Natural Product Research, 2016

http://dx.doi.org/10.1080/14786419.2016.1138299

Two new polyhydroxylated triterpenoids from Salvia

urmiensis and their cytotoxic activity
Mahdi Moridi Farimani and Mahdi Abbas-Mohammadi
Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University,
Tehran, Iran

ABSTRACT ARTICLE HISTORY

Two new polyhydroxylated triterpenoids were isolated from the Received 20 October 2015
acetone extract of the aerial parts of Salvia urmiensis Bunge. Their Accepted 17 December 2015
structures were elucidated by 1D and 2D NMR and HR-ESI-MS KEYWORDS
analyses as olean-12-ene-1β,3β,11α,22α-tetraol (1) and urs-12-ene- Salvia urmiensis;
1β,3β,11β,22α-tetraol (2). The effect of these compounds on cell triterpenoid;
viability of MCF-7 cells was investigated by the MTT assay. Compounds polyhydroxylation; cytotoxic
1 and 2 showed weak cytotoxicity with IC50 values of 110.23 ± 0.12 activity
and 88.35 ± 0.09 μM, respectively.

1. Introduction
The genus Salvia is one of the largest members of the family Lamiaceae, comprising more
than 900 species, large widespread all over the world. Salvia species have been used in
traditional medicine all around the world since the ancient times. Their essential oils and
extracts have shown antimicrobial, antioxidant, antidiabetic, antitumour, antiplasmodial
and anti-inflammatory activities (Sivropoulou et al. 1997; Dorman & Deans 2000; Ulubelen
2003; Tepe et al. 2004; Kamatou et al. 2008; Şenol et al. 2010; Chan et al. 2011; Loizzo et al.
2014; Bahadori et al. 2015). Many Salvia species are used as herbal tea and in food, cosmetics,
CONTACT Mahdi Moridi Farimani [email protected]
 Supplemental data for this article can be accessed at http://dx.doi.org/10.1080/14786419.2016.1138299.
© 2016 Taylor & Francis
2 M. Moridi Farimani and M. Abbas-Mohammadi

perfumery and the pharmaceutical industry, and some species are grown in gardens as orna-
mental plants (Kahraman et al. 2010). A diverse spectrum of secondary metabolites has been
identified in Salvia species (Wu et al. 2012). In Iran, there is a high diversity of Salvia species
and accessions which includes 61 species, 17 of them are endemic (Jamzad 2012). Some
Iranian Salvia species have been investigated from a phytochemical viewpoint, and their
biological activities (Moridi Farimani et al. 2008, 2012; Gandomkar et al. 2011; Rafatian et al.
2012; Farjam et al. 2013; Habibi et al. 2013; Ebrahimi et al. 2014; Esmaeili & Moridi Farimani
2014; Moridi Farimani & Mazarei 2014; Moridi Farimani & Miran 2014; Akaberi et al. 2015;
Salimikia et al. 2016). Salvia urmiensis Bunge is an aromatic perennial herb that is found in the
West Azerbaijan province of northwestern Iran. We recently identified several triterpenoids
with rare carbon skeletons from the n-hexane and acetone extracts of this species (Moridi
Farimani et al. 2013; Moridi Farimani, Bahadori, et al. 2015; Moridi Farimani, Mohammadi,
et al. 2015). Further examination of the acetone extract of S. urmiensis led to the isolation
of two new triterpenoids, with polyhydroxylated oleanane and ursane skeletons (1, 2) on
the basis of extensive spectroscopic data (Figure 1). Also, cytotoxic activity of the purified
compounds was determined on MCF-7 cells.

2. Results and discussion

Compound 1 was obtained as a white, amorphous powder. Its molecular formula, C30H50O4,
was determined on the basis of its HR-ESI-MS spectrum (m/z 497.3593 [M + Na]+, Calcd
497.3601) with 6° of unsaturation. The 13C NMR spectrum revealed 30 carbon resonances
which were resolved into eight methyl, seven methylene, eight methine and seven qua-
ternary carbons as categorised by HSQC and APT experiments. 13C NMR data showed one
tri-substituted C=C group (δC 124.5, 147.0) and four oxygen-bearing sp3 carbons at δC 66.0,
75.0, 75.6, and 76.7. According to the degree of unsaturation, the structure of 1 must be
pentacyclic due to the absence of any other sp or sp2 carbon signals. The 1H NMR spectrum
in conjunction with the HSQC spectrum showed resonances for an olefinic proton at δH
5.15 (1H, d, J = 3.8 Hz), four protons at δH 3.10 (1H, dd, J = 11.5 and 4.5 Hz), δH 3.39 (1H, dd,
J = 11.5 and 5.0 Hz), δH 3.43 (1H, dd, J = 11.5 and 4.5 Hz) and δH 4.15 (1H, dd, J = 8.5 and

Figure 1. Chemical structures of the isolated compounds.

 Natural Product Research  3

3.8 Hz) indicative of oxygenated methines, and eight methyl singlets at δH 0.69, 0.84, 0.86,
0.89, 0.90, 0.94, 0.97 and 1.18. Therefore, the structural features were reminiscent of a poly-
hydroxylated oleane type triterpenoid. Analysis of HMBC correlations confirmed the location
of substituents. The signals of H3-23 (δH 0.89) and H3-24 (δH 0.69) were correlated with the
resonances of an oxygen-bearing carbon (C-3, δC 75.6), an aliphatic methine (C-5, δC 52.1)
and a quaternary carbon (C-4, δC 38.7), suggesting that one hydroxyl group was located at
C-3. A second hydroxyl group was assigned to be at C-1 according to the HMBC cross peaks
of H-1 (δH 3.39) with C-2 (δC 34.7), C-3 and C-25 (δC 12.2), and also of H-3 (δH 3.10) with C-1
(δC 76.7). 1H–1H COSY correlations of methylene protons at C-2 (δH 1.65 and 1.72) with both
H-1 and H-3 supported the A-ring 1,3-dihydroxy moiety. Strong HMBC correlations between
H-11 (δH 4.15) and C-9 (δC 55.5), C-12 (δC 124.5) and C-13 (δC 147.0) were used to assign a
third hydroxy group to C-11. This confirmed by 1H–1H COSY correlations between H-11 and
two other methinic protons at δH 1.63 (H-9) and δH 5.15 (H-12). HMBC correlations of H3-29
(δH 0.84) and H3-30 (δH 0.86) with C-19 (δC 45.3), C-20 (δC 31.0), and C-21 (δC 42.2), H-21
(δH 1.30) with C-22 (δC 75.0), and H3-28 (δH 0.9) with C-17 (δC 38.1), C-18 (δC 46.7), and C-22
(δC 75.0) confirmed the nature of ring E with a hydroxyl group at C-22. The downfield shifts
of C-17 (δC 38.1) and C-21 (δC 42.2), and 1H-1H COSY correlations between H-21 (δH 1.30) and
H-22 (δH 3.43) supported this assignment. The relative configuration of 1 was corroborated by
a NOESY spectrum and coupling constants (3JH−H). Diagnostic cross-peaks between H3-23, H-3
and H-5, between H-5 and H-1, and between H-3 and H-1 clarified the β-orientations of OH-3
and OH-1. The coupling constants of H-1 (dd, 11.5, 5.0 Hz), H-3 (dd, 11.5, 4.5 Hz) and H-5 (dd,
11.5, 2.0 Hz) confirmed their axial orientations. Likewise, NOESY correlations between H-11,
H3-25 and H3-26 confirmed their occupation of the same face of the molecule. The coupling
constants of H-11 (dd, 8.5, 3.8 Hz) confirmed that the hydroxyl group was in an equatorial
orientation. Equally, diagnostic cross peaks between H-22, H-18 and H3-28 were observed
and confirmed their cofacial orientation. Furthermore, the coupling constants of H-22
(dd, 11.5, 4.5 Hz) corroborated the equatorial orientation of the hydroxyl group. Therefore,
the structure of 1 was determined as olean-12-ene-1β,3β,11α,22α-tetraol.
Compound 2 was isolated as an amorphous powder. It had the same molecular formula
C30H50O4 (m/z 497.3605 [M + Na]+, Calcd 497.3601), as 1. The NMR spectroscopic data of 2
showed strong similarities to those of 1. In particular, rings A, B, C and D appeared to be
identical. However, in the 1H and 13C NMR spectrum of 2, the signals of two methyl singlets at
δH/δC 0.84/33.0 and 0.86/23.9 in 1 were replaced by two methyl doublets (δH/δC 0.85/17.2 and
0.86/20.9). Also, the resonances of a methylene (δH 1.01 and 1.65; δC 45.3) and a quaternary
carbon (δC 45.3) in 1 were replaced by those of two methine at δH/δC 1.32/38.8 and 1.35/31.6.
Careful inspection of the resonances in the E-ring region revealed the ursane skeleton of
2 with the hydroxyl group at C-22, as in 1. Analysis of the NOESY spectrum confirmed the
relative configuration of all stereochemically centres as obtained for 1. Thus, the structure
of compound 2 was elucidated to be urs-12-ene-1β,3β,11α,22α-tetraol (Figure 1).
The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used
to measure the viability of MCF-7 tumour cell line after exposure to compounds 1 and 2,
compared with paclitaxel as positive control (0.032 ± 0.005 μM). Both compounds reduced
weakly the cell viability of MCF-7 cell line in a dose-dependent manner. The IC50 values of
compounds 1 and 2 were determined as 110.23 ± 0.12 and 88.35 ± 0.09 μM, respectively.
4 M. Moridi Farimani and M. Abbas-Mohammadi

3. Experimental section
3.1. General experimental procedures
HR-ESI-MS was carried out on a Bruker 147 microTOF-ESI-MS system. NMR spectra were
recorded on Bruker AVANCE III-500 spectrometer operating at 500.13 MHz for 1H NMR and
125.77 MHz for 13C NMR with TMS as an internal standard. IR spectra were recorded using a
Bruker Tensor 27 spectrometer. Optical rotations were measured using a Perkin Elmer-341
automatic digital polarimeter. Silica gel (70–230 mesh) was used for column chromatography
(CC), and precoated silica gel F254 (20 cm × 20 cm) plates for TLC, both supplied by the Merck.

3.2. Plant material

The aerial parts of S. urmiensis were collected at full flowering stage in May 2012 in Takab,
West Azarbaijan province in Iran. A voucher specimen (MPH-1220) has been deposited in the
herbarium of Medicinal Plants and Drugs Research Institute of Shahid Beheshti University,
Tehran, Iran.

3.3. Extraction and isolation

Aerial parts of S. urmiensis Bunge Sw. (5.0 kg) were crushed and extracted with n-hexane
(2 L × 30 L) to remove the less polar components. Then, the residue was extracted with
acetone (4 L × 30 L) at room temperature for 7 days. The solution was concentrated under
reduced pressure. The crude acetone extract (160 g) was mixed with H2O (1.0 L) to form a
suspension and partitioned successively with n-hexane and EtOAc to yield n-hexane (80 g),
EtOAc (60 g) and H2O (20 g) soluble fractions. The EtOAc-soluble fraction was subjected to a
silica gel CC with a gradient of the n-hexane–EtOAc and then EtOAc–MeOH as eluent. A total
of 15 fractions (F1–F15) were combined with the aid of TLC analysis. Fraction 12 [0.7 g, eluted
with EtOAc–MeOH (98:2)] was applied on silica gel CC and eluted with CH2Cl2–MeOH (10:1)
to afford five subfractions (frs. 12a–12e). Subfraction 12a was recrystallised in methanol to
give compound 1 (6 mg). Fraction 13 [2.6 g, eluted with EtOAc–MeOH (95:5)] was subjected
to another silica gel CC eluted with chloroform–acetone (80:20 to 65:35) to afford nine sub-
fractions (frs. 13a–13i). Subfraction 13d was further separated on silica gel CC, eluted with
CH2Cl2-acetone (1:1) to give compound 2 (15 mg).

3.3.1. Olean-12-ene-1β,3β,11α,22α-tetraol (1)

White amorphous powder; [𝛼]25 D +37 (c 0.1, DMSO); IR (KBr): vmax 3420, 2927, 1642, 1461, 1386,
1010 cm ; H NMR (CDCl3 + CD3OD, 500 MHz): δ 0.58 (1H, dd, J = 2.0, 11.5 Hz, H-5), 0.69 (3H, s,
−1 1

H-24), 0.84 (3H, s, H-29), 0.86 (3H, s, H-30), 0.89 (3H, s, H-23), 0.90 (3H, s, H-28), 0.94 (3H, s,
H-26), 0.97 (3H, s, H-25), 0.98 (1H, m, H-15α), 1.01 (1H, m, H-19α), 1.18 (3H, s, H-27), 1.28 (1H, m,
H-16β), 1.30 (2H, m, H-21), 1.24 (1H, m, H-7β), 1.44 (1H, m, H-7α), 1.45 (1H, m, H-6α), 1.55 (1H,
m, H-15β), 1.57 (1H, m, H-6β), 1.63 (1H, d, J = 8.5 Hz, H-9), 1.65 (1H, m, H-2α), 1.65 (1H, m, H-16α),
1.65 (1H, m, H-19β), 1.72 (1H, m, H-2β), 1.95 (1H, dd, J = 3.5, 10.0 Hz, H-18), 3.10 (1H, dd, J = 4.5,
11.5 Hz, H-3), 3.39 (1H, dd, J = 5.0, 11.5 Hz, H-1), 3.43 (1H, dd, J = 4.5, 11.5 Hz, H-22), 4.15 (1H,
dd, J = 3.8, 8.5 Hz, H-11), 5.15 (1H, d, J = 3.8 Hz, H-12), 13C NMR (125 MHz, CDCl3+CD3OD): δ
12.2 (C-25), 15.1 (C-24), 17.6 (C-26), 18.0 (C-6), 18.8 (C-16), 23.9 (C-30), 24.1 (C-28), 25.0 (C-27),
25.7 (C-15), 27.7 (C-23), 31.0 (C-20), 33.0 (C-29), 33.1 (C-7), 34.7 (C-2), 38.1 (C-17), 38.7 (C-4),
 Natural Product Research  5

42.2 (C-21), 42.5 (C-8), 43.0 (C-14), 44.4 (C-10), 45.3 (C-19), 46.7 (C-18), 52.1 (C-5), 55.5 (C-9),
66.0 (C-11), 75.0 (C-22), 75.6 (C-3), 76.7 (C-1), 124.5 (C-12), 147.0 (C-13); HR-ESI-MS 497.3593
[M + Na]+ (Calcd 497.3601 for C30H50NaO4).

3.3.2. Urs-12-ene-1β,3β,11α,22α-tetraol (2)

White amorphous powder; [𝛼]25 D +30 (c 0.1, DMSO); IR (KBr): vmax 3432, 2931, 2868, 1632,
1459, 1378, 1006 cm−1; 1H NMR (CDCl3 + CD3OD, 500 MHz): δ 0.55 (1H, d, J = 9.9 Hz, H-5), 0.70
(3H, s, H-24), 0.81 (3H, s, H-28), 0.85 (3H, d, J = 5.8 Hz, H-29), 0.86 (1H, m, H-16α), 0.86 (3H, d,
J = 5.9 Hz, H-30), 0.90 (3H, s, H-23), 0.95 (1H, m, H-15α), 0.98 (3H, s, H-25), 0.98 (3H, s, H-26),
1.11 (3H, s, H-27), 1.23 (1H, m, H-7α), 1.32 (1H, m, H-19), 1.35 (1H, m, H-20), 1.45 (1H, m, H-7β),
1.49 (1H, m, H-6α), 1.53 (2H, m, H-21), 1.57 (1H, d, J = 8.4 Hz, H-6β), 1.59 (1H, d, J = 8.4 Hz,
H-9), 1.63 (1H, m, H-2β), 1.64 (1H, m, H-18), 1.68 (1H, m, H-15β), 1.72 (1H, m, H-2α), 1.84 (1H,
dt, J = 4.5, 13.2 Hz, H-16β), 3.14 (1H, dd, J = 4.4, 11.6 Hz, H-3), 3.27 (1H, brt, J = 2.9 Hz, H-22),
3.39 (1H, dd, J = 4.4, 11.5 Hz, H-1), 4.15 (1H, dd, J = 3.5, 8.4 Hz, H-11), 5.18 (1H, d, J = 3.5 Hz,
H-12), 13C NMR (125 MHz, CDCl3): δ 12.9 (C-25), 15.0 (C-24), 17.6 (C-26), 18.0 (C-6), 27.6 (C-16),
20.9 (C-30), 21.8 (C-28), 23.1 (C-27), 26.3 (C-15), 27.7 (C-23), 31.6 (C-20), 17.2 (C-29), 33.2 (C-7),
34.9 (C-2), 37.5 (C-17), 38.9 (C-4), 37.7 (C-21), 43.0 (C-8), 43.0 (C-14), 43.7 (C-10), 38.8 (C-19),
53.0 (C-18), 52.4 (C-5), 56.0 (C-9), 66.1 (C-11), 75.1 (C-22), 75.4 (C-3), 77.0 (C-1), 127.4 (C-12),
142.0 (C-13); HR-ESI-MS 497.3605 [M + Na]+ (Calcd 497.3601 for C30H50NaO4).

3.4. Cytotoxicity assay

3.4.1. Cell culture and treatment
The human breast adenocarcinoma (MCF-7) cell line was purchased from National Cell Bank
of Iran, Pasteur Institute (Tehran, Iran), and maintained in DMEM medium supplemented
with 10% fetal bovine serum and 100 U/mL penicillin and 100 μg/mL streptomycin. This cell
was kept at 37 °C in a humidified atmosphere containing 5% CO2. Compounds 1 and 2 were
dissolved in DMSO to make a stock of 1 mM and further diluted to final concentrations of
10–1000 μM with the serum free culture medium.

3.4.2. Cell viability assay

Cell viability was determined using the MTT assay. Briefly, 2.5 × 104 cells were seeded in
96-well plates at 37 °C with 5% CO2 for overnight incubation and treated with appropriate
concentrations of compounds of 1 and 2 for 24 h. The cells were then incubated with a serum-
free medium containing MTT at a final concentration of 0.5 mg/mL for 4 h. The dark formazan
crystals formed were dissolved in DMSO and the absorbance was measured at 570 nm.

4. Conclusion
Two new polyhydroxylated triterpenoids were isolated from the acetone extract of aerial
parts of S. urmiensis Bunge. All previously reported triterpenoids of this plant were rare in
nature having a ε-lactone E-ring or a C17–C22 E-seco-ursane skeletons (Moridi Farimani et al.
2013, Farimani, Bahadori, et al. 2015, Farimani, Mohammadi, et al. 2015). While compounds
1 and 2 have usual skeletons as pentacyclic triterpenoids with four hydroxyl group at C-1,
C-3, C-11 and C-22. Several polyhydroxylated ursane and oleanane type triterpenoids were
previously found in different Salvia species (e.g. Salvia kronenburgii, Salvia argentea L. and
6 M. Moridi Farimani and M. Abbas-Mohammadi

Salvia argentea var. aurasiaca (Pomel) Batt. & Trab.) (Bruno et al. 1987; Topçu et al. 2004;
Lakhal et al. 2014). All of these compounds possess some hydroxyl or acetoxy group at dif-
ferent situations. However, the most distinguished feature of the isolated compounds from
S. urmiensis is their hydroxylation at C-22.

Supplementary material
1D and 2D NMR spectra of compounds 1 and 2 can be found as Supporting Information.

Acknowledgements
Financial support by the Shahid Beheshti University Research Council is gratefully acknowledged. All
spectra were performed at the Department of Pharmaceutical Sciences, Division of Pharmaceutical
Biology, University of Basel. The kind assistance of Prof M. Hamburger, Dr S.N. Ebrahimi, and all other
staff is gratefully appreciated.

Disclosure statement
No potential conflict of interest was reported by the authors.

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