2-[(Carboxymethyl)sulfanyl]-4-oxo-4-arylbutanoic acids selectively suppressed proliferation of neoplastic human HeLa cells. A SAR/QSAR study

Article abstract of DOI:10.1021/jm0502889

A series of twenty alkyl-, halo-, and methoxy-aryl-substituted 2-[(carboxymethyl)sulfanyl]-4-oxo-4-arylbutanoic acids were synthesized. The new compounds, called CSAB, suppressed proliferation of human cervix carcinoma, HeLa cells, in vitro in a concentration range of 0.644 to 29.48 μM/L. Two compounds exhibit antiproliferative activity in sub-micromolar concentrations (16, 19). Five compounds act in low micromolar concentrations (<2 μM/L). The most active compounds exert lower cytotoxicity toward healthy human peripheral blood mononuclear cells (PBMC and PBMC+PHA) (selectivity indexes > 10). A strong structure-activity relationship, using estimated log P values and BCUT descriptors, was observed.

Full text of DOI:10.1021/jm0502889

5
600
J. Med. Chem. 2005, 48, 5600-5603
Brief Articles
2
-[(Carboxymethyl)sulfanyl]-4-oxo-4-arylbutanoic Acids Selectively Suppressed
Proliferation of Neoplastic Human HeLa Cells. A SAR/QSAR Study
,†
‡
‡
§
Branko J. Drakuli c´ ,* Zorica D. Jurani c´ , Tatjana P. Stanojkovi c´ , and Ivan O. Jurani c´
Institute for Chemistry, Technology and Metallurgy, Njego sˇ eva 12, Belgrade, Institute for Oncology and
Radiology of Serbia, Pasterova 14, Belgrade, and Faculty of Chemistry, University of Belgrade, Studentski Trg 12-16,
Belgrade; Serbia and Montenegro
Received March 31, 2005
A series of twenty alkyl-, halo-, and methoxy-aryl-substituted 2-[(carboxymethyl)sulfanyl]-4-
oxo-4-arylbutanoic acids were synthesized. The new compounds, called CSAB, suppressed
proliferation of human cervix carcinoma, HeLa cells, in vitro in a concentration range of 0.644
to 29.48 µM/L. Two compounds exhibit antiproliferative activity in sub-micromolar concentra-
tions (16, 19). Five compounds act in low micromolar concentrations (<2 µM/L). The most active
compounds exert lower cytotoxicity toward healthy human peripheral blood mononuclear cells
(
PBMC and PBMC+PHA) (selectivity indexes > 10). A strong structure-activity relationship,
using estimated log P values and BCUT descriptors, was observed.
Scheme 1. Syntheses of Compounds 1-20a
Introduction
1
In our previous paper antiproliferative action of (E)-
-aryl-4-oxo-2-butenoic acids (ArC(O)CHdCHCOOH)
4
toward human cervix carcinoma HeLa cells was re-
ported. It was suggested that cytostatic actions of those
compounds were attributed to Michael-type addition of
thiol groups on the ketovinyl moiety of the molecules.
Similar molecules exert high affinity toward thiol groups
2
-4
of biologically important molecules.
-aryl-4-oxobutanoic acid derivatives, having mercapto
group in their structures, exert a potent immunosup-
It is known that
a
4
R ) H (1), 3,4-di-Me (2), 2,4-di-Me (3), 2,5-di-Me (4), 4-Me (5),
4
-Et (6), 4-i-Pr (7), 4-n-Bu (8), 4-tert-Bu (9), 4-n-dodecyl (10), 2-Cl-
-Me (11), 4-F (12), 4-Cl (13), 4-Br (14), 2,3,4-tri-MeO (15), 2,5-
4
5
6
7,8
pressive, cytostatic, and antibacterial activity.
Results presented in this article show that 2-[(car-
boxymethyl)sulfanyl]-4-oxo-4-arylbutanoic acids (CSAB),
obtained by the Michael addition of inactive thioglicolic
acid on the ketovinyl moiety of (E)-4-aryl-4-oxo-2-
butenoic acids, exert stronger cytostatic activity toward
HeLa cells in vitro in comparison to corresponding
parent (E)-4-aryl-4-oxo-2-butenoic acids, by approxi-
mately one order of magnitude. The most active com-
pounds (16-20) acts selectively, i.e. exert lower cyto-
toxicity toward healthy human peripheral mononuclear
blood cells (PBMC and PBMC+PHA).
di-i-Pr (16), 2,4-di-i-Pr (17), 2,5-di- tert-Bu (18); 2,4,6-tri-Et (19),
2,4,6-tri-i-Pr (20).
The structures of synthesized compounds were con-
1
13
firmed by infrared (IR) and H and C nuclear magnetic
resonance (NMR) spectra (see Experimental Section).
The crystal structure of the lead compound, 2-[(car-
boxymethyl)sulfanyl]-4-oxo-4-phenylbutanoic acid (1),
was determined, too.10 Crystallization solvent, melting
points, yields, and analysis of compounds 1-20 are
given in Table 1.
The NMR data are used as a basis for structure
elucidation. This series contains closely related struc-
tures that share a common major structural component
and have very similar spectral features. The assignment
of the peaks is shown in the example of 2-[(carboxy-
methyl)sulfanyl]-4-oxo-4-(4-ethylphenyl)butanoic acid
(6) in Charts 1 and 2.
The 2-[(carboxymethyl)sulfanyl]-4-oxo-4-arylbutanoic
acids (III) (Scheme 1) were synthesized in Michael-type
addition of the thioglycolic acid (II) to series of (E)-4-
aryl-4-oxo-2-butenoic acids (I) (Scheme 1). (E)-4-Aryl-
4
-oxo-2-butenoic acids were prepared by Friedel-Crafts
1,9
acylation using maleic acid anhydride. All synthesized
-[(carboxymethyl)sulfanyl]-4-oxo-4-arylbutanoic acids
are the mixtures of R and S enantiomers.
2
Experimental Section
Substituted benzenes, thiogycolic acid, and anhydrous AlCl
3
were purchased from Sigma-Aldrich or Fluka. For the syn-
thesis of 1 and for crystallization, thiophene-free benzene was
used. All other solvents were p.a. grade. Melting points were
determined in open capillary tubes on B u¨ chi apparatus and
are uncorrected. Infrared (IR) spectra were recorded with a
*
Address for correspondence: Njegoseva 12 str., 11000 Belgrade,
Serbia and Montenegro; Europe; Phone/Fax: (+38111)3281867; E-mail
address: bdrakuli@helix.chem.bg.ac.yu.
†
Institute for Chemistry, Technology and Metallurgy.
Institute for Oncology and Radiology of Serbia.
University of Belgrade.
‡
§
1
Perkin-Elmer 1725X spectrophotometer, (KBr disk). H and
1
0.1021/jm0502889 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/16/2005

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 17 5601
Table 1. Crystallization Solvent, Melting Points, Yields, and Analysis of Compounds 1-20
R
mp, °C
solvent
water
benzene
benzene
benzene
benzene
benzene
water
benzene
benzene
cyclohexane
benzene
benzene
benzene
benzene
benzene
cyclohexane
cyclohexane
benzene
benzene
benzene
yield, %
Mw
analysisa
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
H
96
77
79
80
86
83
87
78
82
84
71
81
86
86
86
75
74
68
40
70
75
268.29
296.34
296.34
296.34
282.31
296.34
310.37
324.39
324.39
436.61
316.76
286.28
302.73
347.18
358.36
352.45
352.45
380.50
352.45
394.53
(C12H12O5S) C,H,S
(C14H16O5S) C,H,S
(C14H16O5S) C,H,S
(C14H16O5S) C,H,S
(C13H14O5S) C,H,S
(C14H16O5S) C,H,S
(C15H18O5S) C,H,S
(C16H20O5S) C,H,S
(C16H20O5S) C,H,S
(C24H36O5S) C,H,S
(C13H13ClO5S) C,H,S
(C12H11FO5S)
(C12H11ClO5S) C,H,S
(C12H11BrO5S) C,H,S
(C15H18O8S) C,H,S
(C18H24O5S) C,H,S
(C18H24O5S) C,H,S
(C20H28O5S) C,H,S
(C18H24O5S) C,H,S
(C21H30O5S) C,H,S
3,4-di-Me
2,4-di-Me
2,5-di-Me
4-Me
163
138
140
174
132
106
120
139
90
4-Et
4-i-Pr
4-n-Bu
4-tert-Bu
4-n-dodecyl
2-Cl-4-Me
4-F
0
1
2
3
4
5
6
7
8
9
0
121
148
141
145
161
118
126
163
125
168
4-Cl
4-Br
2,3,4-tri-MeO
2,5-di-i-Pr
2,4-di-i-Pr
2,5-di-tert-Bu
2,4,6-tri-i-Et
2,4,6-tri-i-Pr
a
Analysis for C, H, S within (0.4% of calculated values.
1
Chart 1. Hydrogen Labels Correspond to the List of H
Antiproliferative Action. A stock solution of examined
compounds was made in dimethyl sufoxide, at 10 mM/L
concentration, and then various dilutions were prepared in
nutrient medium (RPMI 1640 medium without phenol red,
supplemented with L-glutamine (3 mmol/L), streptomycin (100
µg/mL), and penicillin (100 IU/mL), 10% heat-inactivated fetal
bovine serum, FBS, and 25 mM HEPES, adjusted to pH 7.2
a
NMR Shifts
(
(
by bicarbonate solution)) to various final concentrations
between 3.12 and 50 or 100 µM/L). 3-(4,5-Dimethylthiazol-2-
a
δ 1.20 (3H, t, J ) 7.68 Hz) [12]; 2.68 (2H, q, J ) 7.67 Hz) [13];
yl)-2,5-diphenyltetrazolium bromide (MTT) was purchased
from Sigma Chemicals (St. Louis, MO). MTT was dissolved (5
mg/mL) in phosphate-buffered saline, pH 7.2, and filtered
through a Millipore filter, 0.22 µm, before use. RPMI 1640 cell
culture medium and FBS were products of ICN Pharmaceu-
ticals Co. (Costa Mesa, CA).
3
.34 (1H, dd, J ) 17.76, 3.73) [4]; 3.52 (2H, s) [9 and 10]; 3.65
(
1H, dd, J ) 18.41, 10.73) [3]; 3.85 (1H, dd, J ) 10.52, 3.73) [2];
7
.37 (2H, d, J ) 8.11 Hz) [5 and 8]; 7.91 (2H, d, J ) 8.11 Hz) [6
and 7]; 12.70 (2H, b) [1 and 11].
Chart 2. Carbon Labels Correspond to the List of 13C
NMR Shifts
a
Treatment of HeLa Cells. HeLa cells were seeded into
9
6-well microtiter plates, 2000 cells in 0.1 mL of nutrient
medium per well. After 20 h, to wells with HeLa cells, five
different concentrations of investigated substituted 2-[(car-
boxymethyl)sulfanyl]-4-oxo-4-arylbutanoic acids derivative were
applied, except to the control wells, the wells with cells grown
in a nutrient medium only. All concentrations were set up in
triplicate. Nutrient medium with corresponding concentrations
of investigated agent, but without cells, was used as a blank,
also in triplicate.
a
δ 15.449 [14]; 28.485 [13]; 33.401 [11]; 40.665 [3]; 41.136 [2];
1
1
28.475 [7 and 9]; 128.529 [6 and 10]; 133.991 [5];150.377 [8];
71.260 [12]; 172.880 [1]; 197.004 [4].
Preparation of Peripheral Blood Mononuclear Cells,
PBMC. PBMC were separated from whole heparinized blood
of two healthy volunteers by Lymphoprep gradient centrifuga-
13C nuclear magnetic resonance (NMR) spectra were recorded
at 200/50 MHz with tetramethylsilane (TMS) as internal
standard on a Varian “Gemini 200” spectrometer in DMSO-
tion. Interface cells, washed three times with Haemaccel
+
(
aqueous solution supplemented with 145 mM Na , 5. 1 mM
6
d . The chemical shifts are expressed as ppm downfield from
+
2+
-
K , 6. 2 mM. Ca , 145 mM Cl , and 35 g/L gelatin polymers,
pH 7.4) were counted and resuspended in nutrient medium.
TMS. The following abbreviations are used: s ) singlet, d )
doublet, t ) triplet, q ) quartet, sx ) sextet, sp ) septet, m )
multiplet, and b ) broad. The mass spectrum was taken on a
Treatment of PBMC. PBMC were seeded (150 000 cells
per well) into nutrient medium or in nutrient medium enriched
with (5 µg/mL) phytohaemaglutinin (PHA) (Welcome) in 96-
well microtiter plates, and 2 h later, investigated substances
were added to the wells, in triplicate, to five final concentra-
tions, except to the control wells where a nutrient medium
only was added to the cells. Nutrient medium with corre-
sponding concentrations of compounds, but void of cells was
used as blank.
4
Finnigan-MAT 8230 BE MS, chemical ionization (i-C H10).
Typical Experimental Procedure. In a 10 mL flask
equipped with a magnetic stirrer, 0.001 mol of (E)-4-aryl-4-
oxo-2-butenoic acid and 0.0015-0.002 mol of thioglycolic acid
in 5 mL of methanol was stirred 3-4 h at room temperature.
Solvent was removed under reduced pressure. Addition of
water precipitated crystalline 2-[(carboxymethyl)sulfanyl]-4-
oxo-4-phenylbutanoic acid (1) and 2-[(carboxymethyl)sulfanyl]-
4
-oxo-4-(4-i-Pr-phenyl)butanoic acid (7), which were separated
Determination of Cell Survival. HeLa cell survival, or
by filtration. Other 2-[(carboxymethyl)sulfanyl]-4-oxo-4-arylbu-
tanoic acids were isolated by crystallization from the proper
solvent.
PBMC survival, was determined by MTT test, according to
1
1
12
Mosmann, with modification by Ohno and Abe, 72 h upon
1
3
addition of the drug, as it was described earlier. Briefly, 20

5
602 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 17
Brief Articles
Table 2. Concentrations of Examined Agents that Induced a
0% Decrease in HeLa Cell Survival (IC50), Observed log(1/
IC50)) - Observed Activities, Predicted log(1/(IC50)) -
Table 3. Concentrations of Examined Compounds (16-20)
5
That Induced the 50% Decrease in PBMC and PBMC+PHA
Cell Survival (IC50) and Selectivity Indexes (Si)
(
Predicted Activities (derived from eq 1), and Descriptors Used
in QSAR
R
IC50 (µM)
Si
PBMC+PHA
16
17
18
19
20
2,5-di-i-Pr
2,4-di-i-Pr
15.67
7.14
24.33
6.49
8.50
22.63
2.58
/
2,6-di-tert-Bu
2,4,6-tri-Et
2,4,6-tri-i-Pr
thioglycolic acid
37.1
19.92
4.78
> 200
cell line HeLa
IC50
observed,
predicted,
PBMC
R
(µmol/L) log(1/(IC50)) log(1/(IC50)) BEHv5 log P
1
6
2,5-di-i-Pr
13.3
20.65
6.17
10
21.56
2.00
/
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
/
H
14.98
3.81
3.83
2.68
17.30
4.79
3.33
1.915
1.39
1.71
4.73
4.824
5.419
5.417
5.572
4.762
5.320
5.478
5.718
5.857
5.767
5.325
4.684
4.763
5.022
4.530
6.191
5.959
5.361
6.056
5.780
/
4.613
5.394
5.449
5.416
4.912
5.299
5.488
5.793
5.660
5.695
5.229
4.717
4.950
5.086
4.609
6.012
6.025
6.082
6.079
6.053
/
2.655 0.71
2.878 1.68
2.928 1.68
2.898 1.68
2.655 1.20
2.820 1.61
2.867 1.94
2.997 2.45
2.885 2.41
3.275 5.79
2.700 1.75
2.655 0.87
2.655 1.27
2.655 1.54
2.898 0.33
3.081 3.18
3.093 3.18
3.163 4.12
3.129 3.42
3.180 4.41
17
18
19
20
2,4-di-i-Pr
6.79
3,4-di-Me
2,4-di-Me
2,5-di-Me
4-Me
2,6-di-tert-Bu
2,4,6-tri-Et
43.72
18.97
3.32
2,4,6-tri-i-Pr
thioglycolic acid
> 200
4-Et
4-i-Pr
a markedly improved activity. Introduction of two alkyl
substituents moderately increase activity. Preferred
positions on phenyl ring are 2 and 5, rendering com-
pound 4 more active than compounds 2 and 3. Observa-
tion that alkyl substitution in positions 2, 4, and 5 of
the phenyl ring improves activity, and that branched
alkyl chains are preferred for higher activity, prompted
us to substitute positions 2, 4, and 5 with branched alkyl
chains. Moreover, we observed that compounds with
long alkyl chains in position 4 exert significant activity.
Having in mind that one of the ortho positions should
be occupied for high activity, we assumed that (because
of conformational flexibility of n-alkyl chains) part of
or the free end of the 4-n-alkyl chain occupies a position
near the ortho position of the phenyl ring, within the
receptor. Compounds 16-20, with two or three alkyl
substituents longer than one C, were synthesized. These
derivatives have been drastically more active than all
other compounds. The most active compounds have an
i-Pr group in positions 2 and 5 (16), an Et group in
positions 2, 4, and 6 (19), and an i-Pr group in positions
2 and 4 (17), in decreasing order of activity. A tri-i-Pr-
substituted derivative (positions 2, 4, and 6) (20) is
slightly less active. Compounds 16 and 19 are active in
sub-micromolar concentrations (0.64 and 0.88 µM/L),
while compounds 8, 9, 10, and 20 exert activity in low
micromolar concentrations (<2 µM/L). The two tert-Bu
groups in positions 2 and 5 (18) reduce the activity
related to other compounds substituted with branched
alkyl chains. Introduction of one o-halo substituent in
place of alkyl, in disubstituted compounds, decreased
the activity (11). Occupation of positions 2 and 4 with
methoxy substituents (15) makes the least active mem-
ber of series.
4-n-Bu
4-tert-Bu
4-n-dodecyl
2-Cl-4-Me
4-F
0
1
2
3
4
5
6
7
8
9
0
20.69
17.24
9.50
4-Cl
4-Br
2,3,4-tri-MeO 29.48
2,5-di-i-Pr
2,4-di-i-Pr
0.644
1.10
2,5-di-tert-Bu 4.36
a
2,4,6-tri-Et
2,4,6-tri-i-Pr
thioglycolic
acid
0.88
1.66
>200
/
/
a
Omitted from derivation of equation.
µL of MTT solution (5 mg/mL PBS) were added to each well.
Samples were incubated for further 4 h at 37 °C in 5% CO
2
and humidified air atmosphere. Then, 100 µL of 10% SDS were
added to the wells. Absorbance at 570 nm was red the next
day. To get cell survival (%), absorbance A of a sample with
cells grown in the presence of various concentration of
substituted 2-[(carboxymethyl)sulfanyl]-4-oxo-4-arylbutanoic
c
acid derivative was divided by the control absorbance A (the
absorbance of sample with cells grown only in nutrient
medium) × 100. (It was implied that A of blank was always
subtracted from A of a corresponding sample with target cells.)
IC50 concentration was defined as the concentration of a drug
that inhibits cell survival by 50%, compared with vehicle-
treated control.
Results and Discussion
(
a) HeLa Cells. Concentrations of examined com-
pounds (1-20) that induced the 50% decrease in HeLa
cell survival (IC50), determined under exactly same
experimental conditions, are given in Table 2.
Our first observation that 2-[(carboxymethyl)sulfa-
nyl]-4-oxo-4-phenylbutanoic acid (1) inhibited prolifera-
tion of the human cervix carcinoma HeLa cells in vitro
led us to assume that the structure of 1 is a minimal
scaffold enabling activity. By using 1 as a template, one
to three alkyl, halo, or alkoxy substituents were intro-
duced in the phenyl ring to explore structure-activity
relationships. Increases in cytostatic activity were ob-
served as the halo substituent changes from 4-F (12) to
To quantify above-reported facts, a QSAR study was
performed. Correlation between activity and lipophilic-
ity was observed (by increasing activity in the series 4-F
(12), 4-Cl (13), 4-Br (14) and 4-Me (5), 4-Et (6), 4-i-Pr
(7), 4-n-Bu (8), 4-n-dodecyl (10)). Therefore, log P and
number of 2D whole-molecule descriptors were calcu-
lated. Estimation of the logarithm of partition coefficient
[n-octanol/water] log(P) ) log(KOW) was done by Crip-
pen’s fragmentation method.14 Whole molecular descrip-
tors that can quantitavely describe diversity between
4
-Cl (13) to 4-Br (14). Only the 4-Br derivative (14)
exerts higher activity than the lead compound (1).
Introduction of one alkyl substituent larger than methyl
group in para position moderately improves activity.
Presence of one tert-Bu (9) group or n-alkyl chain (more
than four C atoms) (8, 10) in the para position caused
15
the most active compounds (structural isomers), BCUT,
were calculated by using Dragon16 program. The sig-
nificant parabolic (eq 1) and bilinear (eq 2) dependencies
were assessed17 using Crippen log P values and BEHv5

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 17 5603
(
highest eigenvalue n.5 of Burden matrix/weighted by
Supporting Information Available: Analytical and spec-
tral data for all synthesized compounds. Statistics of IC50 data
toward HeLa cells. Regression data for eqs 1 and 2. Mi-
croanalysis data. This material is available free of charge via
the Internet at http://pubs.acs.org.
18
atomic van der Waals volumes - BCUT descriptor),
for 19 compounds (1-17, 19, 20):
2
log(1/C) ) -0.117 ((0.032) [log P] +
0
.832 ((0.22) log P + 1.096 ((0.73) BEHv5 -
.172 ((1.91) (1)
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(
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relations (eqs 1 and 2). Inclusion of compound 18 results
in an inferior correlation, probably because of steric
hindrance of substrate binding by the receptor. Intro-
duction of a bulky tert-Bu group in position 5 (18)
induces steric congestion on the area covered by sub-
stituents 4, 5, and 6, which cannot be accommodated
by the receptor. Implicitly, proof for this is lower activity
of compound 20 (two i-Pr groups in positions 4 and 6)
than of compounds 16 (one i-Pr group in position 5) and
(
7) Kirchner, F. K.; Bailey, J. H.; Cavallito, C. J. Ring Substituted
Benzoylacrylic Acids as Antibacterial Agents. J. Am.Chem. Soc.
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2
1
9 (two Et groups in positions 4 and 6). Compound 20
is 1.9-fold less active than compound 19.
b) PBMC and PBMC+PHA Cells. Concentrations
th
stracts II; 3 International Conferences of the South-Eastern
European Countries, Bucharest (Romania), Sept 22-25, 2002;
p 189.
(
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9) Papa, D.; Schwenk, E.; Villani, F.; Klingsberg, E. â-Aroylacrylic
Acids. J. Am. Chem. Soc. 1948, 70, 3356-3360.
of examined compounds 16-20 that induced 50% de-
crease in PBMC and PBMC+PHA (healthy human’s
peripheral blood cells) cells survival (IC50), determined
under exactly same experimental conditions, are given
in Table 3.
(10) Drakuli c´ , B. J.; Bogdanovi c´ , G. A.; Novakovi c´ , S. B.; Jurani c´ , I.
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nylbutyric Acids. Book of abstracts I; 3 International Confer-
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(Romania), Sept 22-25, 2002; p 229.
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11) Mosmann, T. Rapid Colorimetric Assay for Cellular Growth and
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The results were assessed by a single measurement
done in triplicate. In the fourth column of the Table 3
selectivity indexes Si are shown. The Sis were calculated
as IC50(toward normal cells)/IC50(toward malignant
cells), for the every examined compound (16-20).
Compounds 16 and 19, which act in sub-micromolar
concentrations toward human cervix carcinoma HeLa
cells, exert the highest selectivity and will be further
examined. Also, parabolic dependencies between activity
toward healthy cells (implying selectivity) and lipophi-
licity were observed. Because of the small set of com-
pounds tested on normal cells (PBMC and PBMC+PHA),
this observation was given only as an indication. The
above conclusions provide a basis for planning syntheses
of new congeners with expected higher activity.
(
12) Ohno, M.; Abe, T. Rapid Colorimetric Assay for the Quantifica-
tion of Leukemia Inhibitory Factor (Lif) and Interleukin-6 (Il-
6
). J. Immunol. Methods 1991, 145, 199-203.
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V.; Milovanovi c´ , S. R.; Jurani c´ , I.; Bijelogrli c´ , S.; Vuleti c´ , N.;
Radulovi c´ , S. T-2 Toxin Affects Proliferatiom of Three Different
Neoplastic Cell Lines. J. Exp. Clin. Cancer Res. 1998, 17, 33-
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14) Ghose, A. K.; Crippen, G. M. Atomic Physicochemical Parameters
for Three-Dimensional-Structure-Directed Quantative Structure-
Activity Relationships. 2.Modeling Dispersive and Hydro-
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3
5.
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15) Pearlman, R. S.; Smith, K. M. In 3D-QSAR and Drug Design:
Recent Advances; Kubinyi, H., Martin, Y., Folkers, G., Eds.;
Kluwer Academic: Dordrecht, Netherlands, 1997; pp 339-353.
16) Todescini, R.; Consonni, V.; Mauri, A.; Pavan, M. Dragon - web
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17) BILIN program by Professor Hugo Kubinyi, BASF A.G., 1998.
Acknowledgment. To Ministry of Science and
Environmental Protection of Serbia (Research Grants
(18) Todescini,R.; Consonni, V.; Mauri, A.; Pavan, M. Dragon - web
version 3.0, 2003; Dragon Varfile.
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