Two pairs of unusual melibiose and raffinose esters from Scrophularia ningpoensis

Article abstract of DOI:10.1080/10286020.2017.1329301

A pair of unusual melibiose esters (1α/1β) and a pair of unusual raffinose esters (2α/2β), were isolated from Scrophularia ningpoensis. Structures of them were established by detailed spectroscopic analyses to be 6-O-(E)-cinnamoyl-α-d-galactopyranosyl-(1→6)-α(β)-d-glucopyranose (1α/1β) and 6-O-(E)/(Z)-cinnamoyl-α-d-galactopyranosyl-(1→6)-α-d-glucopyranosyl-(1→2)-β-d-fructofuranose (2α/2β), respectively. All these compounds were evaluated for antifouling activity against the settlement of Balanus amphitrite larvae, along with the cytotoxic effect against the proliferation of HeLa cell lines.

Full text of DOI:10.1080/10286020.2017.1329301

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: http://www.tandfonline.com/loi/ganp20
Two pairs of unusual melibiose and raffinose
esters from Scrophularia ningpoensis
Jun Zhang, Yan Liang, Fanny C. F. Ip, Nancy Y. Ip, Ting-Ting Liu, Ba-Lian Zhong
& Shi-Hai Xu
To cite this article: Jun Zhang, Yan Liang, Fanny C. F. Ip, Nancy Y. Ip, Ting-Ting Liu, Ba-Lian
Zhong & Shi-Hai Xu (2017): Two pairs of unusual melibiose and raffinose esters from Scrophularia
ningpoensis, Journal of Asian Natural Products Research, DOI: 10.1080/10286020.2017.1329301
To link to this article: http://dx.doi.org/10.1080/10286020.2017.1329301
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Date: 26 May 2017, At: 06:57

Journal of asian natural Products research, 2017
https://doi.org/10.1080/10286020.2017.1329301
Two pairs of unusual melibiose and raffinose esters from
Scrophularia ningpoensis
Jun Zhanga,b,c, Yan Lianga,b, Fanny C. F. Ipb, Nancy Y. Ipb, Ting-Ting Liua, Ba-Lian Zhonga
and Shi-Hai Xuc
anational engineering research center of navel orange, Gannan normal university, Ganzhou 341000, china;
bdivision of life science, the hong Kong university of science and technology, hongkong 999077, china;
ccollege of science and engineering, Jinan university, Guangzhou 510632, china
ARTICLE HISTORY
received 13 January 2017
accepted 8 May 2017
ABSTRACT
Apairofunusualmelibioseesters(1α/1β)andapairofunusualraffinose
esters (2α/2β), were isolated from Scrophularia ningpoensis. Structures
of them were established by detailed spectroscopic analyses to be
KEYWORDS
6-O-(E)-cinnamoyl-α-
d
-galactopyranosyl-(1→6)-α(β)-d-glucopyranose
scrophulariaceae;
Scrophularia ningpoensis;
phenylpropanoid glycoside;
melibiose ester; raffinose
ester
(1α/1β) and 6-O-(E)/(Z)-cinnamoyl-α-d-galactopyranosyl-(1→6)-α-d-
glucopyranosyl-(1→2)-β-d-fructofuranose (2α/2β), respectively. All
these compounds were evaluated for antifouling activity against the
settlement of Balanus amphitrite larvae, along with the cytotoxic effect
against the proliferation of HeLa cell lines.
CONTACT Jun Zhang
junyan@jnu.edu.cn
the supplemental data for this article can be accessed at https://doi.org/10.1080/10.1080/10286020.2017.1329301.
© 2017 informa uK limited, trading as taylor & francis Group

2
J. ZHANG ET AL.
1. Introduction
e genus Scrophularia of the family Scrophulariaceae encloses more than 300 species
with a wide distribution in south and northwest China. Scrophularia ningpoensis Hemsl,
commonly known as “Xuanshen” in Chinese, has been used in TCM practice for over
2000 years. Low doses of S. ningpoensis are cardiotonic and this plant is frequently utilized
in combination with other herbs as a nutrient and a health strengthening agent [1]. It has
been reported that the extract of S. ningpoensis exhibits antidepressant-like effect in mice
and alleviates the progression of neurodegenerative diseases by modulating anti-apoptotic
gene expression [2,3].
Previous chemical investigations have shown that a broad spectrum of phenylpropanoid
glycosides have been isolated from S. ningpoensis [4–9]. Some of these compounds were
found to exhibit varieties of medicinal properties, involving antioxidative [10], antiasth-
matic [11], hepatoprotective [12], tyrosinase inhibitory [13], and neuroprotective [14,15]
activities. In view of the herb’s biological effect, S. ningpoensis was selected and subjected to
fractionation to isolate structurally and biologically interesting constituents, leading to the
identification of three unusual zwitterionic alkaloids in our previous investigation [16]. In
this paper, we report here on the isolation and structural elucidation of two pairs of novel
phenylpropanoid glycosides from other fraction of the same crude extract as described
previously. Structurally, these new phenylpropanoid glycosides are unusual, assigned to be a
pair of melibiose esters (1α/1β) and a pair of raffinose esters (2α/2β), respectively (Figure 1).
Worthy to be noted, despite high amount of melibiose and raffinose presented in nature,
this is the first report of identification of naturally occurring melibiose and raffinose esters.
Figure 1. chemical structures of compounds 1α/1β and 2α/2β.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Table 1. 1h (300 Mhz) and 13c nMr (75 Mhz) spectral data of compounds 1α/1β and 2α/2β in cd3od.
1α/1β
δH (mult., J in Hz)
2α/2β
δH (mult., J in Hz)
No
δC
δC
1
2
3
4
5
6
7
8
–
135.7
130.0
129.3
131.6
129.3
130.0
146.6
118.7
168.5
–
135.6/136.2
130.1/130.8
129.3/129.2
131.6/130.2
129.3/129.2
130.1/130.8
146.7/144.8
118.6/120.1
168.6/167.8
100.4
70.3
71.1
71.0/70.9
70.0/69.8
65.3/65.0
93.4
7.59–7.63 (m)
7.39–7.42 (m)
7.39–7.42 (m)
7.39–7.42 (m)
7.59–7.63 (m)/7.57–7.59 (m)
7.39–7.42 (m)/7.34–7.37 (m)
7.39–7.42 (m)/7.34–7.37 (m)
7.39–7.42 (m)/7.34–7.37 (m)
7.59–7.63 (m)/7.57–7.59 (m)
7.73 (d, J = 15.9)/7.04 (d, J = 12.6)
6.54 (d, J = 15.9)/6.00 (d, J = 12.6)
–
7.59–7.63 (m)
7.73 (d, J = 16.2)
6.53 (d, J = 16.2)
9
–
1′
2′
3′
4′
5′
6′
1″
2″
3″
4″
5″
6″
1′″
2′″
3′″
4′″
5′″
6′″
4.90a, 5.56 (d, J = 3.3)b
3.79–3.81 (m)
100.1/100.2
70.4
4.89a, 5.44 (br. s)b/5.41 (br. s)b
3.75–3.80 (m)
3.79–3.81 (m)
3.90–3.94 (m)
4.18–4.24 (m)
4.32–4.38 (m)
71.4
71.1
69.9
65.2
94.1/98.4
73.8/76.2
75.0/78.2
72.1/71.5
71.5/76.2
67.5/67.8
3.83–3.85 (m)
3.93–3.95 (m)
4.14–4.18 (m)
4.34–4.38 (m)/4.26–4.30 (m)
5.39 (d, J = 4.2)/5.36 (d, J = 4.2)
3.40 (dd, J = 9.9, 3.6)
3.66–3.69 (m)
3.23–3.28 (m)
4.01–4.06 (m)
3.88–3.92(m), 3.67–3.71 (m)
3.59–3.61 (m)
5.11 (d, J = 3.6)/4.51 (d, J = 7.8)
3.34–3.38 (m)/3.16–3.20 (m)
3.64–3.70 (m)/3.34–3.38 (m)
3.31–3.35 (m)/3.36–3.40 (m)
3.96–4.02 (m)/3.46–3.50 (m)
3.96–4.02 (m), 3.66–3.72 (m)
73.0
74.5
71.9
73.1
68.3
64.1
105.4/105.3
79.0
4.08–4.10 (m)
4.01–4.06 (m)
3.74–3.79 (m)
3.73–3.80 (m)
75.4
83.4
63.3
aMasked by solvent peak.
brecorded in pyridine-d5.
2. Results and discussion
e 70% EtOH/H2O crude extract of the dried root of S. ningpoensis was suspended in
water and extracted subsequently with petroleum ether, EtOAc, and n-BuOH. From the
n-BuOH extract, two pairs of phenylpropanoid glycosides (1α/1β-2α/2β) were isolated by
means of macroporous resin column chromatograph (CC), silica gel CC, and prep. HPLC.
Compounds 1α/1β, a brown amorphous powder, were obtained as a pair of insepara-
ble epimers. e same molecular formula of 1α/1β, being C21H28O12, was determined by
HR-ESI-MS showing ion peaks at m/z 495.1453 [M + Na]+, 473.1654 [M + H]+, and 455.1540
[M – H2O + H]+. e IR spectrum showed absorption bands of hydroxyl (3371 cm−1), ole-
finic bond (1635 cm−1), and conjugated ester groups (1704 cm−1). Afer acid hydrolysis of
1α/1β, d-glucose and d-galactose were detected by GC analysis (Supporting information,
SI). e NMR spectra exhibited pairs of signals at the positions of from C-1″ to C-6″, with
a rough ratio of 1:1, suggesting that 1α/1β might be a pair of anomers due to the inter-
conversion of stereochemistry at C-1″ of the glucose moiety, similar to that of cistanoside
F [17]. HPLC was tried repeatedly to isolate the epimers 1α/1β, but it was not possible to
separate them due to their interconversion. e 1H NMR spectrum of 1α/1β (Table 1) dis-
played typical signals of anomeric protons indicative of the presence of β-d-glucopyranosyl
at δ 4.51 (d, J = 7.8 Hz, Hβ -1″), α-d-glucopyranosyl at δ 5.11 (d, J = 3.6 Hz, Hα -1″), and
α-d-galapyranosyl at δ 4.90 (overlapped with CD3OD signal, H-1′). e α-configuration
of d-galapyranosyl was supported by the small coupling constant of J1′,2′ being 3.3 Hz,

4
J. ZHANG ET AL.
Figure 2. the key hMBc correlations of compounds 1α/1β and 2α/2β.
which was identified in the 1H NMR spectrum recorded in pyridine-d5 (SI). Furthermore,
the 1H NMR spectrum indicated the presence of one monosubstituted aromatic ring at δ
7.59–7.63 (m, H-2/H-6), 7.39–7.42 (m, H-3/H-4/H-5), two trans olefinic protons at δ 7.73
(d, J = 16.2 Hz, H-7), 6.53 (d, J = 16.2 Hz, H-8) in 1α/1β, suggesting the structural skeleton
of 1α/1β might be phenylpropanoid glycoside. is suggestion was further supported by
the 13C NMR data (Table 1) and the detailed 2D NMR (1H–1H COSY, HSQC, and HMBC)
analyses. e cinnamoyl moiety was identified by the 1H–1H COSY cross peaks, in combi-
nation with the correlations from H-8 to C-1 (δ 135.7) and H-7 to C-9 (δ 168.5) in HMBC
spectrum. Diagnostic HMBC correlations between H-1′ and C-6″ (δ 67.5/67.8), and in
turn between H-6″ (δ 3.96–4.02, 3.66–3.72) and C-1′ (δ 100.1/100.2), indicated that the
galactose unit was linked to the glucose unit by a (1→6) linkage. A key cross peak between
H-6′ (δ 4.32–4.38) and C-9 in HMBC spectrum (Figure 2) established the linkage between
the aglycon and the sugar moiety, as shown in Figure 1. On the basis of above information,
compounds 1α/1β, therefore, were assigned as 6-O-(E)-cinnamoyl-α-d-galactopyranosyl-
(1→6)-α(β)-d-glucopyranose. Structurally, compounds 1α/1β are very interesting, as unu-
sual melibiose esters. As far as we know, it is the first report of the presence of naturally
occurring melibiose ester, despite high content of melibiose being found in nature.
Compounds 2α/2β, also being a pair of isomers, were isolated as a brown amorphous
powder. Due partly to the limited amount obtained, we failed to separate them successfully.
e 1H NMR spectrum displayed pairs of signals in the downfield region. In particularly, a
pair of trans/cis double bonds with signal strength ratio being about 2:1 (trans: cis), could
be easily identified, suggesting compounds 2α/2β might be a pair of geometric isomers.
1
Comprehensive analyses of the H, 13C NMR spectra supported that compounds 2α/2β
were phenylpropanoid glycosides as well, similar to 1α/1β. e HR-ESI-MS at m/z 657.2012
[M + Na]+ assigned molecular formula of C27H38O17 to compounds 2α/2β. e IR spectrum

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
suggested the presence of OH (3377 cm−1), olefinic bond (1636 cm−1), and conjugated ester
(1701 cm−1) groups. Furthermore, d-glucose, d-galactose, and d-fructose were detected by
the GC analyses afer acid hydrolysis of 2α/2β (SI). e chemical shif and the signal pattern
of the anomeric proton H-1′ at δ 5.44 (br.s)/5.41 (br.s) (recorded in pyridine-d5) for 2α/2β,
respectively, supported the assignment of α-configuration to galactose unit. Meanwhile, the
α-configuration of the glucose unit was indicated by the small coupling constant of J1″,2″
= 4.2 Hz, whereas, the β-configuration for fructose unit was determined by comparison
of NMR data with those reported in literature [18,19]. e assignment of trans/cis-cin-
1
namoyl moieties in 2α/2β, respectively, could be determined by the H NMR spectrum
showing typical signals for trans olefinic protons at δ 7.73 (d, J = 15.9 Hz, Hα -7) and 6.54
(d, J = 15.9 Hz, Hα -8), and cis olefinic protons at δ 7.04 (d, J = 12.6 Hz, Hβ -7) and 6.00 (d,
J = 12.6 Hz, Hβ -8), together with the HMBC correlations from H-7 to C-9 (δ 168.6/167.8
for 2α/2β, respectively) and H-8 to C-1 (δ 135.6/136.2 for 2α/2β, respectively) (Figure 2).
Starting from the anomeric proton/carbon signals, all 1H and 13C NMR chemical shifs of the
sugar units (Table 1) could be assigned by the careful analyses of 1H–1H COSY, HSQC, and
HMBC. e connection sequence of the three sugar units and the aglycon was determined
by HMBC experiment. e diagnostic correlations between H-6′ (δ 4.34–4.38/4.26–4.30 for
2α/2β, respectively) and C-9, H-6″ (δ 3.88–3.92, 3.67–3.71) and C-1′ (δ 100.4), as well as
H-1″ (δ 5.39/5.36 for 2α/2β, respectively) and C-2″′ (δ 105.4/105.3 for 2α/2β, respectively)
in HMBC spectrum, established the linkage sequence of these moieties (Figure 2), com-
pletely achieving the structure elucidation. erefore, compounds 2α/2β were determined
to be 6-O-(E)/(Z)-cinnamoyl-α-d-galactopyranosyl-(1→6)-α-d-glucopyranosyl-(1→2)-β-
d-fructofuranose. Interestingly, compounds 2α/2β are a pair of raffinose esters. It is the first
report of the presence of naturally occurring raffinose ester.
Compounds 1α/1β, 2α/2β were evaluated for antifouling effect against the settlement
of Balanus amphitrite larvae. Unfortunately, none of them exhibited inhibitory effect at the
concentrations up to 25 μg/ml. e cytotoxic activity of these isolates against the HeLa cell
lines was evaluated as well, compounds 1α/1β showed weak cytotoxicity with IC50 being
20.3 μg/ml, while 2α/2β having no biological effect inhibiting the proliferation of HeLa cell
lines at the concentrations up to 25 μg/ml.
3. Experimental
3.1. General experimental procedures
Optical rotation was measured on JASCO P-2000 digital polarimeter (Jasco, Tokyo, Japan).
UV spectrum was recorded on Shimadzu UV2401PC spectrophotometer (Shimadzu, Kyoto,
Japan). IR spectra were recorded on Perkin–Elmer 16 PC FT-IR spectrometer (Perkin–Elmer,
Boston, U.S.A). NMR experiments were measured on Varian Mercury VX 300 spectrometer
(Varian, Tokyo, Japan) operating at 300 and 75 MHz for 1H and 13C, respectively, with TMS
as internal standard and chemical shifs reported in ppm. High-resolution mass spectra
(HRMS) were performed on QSTAR XL mass spectrometry system (Applied Biosystems,
California, U.S.A). e preparative HPLC was performed on Waters systems (Waters,
Watford, UK) involving Waters 2545 binary gradient module, Waters 2996 PDA detector,
MassLynx V4.1 workstation, and XBridge RP18 column (19×300 mm, 5 μm). Column
chromatography (CC) was performed with silica gel (230–400 mesh, Merck, Darmstadt,

6
J. ZHANG ET AL.
Germany) or macroporous absorptive resin D101 (250–300 μm, Tianjin Pesticide Factory,
Tianjin, China). TLC was performed on aluminum sheet precoated with silica gel G60
(Merck, Darmstadt, Germany). GC analysis was performed on HP 6850 gas chromato-
graph (Hewlett–Packard, California, U.S.A) equiped with FID detector and HP-1 column
(30 m×0.25 mm×0.25 μm).
3.2. Plant material
Roots of Scrophularia ningpoensis were collected in August 2006 in Ningbo, Zhejiang prov-
ince of China. e plant was identified by Dr. Guangmiao Fu and a voucher specimen
(TCM-203) was deposited in the Biotechnology Research Institute of e Hong Kong
University of Science and Technology.
3.3. Extraction and isolation
Dried roots of S. ningpoensis (4.3 kg) were crushed and extracted with 70% EtOH aqueous
solution (3×10 L) for 2 h each time under refluxing condition. e extract was concen-
trated in vacuo to give a residue (505 g), which was suspended in water (0.8 L), followed
by successive extraction using petroleum ether (1 L×3), EtOAc (1 L×3), and n-BuOH
(1 L×3). e n-BuOH extract (126.4 g) was subjected to macroporous absorptive resin
D101 column chromatography (CC) and eluted with a gradient mixture of EtOH/H2O
(0, 30%, 60%, 95%) to give eight fractions (Frs. A-H). Fr. E (11.0 g) was subjected to silica gel
CC eluted with increasing polarity mixture of CHCl3-MeOH-H2O (from 5:95:0 to 30:70:5)
to give 20 fractions (Frs. E1-E20). Fr. E10 (0.1 g) was further purified by prep. RP-HPLC,
which was eluted with 15% CH3CN-H2O to give compounds 1α/1β (11.5 mg, tR 12.8 min)
and 2α/2β (9.4 mg, tR 8.6 min).
3.3.1. 6-O-(E)-Cinnamoyl-α-d-galactopyranosyl-(1→6)-α(β)-d-glucopyranose (1α/1β)
Amorphous brown powder. [ꢀ]2D5 + 64.1(c 1.03, MeOH). IR (film) νmax: 3371, 2927, 1704,
1635, 1313, 1152, 1082, 1027 cm−1. UV (MeOH) λmax (log ε): 205 (2.46), 216 (2.35), 225
(2.38), 278 (2.41) nm; 1H and 13C NMR spectral data, see Table 1. HR-ESI-MS: m/z 495.1453
[M + Na]+ (calcd for C21H28NaO12, 495.1478), 473.1654 [M + H]+ (calcd for C21H29O12,
473.1659), 455.1540 [M – H2O + H]+ (calcd for C21H27O11, 455.1553).
3.3.2. 6-O-(E)/(Z)-Cinnamoyl-α-d-galactopyranosyl-(1→6)-α-d-glucopyranosyl-(1→2)-
β-d-fructofuranose (2α/2β)
Amorphous brown powder. [ꢀ]2D5 + 66.2 (c 0.91, MeOH). IR (film) νmax: 3377, 2931, 1701,
1636, 1055, 995 cm−1. UV (MeOH) λmax (log ε): 204 (2.64), 217 (2.75), 223 (2.43), 279 (2.57)
nm. 1H and 13C NMR spectral data, see Table 1. HR-ESI-MS: m/z 657.2012 [M + Na]+ (calcd
for C27H38NaO17, 657.2007).
3.4. Acid hydrolysis
e acid hydrolysis of the glycosides was performed according to the literature [20]. Briefly,
the isolated compounds 1α/1β, 2α/2β (each 1.2 mg) were hydrolyzed in 2 M CF3COOH
(0.5 ml) at 120 °C for 1 h, respectively. en the solvent was evaporated by flushing with

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
N2 to give a residue, to which 1 M NH4OH (0.2 ml) was added, followed by the addition of
the solution of NaBH4 (4 mg) in 1 M NH4OH (0.3 ml). e mixture was then reacted for
1 h at 40 °C. Excess NaBH4 was quenched with 0.5 ml AcOH, and the boric acid formed
was removed by co-distillation with 10% AcOH in MeOH (3×0.5 ml) followed by MeOH
(3×0.5 ml). e resulting alditols were acetylated with Ac2O-pyridine (1:1, 0.6 ml) at 120 °C
for 40 min. en the solvent was evaporated by flushing with N2, and the resulting residue
was extracted with DCM (0.5 ml). e obtained DCM solution was subject to GC analysis
under the following conditions: HP 6850 gas chromatograph equipped with an FID detec-
tor. Column: HP-1 column (30 m×0.25 mm×0.25 μm). Column temperature: 170 °C.
Carrier gas: H2 (2.0 ml/min). Injector and detector temperature: 220 °C/300 °C. Injection
volume: 1 μl. GC analysis showed the presence of d-galactose (tR 12.83 min) and d-glucose
(tR 12.43 min) in 1α/1β with a ratio of 1:1. Meanwhile, the GC result also indicated the pres-
ence of d-galactose (tR 12.84 min), d-glucose (tR 12.44 min), and d-fructose (tR 11.93 min
and 12.44 min) in 2α/2β with a ratio of 1:1:1. Retention times of the authentic samples afer
being treated with the same procedure as that of 1α/1β or 2α/2β, were detected at 12.84 min
(d-galactose), 12.44 min (d-glucose), 11.93 min and 12.44 min (d-fructose).
3.5. Antifouling assay
e antifouling effect was evaluated according to our previously established procedure [21].
Fresh cyprids of the barnacle Balanus amphitrite were used in the testing. Larval settlement
assays were examined using 24-well polystyrene plates. e tested samples were first dis-
solved with small amount of dimethyl sulfoxide (DMSO) and then diluted with 0.22 μm
filtered seawater (FSW) to achieve the final concentrations of 25.0, 12.5, 6.25, and 3.13 μg/
ml. About 15−20 competent larvae were added to each well containing 1 ml of test solution
in triplicate, and wells having only FSW, DMSO, and larvae served as the control. e plates
were incubated at 25 °C for 48 h, which were then examined under a microscope to count
settled, unsettled larvae, and where appropriate, potential toxic effects were recorded. e
number of settled larvae was expressed as a percentage of the total number of larvae per
well. e EC50 was calculated as the concentration where 50% of the larval individuals were
inhibited to settle as compared to the control, while LC50 was calculated as the concentration
where 50% of the larval population was dead.
3.6. Cytotoxicity assay
e cytotoxic effect against the proliferation of HeLa cervical cancer cells was evaluated
by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] method. In
briefly, the HeLa cells were cultured in a 96-well plate at a density of 1×104 cells per well
and incubated for 20 hours, followed by the treatment of testing samples at various con-
centrations. en the plate was incubated at 37 °C for 48 h in a 5% CO2 atmosphere. e
supernatant was removed, followed by addition of 25 μl of MTT [2.5 mg ml−1 in PBS (phos-
phate-buffered saline)] to each well. Afer incubation at 37 °C for 4 h, 100 μl of dimethyl
sulfoxide (DMSO) was added to each well and incubated for another 20 min. e absorbance
of each well was then measured at 570 nm using a ermo scientific Multiskan FC multiplate
photometer (Waltham, MA, U.S.A).

8
J. ZHANG ET AL.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
is work was financially supported in part by the National Natural Science Fund of China [41506156],
Natural Science Fund of Guangdong Province [2016A030310095], Research Foundation from
Department of Education of Jiangxi Province [460911], and Hong Kong Research Grants Council
eme-based Research Scheme [T13-607/12R].
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