Synthesis, X-ray structure and antiproliferative activity of 3-benzylthio-4-propargylselenoquinoline

Article abstract of DOI:10.1007/s00044-009-9212-x

Synthesis, antiproliferative activity and the X-ray single-crystal structure of the 3-benzylthio-4-propargylselenoquinoline are described. The title compound belongs to the group of the acetylenic derivatives of thioquinolines, which have been intensively investigated as a source of new anticancer agents. The comparative study regarding the X-ray structure, the molecular electrostatic potential analysis, and structure-activity relationship for the title compound and the 3-methylthio-4-propargylthioquinoline and 3-methylthio-4-propargylselenoquinoline are presented. Birkhaeuser Boston 2009.

Full text of DOI:10.1007/s00044-009-9212-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:551–564
DOI 10.1007/s00044-009-9212-x
ORIGINAL RESEARCH
Synthesis, X-ray structure and antiproliferative activity
of 3-benzylthio-4-propargylselenoquinoline
Stanislaw Boryczka Æ Maria Jastrzebska Æ
Maria Nowak Æ Joachim Kusz Æ Roman Wrzalik Æ
Joanna Wietrzyk Æ Małgorzata Matyja
Received: 23 December 2008 / Accepted: 15 April 2009 / Published online: 27 May 2009
¨
Ó Birkhauser Boston 2009
Abstract Synthesis, antiproliferative activity and the X-ray single-crystal struc-
ture of the 3-benzylthio-4-propargylselenoquinoline are described. The title com-
pound belongs to the group of the acetylenic derivatives of thioquinolines, which
have been intensively investigated as a source of new anticancer agents. The
comparative study regarding the X-ray structure, the molecular electrostatic
potential analysis, and structure-activity relationship for the title compound and the
3-methylthio-4-propargylthioquinoline and 3-methylthio-4-propargylselenoquino-
line are presented.
Keywords Structure-activity relationship ꢀ Antiproliferative activity ꢀ
Electrostatic potential
S. Boryczka ꢀ M. Matyja
Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Silesia,
41-200 Sosnowiec, Jagiellonska 4, Poland
M. Jastrzebska (&)
Department of Radioisotope Diagnostics and Radiopharmaceuticals, Faculty of Pharmacy,
Medical University of Silesia, 41-200 Sosnowiec, Jagiellonska 4, Poland
e-mail: maja@sum.edu.pl
M. Nowak ꢀ J. Kusz
Institute of Physics, Department of Physics of Crystals, University of Silesia,
Uniwersytecka 4, 40-007 Katowice, Poland
R. Wrzalik
Department of Biophysics and Molecular Physics, Institute of Physics,
University of Silesia, Uniwersytecka 4, 40-007 Katowice, Poland
J. Wietrzyk
Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology
and Experimental Therapy, Polish Academy of Sciences, Weigla 12, Wrocław, Poland

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Introduction
Acetylenic derivatives of thioquinolines are an important class of compounds that
has attracted increasing attention as a source of new anticancer agents. The synthetic
methods for their preparation are of interest especially with regard to the synthesis
of biologically active enediyne antitumor antibiotics or similar model molecules
(Grissom et al., 1996; Jones and Found, 2002; Nicolaou and Dai, 1991; Gredicak
and Jeric, 2007).
Recently, we have reported a simple and efficient method for the synthesis of
thioquinolines, which possess the S, Se-acetylenic groups. It has been found that Se-
acetylenic thioquinolines are more active in vitro than S-acetylenic derivatives against a
broadpanelofhumanandmurinecancercelllineswithID50 valuescomparabletothatof
´
referential anticancer drug, cisplatin (Boryczka et al., 2002a, b; Mol et al., 2006, 2008).
The chemical and physical properties of Se are similar to those of sulfur, but the
biochemistry differs in at least two respects that distinguish them in biological systems
(Aboul-Fadl,2005). First, inbiologicalsystemsseleniumcompoundsaremetabolizedto
morereducedstates, whereassulfurcompoundsaremetabolizedtomoreoxidizedstates.
Second, selenols are more acidic than thiols, and they are readily oxidized. In general,
organoselenium compounds are more reactive than their sulfur analogues due to weaker
C–Se bond than the C–S bond. These properties can be involved in higher activity of the
Se-compounds against cancer cells than S-derivatives (Aboul-Fadl, 2005).
Apart from the synthesis and interest in the anticancer activity, these compounds
are of relevance in the context of intermolecular interactions and the structure-
activity relationship. The terminal alkyne group is expected to form C:C–HꢀꢀꢀX
hydrogen bond, with X being one of the potential hydrogen-bond acceptors of the
molecule. Recently, we reported the crystal structures of 3-methylthio-4-propar-
gylthioquinoline 1 and 3-methylthio-4-propargylselenoquinoline 2, which contain an
˚
unusually short C:C–HꢀꢀꢀN hydrogen bonds with distances HꢀꢀꢀN = 2.28 A,
˚
˚
˚
CꢀꢀꢀN = 3.305 A and HꢀꢀꢀN = 2.17 A, CꢀꢀꢀN = 3.225 A, respectively (Boryczka
et al., 2000a, 2001, 2002b). It also has been observed that compound 2 is more
cytotoxic than 1, with ID50 values ranging from 0.6 to 2.5 lg/ml (Table 1), against
human cancer cell lines: lung cancer (A549), colon cancer (SW707), bladder cancer
(HCV29T), breast cancer (T47D) (Boryczka et al., 2002a, b). It is well known that
formation of hydrogen bonds and lipophilicity play an important role in several
Table 1 Hydrogen bond distances and antiproliferative activity in vitro of propargyl thioquinolines 1–3
against the human cancer cell lines
˚
Hydrogen bond distances (A)
Compound
Cell line/ID50 (lg/ml)
HꢀꢀꢀN
CꢀꢀꢀN
A549
SW707
HCV29T
T47D
1*
2.28
2.17
Lack
3.305
3.225
6.8 1.7
18.4 2.2
2.5 1.6
[100
17.6 1.6
0.6 1.6
[100
5.7 1.1
1.8 1.4
[100
2*
–
3
[100
Cis-platin
–
2.3 1.1
0.7 1.0
2.1 1.8
* Boryczka et al., 2002a, b

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553
ADME aspects, which are adsorption, distribution, metabolism, and excretion in
biological systems (Gensmantel, 2001). It was argued that the activity of compound 2
can be attributed to the presence of a propargylseleno group in the context of its very
short intermolecular interactions.
To study the influence of the intermolecular interactions of the propargyl group
on the cytotoxic activity of this class of compounds, we have prepared 3-benzylthio-
4-propargylselenoquinoline 3. Formation of the short hydrogen bonds could be a
favorable event in the course of antiproliferative activity of the compounds being
tested; however, this suggestion needs strong experimental verification.
XCH2C CH
SR
N
1. X = S, R = Me
2. X = Se, R = Me
3. X = Se, R = CH2Ph
It also is of interest to examine the correlation between the antiproliferative
activity of propargyl thioquinoline compounds and their reactive behavior predicted
by the molecular electrostatic potential (MEP) analysis. The MEP can be
particularly useful as an indicator of the sites of a molecule, to which an
approaching electrophile is initially attracted (Murray et al., 1991; Politzer et al.,
1985; Weiner et al., 1982).
Results and discussion
Chemistry
The 3-benzylthio-4-propargylselenoquinoline 3 was synthesized by nucleophilic
displacement of chloride in the corresponding 4-chloro-3-benzylthioquinolines 4 by
selenourea in ethanol and subsequent S-alkylation of sodium salt 4-B with propargyl
bromide (Scheme 1) according to the reported method (Boryczka et al., 2002a, b).
´
Compound 4 was obtained following procedures described by Maslankiewicz and
Boryczka (1993).
X-ray structure
The title compound (3) crystallizes in the centrosymmetric space group P21/c with
one molecule in the asymmetric unit cell. The refined molecule and the atomic
numbering scheme are shown in Fig. 1. The crystal packing and selected geometric
parameters are presented in Fig. 2 and Table 2, respectively.

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+
NH2
-
Se
C
NH2
Cl
Cl
CSe(NH2)2
EtOH / rt
SCH2Ph
SCH2Ph
4
4-A
NaOH aq
SeNa
SeCH2C CH
SCH2Ph
SCH2Ph
HC CCH2Br
NaOH aq
3
Scheme 1 Synthesis of 3-benzylthio-4-propargylselenoquinoline 3
4-B
Fig. 1 View of the molecule 3 showing the atom-labeling scheme. Displacement ellipsoids are drawn at
the 50% probability level and H atoms are shown as small spheres of arbitrary radii
The heterocyclic and carbocyclic rings of the quinoline core are, separately,
essentially planar. The r.m.s. deviations of an atom from the best fit planes
˚
describing the rings are -0.0118 A and 0.0020 A, respectively. Because the angle
˚
between the planes of these rings is only 1.06(10)°, the quinoline core as a whole is
nearly planar with r.m.s. deviations from the mean core plane of 0.0106 A. The
˚
molecular dimensions in the quinoline core show the usual values reflecting in the
heterocyclic ring somewhat more marked alternation of single- and double-bond
character, e.g., the short N1–C1 and the longer N1–C8 bonds, the short C2–C3 and
long C3–C9. They are comparable with similar structures: CSD refcode: ASAFUV

Med Chem Res (2010) 19:551–564
555
Fig. 2 The crystal packing of the compound 3, viewed approximately along [001]
˚
Table 2 Selected geometric parameters (A, °) for compound 3
N1–C1
1.307(2)
1.373(2)
Se1–C3
1.929(2)
1.970(2)
1.436(2)
1.171(3)
0.95
N1–C8
Se1–C17
C17–C18
C18–C19
C19–H19
S1–C2
1.757(2)
S1–C10
1.821(2)
C10–C11
1.508(2)
S1–Se1
3.198(8)
C1–N1–C8
C1–C2–S1
C3–C2–S1
C2–S1–C10
S1–C10–C11
N1–C1–C3–S1
C1–C2–S1–C10
C2–S1–C10–C11
S1–C10–C11–C12
117.80(15)
123.14(13)
119.02(13)
104.84(8)
106.54(11)
-177.35(11)
11.57(16)
158.72(12)
93.56(17)
C2–C3–Se1
C9–C3–Se1
C3–Se1–C17
Se1–C17–C18
119.82(13)
120.87(12)
96.54(7)
112.65(12)
C1–C2–C3–Se1
C2–C3–Se1–C17
C3–Se1–C17–C18
S1–C2–C3–Se1
177.72(12)
-72.25 (14)
-63.15 (14)
-2.12 (18)
(Duann et al., 2003); CSD refcode: EDAVUA (Davies and Bond, 2001); CSD
refcode: BAPBOK (Skrzypek and Suwinska, 2002); CSD refcode: FOCYUS
(Fitchett et al., 2005); CSD, Version 5.28; Conquest, Version 1.9 (Allen, 2002).
˚
The triple-bond distance C18–C19 equals 1.171(3) A and is shorter than that
˚
found previously in 1 and 2 (1.181(4) A and 1.183 A, respectively).
˚
˚
The length of the bonds C3–Se1 and Se1–C17 are equal to 1.929(2) A and
˚
1.970(2) A, respectively, and they are similar to those in compound 2. The selenium
bond angle C3–Se1–C17 is 96.54(7)° and corresponds to quinolinyl–selenium bond
angle present in compound 2 (95.84°). The C3–Se1 bond is nearly coplanar with the
ring system, but the Se1–C17 bond, involving the propargyl group, is rotated almost
perpendicularly out of the quinoline plane. The dihedral angle C2–C3–Se1–C17 is
-72.25(14)° and this angle is smaller compared with compound 2 (-103.95)
(Boryczka et al., 2001). The propargyl group is pointing out of quinoline plane. The
dihedral angle C3–Se1–C17–C18 is -63.15(14)° and it is smaller than in 2
(176.35°) (Boryczka et al., 2001). This situation is similar to that observed for the
orientation of propargyl groups in the crystal structure of the bis(4-propargyloxy-3-
quinolylthio)methane (Boryczka et al., 2000b), but it has different orientation to that

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Med Chem Res (2010) 19:551–564
observed in 1 and 2, where the propargyl group is oriented parallel to the C3–Se(S)
bonds (Boryczka et al., 2000a, 2001). This conformation about the Se1–C17 bond in
3 causes such position of the acetylenic hydrogen atom H19 that it is not favorable
for C–HꢀꢀꢀN intermolecular hydrogen bonding.
˚
The length of the bond C2–S1 is equal to 1.757(2) A and is similar to those found
earlier in compounds 1 and 2 (Boryczka et al., 2000a, b, 2001). The bond length of
˚
S1–C10 is 1.821(2) A and is close to the Caliphatic – S bonds (Mott and Barany,
1984). The sulfur bond angle C2–S1–C10 is 104.84(8)° and corresponds to the
quinolinyl–sulfur bond angle of 103.79° and 103.25° in the sulfide 1 and 2,
respectively (Boryczka et al., 2000a, b, 2001).
The quinoline ring also is coplanar with the central C–S bond (maximum out of
˚
plane distance is equal to 0.0242 A). The torsion angle about this bond is 158.72
(12)°. The mean plane through benzyl group is twisted by 80.99(5)° with respect to
the thioquinoline plane.
˚
The S1–Se1 distance is equal to 3.198(1) A and is less than the sum of the van
˚
der Waals radii of the sulfur and selenium atoms, which equals 3.85 A (Bondi,
1964). The characteristic feature of the intramolecular nonbonded 1,4 SꢀꢀꢀSe contact
in 3 is that the S1 and Se1 atoms are held in a nearly coplanar environment
containing S1, C2, C3, and Se1, which form a four-member quasi-ring by a S1ꢀꢀꢀSe1
˚
interaction with a deviation of Se1 of 0.0045(4)A. Also the arrangement of C10–
S1ꢀꢀꢀSe1 atoms is almost linear, the angle C10–S1ꢀꢀꢀSe1 is equal to 164.92(6)° and it
promotes the 1,4 close contact. A similar 1,4 short contact between S and Se atoms
˚
has been characterized in the structure of 2 with SꢀꢀꢀSe distance of 3.199 A
(Boryczka et al., 2001). The nonbonding selenium–sulfur interaction and its
importance in asymmetric synthesis were observed in arylselenenyl halides (Tiecco
et al., 2006).
As a result of interaction between S1 and Se1 the corresponding adjacent outer
angles are enlarged. The angles C1–C2–S1 [123.14(13)°] and C9–C3–Se1
[120.87(12)°] are clearly larger than neighboring angles C3–C2–S1 [119.02(13)°]
and C2–C3–Se1 [119.82(13)°], respectively.
There are no direction-specific intermolecular interactions between adjacent
molecules in the structure of compound 3. In particular, C–HꢀꢀꢀN hydrogen bonds
are absent, so that the structure consists of effectively isolated molecules. Probably
it may be caused by the awkward shape of the title molecule that does not allow to
create efficient crystal packing and to generate hydrogen bonding at the same time.
The shortest distances between quinoline rings from different pairs occur for
˚
C19–C19 (symmetry code: x, ‘ - y, -‘ ? z): 3.186(2) A, N1–C17 (symmetry
˚
code: 1 ? x, y, z): 3.308(2) A, S1–C14 (symmetry code: -x, -y, -z): 3.553(2) A,
˚
˚
C15–C1 (symmetry code: 1 - x, -y, 1 -z): 3.662(2) A and C12 – S1 (symmetry
˚
code: x, y, -1 ?z): 3.897(2) A.
Antiproliferative activity
Compound 3 was tested for its antiproliferative activity in vitro against four human
cancer cell lines: lung cancer (A549), colon cancer (SW707), bladder cancer
(HCV29T), breast cancer (T47D). The results of cytotoxic activity in vitro were

Med Chem Res (2010) 19:551–564
557
expressed as an ID50 (lg/ml), i.e., the concentration of compound, which inhibits
the proliferation of 50% of tumor cells compared with the control untreated cells.
Cisplatin was applied as a referential cytotoxic agent (positive test control). A
value \4 lg/ml is considered as an antiproliferative activity criterion for synthetic
compounds. The results are summarized in Table 1; previously reported data for
compounds 1 and 2 are included for comparison (Boryczka et al., 2002a, b).
The data show that compound 2 exhibits high anticancer activity in vitro against the
cells of all human cancer lines applied with ID50 values comparable to those of
cisplatin. Compound 1 revealed relatively moderate cytotoxic activity with ID50
values ranging from 5.7 to 18.4 lg/ml. It is important to note that compound 3 does not
show any significant activity (ID50 [100 lg/ml) in the concentration range applied.
Molecular electrostatic potential analysis
The electrostatic potential is a powerful tool that has provided insights into
molecular properties of small molecules and intermolecular association as well as
action of drug molecules and their analogs (Murray et al., 1991; Politzer et al.,
1985; Weiner et al., 1982; Marin et al., 2008).
It is a scalar field that can be calculated from the expression:
Z
qðr0Þdr0
X
ZA
VðrÞ ¼
ꢁ
=RA ꢁ r=
=r0 ꢁ r=
where q(r0) is the electronic density function obtained from the standard electronic
wave function.
In this work, the electrostatic potentials in the surrounding of the molecule and the
color-coded computer graphics representation of the molecular isopotential surfaces
for molecules 1, 2, and 3, with the equilibrium geometrics in the gaseous phase, have
been determined. The optimized gaseous structures were calculated using GAUS-
SIANW03 program (Gaussian 03, Revision C.02; Frisch et al., 2004). The DFT
(Density Functional Theory) at level B3LYP/6 - 311 ? G(d.p) was applied and
Berny optimization under tight convergence criteria was used. Initial molecular
geometry was taken from the X-ray experimental data for each of the molecule. All
optimized structures showed positive harmonic vibrations; this meant that a true
energy minimum was reached in all performed structure calculations. These
geometries were used to compute electrostatic potential V(r) and the electronic
densities, which defined the molecular surfaces. Atomic charges were calculated using
Charges-from-Electrostatic-Potential, Grid Method (CHELPG), giving charges fit to
the electrostatic potential. The MEPs were visualized with Gauss View 4.0 program.
Figure 3a–c show calculated electrostatic potentials for compounds 1, 2 and 3,
respectively. The total SCF electron density was calculated for the isovalue density
of 0.0004 and surface was painted according to the value of the electrostatic
potential, i.e., the more red an area is, the more negative electrostatic potential, and
the more blue an area is, the more positive electrostatic potential. The projection of
the electrostatic potential into a plane of the quinoline ring was plotted for a series
of isovalue.

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Med Chem Res (2010) 19:551–564

Med Chem Res (2010) 19:551–564
559
Fig. 3 Color-coded computer graphics representations of the electrostatic potentials of compounds 1 (a),
2 (b), and 3 (c), respectively. The more red an area is, the more negative V(r) and the more blue an area is,
the more positive V(r). Projections are in the plane of quinoline ring. The positions of the potential
minima (in kcal/mol) are indicated. (Color figure online)
b
For compound 1 (Fig. 3a), one can observe three main areas of negative
electrostatic potential. The first comprises nitrogen atom and carbocyclic ring of the
quinoline core with the value of potential minimum equal to -54.6 kcal/mol
centered close to nitrogen. This is the most negative value and is associated with the
nitrogen lone pair. The potential is strongly negative above and below the aromatic
rings, reflecting the presence of p electrons. The other two areas include proximity
of sulfur atoms and the triple bond of the propargyl group with the potential minima
equal to -17.5 kcal/mol and -14.0 kcal/mol, respectively. In those regions where
V(r) is negative the effect of electrons predominates and these are accordingly
attractive to an approaching electrophile. Similar arrangement of potentials is seen
for molecule 2 in Fig. 3b; however, one can observe changes in the proximity of
nonbonded 1,4 S–Se contact and near the triple bond of the propargyl group. The
local potential minima for compound 2 are -54.6 kcal/mol, -16.8 kcal/mol, and
-13.3 kcal/mol, respectively. For compound 3 (Fig. 3c), the following three main
local minima of electrostatic potential can be seen: near the nitrogen atom
(-57.0 kcal/mol), the proximity to the 1,4 S–Se quasi-ring (-20.2 kcal/mol), and the
proximity to the triple bond of the propargyl group (-16.6 kcal/mol), which is now
separately located due to the distinct spatial configuration of the propargyl group.
The electrostatic potential minima are associated with the reactive centers of the
molecules 1–3. For compounds 1 and 2, the most negative region (-54.6 kcal/mol)
is involved in formation of short C–HꢀꢀꢀN hydrogen bonds, whereas the other two
regions, which are associated with the nonbonded 1,4 S–Se(S) contact and the
propargyl triple bond, are less negative for compound 2 than 1. Molecule 3 shows
three potential minima, none of them is involved in hydrogen bonding and the
compound does not show any significant cytotoxic activity. As shown in Table 3,
compound 2 containing selenopropargyl group, exhibits the highest antiproliferative
activity compared with 1 and 3. The presented results suggest that there is a
relationship between the cytotoxic activity and the regions associated with the
structure-dependent electrostatic potential minima. Less negative potential minima
give weaker nucleophilic properties of the compound. Formation of one, strong and
short H-bond by the reactive center with the most negative potential is the first
favorable event in the course of high cytotoxic activity. The second is a reduction in
the negative potential minima located near 1,4 SꢀꢀꢀSe/S contact and the propargyl
triple bond. This reduction can be achieved by the substitution of selenium into the
propargyl group. Also important is the spatial orientation of the propargyl group.
The orientation parallel to the Se1–C3 bond is preferred to achieve less negative
potential minima, i.e., -13.3 kcal/mol and -16.8 kcal/mol, respectively (Fig. 3b).
For compound 3 (Fig. 3c), the propargyl group is oriented almost perpendicularly to
the Se1–C3 bond and the potential minima are significantly higher, i.e., -16.6 kcal/
mol and -20.2 kcal/mol, respectively.
The charges derived from the CHELPG methode allowed us to analyze atomic
charge distribution over atoms of the 1,4 SꢀꢀꢀSe(S) quasi-ring and the propargyl

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Table 3 Atomic charge
1
2
3
distribution over selected atoms
of the 1,4 SꢀꢀꢀSe/S quasi-ring and
the propargyl group, main
1.4 SꢀꢀꢀSe/S semi-ring group
S1 -0.193
S1 -0.246
C2 -0.183
S1 -0.263
C2 -0.199
C3 ?0.349
Se1 -0.143
electrostatic potential minima,
and the antiproliferative activity
in vitro for compounds 1–3
C2 -0.114
C3 ?0.247
C3 ?0.309
Se1 -0.128
S2 -0.227
Propargyl group
C11 ?0.361
C12 -0.032
C13 -0.348
C11 ? 0.281
C12 - 0.006
C13 - 0.362
C17 ?0.278
C18 -0.072
C19 -0.365
Main electrostatic potential minima [kcal/mol]
-17.5
-16.8
-20.2
-57.0
-16.6
-54.6 (H)
-14.0
-54.6 (H)
-13.3
Antiproliferative activity
Moderate
(H) means the hydrogen-bond
occupied center
High
Lack
group. Computational results indicate that the intramolecular nonbonded 1,4 SꢀꢀꢀSe
contact (compounds 2 and 3) is involved in the electrostatic interaction between S
and Se atoms, which are both negatively charged. The net charge located on Se is
lower compared with the charge of S (Table 3). Substitution of the Se by S (see
compound 1 and Table 3) leads to the considerable changes in charge distribution
over atoms of the 1,4 SꢀꢀꢀS quasi-ring, but the distance between S1 and S2 atoms is
almost the same. Selenium influences also charge distribution over atoms in the
propargyl group, especially charge located on carbon atom involved in the triple-
bond formation.
Conclusions
X-ray structure and the molecular electrostatic potential studies performed for the
title compound 3 as well as comparative structure-activity analysis for compounds
1–3 allowed for the determination of the main structural features, which are
favorable for higher cytotoxic activity of the propargyl thioquinoline compounds. It
has been found that spatial orientation of the propargyl group and the substitution of
the Se into this group significantly influence the structural arrangement of the
electrostatic potential minima, which are responsible for the reactive behavior of the
molecules tested. Formation of one short and strong H-bond could be a favorable
event in the course of antiproliferative activity. The atomic charges fitted to the
electrostatic potential surfaces revealed the selenium influence on charge distribu-
tion over atoms of the propargyl group and the intramolecular electrostatic repulsive
selenium–sulfur interaction.
Results of the X-ray structure analysis performed for the title compound 3
highlighted the influence of spatial orientation of the propargyl group on the

Med Chem Res (2010) 19:551–564
561
molecular reactive centers. The presented results can be of interest especially with
regard to the synthesis of biologically active enediyne antitumor antibiotics or
similar model molecules.
Experimental
General techniques
Melting points were determined in open capillary tubes on a Boetius melting point
apparatus and are uncorrected. The 1H-(500 MHz) and 13C-(125 MHz) NMR
spectra were recorded on Bruker AMX-500 spectrometer; chemical shifts are
referenced to the residual solvent signal (CDCl3, dH = 7.26, dC = 77.0). Homo-
nuclear 1H connectivities were determined by performing COSY experiments. One-
bond heteronuclear 1H-13C connectivities were determined by HMQC experiments.
Two- and three-bond 1H-13C connectivities were determined by HMBC experiments
optimized for a 2,3J of 10 Hz. EI MS spectra were run on a a Finnigan MAT 95
spectrometer. Elemental C, H, N, S analyses were obtained on a Carlo Erba Model
1108 analyzer.
Synthesis of 3-benzylthio-4-propargylselenoquinoline 3
A mixture of 4-chloro-3-benzylthioquinoline 4 (0.57 g, 2.0 mmol), selenourea
(0.26 g, 2.1 mmol), and 99.8% ethanol (8 ml) was stirred at room temperature for 30
minutes. The reaction mixture was poured into 20 ml of 5% aqueous sodium
hydroxide. Propargyl bromide (0.28 g, 2.4 mmol) was added dropwise to the aqueous
layer, and the mixture was stirred for 15 minutes. The resultant solid was filtered off
and air-dried to give a crude product, which was purified by column chromatography
[silica gel 60, \63 lm (Merck) using a mixture of chloroform and ethanol (30:1, v/v)
as an eluent] and then crystallized from benzene-hexane to give 0.48 g (65 %) of 3
1
with m.p. 116–117°C. H NMR (in the NMR spectrum, we applied systematic
numbering according to IUPAC rules) (CDCl3, 500 MHz) d: 2.09 (t, J = 2.5 Hz, 1H,
CH), 3.53 (d, J = 2.5 Hz, 2H, CH2Se), 4.32 (s, 2H, CH2S), 7.59 (m, 3J(5,6) = 8.3 Hz,
4
3
3
3J(6,7) = 6.9 Hz, J(6,8) = 1.4 Hz, 1H, H-6), 7.66 (m, J(7,8) = 8.3 Hz, J(6,7)
=
6.9 Hz, 4J(5,7) = 1.5 Hz, 1H, H-7), 8.05 (dd, 3J(7,8) = 8.3 Hz, 4J(6,8) = 1.4 Hz, 1H, H-
8), 8.51 (dd, 3J(5,6) = 8.3 Hz, 4J(5,7) = 1.4 Hz, 1H, H-5), 8.79 (s, 1H, H-2). 13C NMR
(CDCl3, 125 MHz) d: 145.98 (C-2), 139.52 (C-3), 135.26(C-4), 130.30 (C-4a), 127.64
(C-5), 128.00 (C-6), 128.64 (C-7), 129.88 (C-8), 145.64 (C-8a), 12.53 (CH2), 79.69
(CH2–C), 72.48 (CH), 16.56 (CH3). EI MS (15 eV) m/z (rel. intensity) 369 (M?, 42),
278 (86). Anal. Calcd for C19H15NSSe: C 61.95, H 4.10, N 3.80, S 8.70. Found: C
61.88, H 4.22, N 3.71, S 8.65.
X-ray diffraction experiment
The single crystal X-ray experiments were performed at 150 K. For these
measurements, a colorless, small, single crystal (0.09 9 0.06 9 0.03 mm3) of

562
Med Chem Res (2010) 19:551–564
good quality was preselected under a polarizating microscope. The crystal was
mounted on a quartz glass capillary and cooled by a cold, dry, nitrogen gas stream
(Oxford Cryosystems equipment). The temperature stability of the measurement
was 0.1 K. The X-ray measurements were performed with Oxford Diffraction
Table 4 Crystallographic data
Crystal data
and refinement details for
compound 3. Crystallographic
data – CCDC 710965
Chemical formula
C19H15NSSe
Cell setting, space group
Temperature (K)
Monoclinic, P21/c
150
´
˚
a (A)
8.3700(17)
34.735(7)
5.4980(11)
97.29(3)
´
˚
b (A)
´
˚
c (A)
b (°)
´
3
˚
V (A )
1585.5(6)
4
Z
Dx (Mg m-3
Radiation type
l (mm-1
)
1.543
Mo Ka
)
2.495
Crystal form, color
Crystal size (mm)
Data collection
Diffractometer
Needle, colorless
0.09 9 0.06 9 0.03
KM4 CCD Sapphire3
Dx–scan
Data collection method
Absorption correction
No. of reflections
Measured
Multiscan
15506
5338
Independent
Observed
3122
Criterion for observed
reflections
I [ 2r(I)
Rint
0.042
32.72
hmax (°)
Refinement
Refinement on
R[F2 [ 2r(F2)]
wR(F2)
F2
0.0336
0.0488
0.999
5338
199
S
No. of reflections
No. of parameters
Weighting scheme
Calculated w = 1/
[r2(F2o) ? (0.0533P)2 ? 0.1207P]
where P = (F2o ? 2Fc2)/3
(D/r)max
\0.0001
´
-3
˚
Dqmax, Dqmin (eA
)
0.511, -0.331

Med Chem Res (2010) 19:551–564
563
KM4 kappa diffractometer equipped with a Sapphire3 CCD detector and graphite-
´
˚
monochromated Mo Ka radiation (k = 0.71073 A). During data collection, x scans
were performed. Multiscan absorption correction was used. Accurate cell param-
eters (Table 4) were determined and refined using the program CrysAlis CCD. For
the integration of the collected data, the program CrysAlis RED was used (Oxford
Diffraction, 2006). The structure was first solved using the direct method with
SHELXS-97 software, and then the solution was refined with SHELXL-97
(Sheldrick, 2008). All nonhydrogen atoms were refined with anisotropic temper-
ature factors. Aromatic H atoms were treated as riding on their parent C atoms with
˚
C–H = 0.95 A and with Uiso(H) = 1.2Ueq(C). Methylene H atoms also were
˚
treated as riding on their parent C atoms with C–H = 0.99 A and with
Uiso(H) = 1.2Ueq(C). Acetylenic H atom was treated as riding on its parent C
˚
atom too with C–H = 0.95A and with Uiso(H) = 1.2Ueq(C). More crystallo-
graphic, experimental, and computational details are given in Table 4.
The crystal structure has been deposited at the Cambridge Crystallographic Data
Centre and allocated the deposition number: CCDC 710965.
Antiproliferative activity testing
Compound 3 was tested in SRB assay for their antiproliferative activity in vitro
against four human cancer cell lines: A549 (lung cancer), SW707 (colon cancer),
HCV29T (bladder cancer), T47D (breast cancer) with ID50 [100 lg/ml, following
´
published procedures (Boryczka et al., 2002a, b; Mol et al., 2006, 2008). Cisplatin
was applied as a referential cytotoxic agent (positive test control). A value \4 lg/
ml is considered as an antiproliferative activity criterion for synthetic compounds.
Acknowledgments This work was supported by the Polish Ministry of Science and Higher Education,
Grant No. N405 036 31/2655.
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