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Clerodendrum glabrum is an indigenous medicinal plant that is used to treat cough, cold, sore throat and chest complaints. The stem bark of Clerodendrum glabrum afforded four tritepenoids namely, 3β-olean-12-en-3-yl palmitate (β-amyrin palmitate), (1), 3β‑hydroxy‑5-glutinene (glutinol), (2), 3β-lup-20(29)-en-3-palmitate (Lupeol-3-palmitate), (3), 3β-lup-20(29)-en-3-ol (lupeol) (4) and one common phytosterol (stigmasterol) (5). The structures were established on the basis of their spectroscopic analysis. The compounds were screened for cytotoxicity against the HCC70 triple negative breast cancer (TNBC), MCF-7 hormone receptor positive breast cancer and MCF-12A non-cancerous mammary epithelial cell lines. Interestingly, none of the compounds were toxic towards hormone receptor positive breast cancer cells, while displaying varying toxicity against the TNBC and non-cancerous breast epithelial cells. In particular, lupeol-3-palmitate (47.6 ± 1.50 μM) and glutinol (26.9 ± 1.30 μM) displayed the greatest inhibitory activity against the HCC70 cell line, with the former being selectively toxic to HCC70 and not MCF-12A non-cancerous cells.
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Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Ent-abietane diterpenoids from Suregada
zanzibariensis Baill. (Euphorbiaceae), their
cytotoxic and anticancer properties
Mandisa Mangisa, Vuyelwa J. Tembu, Gerda Fouche, Rudzani Nthambeleni,
Xolani Peter & Moses K. Langat
To cite this article: Mandisa Mangisa, Vuyelwa J. Tembu, Gerda Fouche, Rudzani Nthambeleni,
Xolani Peter & Moses K. Langat (2019) Ent-abietane diterpenoids from Suregada�zanzibariensis
Baill. (Euphorbiaceae), their cytotoxic and anticancer properties, Natural Product Research, 33:22,
3240-3247, DOI: 10.1080/14786419.2018.1470628
To link to this article: https://doi.org/10.1080/14786419.2018.1470628
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Published online: 09 May 2018.
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https://doi.org/10.1080/14786419.2018.1470628
Ent-abietane diterpenoids from Suregada zanzibariensis Baill.
(Euphorbiaceae), their cytotoxic and anticancer properties
MandisaMangisaa, Vuyelwa J.Tembua, GerdaFoucheb, RudzaniNthambelenib,
XolaniPeterc and Moses K.Langatd
aDepartment of Chemistry, Tshwane University of Technology, Pretoria, South Africa; bBiosciences, Council
for Scientific and Industrial Research, Pretoria, South Africa; cDefence, Peace, Safety and Security, Council
for Scientific and Industrial Research, Pretoria, South Africa; dNatural Products Research Group, Faculty of
Engineering and Physical Sciences, Department of Chemistry, University of Surrey, Guildford, Surrey, UK
ABSTRACT
The stem bark extract of Suregada zanzibariensis aorded a previously
undescribed ent-abietane diterpenoid trivially named mangiolide
(1) and a known jolkinolide B (2) via anticancer bioassay-guided
fractionation. The CH2Cl2:MeOH extract of S. zanzibariensis was initially
analysed for its anticancer properties against three cancer cell lines,
renal (TK10), melanoma (UACC62), and breast (MCF7) and was found
to be potent at low μg/mL ranges. Compound 1, 6α-acetoxy-14-keto-
ent-abieta-7(8),13(15)-diene-16,12-olide (mangiolide) inhibited the
growth of renal (TK10) with a GI50 of 0.02μg/mL; a GI50 of 0.03μg/mL for
melanoma (UACC62) and a GI
50
of 0.05μg/mL for breast (MCF7) cancer
cell lines. Compound 2, 8,13-diepoxy-13,15-ent-abietene-16,12-olide
(jolkinolide B) inhibited the growth (GI50) of the cell lines at 3.31μg/
mL for renal (TK10), 0.94μg/mL for melanoma (UACC62) and 2.99μg/
mL for the breast (MCF7). The structures were established on the basis
of their spectroscopic analysis and the absolute stereostructures
assigned using electronic circular dichroism (ECD).
© 2018 Informa UK Limited, trading as Taylor & Francis Group
KEYWORDS
Cytotoxicity; cancer
cell lines; ent-abietane
diterpenoid lactone;
Suregada zanzibariensis;
Euphorbiaceae
ARTICLE HISTORY
Received 19 January 2018
Accepted25 April 2018
CONTACT Vuyelwa J. Tembu Tembuvj@tut.ac.za
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2018.1470628.
NATURAL PRODUCT RESEARCH
2019, VOL. 33, NO. 22, 3240–3247
1. Introduction
The World Health Organization reported 8.2 million deaths in 2012 due to cancer, with lung
cancer, 1.82 million deaths, being the most common cause of cancer death (Ferlay et al.
2015). Cancer remains a leading disease threatening human life worldwide, more than the
number of cases of deaths and illness due to HIV/AIDS, malaria and tuberculosis (Vorobiof
and Abratt 2007). Cancer is described as a group of diseases characterized by the uncontrol-
lable growth and spread of abnormal cells (Mathur et al. 2015). In 2012, the cancer burden
increased to an estimated 14 million new diagnosed cases (Ferlay et al. 2015). The current
cancer treatments include radiation, surgery of tumor, chemotherapy and chemically derived
drugs (Mathur et al. 2015). Chemotherapy can provide impermanent relief but possesses
various toxic side eects which can put patients under a lot of strain and damage their health
further (Kaur et al. 2011; Lakshmi et al. 2015). However, cancer can be cured or treated if
detected early. Therefore, there is a need to develop new, safe and eective anticancer drugs
to combat cancer. In this work Suregada zanzibariensis plant extracts were screened for their
anticancer properties.
The genus Suregada, also named Gelonium, belongs to the tribe of Gelonieae, subfamily
of Crotonoideae of the Euphorbiaceae family. The genus Suregada comprises about 30 spe-
cies, 8 of which occur in Africa and 14 in Madagascar. S. zanzibariensis Baill. is widely spread
in the east coastal belt of Africa from Somalia, southwards to South Africa and in Madagascar
(Schmelzer and Wageningen 2008). S. zanzibariensis is an evergreen shrub or a small tree
with horizontal branches that grows up to 0.5–10 m tall. The plant generally has smooth,
bark grey, green stems and obovate leaf blade to elliptic obovate (Palgrave 2002). The root
and stem bark extracts are used in Tanzania to treat ankylostamiasis and a tea from the roots
is drunk to treat gonorrhoea, stomach ache, chest pain, hernia, pneumonia and snake bites
and the leaves are used to treat skin infections, Innocent et al. 2009 further reported that
the essential oil of the leaves of S. zanzibariensis were found to be mosquito repellent.
Previous phytochemical investigation of the Suregada genus has aorded various abie-
tane lactone diterpenoids, kaurane, avonoids and triterpenoids (Choudhary et al. 2004;
Jahan et al. 2004; Lee et al. 2008). It has been reported that the extract and previously isolated
compounds from the plant species of Suregada have been tested against cancer cell lines.
Jahan et al. 2002 reported that the CH2Cl2/MeOH extract of Suregada multiora exhibited
signicant cytotoxicity for non-small cell lung (NCI-H322 M), colon (SW-620), CNS (U2S1)
and breast (MDA-MB-435) human tumor cell lines. The extract and isolated compounds of
Gelonium aequoreum, a synonym of Suregada aequoreum were evaluated for their moderate
cytotoxicity against lung (A549), breast (MDA MB 231 and MCF7) and liver (HepG2) cancer
lines (Lee et al. 2008). The compound bauerenol, isolated from S. anguistifolia was found to
possess cytotoxic and apoptic potential against HepG2 cancer cells (Kumar et al. 2017).
As part of the CSIR Bioprospecting platform research, 11 000 plants were collected
throughout South Africa. Approximately 7 500 plant extracts were made from these plants
and randomly screened for their anti-cancer properties against three cancer cell lines, mel-
anoma UACC62, breast MCF7 and renal TK10. Based on the screening results S. zanzibariensis
(Euphorbiaceae) extract exhibited potent anticancer activity against all the cell lines tested,
thus prompted further research to isolate the active compounds. Through bioassay guided
fractionation, we report the isolation and structural elucidation of previously undescribed
lactonized ent-abietane diterpenoid 1 and the known compound 2.
NATURAL PRODUCT RESEARCH 3241
2. Results and discussion
2.1. Structural elucidation of 1 and 2
Compound 1 (Figure 1) was isolated as a white solid and its mass spectrometric analysis
gave a pseudomolecular ion peak [M−H] of 371.1794 that supported a molecular formula
of C22H28O5 (calculated M = 372.1934). A double bond equivalence of nine was deduced.
The IR spectrum of 1 showed absorption bands at 1770, 1732 and 1691 for three carbonyls
stretches, and 1630 cm−1 for double bond stretches. The 1H NMR spectrum of 1 displayed
resonances for ve methyl singlets groups resonating at δ 0.98, δ 1.12, δ 1.15, δ 2.06 and
δ 2.20 ppm that were assigned to 3H-18, 3H-19, 3H-20, methyl group of the acetate and a
3H-17, vinylic methyl group respectively. Two distinct downeld methine proton resonances
at δ 5.78 (br s) and δ 4.98 (m) which were ascribed to H-6 and H-12 were also seen and
observed to correspond with carbon resonances at δ 66.1 and δ 77.8 in the HSQC spectrum
respectively.
The 13C NMR spectrum showed 22 carbon resonances, which included two double bonds,
an acetate group, a ketone and lactone carbonyl resonances at δ 138.3, δ 150.1, δ 169.8,
δ 173.1 and 186.9 ppm. All of which accounted for a nine double bond equivalence, which
in turn indicated that, the molecule was tetracyclic. The 1H and 13C NMR spectra suggested
that the compound was an acetylated diterpenoid.
The upeld ketone chemical shift at δ 186.9 in the 13C NMR spectrum suggested the
presence of an α-β unsaturated ketone carbonyl. The 13C NMR spectrum showed a carbonyl
carbon resonance at δ 173.08 ascribed to C-16 which was seen to correlate in the HMBC
spectrum with the methyl proton resonance at 3H-17. The 3H-17 resonance showed a cor-
relation in the HMBC spectrum with a carbon resonance at δ 150.6 which was ascribed to
C-15 (Figure 1). Furthermore, the C-15 carbon resonance showed HMBC correlation with the
two methylene proton resonances at δ 2.60 and δ 1.59 for the two H-11 protons. The 2H-11
showed coupling in the COSY spectrum with the resonances at δ 2.43 and δ 4.98 correspond-
ing to protons to H-9 and H-12 respectively.
More correlations were observed in the HMBC spectrum between the H-9 and the methyl
carbon resonance at δ 15.07 which was ascribed as C-20 and with the methylene carbon
Figure 1.Structures of compounds isolated from Suregada zanzibariensis.
M. MANGISA ET AL.
3242
resonance at δ 39.8 which was ascribed to C-1. The 2H-1 methylene proton resonance at δ
1.97 and δ 1.03 were seen to couple in the COSY spectrum with the two methylene proton
resonance at δ 1.67 and δ 1.56 that were assigned to 2H-2. The 2H-2 in turn showed COSY
coupling with the two methylene proton resonance at δ 1.43 and δ 1.21 for 2H-3. The cor-
responding carbon resonance, δ 44.5 showed correlation in the HMBC spectrum with the
methyl group proton resonances at δ 1.12 and δ 0.98 which were ascribed to 3H-18 and
3H-19 and with the methine proton resonance at δ 1.37 which was assigned as H-5. The H-5
methine proton resonance showed coupling in the COSY spectrum with the H-6 methine
proton resonance at δ 5.78.
The H-6 methine proton resonance showed a correlation in the HMBC spectrum with the
acetate carbonyl carbon resonance at δ 169.8. The acetate was then placed at C-6 due to
the correlation seen in the HMBC spectrum between the acetate group and H-6 resonance.
The H-6, in turn was coupled with the H-7 methine proton resonance at δ 6.70. The H-7
methine resonance showed a correlation in the HMBC with the carbonyl carbon resonance
at δ 186.9 which was assigned to C-14 and with the previously assigned C-5 and C-9. The
above information supported a 6-acetoxy-14-keto-abieta-7(8),13(15)-diene-16,12-olide. Use
of NOESY spectrum suggested the assigned relative conguration due to the following
correlations that were observed between: H-1α (1.97)/H-11α (2.60), H-5β (1.37)/H-9β (2.43),
H-9β/H-1β (1.03), H-9β/H-11β (1.59), 3H-20 (1.15)/H-11α, 3H-20/H-1α, 3H-20/H-2α, 3H-18β
(0.98)/H-5β (1.37), 3H-18/H-6β (5.78) and H-11α/H-12α (4.98). Compound 1 gave a specic
rotation value of +25.39° to suggest an ent-abietane series. An electronic circular dichroism
analysis of 1 gave Cotton eects at 324 (-2.0), 290 (+20.1), 237 (+1.5), 217 (−7.4) and 194
(+13.3) nm (S12). These data were similar to those reported by Lee et al. (2008) and Wang et
al. (2017) for ent-abietane diterpenoids with similar chromophores and opposite to those
reported for the normal series of abietane diterpenoids (Machumi et al. 2010). Compound
1 was assigned ent-abietane series and trivially named mangiolide.
Compound 2 (Figure 1) was found to be the known jolkinolide B. The 1H and 13C NMR
data for this compound were comparable to those reported earlier. Jolkinolide B has been
reported from Euphorbia scheriana (Wu et al. 2009; Geng et al. 2011) but this is the rst
report of jolkinolide B from a Suregada species (S1). The electronic circular dichroism analysis
of 2 gave Cotton eects at 251 (+49.6), 221 (−19.6) and 186 (−28.1) nm which were similar
to those reported by (Wang et al. 2017) for ent-abietane diterpenoids with similar chromo-
phores and supported the assignment of compound as an ent-abietane.
2.2. In vitro anticancer activity
The CH2Cl2:MeOH (1:1) extract of S. zanzibariensis was initially screened at a single dose
(100 μg/mL concentration) to determine its anticancer activity against the three cell lines,
renal (TK10), melanoma (UACC62) and breast (MCF7). The extract exhibited potent anticancer
activities when tested against the cancer cell lines with TGI (Total Growth Inhibition) values
of 0.60 μg/mL for TK10, 0.54 μg/mL for UACC62 and 5.27 μg/mL for MCF7 and GI50 (50%
Growth Inhibition) values of 0.26 μg/mL for TK10, 0.25 μg/mL for UACC62 and 0.81 μg/mL
for MCF7. Compound 1 and compound 2 were evaluated for anticancer activity against three
cancer cell lines. Compound 1 showed activity with the TGI values between 0.07 μg/mL for
TK10, 0.06 μg/mL for UACC62 and 0.33 μg/mL for MCF7 and GI50 of 0.02 μg/mL for TK10,
0.03 μg/mL for UACC62 and 0.05 μg/mL for MCF7. Compound 2 showed activity with TGI
NATURAL PRODUCT RESEARCH 3243
values 13.99 μg/mL for TK10, 5.03 μg/mL for UACC62 and 62.03 μg/mL for MCF7 and GI50
of 3.31 μg/mL for TK10, 0.94 μg/mL for UACC62 and 2.99 μg/mL for MCF7. Compound 2
showed selectivity against melanoma (UACC62) at GI50 value of 0.94 μg/mL. Both com-
pounds were tested for their cytotoxicity. According to IC50 (LC50) standard cytotoxicity cri-
teria, compound 1 was classied as toxic with the LC
50
< 10 μM. Compound 2 was previously
tested for its biological activities and showed a signicant antitumor activity against sarcoma
180 and Ehrlich ascites carcinoma in mice (Wu et al. 2009). Furthermore, the compound
regulated proliferation and induced apoptosis in human prostate cancer and K562 cells
in vitro (Geng et al. 2011). The CH
2
Cl
2
:MeOH (1:1) extract of S. zanzibariensis and compounds
1 and 2 isolated were screened at the CSIR, South Africa for their activity against three cancer
cell lines (Table 1).
3. Experimental
3.1. General procedures
The 1D and 2D NMR spectra for 1 and 2 were recorded in CDCl3 on a 600 MHz Varian NMR
Spectrometer. All NMR spectra were recorded at room temperature and the chemical shifts
were recorded in parts per million (ppm) and coupling constants (J) calculated in Hz. The
chemical shifts are recorded relative to the solvent chemical shifts at δ 7.24 in the 1H NMR
and δ 77.23 ppm in the 13C NMR spectra. Infrared Spectroscopy was carried out on a Perkin
Elmer FT-IR spectrometer, spectrum two (UATR TWO). Melting points were determined using
Stuart melting point apparatus SMP 20, 50 Hz power, 75 W. The optical rotation analyses
were done using Jasco P-2000 Series. Electonic circular dichroism studies were measured
using an Applied Photophysics chirascan spectrophotometer at the University of Surrey,
Guildford, UK using a 1 mm cell and CH3CN as the solvent. The MS analysis was performed
on a UPLC qTOF MS. Chromatographic separation was performed on an ACQUITY UPLC
system (Waters Corporations, Milford, MA) using a conditioned auto sampler at 4 °C. One (1)
μL of the extracts was separated on a Waters BEHC8 column (150 mm × 2.1 mm, 1.7 μm).
TLC was carried out on pre-coated aluminium backed silica plates and glass plates (Merck,
SlL G-25 F254, and 20 cm x 20 cm). Spots were visualised under UV light or by spraying with
vanillin staining reagent followed by heating. Column chromatography gravimetric (CC),
was performed on a silica gel 60, high purity grade and pore size at 60 Å, 70–230 mesh,
63–200 μm. The small quantities of fractions that required further purication, the PTLC plate
method was used to separate and obtain the pure compounds.
Table 1.Anticancer activities of CH2Cl2: MeOH (1:1) extract, compounds 1 and 2 against a panel of three
cancer cell lines.
Notes: TGI values of etoposide used as a positive control: [renal TK10: 27.00_g/mL; breast MCF7:>100_g/mL; melanoma
UACC62: 36.20_g/mL].
TK10 UACC62 MCF7
Extract 1 2 Extract 1 2 Extract 1 2
GI50 0.26 0.02 3.31 0.25 0.03 0.94 0.81 0.05 2.99
TGI 0.6 0.07 13.99 0.54 0.06 5.03 5.27 0.33 62.03
LC50 0.93 0.37 N/A 0.83 0.09 9.31 N/A N/A N/A
LC100 N/A 35.31 N/A N/A N/A N/A N/A N/A N/A
M. MANGISA ET AL.
3244
3.2. Plant material
The stem barks of the S. zanzibariensis were collected from KwaZulu Natal. The plant was
authenticated at the South African National Biodiversity Institute (SANBI), where voucher
specimens (HV00345), were deposited.
3.3. Extraction, liquid-liquid partitioning and isolation
The stem and roots plant material of S. zanzibariensis (1.5 kg) were extracted with 1:1 dichlo-
romethane/methanol organic solvents (1 L) for 24 h. The organic extract was concentrated
using rotary evaporator to give 20 g of residue. Through liquid-liquid partitioning of the
crude extract, hexane, dichloromethane (CH2Cl2) and aqueous water extracts were tested.
The active CH
2
Cl
2
extract was fractionated using column chromatography. The enriched and
pooled CH2Cl2 extract fractions were further puried using column and preparative thin
layer chromatography (TLC) plates and two diterpenoids 1 and 2 were isolated. The extract
was fractionated using column chromatography and eluted with mobile phase solvent with
increasing polarity, 100% hexane, 50/50 hexane/dichloromethane, 70/30 dichloromethane/
hexane, 100% dichloromethane, 10/90% methanol/dichloromethane, 50/50% methanol/
dichloromethane and 100% methanol solvent mixtures. Thirteen semi-pure fractions were
collected and concentrated using rotary evaporator and spotted in a TLC plate. Similar frac-
tions were combined. Fractions 4–8 were combined due to similarity and were further puri-
ed using column chromatography and eluted with a mobile phase 70%/30 dichloromethane/
hexane. Further purication using preparative TLC gave two UV active compounds 1 and 2.
3.4. In vitro anticancer assay
Plant extracts and compounds isolated were screened against a panel of three cancer cell
lines. This was carried out at the CSIR, Biosciences, South Africa using renal (TK10), breast
(MCF7) and melanoma (UACC62) cancer cell lines. The samples were tested at a single con-
centration of 100 μg/mL. The cultures were incubated for 48 h. Endpoint determinations
were made with a protein-binding dye, sulforhodamine B (SRB). The growth percentage was
evaluated spectrophotometrically versus controls not treated with test agents. Results for
the extract and each compound observed were reported as the growth percentage of the
treated cells, compared to that of the untreated control cells. Compounds with reduced
growth were further tested at ve concentrations ranging from 6.25–100 ppm and their TGI
(Total growth inhibition) and GI50 (50% growth inhibition) reported. Etoposide was used as
positive control (Fouche et al. 2008).
4. Compound characterization
4.1. Mangiolide
Mangiolide (1) was obtained as yellowish amorphous powder (10 mg), (m.p 187–195 °C),
[
𝛼]
22.1
D
+
25.39
(c = 0.50, CHCl3) IR (neat, CHCl3): 2924 cm−1 and 2854 cm−1 (CH), 1770 cm−1
(C = O) stretch of carbonyl carbon of an ester, 1637 cm−1 (C=C) stretch; 1H (600 MHz, CDCl3):
13C (125 MHz, CDCl3) NMR data, see Table S1, HRMS: ion [M-H]- of 371.1794 that supported
NATURAL PRODUCT RESEARCH 3245
a molecular formula of C22H28O5 (calculated M = 372.1934) for C22H28O5, UV: 263 nm. ECD
(CH3CN, 0.0001 g/mL): 324 (-2.0), 290 (+20.1), 237 (+1.5), 217 (-7.4) and 194 (+13.3) nm.
Supplementary material
Supplementary material relating to this article is available online together with Tables, Figures and
Diagrams.
Acknowledgements
The authors would like to thank the South African National Biodiversity Institute (SANBI) for the iden-
tication of plant specimens, NRF Thuthuka grant for funding the project.
Disclosure statement
No potential conict of interest was reported by the authors.
Funding
This work was supported by the Soth African National Research Foundation, Thuthuka grant [grant
number 99358].
ORCID
Vuyelwa J. Tembu http://orcid.org/0000-0002-7421-6467
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... Previously, β-amyrin palmitate was isolated from diferent plant species [22,23]. It exhibits a wide range of pharmacological and biological activities, cytotoxicity against breast cancer cells [20], antidiabetes [23], antidepressants [24], anti-infammatory [21], and antidyslipidemic [22]. [27,28] ( Table 4). ...
... it was obtained as a yellow amorphous(26 mg) with melting point of 69-70°C which is comparable with the literature reported melting point 72-73°C[20] and has an R f value of 0.5 (n-hexane/EtOAc; 19 : 1). Te compound was not readily visible on TLC plates under UV 254 / 365 nm lamp but visualized and detected as yellow color following exposure to iodine vapor. ...
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... Interestingly, less than 5% of the toxicity studies evaluated the toxicity of individual bioactive compounds (Table 1) and evaluation of the toxicity of the individual compounds is required. Furthermore, in cases where individual compounds were tested, most of the studies screened against cancer cell lines rather than normal cells (Zhou et al., 2006;Gamal-Eldeen et al., 2007;Yelani et al., 2010;Xuan and Khanh, 2016;Teclegeorgish et al., 2020). Fig. 3 summarises the most commonly used toxicological screening assays for evaluating southern African medicinal plants used to treat pain and inflammatory disorders. ...
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... Terpenoids [285] Terpenoids [286] Terpenoids [287] Terpenoids [288] Teucrium T. africanum α-Cubebene β-Cubebene 3 d 29 [ Terpenoids [297] Terpenoids [298] a Samples collected from one locality with no mention of replicates, b Cultivated/grown from seed/propagated, c Seasonal samples/different vegetative stages, d More than one locality specified, # Review article data,ˆCompounds occurring greater than 10% are listed as major compounds, * Naturalized exotic species. Essential oil studies: = GC Trace peaks, no identity, = <10 compounds identified, = many compounds identified. ...
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