taken on a VG 7070
E-HF at VPI&SU, and exact mass measurements were
obtained at the Nebraska Center for Mass Spectrom-
etry. Other conditions were as previously described.25
Yea st Bioa ssa y. The bioassay was carried out as
previously described.2
Isop lu m er icin (1): colorless needles, mp 199-200 °C
(CH2Cl2-MeOH) (lit.9 mp 200.5-201.5 °C); [R]26D +189°
(c 0.61, CHCl3) (lit.9 [R]29D +216.4°); 13C-NMR data, see
Table 1.
P la n t Collection a n d Extr a ction of A. ca th a r tica
a n d H. fa lla x. Leaves of A. cathartica and stems of
H. fallax were collected in J uly 1994, near Asindopo
Village, Suriname, and were assigned collection num-
bers EV1887 and EV1874, respectively. Voucher speci-
mens are preserved at the National Herbarium of
Suriname and at the herbarium of the Missouri Botani-
cal Garden. Extraction of ca. 500 g of dried EV1887 at
BGVS yielded 27.4 g of EtOAc extract as BGVS
E-940241, and extraction of ca. 500 g of dried EV1874
at BGVS yielded 16.5 g of EtOAc extract as BGVS
E-940200.
P lu m er icin (2): colorless needles, mp 205-206 °C
(CH2Cl2-MeOH) (lit.9 mp 211.5-212.5 °C); [R]26D +173°
(c 1.10, CHCl3) (lit.9 [R]26D +197.3°); 13C-NMR data, see
Table 1.
P lu m ier id e (3): colorless crystals; mp 225-226 °C
(MeOH) (lit.26 mp 224-225 °C); [R]26 -68° (c 0.90,
D
MeOH) (lit.26 [R]26 -114°(H2O)).
D
P in or esin ol (4): yellowish gum; [R]26D +70° (c 0.60,
MeOH) (lit.27 [R]26 +64°).
D
Ma ta ir esin ol (5): yellowish gum; [R]26D -45° (c 1.0,
MeOH) (lit.13 [R]26 -50°).
D
(7R)-Meth oxy-8-epi-m a ta ir esin ol (6): white crys-
Isola tion of P lu m er icin (1) a n d Isop lu m er icin (2)
fr om A. ca th a r tica . The bioactive EtOAc extract (IC12
690 µg/mL, 27.4 g) was dissolved in 250 mL of 80%
aqueous MeOH and defatted with hexane (150 mL ×
4). The aqueous MeOH fraction was diluted with H2O
until a 60% aqueous MeOH mixture was produced, and
this was then partitioned with CHCl3 (150 mL × 4) to
afford 6.0 g of the bioactive CHCl3-soluble extract. This
fraction was purified by chromatography on Sephadex
LH-20 (5 × 50 cm) using the solvents hexane-CH2Cl2
(1:4, 1 L), CH2Cl2-Me2CO (3:2, 1 L), CH2Cl2-Me2CO
(1:4, 1 L), and MeOH (2 L). The active fraction (0.5 g)
eluted with hexane-CH2Cl2 (1:4) was separated on a
Si gel column (25 g) eluted with 1% Me2CO in CHCl3,
then with 2% Me2CO in CHCl3, and finally with MeOH.
Fractions 6 and 7, eluted with 1% Me2CO in CHCl3 (43
mg), were separated by preparative TLC (Si gel, 10%
Me2CO in CHCl3) to obtain isoplumericin (1, 7 mg).
Fractions 8-12 (2% Me2CO in CHCl3, 75 mg) were
crystallized from CH2Cl2-MeOH to afford plumericin
(2, 60 mg).
Isola tion of P lu m er icin (1), Isop lu m er icin (2),
P lu m ier id e (3), P in or esin ol (4), Ma ta ir esin ol (5),
a n d 7(R)-Meth oxy-8-epi-m a ta ir esin ol (6) fr om H.
fa lla x. The bioactive EtOAc extract was treated as
above, and the active fraction, eluted with hexane-CH2-
Cl2 (1:4; 1.2 g) from the Sephadex LH-20 chromatogra-
phy (5 × 50 cm column), was crystallized from CH2Cl2-
MeOH to afford 0.4 g of inactive crystals. The bioactive
supernatant (0.8 g) (IC12 890 µg/mL) was fractionated
by VLC (3.5 cm × 4.5 cm, 30 g Si gel) eluted with
hexane-Me2CO mixtures. The bioactive fraction eluted
with 20% Me2CO in hexane (161 mg) was further
purified using a Si gel (15 g) flash column eluted with
5% Me2CO in CHCl3. The active fractions (32 mg) were
separated by preparative TLC (Si gel, 10% Me2CO in
tals, mp 160-162 °C (C6H6); [R]26 +29.57°(c 0.71,
D
MeOH); UV (MeOH) λmax (ꢀ) 214 (11 600), 225 (4900),
280 (4400) nm; (NaOMe) λmax (ꢀ) 214 (1200), 245 (6000),
294 (4200) nm; CD (MeOH, c 0.1) λmax (∆ꢀ) 218 (-2.6),
240 (+2.4), 253 (-1.2), 279 (+3.8) nm; 1H and 13C NMR
in CDCl3 , see Table 2; 1H NMR (C6D6) δ 6.39 (1H, d, J
) 1.9 Hz, H-2′) 6.48 (1H, dd J ) 1.9, 8 Hz, H-6′), 6.93
(1H, d, J ) 8 Hz, H-5′), 6.94 (1H, m, H-2), 6.97 (1H, dd
J ) 1.9, 8 Hz, H-6), 7.01 (1H, d J ) 8 Hz, H-5); EIMS
m/z 388 (M+, 58), 249 (12), 191(20), 180 (74), 151
(C8H7O3, 57), 137 (C8H9O2, 75), 122 (C7H6O2, 9), 99
(C5H7O2, 100), 77 (6); HREIMS m/z 388.152 (M+), calcd
for C21H24O7, 388.152.
7(R)-Met h oxy-8-ep i-m a t a ir esin ol Dia cet a t e (7).
Compound 6 (2.0 mg) in pyridine (2.0 mL) was treated
with Ac2O (0.2 mL) for 24 h at room temperature.
Evaporation of the resulting solution under a stream
of argon yielded chromatographically homogeneous 7
(2.0 mg): 1H NMR (CDCl3) δ 1.86 (3H, s, COCH3), 2.55
(1H, dd, J ) 10.4, 13.5 Hz, H-7′â), 2.65 (1H, m , H-8′),
2.76 (1H, dd, J ) 5.3, 13.5 Hz, H-7′R), 3.05 (1H, dd, J )
7.2, 8.7 Hz, H-8), 3.28 (3H, s, OCH3-7), 3.30 (6H, s, 2 ×
OCH3), 3.84 (1H, dd, J ) 6.4, 8.8 Hz, H-9′â), 3.94 (1H,
dd, J ) 6.7, 8.8 Hz, H-9′R), 5.59 (1H, d, J ) 7.2 Hz,
H-7â), 6.13 (1H, d, J ) 1.9 Hz, H-2′), 6.49 (2H, m, H-6,
H-6′), 6.90 (1H, d, J ) 8 Hz, H-5′), 7.00 (1H, br s, H-2),
7.1 (1H, d, H-5).
7(R)-Meth oxym a ta ir esin ol (8). Compound 6 (4
mg) was dissolved in 3% methanolic KOH (3 mL), and
the solution was allowed to stand at room temperature
for 3 days. The solution was then neutralized with
HOAc and extracted with CHCl3. The CHCl3 layer was
then washed with 5% aqueous Na2CO3 followed by H2O,
dried, and evaporated to give a product that was
homogeneous on TLC but was shown by 1H-NMR

Notes
J ournal of Natural Products, 1997, Vol. 60, No. 12 1297
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45:55) afforded 1.0 mg of the epimer 8 and 1.3 mg of
unepimerized 6. Compound 8 showed the following
spectral characteristics: CD (MeOH, c 0.09) λmax (∆ꢀ)
1
238 (+0.74), 247 (-7.9), 279 (+0.83); H NMR (CDCl3)
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(3H each, s, 2 × OCH3), 4.32 (1H, dd, J ) 6.7, 8.7 Hz,
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35, 415-427.
Ack n ow led gm en t. This work was supported by an
International Collaborative Biodiversity Grant, number
U01 TW/CA-00313 from the Fogarty Center, NIH. The
authors thank Dr. Mamber of Bristol-Myers Squibb
Pharmaceutical Research Institute for the Sc-7 yeast
strain, Dr. I. Bursuker of Bristol-Myers Squibb Phar-
maceutical Research Institute for the cytotoxicity assay,
and Ms. Nina Baj of Virginia Polytechnic Institute and
State University for technical assistance. The authors
also thank Dr. M. A. Castro, Departamento de Quimica
Organica, Facultad de Farmacia, Universidad de Sala-
manca, for a gift of a sample of podorhizol.28 Mass
spectra and CD spectra were obtained by Mr. Kim
Harich of Virginia Polytechnic Institute and State
University and the Nebraska Center for Mass Spec-
trometry.
(27) Fonseca, S. F.; Nielsen L. T.; Ruveda E. A.; Phytochemistry 1979,
18, 1703-1708.
(28) San Feliciano, A.; del Corral, J . M. M.; Gordaliza, M.; Castro,
A. Phytochemistry 1990, 29, 1335-1338.
Refer en ces a n d Notes
(1) Biodiversity Conservation and Drug Discovery in Suriname, Part
2. For Part 1, see Zhou et al.2
(2) Zhou, B.-N.; Baj, N. J .; Glass, T. E.; Malone, S.; Werkhoven, M.
C. M.; van Troon, F.; David; Wisse, J .; Kingston, D. G. I. J . Nat.
Prod. 1997, 60, 1287-1293.
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