molecules
Communication
Sugar Containing Compounds and Biological Activities of
Lagochilus setulosus
Davlat Kh. Akramov 1 , Nilufar Z. Mamadalieva 1,2, * , Andrea Porzel 2 , Hidayat Hussain 2 , Mthandazo Dube 2 ,
Akbar Akhmedov 3 , Ahmed E. Altyar 4 , Mohamed L. Ashour 5,6, * and Ludger A. Wessjohann 2
1
2
3
4
5
6
*
Citation: Akramov, D.K..;
Mamadalieva, N.Z.; Porzel, A.;
Hussain, H.; Dube, M.; Akhmedov,
A.; Altyar, A.E.; Ashour, M.L.;
Wessjohann, L.A. Sugar Containing
Compounds and Biological Activities
of Lagochilus setulosus. Molecules 2021,
26, 1755. https://doi.org/10.3390/
molecules26061755
Academic Editors:
Institute of the Chemistry of Plant Substances, Uzbekistan Academy of Sciences, M. Ulugbek Str 77,
Tashkent 100170, Uzbekistan; a.davlat@inbox.ru
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3,
06120 Halle, Germany; andrea.porzel@ipb-halle.de (A.P.); hidayat.hussain@ipb-halle.de (H.H.);
mthandazo.dube@ipb-halle.de (M.D.); ludger.wessjohann@ipb-halle.de (L.A.W.)
Department of Botany and Plant Physiology, Samarkand State University, University Blv. 15,
Samarkand 140104, Uzbekistan; rakbar@rambler.ru
Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University,
Jeddah 21589, Saudi Arabia; aealtyar@kau.edu.sa
Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College,
Jeddah 21442, Saudi Arabia
Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
Correspondence: nmamadalieva@yahoo.com (N.Z.M.); mohamed.ashour@bmc.edu.sa (M.L.A.)
Abstract: Phytochemical investigation of the methanolic extract obtained from the aerial parts of
Lagochilus setulosus (Lamiaceae) afforded the new compound 1-methoxy-3-O-β-glucopyranosyl-α-Loliose (1) together with five known glycosides, namely sitosterol-3-O-β-glucoside (2), stigmasterol-3O-β-glucoside (3), pinitol (4), 6β-hydroxyl-7-epi-loganin (5), and chlorotuberoside (6). The structures
of these compounds were elucidated by extensive spectroscopic analyses, especially HR-MS, 1D
and 2D NMR spectroscopy. The in vitro cytotoxic activity of the methanolic extract and the isolated
compounds was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)
and crystal violet (CV) staining assays. In addition, the antifungal activities of the components
were evaluated against Botrytis cinerea, Septoria tritici, and Phytophthora infestans. The anthelmintic
potential was determined against Caenorhabditis elegans nematodes. Neither the extract nor the
isolated compounds showed promising activity in all the bioassays.
Alessandra Morana and
Giuseppe Squillaci
Keywords: Lamiaceae; Lagochilus setulosus; 1-Methoxy-3-O-β-glucopyranosyl-α-L-oliose; NMR;
HR-MS; anthelmintic; antifungal; cytotoxic
Received: 4 March 2021
Accepted: 19 March 2021
Published: 21 March 2021
1. Introduction
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The genus Lagochilus (Lamiaceae) is native to central, south-central, and eastern Asia.
It consists of 46 species with 18 of them growing in Uzbekistan. Taxa of the genus Lagochilus
basically occur throughout the territory of Uzbekistan, starting from the deserts to TianShan and Pamir-Alay mountain systems. The majority of species can be found in the
Pamir-Alai Mountain, southwest of Tian-Shan and Turanian lowland. Species from the
genus Lagochilus belong to the most vulnerable plant species from the Lamiaceae family [1],
with a decoction of herb and roots of Lagochilus species used in folk medicine mainly
as styptics, hemostatics, and tranquilizers, and also for skin conditions, stomach pain,
hemorrhages, and inflammation. Previous phytochemical investigations on Lagochilus
species revealed the presence of essential oils, flavonoids, polysaccharides, sterols, iridoids,
terpenoids, and more frequently diterpenes, which are considered as chemical markers
for this genus. About 150 metabolites have been reported from all previous classes in the
genus [2–4].
4.0/).
Molecules 2021, 26, 1755. https://doi.org/10.3390/molecules26061755
https://www.mdpi.com/journal/molecules
Molecules 2021, 26, 1755
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The species of Lagochilus setulosus Vved. is endemic of the southwestern area of TianShan, and it can be found distributed in low mountains between the border of the regions
Chimkent (Kazakhstan) and Tashkent (Uzbekistan) [1]. A literature survey reveals that
there are no reports on traditional use, biological activity, or chemical investigations of L.
setulosus, except our previous report on the volatile components of the aerial parts and their
antioxidant and enzyme inhibitory activities [5]. In continuation of our phytochemical
β
studies on L. setulosus, herein, we report
the isolationαand structure identification of a new
β L-oliose (1) (Figure 1) together with two
disaccharide 1-methoxy-3-O-β-glucopyranosyl-αknown sterol
β glucosides: sitosterol-3-O-β-glucoside (daucosterol) (2) and stigmasterol-3O-β-glucoside (3), as well as cyclitol–pinitol
[3-(O-methyl-D-chiro-inositol)] (4), and the
β
two iridoid glycosides 6β-hydroxyl-7-epi-loganin (5) and chlorotuberoside (6) (Figure 1). In
addition, the anthelmintic, antifungal, and cytotoxic effects of the isolated compounds 1, 4,
a mixture of 5 and 6, and the methanolic extract of L. setulosus have been evaluated.
Figure 1. Chemical structures of the isolated compounds from the aerial parts of L. setulosus.
2. Results and Discussion
2.1. Chemical Composition of L. setulosus
Since no publications were found regarding the chemical composition of the aerial
parts of L. setulosus, this is the first report on the occurrence of sugar-containing compounds
1–6. The chromatographic fractionation of the methanolic extract of this species afforded
sitosterol-3-O-β-D-glucoside
(2) and stigmasterol-3-O-β-D-glucoside
(3) as an inseparable
β
β
mixture (with a ratio of 1:1), and the new compound 1. The chemical structure of compounds 2 and 3 was determined based on spectral analysis and comparisons with relevant
literature [6]. These compounds were also found in other Lagochilus species viz. L. inebrians
and L. gypsaceus [7]. Further investigations of the methanolic extract of L. setulosus afforded
pinitol (4) and an inseparable mixture (with a ratio of 1.2:1) of 6β-hydroxyl-7-epi-loganin
β
(5) and chlorotuberoside (6). Most recently, the iridoid glycoside 5 has been reported
from several species of Eremostachys [8,9] and Picconia excelsa [10]. Chlorotuberoside (6)
was previously isolated from different genera of Lamiaceae, such as Phlomis [11–13], Eremostachys [14], Lamiophlomis [15], which are taxonomically close to Lagochilus. Pinitol (4)
is a cyclitol [16] and has been detected in gymnosperm (Pinus, Abies) and angiosperm
Molecules 2021, 26, 1755
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(Fabaceae, Nyctaginaceae, Asteraceae, Zygophyllaceae, Caryophyllaceae, Aristolochiaceae,
Sapindaceae, Santalaceae, and Aizoaceae) families [17]. Compounds 1, 3–6 were isolated
for the first time from the genus Lagochilus.
Compound 1 was obtained as a white powder soluble in methanol. Its molecular
formula C13 H24 O9 was deduced
− from its negative mode HR-ESI-MS showing
− the depro−
tonated molecular ion peak [M-H] at m/z 323.1336 (calcd. 323.1348, for C13 H23 O9 − )
(Supplementary Figures S1 and S2). The 1 H and HSQC spectra of 1 show typical signals
δ δ
δ δ
δ δ
of two anomeric centres (δH/δC 4.77/100.1 ppm; δH/δC 4.38/102.8 ppm), a CH3 signal
δ δ
(δH/δC 1.23/17.1 ppm), and a methoxy signal (δH/δC 3.30/55.0 ppm). Together with the
molecular formula C13 H24 O9 suggests the presence of a disaccharide including one deoxy
β
sugar. COSY correlations and vicinal 1 H-1 H coupling constants indicate the presence of a βD-glucose unit (Díaz et al. 2019). For the second sugar moiety, two spin systems were found
(H-1/H-2A/B-H3-H4 and H-5/CH3 -6) (Figure 2). HMBC correlations of the methyl group
protons with both carbon signals C-5 (67.2 ppm) and C-4 (71.4 ppm), as well as the correlation of the methoxy protons with C-1 (100.1 ppm), revealed the presence of a 1-methoxy-2,6dideoxy sugar unit. Vicinal 1 H,1 H coupling constants δHδ4.38 (1H, d, J = 7.7 Hz, H-1′ ) and
δHδ4.09 (1H, ddd, J = 11.4, 7.7, 2.9 Hz) (Supplementary Table S1), and ROESY correlations
between H-3/H-4 and H-3/H-5 show OR-3, OR-4 and CH3 -6 positioned at one face and
OMe-7 on the other face of the molecule. 2,6-Dideoxy glycosides and their methyl ethers
occur as glycosides in natural products and the majority of them contains →
1→3 or→
1→4 link′
′
ꞌ
ꞌ
ages [18,19]. HMBC correlations of H-3/C-1 , as well as H-1 /C-3, confirmed compound 1
β
α
β D-glucopyranosyl-2,6as 1-methoxy-3-O-β-glucopyranosyl-αL-oliose (or 1-methoxy-3-O-βα
dideoxy-α-lyxo-hexopyranose). Detailed NMR spectra of compound 1 are included in the
Supplementary data (Supplementary Figures S3–S8).
Figure 2. Selected 2D NMR correlations for 1-methoxy-3-O-β-glucopyranosyl-α-L-oliose (1).
β
α
2.2. Biological Activities
The cytotoxicity of the crude methanolic extract of L. setulosus, compounds 1, 4, and
the mixture of 5 and 6 was evaluated in MTT and CV assays against the human cancer
cell lines PC-3 (prostate cancer) and HT-29 (colon adenocarcinoma). Results of the tests
showed weak effects. In addition, the methanolic extract and isolated compounds were
tested against the phytopathogenic ascomycetes Botrytis cinerea Pers. and Septoria tritici
Desm. and the oomycete Phytophthora infestans (Mont.) de Bary., but the samples did not
show any promising activity up to the highest tested concentration of 125 ppm. The results
of anthelmintic assays showed that the samples did not significantly kill Caenorhabditis
elegans under the testing concentration of 500 µg/mL.
μ
3. Materials and Methods
3.1. General Methods
UV-visible spectra of samples diluted in MeOH were obtained using a Jasco V770 UV/Vis
spectrophotometer (JASCO GmbH, Pfungstadt, Germany). IR spectra were recorded with
a Thermo Nicolet 5700 FT-IR spectrometer (Thermo Electron Corporation, Langenselbold,
Germany). The HR-MS measurements were performed on a SciexTripleTOF 6600 LC-MS
Molecules 2021, 26, 1755
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spectrometer (AB Sciex, Darmstadt, Germany) with an Acquity UPLC System (Waters
GmbH, Eschborn, Germany) equipped with EC 150/2 NUCLEOSHELL RP18 column
(150 × 2 mm, particle size 2.7 µm). The samples were measured in the negative and
positive ion modes. 1D and 2D NMR spectra were recorded on a Varian/Agilent 400 and
600 NMR spectrometer (Agilent Technologies, Santa Clara, CA, USA). CD3 OD and C5 D5 N
were used as NMR solvent. Chemical shifts (δ) are referenced to internal tetramethylsilane
(TMS) (δ = 0 ppm, 1 H) and internal CD3 OD (δ = 49.0 ppm, 13 C) or internal pyridine-d5
(δ = 123.5 ppm, 13 C). Thin-layer chromatography was performed on Merck pre-coated silica
gel 60 F254 aluminum foil plates (Merck, Darmstadt, Germany). Spots were detected on
TLC under UV lamp (254 and 365 nm) or by heating to 100 ◦ C after spraying with vanillin
sulfuric solution. Eluting solvents (MeOH, CHCl3 , EtOAc) were distilled before use.
3.2. Plant Material
The aerial parts (flowers, leaves, and stems) of L. setulosus were collected in Oqtepa
Yunusabad, Tashkent region (Uzbekistan), in May 2019. A voucher specimen (N273) is
deposited at the Herbarium the Botany Institute of Uzbekistan and verified by Dr. Akbar
Akhmedov. The aerial parts were air-dried in shadow and powdered in a mortar before
use (moisture content was 11%, w/w).
3.3. Extraction and Isolation
Powdered aerial parts of L. setulosus (380 g) were extracted with MeOH (4 × 1.5 L).
The resulting methanolic extracts were combined and evaporated at 40 ◦ C to afford dry
extract. The crude methanolic extract (41 g) was mixed with silica gel and placed onto a
chromatography column (CC) (column size 10 × 80 cm) of silica gel (100–200 mesh, Tianjin
Sinomed Pharmaceutical, China). The extract was eluted by CHCl3 /MeOH gradients
with increasing polarity to 20% MeOH to give 3 fractions A (100% CHCl3 , 800 mL), B
(CHCl3 :MeOH, 9:1, v/v, 1.2 L) and C (CHCl3 :MeOH, 4:1, v/v, 1.2 L). Fraction B (11.7 g)
was re-chromatographed on silica gel CC (column size 6 × 65 cm) using CHCl3 /MeOH in
gradient mode of elution analysis and B1–13 subfractions (each 200 mL) were collected.
Evaporation of the solvents from the subfractions, B3–4 and purification by PTLC produced
a mixture of the compounds 2 and 3 (1.1 mg). The subfractions B10–11 (156 mg) were
separated over silica gel using CHCl3 :MeOH (9:1, v/v, 300 mL) to isolate 1. Compound 1
(8 mg) was purified from the fraction using recrystallization in chloroform. Fr. C (8.8 g)
was subjected to CC (silica gel, column size 4.2 × 70 cm) and eluted with EtOAc/MeOH
gradient increasing the polarity to 20% MeOH. This yielded 23 subfractions which were
combined into five groups (C1-C5). Subfr. C4 (540 mg) was subjected to CC (silica gel,
column size 2 × 70 cm, EtOAc/MeOH: 10:1, v/v, (200 mL), 5:1, v/v, (200 mL) and 1:1, v/v,
(700 mL) to obtain subfr. C4.1-C4.18. Subfr. C4.5-C4.7 gave mixture 5 and 6 (8 mg), while
subfr. C4.15-C4.16 yielded pure 4 (12 mg).
3.4. Physical Properties of Isolated Compounds
1-Methoxy-3-O-β-glucopyranosyl-α-L-oliose (1), C13 H24 O9 , Mr = 324 g/mol. White
crystallin powder; UV λmax (MeOH) nm: 263 nm. IR νmax cm−1 : 3356, 2905, 2361, 1647,
1443, 1359, 1035. HR-ESI-MS: m/z 323.1336 [M-H]+ : (calcd for C13 H23 O9 + , 323.1348); m/z
342.1784 [M + NH4 ]+ : (calcd for C13 H28 NO9 + , 342.1764); 1 H NMR (CD3 OD, 500 MHz) δ:
4.77 (1H, d, J = 2.3 Hz, H-1), 1.94 (1H, m, H-2a), 1.89 (1H, m, H-2b), 4.09 (1H, ddd, J = 11.4,
7.7, 2.9 Hz, H-3), 3.77 (1H, d, J = 2.8 Hz, H-4), 3.84 (1H, m, H-5), 1.23 (3H, d, J = 6.6 Hz,
H-6), 3.30 (3H, s, H-7), 4.38 (1H, d, J = 7.7 Hz, H-1′ ), 3.19 (1H, dd, J = 8.9, 7.8 Hz, H-2′ ),
3.35 (1H, m, H-3′ ), 3.29 (1H, m, H-4′ ), 3.28 (1H, m, H-5′ ), 3.84 (1H, m, H-6′ a), 3.68 (1H, dd,
J = 11.9, 4.8 Hz, H-6′ b). 13 C NMR (CD3 OD, 125 MHz) δ: 100.1 (C-1), 30.4 (C-2), 75.1 (C-3),
71.4 (C-4), 67.2 (C-5), 17.1 (C-6), 55.0 (C-7), 102.8 (C-1′ ), 75.0 (C-2′ ), 77.8 (C-3′ ), 71.4 (C-4′ ),
77.8 (C-5′ ), 62.5 (C-6′ ); UV, IR and NMR Spectra are available in the supplementary file.
Physical properties of the compounds 2–6 are given in the supplementary file.
Molecules 2021, 26, 1755
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3.5. Biological Assays
The anthelmintic, antifungal, and cytotoxic effects of all isolated compounds were
determined by the procedures described below.
3.5.1. Cytotoxic Activity
The cytotoxicity of the methanolic extract and isolated compounds was evaluated
against the human tumor PC-3 (prostate cancer) and HT-29 (colon adenocarcinoma) cell
lines. The extract and isolated compounds were tested at the concentrations of 0.05 and
50 µg/mL, and 0.01 and 10 µM, respectively. The cell maintenance and assay procedure
were performed as described by Dos Santos et al. [20]. The viability of the cells was
determined by MTT and CV assays after 72 h incubation time. The absorbance was
measured with an automated microplate reader at 540 nm with a reference wavelength
of 670 nm [21]. The results are presented as a percentage of control values obtained from
untreated cultures.
3.5.2. Antifungal Activity
The methanol extract and isolated compounds were tested in 96-well microtiter plate
assays against the phytopathogenic ascomycetes Botrytis cinerea Pers. and Septoria tritici
Desm. and the oomycete Phytophthora infestans (Mont.) de Bary according to the monitoring methods approved by the fungicide resistance action committee (FRAC) with minor
modifications as described before [22]. Crude extracts and fractions were examined at
a final concentration of 125 µg/mL, while pure compounds were tested in a serial dilution, ranging from 100 to 0.1 µM. The solvent DMSO was used as negative control (max.
concentration 2.5%), and the commercially used fungicides epoxiconazole and terbinafine
(Sigma-Aldrich, Darmstadt, Germany) served as positive controls. Five to seven days after
inoculation, pathogen growth was evaluated by measurement of the optical density (OD)
at λ 405 nm with a TecanGENios Pro microplate reader (5 measurements per well using
multiple reads in a 3 × 3 square). Each experiment was carried out in triplicates.
3.5.3. Anthelmintic Activity
The Bristol N2 wild type strain of Caenorhabditis elegans was used in the anthelmintic
assay. The nematodes were cultured on NGM (Nematode Growth Media) petri plates using
the uracil auxotroph E. coli strain OP50 as a food source according to the methods described
before [20]. The anthelmintic assay was carried out following the method developed by
Thomsen et al. [23]. Briefly, after 4 days of cultivation, the nematodes were transferred
from the Petri plate to a 15 mL falcon tube by rinsing each plate twice with 2 mL M9
buffer. The worm suspension was centrifuged for 1 min at 800 G. After removal of the
supernatant, the nematodes were washed again with 2 mL M9 buffer under the same
conditions and, depending on the number of individuals, re-suspended in 2 to 8 mL M9
buffer. To this suspension, 10 µL penicillin-streptomycin-solution (10 mg/mL) was added.
After triply counting the nematodes in 10 µL solution droplets under a stereo microscope
(Olympus SZX12), the worm number was adjusted to 20–30 animals per 20 µL. The assay
was performed in 384 well plates. The outer wells were filled with water to minimize
evaporation. To the test wells, 20 µL worm suspension was added and the number of living
and dead animals in each well were counted using the cell culture microscope Olympus
CKX41. The number of living nematodes was set at 100%. At staggered intervals, 20 µL test
solution (test compound in 4% DMSO in M9 buffer) was added followed by a microscopic
enumeration of living and dead test organism after 30 min of incubation. For all test plates,
the solvent DMSO (2%) and the standard anthelmintic drug ivermectin (10 µg/mL) were
used as negative and positive controls, respectively. All the assays were done in triplicate.
4. Conclusions
From the aerial parts of L. setulosus, a new disaccharide, 1-methoxy-3-O-β-glucopyranosylα-L-oliose, and five known glycosides were isolated and identified. All compounds were
Molecules 2021, 26, 1755
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isolated for the first time from this species. The results of anthelmintic, antifungal, and
cytotoxic assays demonstrated that the methanolic extract and isolated compounds of L.
setulosus were not toxic in general in in vitro assays.
Supplementary Materials: The following are available online, Spectral data of the new compound
1 are available as Supporting Information (Tables S1–S4), (Figures S1–S10). Table S1: 13 C and 1 H
NMR data of 1-methoxy-3-O-β-glucopyranosyl-α-L-oliose (1) (600 MHz, δ, ppm, in CD3 OD), Table
S2: 13 C and 1 H NMR data (J in Hz) of the compound 2 and 3 (400 MHz, δ, ppm, in C5 D5 N),
Table S3: NMR spectroscopic data for 6β-hydroxyl-7-epi-loganin (5) (500 MHz, δ, ppm, J/Hz),
Table S4: NMR spectroscopic data for chlorotuberoside (6) (500 MHz, δ, ppm, J/Hz). Figure S1:
HR-ESI-QTOF-MS (+ve) spectrum of 1-methoxy-3-O-β-glucopyranosyl-α-L-oliose (1), Figure S2:
HR-ESI-QTOF-MS (-ve) spectrum of 1-methoxy-3-O-β-glucopyranosyl-α-L-oliose (1), Figure S3: 1 H
NMR spectrum of 1-methoxy-3-O-β-glucopyranosyl-α-L-oliose (1) in CD3 OD (o-oliose, g-glucose),
Figure S4: 13 C NMR spectrum of 1-methoxy-3-O-β-glucopyranosyl-α-L-oliose (1) in CD3 OD, Figure
S5: HSQC spectrum of 1-methoxy-3-O-β-glucopyranosyl-α-L-oliose (1) in CD3 OD, Figure S6: HMBC
spectrum of 1-methoxy-3-O-β-glucopyranosyl-α-L-oliose (1) in CD3 OD, Figure S7: COSY spectrum
of 1-methoxy-3-O-β-glucopyranosyl-α-L-oliose (1) in CD3 OD, Figure S8: NOESY spectrum of 1methoxy-3-O-β-glucopyranosyl-α-L-oliose (1) in CD3 OD, Figure S9: IR spectrum of 1-methoxy-3-Oβ-glucopyranosyl-α-L-oliose (1), Figure S10: UV spectrum of 1-methoxy-3-O-β-glucopyranosyl-α-Loliose (1) in CH3 OH.
Author Contributions: D.K.A., isolation and identification of the compounds, writing the draft of
manuscript; N.Z.M., experiment design and writing the manuscript; A.P. and H.H., performing and
helping with NMR study; M.D., carrying out the anthelmintic assay; A.A., collection and verification
of plant species; L.A.W., supervising, revising of the manuscript, and hosting the biological assays;
A.E.A. and M.L.A., writing and revising the manuscript. All authors have read and agreed to the
published version of the manuscript.
Funding: This work was financially supported by the Alexander von Humboldt Foundation and
Ministry of Innovative Development of the Republic of Uzbekistan (Grant No. PZ-20170927342).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available in article and supplementary material.
Acknowledgments: The authors acknowledge technical assistance by Gudrun Hahn (NMR, IR, UV),
Mandy Dorn (HR-MS), and Martina Brode (bioassays).
Conflicts of Interest: The authors declare no conflict of interest.
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