(E)-2-Benzylidenebenzocyclanones: Part XIII - (E)/(Z)-Isomerization of some cyclic chalcone analogues. Effect of ring size on lipophilicity of geometric isomers

Article abstract of DOI:10.1007/s00706-015-1463-2

Optimized isocratic reverse phase high-performance liquid chromatography (RP-HPLC) method was developed for separation of the respective (E) and (Z) isomers of the cyclic chalcone analogues (E)-2-(4′-X-benzylidene)-1-indanones, -tetralones, and -benzosube

Full text of DOI:10.1007/s00706-015-1463-2

Monatsh Chem
DOI 10.1007/s00706-015-1463-2
ORIGINAL PAPER
(E)-2-Benzylidenebenzocyclanones: part XIII—(E)/(Z)-
Isomerization of some cyclic chalcone analogues. Effect of ring
size on lipophilicity of geometric isomers
1
´
Pal Perjesi
´
Received: 25 August 2014 / Accepted: 23 March 2015
ꢀ Springer-Verlag Wien 2015
Abstract Optimized isocratic reverse phase high-perfor-
mance liquid chromatography (RP-HPLC) method was
developed for separation of the respective (E) and (Z) iso-
mers of the cyclic chalcone analogues (E)-2-(40-X-
benzylidene)-1-indanones, -tetralones, and -benzo-
suberones. The method has been applied to monitor
progress of the light-induced (E)/(Z) isomerization process
in the three series. Data indicate formation of equilibrium
mixtures of the respective geometric isomers. Comparison
of the HPLC retention factors of the respective geometric
isomers showed the (Z) isomers less lipophilic in the
benzosuberone and the tetralone but more lipophilic in the
indanone series. Data provide experimental evidence of
opposite effect of ring size and geometric isomerism on
lipophilicity of conformationally restricted (cyclic) ana-
logues of chalcone, an open chain pharmacophore.
Graphical abstract
Keywords Cyclic chalcone analogues ꢀ Photochemistry ꢀ
(E)/(Z) Isomerization ꢀ Equilibrium isomeric mixtures ꢀ
Lipophilicity
Introduction
Recently, we have reported [2–6] on synthesis and antitumor
(cytotoxic) activity of a series of (E)-2-(X-benzylidene)-1-
indanones 1, -tetralones 2, and -benzosuberones 3 (Fig. 1).
Structurally, these compounds can be regarded as cyclic
analogues of chalcones, a class of flavonoids with a broad
range of biological effects [7–9]. Our previous studies have
revealed that (E)-2-(X-benzylidene)-1-benzosuberones (3)
are a group of useful cytotoxic agents, and some derivatives
can serve as prototypic molecules for subsequent structural
modifications [3]. Results of in vitro cell culture studies
suggested that noncovalent interaction of the compounds
with cellular macromolecules can be the most important
contribution to their biologic effects [5, 6]. UV–Vis and
fluorescence spectroscopic investigations of such interac-
tions demonstrated how the actual molecular environment
affects the spectroscopic characteristics of the compounds
[10, 11].
X
O
(CH2)n
(CH2)n
Theoretically, (E) and (Z) isomers of the investigated
2-(X-benzylidene)-1-benzocycloalkanones can be formed
in the reactions used for synthesis of the compounds. The
(Z) configuration, however, is unfavorable because of a
strong steric interaction between the aryl and the carbonyl
groups [12]. In practice, synthesis of the compounds
yielded the energetically more favored (E) isomers in pure
form [2–4]. On the other hand, photoisomerization and
photodimerization of alkenes and a,b-unsaturated ketones,
including chalcones, are well-known phenomena in the
literature [13]. UV light-induced (E)/(Z) isomerization of
X
For part XII of this series, see Ref. [1].
´
´
& Pal Perjesi
pal.perjesi@aok.pte.hu
1
´
Institute of Pharmaceutical Chemistry, University of Pecs,
´
Pecs, Hungary
123

´
P. Perjesi
X
Results and discussion
Syntheses of the 2-(40-X-benzylidene)-1-benzocycloalka-
nones 1a–3g resulted in isolation of stereohomogeneous
(E) isomers. Isomeric purity of the compounds was
O
1
checked by GC and H NMR methods [2–4]. Earlier we
reported that some (E)-(40-X-benzylidene)-1-benzocy-
cloalkanones 1–3 have been found to undergo light-
catalyzed on-plate and in-solution (E)/(Z) isomerization
[21]. As a continuation of these experiments, isomeric
composition of dichloromethane and methanol solutions of
compounds 1a–3g exposed to scattered laboratory light
was investigated by the previously used GC-FID method
[21]. It was found that each benzylidene derivative except
the 40-dimethylamino-substituted 1g–3g underwent (E)/
(Z) isomerization on standing on the shelve already for
1 day. This latter observation can be explained by the
strong electron-donor capacity of the dimethylamino sub-
stituent, which increases the double bound character (i.e.,
the energy needed for isomerization) of the compounds
[23]. Similar result was obtained with 4-hydroxychalcone;
the methanol solution of the compound resisted daylight-
induced (E)/(Z) isomerization [15].
(CH2)n
(CH2)n
X
(E) isomers
(Z) isomers
1 (n=1, indanones)
2 (n=2, tetralones)
3 (n=3, benzosuberones)
4 (n=1)
5 (n=2)
6 (n=3)
a, X = H; b, X = CH3; c, X = OCH3; d, X = F;
e, X = Cl; f, X = CN; g, X = N(CH3)2
Fig. 1 Structure of the (E) (1–3) and the (Z) (4–6) isomers of the
investigated 2-(40-X-benzylidene)-1-benzocycloalkanones
some chalcones [14–16], (E)-2-arylidene-1-indanones [17–
19], and -tetralones [18, 19] has been published and the
respective (Z) isomers were structurally characterized.
Previously, on-plate and in solution light-catalyzed (E)/
(Z) isomerization of some of the title compounds 1–3 has
been studied by gas chromatographic (GC) and reverse-
phase thin-layer chromatographic (RP-TLC) methods. It
was demonstrated that the logP values—one of the physi-
co-chemical characteristics affecting the biological effects
[20]—of the respective (E)- and (Z)-2-(X-benzylidene)-1-
benzosuberones 3 are different; the (Z) isomers are less
lipophilic [21].
According to our earlier observations [21], GC retention
time of each of the formed (Z)-2-(40-X-benzylidene)-1-
benzocycloalkanones 4a–6f was found to be shorter than
that of the respective (E) isomer. This GC characteristic
(shorter retention times for the less planar (Z) isomers) is in
accordance with the results of similar investigations of the
related (E)- and (Z)-dypnones [24]. GC–MS analysis of the
(E)/(Z) mixtures showed the two isomeric compounds to
give identical molecular ion peak and fragmentation [21].
Similar results were obtained for the previously non-in-
vestigated 1c–3c/4c–6c isomeric pairs. As an example,
GC–MS chromatograms of (E) and (Z) isomers of the five-
membered 2-(40-methoxybenzylidene)-1-indanone (1c and
4c) (retention times 21.19 min and 20.19 min, respective-
ly) are shown in Fig. 2.
The main goal of the present work was to develop an
easy-to-perform reverse-phase high-performance liquid
chromatographic (RP-HPLC) method that can be used to
test isomeric purity of the title compounds. Since the 40-
methoxy (1c–3c) and the 40-dimethylamino (1g–3g)—pre-
viously not investigated—derivatives displayed the most
promising in vitro antitumor activities [3, 4], these com-
pounds have also been involved in the present
investigation. Because both reactivity [12] and biological
activity [15] of the respective (E) and (Z) isomers are ex-
pected to be different, such a chromatographic method is a
valuable tool to test isomeric purity of the compounds. The
developed RP-HPLC method was used to follow the time-
course of the light-catalyzed (E)/(Z) isomerization of
compounds 1–3 and characterize composition of the iso-
meric mixtures as a function of the ring size and the
electronic characteristics of the aromatic substituents.
Based on comparison of the isocratic RP-HPLC retention
factors (k) conclusions could be drawn concerning relative
lipophilicity of the respective (E) and (Z) isomers in all the
three series [22].
In order to obtain samples with higher fraction of the
newly formed (Z) isomers, 3.5 mM benzene solution of the
pure (E) isomers of 1a–3g were illuminated with
3 9 125 W high-pressure mercury lamps for 4 h as de-
scribed before [21]. The illuminated solutions were
evaporated by nitrogen gas and the solid residues were
analyzed by GC and HPLC. Separation of the (E) and the
(Z) isomers could be accomplished by isocratic RP-HPLC
method using 330 nm UV detection. The selected wave-
length is around the absorption maxima of the pure
(E) isomers [10] around which the forming (Z) isomers are
also expected to show (a lower intensity) absorption [21,
25]. HPLC analysis of the illuminated solutions of 1a–3f
showed appearance of a new peak in each chromatogram.
123

(E)-2-Benzylidenebenzocyclanones…
bundance
Fig. 2 GC-MS spectrum of
(E) (1c, tR = 21.19 min) and
(Z) (4c, tR = 20.19 min)
isomers of 2-(40-
methoxybenzylidene)-1-
indanone
TIC: Q-749.D
21.19
140000
120000
100000
80000
60000
40000
20000
20.19
0
Time-->
6.00 8.00 10.0012.0014.0016.0018.0020.0022.0024.0026.0028.00
These observations are in accordance with the results of the
GC investigations of the samples. According to the results
of earlier GC–MS investigations, the formed compounds
are the respective (Z) isomers. As an example, HPLC
chromatograms of (E) and (Z) isomers of the 40-methoxy-
substituted indanone (1c, 4c), tetralone (2c, 5c), and ben-
zosuberone (3c, 6c) derivatives are shown in Fig. 3.
Formation of dimers under our experimental conditions
could not be observed.
been reported to be highly versatile photoinitiator even
under soft irradiation conditions (upon exposure to UV
and/or visible light) [27]. Most of the photosensitizers
suffer degradation by light [28]. Based on such observa-
tions, decomposition of the dimethylamino derivatives can
be considered as a result of photosensitized autoxidation
(photobleaching).
Retention times (tR) and retention factors (k) of the re-
spective (E) and (Z) isomers of the investigated cyclic
chalcone analogues (1a–3g and 4a–6f, respectively) are
shown in Table 1.
On the contrary, HPLC analysis of illuminated solutions
of the 40-dimethylamino derivatives 1g–3g indicated ap-
pearance of several peaks corresponding to more polar
substances than the parent compounds. Similar observation
could be made by GC-FID analysis of the samples as well.
These results suggest decomposition of the parent com-
pounds. Light-induced isomerization and decomposition of
the dimethylamino derivatives 1g–3g have also been pre-
sumed while investigating fluorescence properties of the
compounds [26]. The strong electron-donating capacity of
the 40-dimethylamino substituent results in increased
electron density of the enone moiety [2]. The intense
fluorescence and the pronounced positive solvatochromism
(significant charge transfer (CT) character of the transi-
tions) indicate expressed dipolar character of the excited
state of the compounds [10, 11, 26]. Furthermore, the open
chain analogue 4-dimethylamino-20-hydroxychalcone has
Earlier lipophilicity of the respective (E)/(Z) isomeric
pairs of 2-(X-benzylidene)-1-benzosuberones (3/6a, b, d, e,
f) was characterized by their logP determined by RP-TLC.
It was found that the least planar (Z) isomers were less
lipophilic [21]. According to these earlier results, the RP-
HPLC retention times of the newly formed (Z) isomers
were found to be shorter than those of the corresponding
(E) ones in the benzosuberone (3/6) series (Table 1).
Similar observation was made in the case of the respective
isomeric pairs of the tetralone series (2/5). In these cases,
however, the two peaks appear closer than those of the
corresponding benzosuberone (3/6) pairs. Isocratic RP-
HPLC studies of the respective open chain (E)-s-cis and
(Z)-s-cis chalcones also showed the (Z) isomers to have
shorter retention times (lower retention factors) [29]. On
123

´
P. Perjesi
Fig. 3 HPLC chromatograms
of the (E) (1c–3c) and the
(Z) isomers (4c–6c) of the
investigated 2-(40-
methoxybenzylidene)-1-
benzocycloalkanones
Table 1 RP-HPLC retention times (tR/min) and retention factors (k) of the (E)- and (Z)-2-(40-X-benzylidene)-1-indanones 1,3, -tetralones 2,5,
and -benzosuberones 3,6
1
4
2
5
3
6
tR
k
tR
k
tR
k
tR
k
tR
k
tR
k
a
b
c
d
e
f
6.25
8.83
7.43
11.82
9.22
8.29
13.56
5.19
–
10.70
17.80
13.44
12.03
20.49
7.09
10.08
15.80
8.30
14.45
23.19
11.67
14.75
25.48
8.87
8.73
13.80
7.78
9.81
15.53
6.06
–
12.39
20.14
10.87
14.06
22.74
8.33
12.95
20.31
14.05
13.32
22.61
8.15
18.68
30.16
20.41
19.21
33.68
11.52
18.68
9.95
15.22
11.94
10.94
17.07
6.94
–
14.12
22.34
17.19
15.60
25.19
9.66
9.69
6.85
6.32
10.75
4.24
8.92
14.41
9.72
8.94
16.03
5.62
8.83
10.25
17.32
6.40
g
–
14.62
–
–
20.61
–
Data represent average of three parallel experiments
the contrary, the order of the two isomeric peaks of the
five-membered indanones (1/4) is opposite (Table 1). Since
isocratic RP-HPLC retention factors (k) represent a relative
scale of lipophilicity [21], this observation indicates the
formed (Z) isomers in the indanone series (4) to be more
lipophilic than the corresponding (E) ones (Table 1).
The effect of geometric isomerism on lipophilicity is a
relatively unexplored field of medicinal chemistry [30].
Changing configuration of the chalcone core induces
changes in molecular volume, surface area, polarizability,
and dipole moments of the respective isomers. Investiga-
tion of effectiveness of transmission of substituent effects
of the respective (E) and (Z) isomers of the compounds by
1H and 13C NMR methods showed the enone moiety to be
the most planar in the indanone series (1 and 4). Deviation
from the planar structure is more pronounced in the six-
123

(E)-2-Benzylidenebenzocyclanones…
membered (2 and 5) and seven-membered (3 and 6) cyclic
chalcone analogues [21, 31, 32]. Cumulative effect of
difference in geometry (and conjugation) on the above
mentioned molecular characteristics is likely to be re-
sponsible for the observed effect of ring size on
lipophilicity of the (E) and (Z) isomers (1–3/4–6). To the
best of our knowledge, this is the first example of opposite
effect of ring size and geometric isomerism on lipophilicity
of conformationally restricted (cyclic) analogues of an
open-chain pharmacophore.
be explained by proximity of the carbonyl and the ben-
zylidene moieties in the (Z) isomers, which is more
dominant in the most planar indanones 4 than in the series
of 5 and 6, where the enone moiety is deviated from pla-
narity [21]. Pronounced substituent effect—lowering the
fraction of the (Z) isomer in the photostationary mixtures—
could only be observed in the case of 1c (Table 2). This
observation can be rationalized by the electron-donor ca-
pacity of the 40-methoxy substituent (c), which is the most
effective in the most planar (most strongly conjugated)
indanone (1/4) series [31, 32].
By means of the optimized HPLC method time-course
of isomerization of selected compounds of the three series
(1a–3d) was followed. Isomeric composition of the solu-
tions illuminated by mercury lamps was analyzed at the 0-,
30-, 60-, 90-, 120-, 180-, and 240-min timepoints over the
4-h illumination period of solutions of the pure (E) isomers.
Composition of the samples was characterized by (a) the
ratio of the integrated peak areas (A) of the starting (E) i-
somers at t = t (At) and t = 0 (Ao) times; and (b) by the
ratio of those of the formed (Z) isomers at t = t (At) and
t = 240 min (A240) timepoints. The numerical values of the
respective ratios are summarized in Tables 2 and 3. Gra-
phical representation of the data obtained for compounds
3c and 6c is shown on Fig. 4. The two asymptotic graphs
indicate formation of equilibrium mixtures of the corre-
sponding (E) and (Z) isomers.
Experimental
Synthesis of (E)-2-(40-X-benzylidene)-1-benzocycloalka-
nones 1a–3g was performed by base-catalyzed Claisen-
Schmidt condensation as published before [2–4]. Each
sample was purified by column chromatography over silica
gel (0.2–0.5 mm; Reanal, Hungary) using toluene or
toluene-methanol (99:1, v/v) as mobile phases. The com-
pounds had melting points in accord with their literature
values [3]. Structure of the investigated samples was ver-
ified by IR (Nicolet Impact 400 FT IR spectrometer) [2],
1H NMR [2, 31, 32], and 13C NMR spectroscopy [31, 32]
(Varian Unity Inova, 400 MHz spectrometer). IR spectra
1
According to the obtained data, formation of the (Z) i-
somers was found to be the most pronounced over the first
30-min period in each case. At the 60-min timepoints
compositions of the photostationary mixtures are very
close to those measured at the endpoint (240 min) of the
experiments. Although only qualitative analysis, the ring
size seems to affect composition of the equilibrium mix-
tures: contribution of the (Z) isomers is lower in case of the
indanones 1 than in the respective mixtures of the te-
tralones 2 and the benzosuberones 3. This observation can
were recorded in KBr pellets. H and 13C NMR spectra
were run in CDCl3 solutions using TMS as internal stan-
dard. Structure of compounds 3b, 3c, and 3g was also
verified by X-ray crystallography [3].
(E)-2-(40-X-Benzylidene)-1-benzocycloalkanones 1a–
3g were subjected to light-induced isomerization either in
2 mg/cm3 methanol or dichloromethane solution allowing
the solutions to be exposed by scattered laboratory light for
1 week, or in 1 mg/cm3 benzene solutions illuminating
them with 3 9 125 W high-pressure mercury lamps
Table 2 Ratios of integrated peak areas (At/A0) of (E)-2-(40-X-benzylidene)-1-benzocyloalkanones 1–3 in the UV-light illuminated solution of
(E)-2-(40-X-benzylidene)-1-benzocyloalkanones 1–3 as a function of time of illumination
At/Aa0
1 (n = 5)
2 (n = 6)
3 (n = 7)
300
600
1200
2400
300
600
1200
2400
300
600
1200
2400
a
b
c
0.362
0.550
0.842
0.456
0.527
0.287
0.482
0.783
0.444
0.444
0.278
0.422
0.748
0.428
0.409
0.278
0.366
0.621
0.377
0.374
0.195
0.279
0.297
0.226
0.221
0.153
0.233
0.220
0.211
0.175
0.153
0.200
0.169
0.219
0.172
0.178
0.215
0.162
0.204
0.175
0.208
0.287
0.391
0.206
0.232
0.172
0.192
0.265
0.193
0.189
0.173
0.192
0.233
0.193
0.184
0.156
0.180
0.209
0.198
0.163
d
e
At integrated peak area at t = tmin, A0 integrated peak area at t = 0
a
Average of three parallel experiments
123

´
P. Perjesi
Table 3 Ratios of integrated peak areas (At/A240) of (Z)-2-(40-X-benzylidene)-1-benzocyloalkanones 4–6 in the UV-light illuminated solution of
(E)-2-(40-X-benzylidene)-1-benzocyloalkanones 1–3 as a function of time of illumination
At/Aa240
4 (n = 5)
5 (n = 6)
6 (n = 7)
300
600
1200
2400
300
600
1200
2400
300
600
1200
2400
a
b
c
0.913
0.872
0.651
1.013
0.879
0.971
1.076
0.964
1.033
1.0073
1.011
1.095
0.931
1.097
1.001
1.000
1.000
1.000
1.000
1.000
1.031
0.970
0.907
0.957
0.960
1.122
1.070
0.970
1.020
1.0457
1.125
1.057
1.023
1.085
1.048
1.000
1.000
1.000
1.000
1.000
0.965
0.989
0.844
0.987
1.011
1.057
1.093
1.003
1.051
1.055
1.054
1.098
1.058
1.041
1.081
1.000
1.000
1.000
1.000
1.000
d
e
At integrated peak area at t = tmin, A240 integrated peak area at t = 240 min
a
Average of three parallel experiments
GC and GC–MS methods for investigation of (E)/
(Z) isomerization
GC investigations of the pure (E) isomers 1a–3g and the
(E)/(Z) mixtures of 1a–3g/4a–6g were performed on HP
5890 Series II gas chromatograph equipped with flame
ionization detector (FID) as described before [21]. Briefly,
the conditions were as follows: column: 25 m 9
0.32 mm 9 0.17 lm HP-5 capillary column; inj. temp.:
280 ꢁC; det. temp.: 280 ꢁC; oven temp. progr.: 100 ꢁC
(1 min) to 200 ꢁC at 5 ꢁC/min (0.5 min) to 250 ꢁC at
15 ꢁC/min (1 min). Carrier: helium, 1.8 cm3/min, constant
flow. Injection: 1 mm3, split 40 cm3/min. Retention data
of the previously non-investigated 1c/4c, 2c/5c, and
3c/6c isomeric pairs were 13.15/12.30, 13.58/12.62, and
13.74/12.55 min, respectively. Retention times of com-
pounds 1g, 2g, and 3g were 16.99, 17.10, and 17.28 min,
respectively.
GC–MS investigations of the previously non-investi-
gated pure (E) isomers 1c–3c and the (E)/(Z) mixtures of
1c–3c/4c–6c were performed on HP 5890 Series II gas
chromatograph coupled with a HP-5971A mass selective
detector as described before [21]. Briefly, the conditions
were as follows: column: 30 m 9 0.32 mm 9 1.00 lm
RTX-5 capillary column; inj. temp.: 280 ꢁC; det. temp.:
280 ꢁC; oven temp. progr.: 50 ꢁC (1 min) to 300 ꢁC at
20 ꢁC/min (16.5 min). Carrier: helium, 1.0 cm3/min, con-
stant flow. Injection: 1 mm3, split 30 cm3/min. The mass
selective detector was operated in scan mode (50–650 m/z).
Retention times and the main fragment peaks of com-
pounds 1c–3c/4c–6c were as follows. 1c/3c: 21.19/
20.19 min; m/z = 250, 249, 235, 219, 207,189, 178, 152,
125, 102, 89, 76. 2c/4c: 21.64/20.58 min; m/z = 264, 263,
249, 233, 221, 203, 178, 121, 103, 90, 77. 3c/6c: 21.91/
20.52 min; m/z = 278, 277, 263, 250, 247, 235, 219, 207,
131, 121, 103, 91, 77.
Fig. 4 Ratios of integrated peak areas of (E)-2-(40-methoxybenzyli-
dene)-1-benzosuberone (3c) (upper panel) and (Z)-2-(40-
methoxybenzylidene)-1-benzosuberone (6c) (lower panel) in UV-
light illuminated solution of (E)-2-(40-methoxybenzylidene)-1-benzo-
suberone (3c) as a function of time of illumination (data points
represent average of three parallel experiments. At integrated peak
area at t = tmin; A0 integrated peak area at t = 0; A240 integrated
peak area at t = 240 min
(Tungsram, Hungary) for 4 h. The solutions were analyzed
by GC and HPLC as described below. Evaporation of the
solutions illuminated by the mercury lamps resulted in
yellowish solids, which were analyzed by GC and HPLC.
Three parallel experiments were performed in each case. In
case of the previously non-investigated 1c–3c/4c–6c (E)/
(Z) pairs the solids were also analyzed by GC–MS.
123

(E)-2-Benzylidenebenzocyclanones…
8. Ni L, Meng CQ, Sikorski JA (2004) Expert Opin Ther Pat
14:1669
9. Go ML, Wu X, Liu XL (2005) Curr Med Chem 12:483
HPLC method for investigation of (E)/
(Z) isomerization
}
´
10. Fodor K, Tomeckova V, Koszegi T, Kron I, Perjesi P (2011)
HPLC investigations of the pure (E) isomers 1a–3g and the
(E)/(Z) mixtures of 1a–3g/4a–6g were performed on an
Agilent 1100 integrated high-performance liquid chro-
matography system equipped with a quaternary pump, a
degasser, an autosampler, an injector with a 100-mm3
sample loop, a column oven, and an ultraviolet–visible
(UV–Vis) detector. Data were recorded and evaluated using
Agilent ChemStation (Rev.B.03.02-SR2) software. Sepa-
ration of the isomers was performed on a 4.6 9 150 mm,
5 lm particle size Waters Spherisorb ODS-2 (Method A) or
on a 3.0 9 125 mm, 5 mm particle size Macharey-Nagel
CC 125/3 LiChrospher 100 RP 18 column (Method B) using
isocratic mobile phase consisting of acetonitrile (WWR
HiPerSolv Chromanorm) and water (Merck Lichrosolv)
(1:1, v/v). Chromatography was performed at room tem-
perature. Flow rate: 2.0 cm3/min. Detection wavelength:
k = 330 nm. Injected volume: 20 mm3.
Monatsh Chem 142:463
11. Tomeckova V, Stefanisinova VM, Velika B, Fodor K, Perjesi P,
´
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