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Eliza et al.
ISBN 978-979-18962-0-7
Proceeding of The International Seminar on Chemistry 2008 (pp. 265-268)
Jatinangor, 30-31 October 2008
Three flavanoid derivates from leaves of Artocarpus Lanceifolius
Eliza, Yana M. Syah, Lia D. Juliawaty, Sjamsul A. Achmad,
Lukman Makmur, Euis H. Hakim*
Natural Product Chemistry Research Group, Department of Chemistry, Institut Teknologi Bandung,
Jalan Ganesha 10, Bandung 40132, Indonesia
*e-mail: [email protected], Fax: 62-22-2504154
Abstract
The roots and stems, but not the leaves, of Artocarpus lanceifolius (Moraceae) have been reported to
produce a number of prenylated flavonoids. As part of chemical investigation on this species, we have
examined the chemical constituents of the leaves of this plant which led to the isolation and
identification of three flavanoid derivatives, namely 7,4’-di-O-methylnaringenin (1), 8-prenyl-4’-Omethyl-naringenin (2) and 3’-geranylnaringenin (3). In this report, the activities of the isolated
compound against P-388 leukemia murine cells will also be described.
Keywords: Moraceae, A. lanceifolius, flavanones
OMe
Introduction
4'
MeO
Artocarpus comprises 45 species and distributed
from Sri Lanka to South China and through to
Solomon Islands and Australia. Artocarpus species
are elements of forest in ever wet climates or where
there is a short dry seasons, mostly below 1000 m.
Some species can be found at altitudes up to 1500 or
to 1800 m. This genus is known as a source of edible
fruits, such as A. heterophyllus (Jackfruit), A. integer
(Chempedak), A. rigidus (Monkeyjack) (Verheij &
Coronel 1991). The lightweight hardwood of several
Artocarpus species is attractive to be used for several
purposes, such as for construction, veneer and various
utensils (Djarwaningsih, 1995). Several Artocarpus
species also produce exudates in the form of latex
(Boer and Ella 2000) to be used as birdlime or as
medicines or stimulants (Van der Vossen & Wessel
2000).
A. lanceifolius Roxb. is a rare species endemic to
the province of West Sumatera, Indonesia, and locally
known as ‘keledang’. Some prenylated flavonoids
with interesting biological activities have been
isolated from the roots and stems of this plant
(Hakim, 2006), but no work has been done to the
leaves part of this plant. This paper reports the
isolation and structural elucidation of three flavanoids
derivatives from the leaves of A. lanceifolius
characterized as 7,4’-di-O-methylnaringenin (1), 8prenyl-4’-O-methyl-naringenin
(2)
and
3’geranylnaringenin (3). The structure of these
compounds was elucidated based on spectroscopic
data and by comparison with literature data. The
occurrence of these compounds in Moraceae family is
for the first time.
O
7
2
2'
3
5
OH O
1
OMe
4'
HO
O
7
2
2'
3
5
OH1 O
2
OH
4'
HO
O
7
1"
2
3
2'
5"
2"
3"
5
OH O
4"
6"
10 "
7"
8"
3
9"
Material and Methods
General
Melting points were determined on a micromelting point apparatus and are uncorrected. UV and
IR spectra were measured with a Varian Conc.100
instrument and Perkin Elmer Spectrum One FTIR
spectrometer, respectively. 1H and 13C NMR spectra
were recorded with Jeol ECP500 operating at 500
265
Eliza et al.
Proceeding of The International Seminar on Chemistry 2008 (pp. 265-268)
Jatinangor, 30-31 October 2008
(1H) and 125 (13C) MHz, using residual and
deuterated solvent peaks as reference standards. VLC
(vacuum liquid chromatography) used Merck silica
gel 60G, radial chromatography was carried out by
using Merck silica gel PF254 and for TLC analysis,
precoated silica gel plates (Merck Kieselgel 60 GF254,
0.25 mm thickness) were used, while other column
chromatography used sephadex LH-20.
2856, 1631, 1506, 1440, 1373. 13C-NMR (d6-acetone3,
125 Hz) see Table.1.
Results and Discussion
Methanol extract of leaves of A lanceifolius Roxb
was partitioned by VLC using increasing polarity of
eluent (N-hexane: EtOAc) and subsequented by radial
chromatography repeatly to obtain compound 1-3.
Compounds 1-3 were identified as 7,4’-di-Omethylnaringenin
(1),
8-prenyl-4’-O-methylnaringenin (2) and 3’-geranylnaringenin (3),
respectively.
Compound
1,
assigned
as
7,4’-di-Omethylnaringenin, was obtained as white needles
crystals. The IR spectrum showed strong absorptions
at 1631 cm-1 (chelated C=O group) and 3300 cm-1
(OH). The characteristic UV absorptions bands
(MeOH) at 215 and 287 nm suggested a flavanone
skeletone, which was corroborated by the observation
of 1H-NMR signals (CDCl3, 500 Hz) characteristic for
this flavonoid type at δH 5.34 (1H, dd, J = 3.1, 13.1
Hz, C-2), 3.10 (1H, dd, J = 13.1, 17.7 Hz, C-3a), 2.73
(1H, dd, J = 3.1 & 17.7 Hz, C-3b) attributed to the
ring C protons. The 13C-NMR spectrum (APT) of 1
exhibited 15 resonances for 17 carbon atoms
distributed into 13 C-sp2, including a conjugated
carbonyl and four oxyaryl carbon atoms, and 4 C-sp2,
two of which were assignable to two methoxyl carbon
atoms. Thus, this compound was assumed to be a
dimethyl derivative of 5,7,4’-trihydroxyflavanone.
Consistent with this assumption, the aromatic proton
signals exhibited a pair of meta-coupled signals at δH
6.02 (1H, d, J = 2.5 Hz), 6.04 (1H, d, J = 2.5 Hz) for
H-6 and H-8, and a pair of ortho-coupled signals of
1,4-disubstituted benzene moiety at δH 7.37 (2H, d, J
= 7.6 Hz) and 6.35 (2H, d, J = 7.6 Hz). Furthermore,
in the 1H-NMR two methoxyl proton signals also
appreared at δH 3.79 and 3.82 and their positions were
suggested at C-7 and C-4’ due to the presence of the
phenolic –OH at δH 12.04. From these spectroscopic
data the structure of 7,4’-di-O-methylnaringenin was
assigned for compound 1.
Plant Material
Leaves of A. lanceifolius were collected in March
2007 from Bukit Tambun Tulang Padang Pariaman
District Indonesia. The plant was identified at the
Herbarium Anda, Biology Department, Andalas
University Padang and Herbarium Bogoriense, Bogor
Botanical Garden, Bogor, Indonesia, and a voucher
specimen was deposited at both herbariums.
Extraction and Isolation
The powdered leaves of A. lanceifolius (2.3 kg)
were extracted with MeOH (3 x 11 L) at room
temperature for each 24 hours. The combined MeOH
extracts were filtered and evaporated in vacuo to give
residue 170 g. A portion of this extract (40 g) was
fractioned by VLC using increasing polarity of
eluents (n-hexane:EtOAc) to give
seven major
fractions (A-G). Recrystalization of fraction C (158
mg) and D (81 mg) with acetone yielded 1 (143 mg),
while with the same methods from fraction E (853
mg) gave 2 (26 mg). Then, fraction F were subjected
to a sephadex LH-20 column (MeOH) repeatly and
then purified with radial chromatography to afford 3.
7,4’-Di-O-methylnaringenin (1): white needles
crystals, mp. 119-120oC and [λ]D25 = -11.19 (CHCl3,
0.042), UV (MeOH); λmax (nm) 215, 287 nm, UV
(MeOH+NaOH) λmax
(nm); 203, 287, UV
(MeOH+AlCl3) λmax (nm); 378, 310, 225, 202, UV
(MeOH+AlCl3+HCl) λmax (nm); 378, 309, 224, 202,
UV (MeOH+NaOAc) λmax (nm); 287, 213, 204. The
IR (KBr) υmax (cm-1): 3444, 3004, 2912, 2842, 1631,
1577, 1519, 1461, 1434. 13C-NMR (CDCl3, 125 Hz)
see Table 1.
Compound 2 was obtained as white needles crystals
and identificated as 8-prenyl-4’-O-methylnaringenin.
The IR and UV spectra of spectrum of 2 were
essentially similar to those 1. The 1H-NMR spectrum
(CDCl3, 500 Hz) showed proton signals at δH 5.35,
(1H, dd, J=3.1, 12.8 Hz, C-2), 3.05 (1H, dd,
J=12.8&17.1 Hz, C-3a) and 2.80 (1H, dd, J = 17.1&
3.1 Hz, C-3b) that comfirmed to the flavanone Cring. The two signals of four aromatic protons at δH
7.37 (2H, d, J = 8.6, C-2’/6’) and 6.94 (2H, d J = 8.6
Hz, C-3’/5’) attributed monosubtituted phenyl of Bring and one signal at δH 6.02 (1H, s, C-6) indicated
four substituted of phenyl A-ring. Moreover, the 1HNMR data indicated the presence of two methyl
groups at δH 1.69 and 1.71(each 3H, s) and one
8-Prenyl-4’-O-methylnaringenin (2): white needles
crystals, mp. 165-167oC, [λ]D25 = -13.28 (CHCl3,
0.007), UV (MeOH) λmax (nm); 225, 287; UV
(MeOH+NaOH) λmax (nm) 287; UV (MeOH+AlCl3)
λmax (nm) 309, 224 and UV (MeOH+NaOAc) λmax
(nm) 202, 288. IR (KBr) υmax (cm-1) 3250, 2991-2854,
1635, 1600, 1517, 1438, 1355. 13C-NMR (CDCl3, 125
Hz) see Table.1.
3’-Geranylnaringenin (3) yellow gum, UV (MeOH)
λmax (nm) 217, 287; UV (MeOH+NaOH) λmax (nm)
325, 322, 246, 217; UV (MeOH+AlCl3) λmax (nm)
216, 287, UV (MeOH+ NaOAc) λmax (nm) 322, 287,
216. IR (KBr) υmax (cm-1) 3427, 3035, 2970, 2922,
266
Eliza et al.
Proceeding of The International Seminar on Chemistry 2008 (pp. 265-268)
Jatinangor, 30-31 October 2008
previous method (Alley,1988). Two of them, 2 and
3, exhibited cytotoxic activity with IC50 3.4 and 3.2
µg/mL, respectively, while 1 showed was not active
(IC50 41.5 µg/ml).
olefinic proton at δH 5.19 (1H, t, J=7.3 Hz) and 3.28
(2H, d, J= 6.8 Hz), attributed to a 2,2-dimethylalyl (or
prenyl) group. Since the 1H-NMR spectrum
compound 2 showed aromatic signals consistent with
a monosubstituted phenyl group of the ring B, the
prenyl group must be located at ring A. In addition,
1
H-NMR spectrum also showed the signal a methoxy
proton at δH 3.79 (3H, s). The 13C-NMR data of 2
showed 21 carbon atoms that were classified as two
methyl carbons (C-4” and C-5”), two methylenes
carbon (C-3 and C-1”), seven methines carbons (C-2,
C-6, C-2’, C-3’, C-5’, C-6’ and C-2”), three quartener
carbons (C-4a, C-1’ and C-3”) and four hydroxylated
carbons (C-5, C-7, C-8a and C-4’) and one carbonyl
carbon (C-4) from APT experiment and HMQC
spectral analysis. From the 1H-NMR and 13C-NMR
data compound 2 must be a flavanone substituted with
one prenyl and one methoxyl groups. The location of
prenyl and methoxy was confirmed by the HMBC
experiments. Long-range correlations were observed
between the following proton and carbons: H-1” was
correlated with C-7, C-2”, C-3” confirming that a
prenyl unit was located at C-8 and correlation
between the methoxyl proton with C-4’ indicated that
this group should be attached at C-4’. From these
spectroscopic data l was assigned as 8-prenyl-4’methoxynarigenin.
Compound 3 was obtained as a yellow gum
designated as 3’-geranylnaringenin. The IR and UV
spectra of 3 also very similar with those compounds 1
and 2, and together with proton signals (d6-acetone,
500Hz) at δH 5.36 (1H, dd, J = 13.1, 3.1 Hz), 3.13
(1H, dd, J = 17.1, 3.1 Hz), and 2.67 (1H, dd, J = 17.1,
3.1 Hz), suggested a flavanone structure. The
presence of a geranyl group was obvious from the
signals of three methyl singlets at δH 1.53, 1.59 and
1.69 and two olefinic protons at δH 5.08 (1H, t, J = 7.3
Hz) and 5.35 (1H, t, J = 7.9 Hz) and three methylenes
proton at δH 3.34 (2H, d, J = 6.7 Hz), 2.07 (2H, m),
2.01(2H, m) in the 1H-NMR spectrum. The coupling
ABX patterns of the B-ring protons, δH 7.26 (d, J=
2.5), 6.86 (d, J=8.0), 7.17 (dd, J=2.5 & 8.0)), and
HMBC correlation data showed that there were longrange correlations between H-1” with C-4’, C-2’
establishing that the geranyl is located at C-3’. The
proton chemical shifts of H-6 and H-8 in acetone-d6
solution gave the same value (δH 5.92) and the
coupling of these protons was not observed. The 13CNMR (APT and HMQC) spectrum were identified 25
carbon atoms that classified as three methyl carbons
(C-4”, C-9”, C-10”), four methylenes carbons (C-3,
C-2”, C-5”, C-6”), eight methines carbons (C-2, C-6,
C-8, C-2’, C-5’, C6’, C2”, C-7”), five quartener
carbons (C-4a, C-1’, C-3’, C-3”, C-8”), four
hydroxylated carbons (C-5, C-7, C-8a, C-4’) and one
carbonyl carbon. Based on all of spectroscopic data,
compound 3 was assigned as 3’-geranyl-4’,5,7trihydroxyflavanone or 3’-geranylnaringenin.
The cytotoxicity of compounds 1 - 3 against
P-388 murine cells were evaluated according to the
Table 1 13C NMR of compound 1-3
Carbon
Number
2
3
4
4a
5
6
δC (ppm)
1
78.9
43.1
196.0
103.1
164.0
94.9
7
167.9
8
94.1
8a
162.8
1’
130.3
2’
127.6
3’
114.1
4’
159.9
5’
114.1
6’
127.6
1”
2”
3”
4”
5”
6”
7”
8”
9”
10”
7-MeO 55.6
4’-MeO 55.3
2
78.7
43.0
196.6
103.0
162.0
96.7
163.8
106.5
159.7
130.7
127.5
114.0
159.8
114.0
127.5
21.7
121.7
134.3
17.8
25.8
-
3
80.6
43.4
197.8
103.0
165.4
97.0
163.4
96.2
164.3
130.9
128.9
129.5
156.7
115.7
126.2
29.1
123.7
137.0
40.8
27.7
125.4
132.2
25.9
16.2
17. 8
Conclusions
The present study has successfully isolated and
identified three flavanones derivatives, compounds 1
– 3, from the leaves of A. lanceifolius. All these
compounds are the first time to be reported from
Artocarpus plant. Compound 2 and 3 are active
against murine leukemia P-388 cells with IC50 3.4 and
3.2 µg/mL, respectively.
Acknowledgements
This work has been partially supported by the
University Research for Graduate Education Project,
Ministry of National Education, Republic of
Indonesia. We are grateful also to the Herbarium
Anda, Padang and Herbarium Bogoriense, Bogor,
Indonesia for the identification of the plant specimen.
We also thank to Indonesia Institute Sciences
Research Centre for NMR facility.
267
Eliza et al.
Proceeding of The International Seminar on Chemistry 2008 (pp. 265-268)
Jatinangor, 30-31 October 2008
Djarwaningsih. T., D.S. Alonso, S. Sudo & M.S.M.
Sosef, 1995, Plant resources South-east Asia 5, 2,
Timber trees: Minor commercial timbers, p. 5971.
Hakim E.H., S.A. Achmad, L.D. Juliawaty, L.
Makmur, Y.M. Syah, N. Aimi, M. Kitajima, H.
Takayama & E.L. Ghisalberti, 2006. Prenylated
flavonoids and related compounds of the
Indonesian Artocarpus (Moraceae). J. Nat. Med.,
60:161-184.
Van Der Vossen H.A.M & M.Vessel, 2000, Plant
resources of South-east Asia 16, Stimulant.
Verheij E.W.M. & R.E. Coronel, 1991. Plant
resources of South-east Asia2, Edible fruits and
nuts.
References
Alley, M.C, D.A Scudiero, A. Monks, M.L Hursey,
M.J. Czerwinski, D.L. Fine, B.J. Abbot J.G.
Mayo, R.H. Shoemaker, M.R. Boyd, 1988, Cancer
Res;48:589.
Berg C.C., E.J.H. Corner & F.M. Jarret, 2006. Flora
Malesiana, Moraceae-genera other than Ficus, Vol
17, p.72-128. National Herbarium Nederland.
Boer, E., A.B. Ella, 2000, Plants resources of Southeast Asia 18, Plants producing exudates, p.139140.
Brink. M. & R.P. Escobin, 2003, Plant resources of
South-east Asia 17, Fibers plants, p. 304-305,
Pudoc. Wageningen.
268
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