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Sanionins: AntiInflammatory and
Antibacterial Agents with Weak Cytotoxicity
from the Antarctic Moss Sanionia
georgicouncinata
Veneta Ivanova
a
, Mariana Kolarova
a
, Krasja Aleksieva
a
, KlausJuergen
Dornberger
b
, Albert Haertl
b
, Ute Moellmann
b
, HansMartin Dahse
b
&
Nesho Chipev
c
a
The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of
Sciences , Sofia, Bulgaria
b
Leibniz Institute for Natural Product Research and Infection
BiologyHansKnoellInstitute , Jena, Germany
c
Central Laboratory of General Ecology , Bulgarian Academy of Sciences ,
Sofia, Bulgaria
Published online: 10 Sep 2007.
To cite this article: Veneta Ivanova , Mariana Kolarova , Krasja Aleksieva , KlausJuergen Dornberger ,
Albert Haertl , Ute Moellmann , HansMartin Dahse & Nesho Chipev (2007) Sanionins: AntiInflammatory and
Antibacterial Agents with Weak Cytotoxicity from the Antarctic Moss Sanionia georgicouncinata , Preparative
Biochemistry and Biotechnology, 37:4, 343-352, DOI: 10.1080/10826060701593241
To link to this article: http://dx.doi.org/10.1080/10826060701593241
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Sanionins: Anti-Inammatory
and Antibacterial Agents with Weak
Cytotoxicity from the Antarctic Moss
Sanionia georgico-uncinata
Veneta Ivanova, Mariana Kolarova, and Krasja Aleksieva
The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of
Sciences, Soa, Bulgaria
Klaus-Juergen Dornberger, Albert Haertl, Ute Moellmann,
and Hans-Martin Dahse
Leibniz Institute for Natural Product Research and Infection Biology-
Hans-Knoell-Institute, Jena, Germany
Nesho Chipev
Central Laboratory of General Ecology, Bulgarian Academy of Sciences,
Soa, Bulgaria
Abstract: Sanionins A (1) and B (2) were isolated from the moss Sanionia georgico-
uncinata, collected on the Antarctic Livingston Island. The compounds 1 and 2 were
puried by solvent extraction, silica gel column chromatography, and preparative
HPLC, consecutively. The structures of the both compounds were elucidated by 1D
and 2D NMR experiments and mass spectrometric investigations. These compounds
showed activity against important Gram-positive pathogens, such as mycobacteria,
multiresistant staphylococci, and vancomycin resistant enterococci. This activity is
combined with antiinammatoric activity and low cytotoxicity.
Keywords: Sanionia georgico-uncinata, Sanionins A and B, Inhibitors of 3a-hydroxy-
steroid dehydrogenase, Weak cytotoxic activity, Antibacterial activity
Address correspondence to Veneta Ivanova, The Stephan Angeloff Institute of
Microbiology, Bulgarian Academy of Sciences, 26 Acad. Georgy Bonchev St., 1113
Soa, Bulgaria. E-mail: venibiva@microbio.bas.bg
Preparative Biochemistry & Biotechnology, 37: 343352, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 1082-6068 print/1532-2297 online
DOI: 10.1080/10826060701593241
343
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INTRODUCTION
The mosses from special regions of the globe have been suggested as a source
of chemically diverse bioactive metabolites.
[1]
Antarctica is a particularly
interesting biosphere, due to the special climatic conditions and the distance
to other continents.
[2,3]
During the course of our screening programme for
inhibitors of 3a-hydroxysteroid dehydrogenase, as one of the key enzymes
involved in inammatory events,
[4]
we disclosed an antarctic moss, identied
as Sanionia georgico-uncinata, as producer of an active principle.
In this paper, we report the isolation, structural elucidation of compounds
1 and 2, based on spectral analyses and chemical correlations, and the bio-
logical activities (antiinammatory, antimicrobial, and cytotoxic).
EXPERIMENTAL
Medicinal Plant
The moss, Sanionia georgico-uncinata, was collected on Antarctic Livingston
Island. Sampling had been performed in the course of the Bulgarian
Expedition to Antarctica (2002).
General Experimental Procedures
Electrospray mass spectrometry (ESI-MS) and high-resolution electron
impact mass spectrometry (HREI-MS) were carried out by use of a triple
quadrupole mass spectrometer (VG Biotech Altrincham, England) and a
Finnigan MAT 95XL mass spectrometer (Finnigan. Bremen, Germany),
respectively. NMR measurements were done with a Bruker Avance DRX
500 instrument (in CDCl
3
), FTIR spectroscopy on a Mattson Satellite instru-
ment equipped with an ATR measuring device. The
13
C multiplicity data were
obtained from DEPT experiments. The chemical shifts are expressed in d
values (ppm).
1
H-
1
H COSY, HMQC, HMBC, and
1
H-
1
H NOESY were
obtained by conventional methods. UV-VIS spectroscopy was recorded with
a Specord 2000 instrument (Analytik Jena, Germany). IR spectra were
recorded with Beckman DU 601 and Shimadzu IR scanning spectropho-
tometers. Specic rotations were determined with a Perkin-Elmer 141
polarimeter.
Extraction and Isolation of Sanionins A and B
The isolation procedure started with extraction of the dried material (200 g) of
Sanionia georgico-uncinata with CHCl
3
/MeOH (1:1, v/v) for 48 h. The
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organic layer was evaporated to dryness under reduced pressure, yielding
1.00 g of crude product, which was dissolved in chloroform and chromato-
graphed on a silica gel 60 column (70230 mesh). The compounds 1 and 2
were eluted from the column by CHCl
3
/MeOH (7:3, v/v). The nal separ-
ation and purication by preparative HPLC on a Nucleosil 100-5 C
18
(column 250 20 mm) using a gradient of 83% acetonitrile in water/0.1%
TFA and monitoring at 230 nm (ow rate, 8 mL/min, Rt of 1 and 2: 12.96
and 13.51 min) delivered the pure compounds sanionin A (1) (27 mg) and
sanionin B (2) (23 mg).
Analytical HPLC/Diode Array Analysis
Analytical HPLC/diode array analysis of 1 and 2 was carried out on a
Nucleosil 100, C
18
column, 125 4.6 mm, 5 mm, using a gradient of aceto-
nitrile in water/0.1%TFA and monitoring at 210 and 230 nm (ow rate,
2.0 mL/min).
Thin Layer Chromatography (TLC)
Thin layer chromatography (TLC) was performed on (SiO
2
, CHCl
3
/MeOH
95:5, v/v; vanillin/sulphuric acid reagent), Rf of 1 and 2: 0.68 and 0.71.
In Vitro Assay for the Search of Non-Steroidal Inhibitors of the 3a-
Hydroxysteroid Dehydrogenase (3a-HSD)
Cell-free systems for the determination of anti-inammatory and antiphlogis-
tic activity are critical, as it is a complex of reactions of living organisms.
Nevertheless, in vitro assays for the screening of inhibitors of key enzymes,
e.g., 3a-hydroxysteroid dehydrogenase and prostaglandin H synthetase are
important tools. 3a-HSD can be inhibited concentration dependent by non-
steroidal antiphlogistics. 3a-hydroxysteroid dehydrogenase catalyses the
reduction of 5b-dihydrocortison under consumption of NADH. The NADH
consumption is determined photometrically as a decrease of extinction at
340 nm. Indomethacin or ibuprofen are used as reference compounds.
[4]
Antimicrobial Activity
Antimicrobial activity was determined by the agar diffusion test, according
to Refs. [5, 6, 7]. Test organisms were suspended in the melted nutrient
agar (Serva) and poured into petri dishes. Holes of 9 mm diameter were
cut in the agar and lled with 50 mL of a 100 mg/L solution of the
Anti-Inammatory and Antibacterial Agents 345
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compounds. Inhibition zones were read after incubation for 18 h at 378C
for bacterial strains and 308C for yeasts and fungi. Test organisms were
from the stock of the Hans Knoell Institute; the epidemic multiresistent
Staphylococcus aureus (MRSA) strain 134/93 and a vancomycin resistant
Enterococcus (VRE) strain were kindly provided by Prof. W. Witte, Wer-
nigerode, Germany. Pseudomonas aeruginosa K 799/61 was described by
Ref. [8].
Antiproliferative and Cytotoxic Assay
Cells of K-562 (DSM ACC10), L-929 (DSM ACC2), and HeLa (DSM
ACC57) were cultured in RPMI1640 medium (GIBCOBRL), supplemented
with gentamicin sulfate (25 mg ml
21
; Cambrex), 10% heat inactivated fetal
bovine serum (GIBCOBRL), and GlutaMAX-1 (GIBCOBRL) at 378C in
high density polyethylene asks (NUNC). Sanionins A (1) and B (2) were
dissolved in ethanol (10 mg mL
21
) before being diluted in RPMI1640. The
adherent cells of L-929 and HeLa were harvested at the logarithmic growth
phase after soft trypsinization, using 0.25% trypsin in PBS (phosphate
buffer saline) containing 0.02% EDTA (Biochrom KG). For cytotoxicity
assays, approximately 10,000 HeLa cells per well of the 96-well microplates
cells were seeded with RPMI1640 (0.2 ml) and pre-incubated for 48 h without
1 and 2. After formation of a subconuent monolayer, cells were treated with
dilutions of 1 and 2 and incubated under physiological conditions (72 h at
378C in a humidied atmosphere and 5% CO
2
). For the antiproliferative
assay, 1 and 2 were tested against L-929 and K-562. For each experiment,
approximately 10,000 cells were seeded with RPMI1640 (0.1 mL) per well
of the 96-well microplates and subsequently exposed to dilutions of 1 and 2
and incubated under physiological conditions for 72 h. The measurement of
cytotoxicity and cell growth inhibition was based on registration of living
cells after incubation with 1 and 2 versus untreated control. Non-adherent
K-562 cells were analyzed by an electronic cell analyzer system CASY1
(Schaerfe). Adherent L-929 and HeLa cells were xed by glutaraldehyde
(Merck) and stained with methylene blue (SERVA) for 15 min. After gentle
washing, the stain was eluted with HCl (0.2 mL, 0.33 N) in the wells. The
optical densities were measured at 660 nm in a Sunrise microplate reader
(Tecan).
[9]
RESULTS AND DISCUSSION
Both substances were soluble in DMSO, MeOH, EtOH, EtOAc, and CHCl
3
,
but insoluble in ether, n-hexane, and water. On silica gel TLC plates, 1 and
2 were visualized by UV (254 nm) and spray reagent of vanillin/H
2
SO
4
(yellow).
V. Ivanova et al. 346
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Sanionin A (1) was obtained as colorless plate crystals, [a]
D
25
20.08
(c 0.1, CHCl
3
). The UV-VIS spectrum gave maximum absorptions at
318, 270, and 226 nm by HPLC/diode array analysis, typical for a chalcone
chromophore. The IR spectrum showed 3270 cm
21
(hydroxyl), 1650 cm
21
(conjugated carbonyl), 1620 cm
21
(olenic bond), 1600, 1580 cm
21
(aromatic ring), and 1280, 1190 cm
21
(aromatic C-O) absorptions.
The structures of 1 and 2 were settled on the basis of electrospray (ESI-
MS), high-resolution electron impact mass spectrometry (HREI-MS) and
extensive NMR studies (
1
H,
13
C, DEPT,
1
H-
1
H COSY, HMQC, HMBC,
and
1
H-
1
H NOESY). The () ESI mass spectrum of 1 displayed pseudo-
molecular ions at m/z 343.6 (MH)

, 707.2 (2MNa)

, and in the
negative ion mode at m/z 341.4 (M-H)
2
. The molecular weight (342 Da)
and the chemical formula C
23
H
18
O
3
were readily determined by EI HRMS
due to m/z 342.1344. The chemical formulas of 1 and 2 suggested the
presence of 15 double bond equivalents.
In the
1
H NMR spectrum of compound 1, the low-eld signals at d
H
6.42 4 7.55 were pecular to eight aromatic protons. Furthermore, two
olenic protons appeared at d
H
7.08 and 8.28 as two doublets. The congur-
ation of the double bond at C-2 was determined as 2E from the large trans
coupling constants of H-2 (J 16.0 Hz) and H-3 (J 16.1 Hz). This fact
suggested the presence of a trans olen conjugated with a carbonyl. The
aliphatic region of
1
H NMR spectrum could be interpreted as methylene
two nonequivalent geminal protons at d
H
2.81 (dd, J 16.7, 3.4 Hz) and
3.05 (dd, J 16.7, 12.9 Hz), and an oxygen-linked methine proton at d
H
5.49 (dd, J 13.0, 3.0 Hz). In the
13
C NMR and DEPT spectra of 1,
nineteen carbon signals were visible (Table 1) which were assignable to one
carbonyl carbon (d
C
192.00), twelve aromatic carbons (8 CH and 4 C
q
signals), two signals of olenic carbons, one methylene and three oxygen-
bonded (C-2
0
, C-6
0
, C-7a
0
) carbons.
A
1
H-
1
H chemical shift correlation spectroscopy (COSY) experiment
(Fig. 1) demonstrated coupling only from the olenic proton of H-2 at d
H
7.08 to the olenic proton of H-3 (d
H
8.28) and the methylene protons of
H-3
0
at d
H
2.81/3.05 to the methine proton at d
H
5.49 (H-2
0
).
The HMBC experiment (Fig. 1) showed, additionally, a long range
coupling from the methylene protons of H-3
0
to the carbonyl C-1 and from
the olenic protons of H-2 and H-3 to the quaternary C-4
0
and C-1
000
, respect-
ively. Cross peaks were also observed from the aromatic doublets of H-5
0
to
a quaternary (C-4
0
, C-3a
0
) and C-7
0
, and H-7
0
to C-5
0
and C-3a
0
. Similarly, a
coupling was established from the aromatic proton of H-4
0 0 0
to C-2
0 0 0
and
C-6
0 0 0
; from the aromatic protons of H-3
0 0
and H-5
0 0 0
to the quaternary C-1
0 0 0
;
from the aromatic protons of H-3
000
and H-5
0 0
to the quaternary C-1
0 0
and from
H-2
0 0
and H-6
0 0
to C-4
0 0
. The stereochemistry of the furanyl ring of 1 and 2
was elucidated mainly on the basis of NOESY cross-peaks for H-2
0
/H-3
0
b
and H-3
0
a/H-3
0
b. Irradiation of H-2
0
enhanced the signals of H-3
0
a and H-3
0
b, suggesting that H-2
0
was gauche to H-3
0
a (equatorial) and H-3
0
b (axial).
Anti-Inammatory and Antibacterial Agents 347
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Sanionin B (2) was obtained as colorless needles, [a]
D
25
229.18 (c 0.1,
CHCl
3
). The compound 2 showed the same molecular weight (342 Da) and the
chemical formula (C
23
H
18
O
3
) by EI HRMS as 1. The UV-VIS spectrum of 2
showed absorption maxima at 294, 270, and 224 nm by HPLC/diode array
Figure 1. Selected
1
H-
1
H COSY (bold lines) and
1
H-
13
C HMBC (arrows) corre-
lations of sanionin A (1) and sanionin B (2).
Table 1.
1
H and
13
C NMR data of sanionin A (1) and sanionin B (2) in CDCl
3
(500 MHz and 125.76 MHz, TMS as internal standard, chemical shifts in ppm)
Position
1 2
d
H
d
C
d
H
d
C
1 192.00 s 191.22 s
2 7.08 d, J 16.0 Hz 131.09 d 6.59 d, J 12.2 Hz 129.22 d
3 8.28 d, J 16.1 Hz 128.81 d 7.04 d, J 12.3 Hz 131.18 d
2
0
5.49 dd, J 13.0, 3.0 Hz 79.28 d 5.44 dd, J 11.1, 3.6 Hz 79.24 d
3
0
2.81 dd, J 16.7, 3.4 Hz 2.84 dd, J 16.8, 3.1 Hz
3.05 dd, J 16.7, 12.9 Hz 45.85 t 3.06 dd, J 16.8, 12.9 Hz 45.48 t
3a
0
112.55 s 113.00 s
4
0
143.60 s 142.30 s
5
0
6.76 d, J 2.2 Hz 108.76 d 6.39 d, J 2.5 Hz 102.99 d
6
0
164.10 s 161.66 s
7
0
6.42 d, J 2.3 Hz 103.11 d 6.26 d, J 2.5 Hz 112.65 d
7a
0
166.00 s 165.21 s
1
0 0
139.20 s 139.00 s
2
0 0
/6
0 0
7.52 d, J 7.3 Hz 126.50 d 7.08 d, J 7.4 Hz 127.04 d
3
0 0
/5
0 0
7.41 t, J 7.4 Hz 129.29 d 7.12 t, J 7.4 Hz 128.67 d
4
0 0
7.35 t, J 7.4 Hz 129.21 d 7.10 t J 7.4 Hz 129.22 d
1
0 0 0
138.54 s 136.92 s
2
0 0 0
/6
0 0 0
7.55 d, J 7.3 Hz 127.40 d 7.54 d, J 7.3 Hz 127.89 d
3
0 0 0
/5
0 0 0
7.35 t, J 7.4 Hz 129.39 d 7.41 t, J 7.3 Hz 128.90 d
4
0 0 0
7.25 t, J 7.4 Hz 128.64 d 7.35 t, J 7.3 Hz 128.90 d
6
0
-OH 5.42 s 5.44 s
V. Ivanova et al. 348
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analysis. This spectrum demonstrated a decrease in the intensity of the corre-
sponding maximum absorption by comparison with that of 1. The conjugated
carbonyl absorption of 2 was shifted to 294 nm from 318 nm in 1. The major
difference arose from the two olenic protons of the a,b-unsaturated ketone
system, which shifted upeld at d
H
6.59 (H-2) and 7.04 (H-3). The congur-
ation of the double bond (in
1
H NMR spectrum) of compound 2 at C-2 was
determined as 2Z from the cis coupling constants of H-2 (J 12.2 Hz) and
H-3 (J 12.3 Hz), typical for a cis-olen. Sanionin B (2) was identied as
cis isomer of 1. The chemical shifts of all protons and carbon atoms of 1
and 2 are summarized in Table 1.
Sanionins A (1) and B (2) were investigated in vitro for antimicrobial
activity against Gram-positive and Gram-negative bacteria, yeasts and la-
mentous fungi (Table 2). Both substances showed activity against Gram-
positive bacteria, such as Bacillus subtilis ATCC 6633, Staphylococcus
aureus SG 511, Staphylococcus aureus 134/93 (MRSA), Mycobacterium
vaccae 10670, and Enterococcus faecalis 1528 (VRE), but were inactive
against Gram-negative bacteria, yeast, and lamentous fungi such as Escher-
ichia coli SG 458, Pseudomonas aeruginosa SG137, Sporobolomyces salmo-
nicolor 549 and Penicillium notatum JP 36.
The antiproliferative and cytotoxic effects of sanionin A (1) and sanionin
B (2) were determined with L-929 mouse broblast cells, K-562 human
leukemia cells, and HeLa human cervix carcinoma. The GI
50
and CC
50
values are summarized in Table 3.
The inhibition effect of sanionin A and sanionin B on 3a-hydroxysteroid
dehydrogenase was investigated by comparison with the polyenic macrolide
antibiotics, such as pimaricin, hexafungin, fungicidin and the standard
compound indomethacin. The polyene macrolide antibiotics displayed an
Table 2. Diameter of inhibition zones (mm) of sanionin A (1) and sanionin B (2) in
the agar diffusion assay
Test organisms
Diameter of inhibition zones (mm)
1 2
Bacillus subtilis ATCC 6633 15.0 14.5
Staphylococcus aureus SG 511 17.0 13.0
Staphylococcus aureus 134/93 (MRSA) 13.5 13.0
Escherichia coli SG 458 0 0
Pseudomonas aeruginosa SG 137 0 0
Pseudomonas aeruginosa K 799/61 0 0
Enterococcus faecalis 1528 (VRE) 12.5 12.0
Mycobacterium vaccae 10670 19.5 19.0
Sporobolomyces salmonicolor 549 0 0
Penicillium notatum JP 36 0 0
Anti-Inammatory and Antibacterial Agents 349
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inhibitory effect
[10]
comparable to sanionin A (1). The sanionin B inhibited the
enzyme too, but with lower efciency than sanionin A. The IC
50
values are
summarized in Table 4.
On the basis of the obtained data (Table 1, Fig. 1), it was established that
sanionin A (1) [1- (2,3-dihydro-6
0
-hydroxy-2
0
-phenyl-4
0
-benzofuranyl)-3-
phenyl-2 (E)-propen-1-one] and sanionin B (2) [1- (2,3-dihydro-6
0
-hydroxy-
2
0
-phenyl-4
0
-benzofuranyl)-3-phenyl-2 (Z)-propen-1-one] were identical
with pallidisetin A and pallidisetin B, isolated from the moss Polytrichum pal-
lidisetum, which showed cytotoxic activity against two human tumor cell lines
(RPMI-7951 and U-251 MG) (1). The sanionin A (trans-isomer) was with
better biological activity than sanionin B (cis-isomer).
CONCLUSION
Both substances, sanionin A (1) and sanionin B (2), for the rst time, were
isolated from the antarctic moss Sanionia georgico-uncinata
[11,12]
and can
be classied into cinnamoyl bibenzyls. We did not nd data about the
Table 4. Inhibition of 3a-hydroxysteroid dehydro-
genase by sanionin A(1) and sanionin B (2)
Compounds IC
50
(mg/mL)
Sanionin A (1) 70
Sanionin B (2) 130
Pimaricin 76
Hexafungin 76
Fungicidin 80
Indomethacin 24
Table 3. Antiproliferative effect and Cytotoxicity of sanionin A (1) and sanionin B
(2) against cell cultures of L-929, K-562 and HeLa cells
Compounds
Antiproliferative effect
GI
50
(mg/mL)
a
Cytotoxicity
CC
50
(mg/mL)
b
L-929 K-562 HeLa
Sanionin A (1) 32.9 23.1 34.1
Sanionin B (2) 31.1 23.3 32.4
a
Cellular growth inhibition.
b
Cytotoxic efcacy.
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isolation of secondary metabolites from the moss Sanionia georgico-uncinata
as 3a-hydroxysteroid dehydrogenase inhibitors and with antiproliferative
and cytotoxic effects against L-929, K-562, and HeLa cell lines. These
compounds showed activity against important Gram-positive pathogens like
mycobacteria, multiresistant staphylococci, and vancomycin resistant
enterococci.
ACKNOWLEDGMENTS
Support of this work by the German Research Foundation, Bonn, Germany
(Project 436 BUL 113/107/0-2) is gratefully acknowledged.
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Received September 29, 2006
Accepted November 3, 2006
Manuscript 7502
V. Ivanova et al. 352
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