Synthesis, molecular docking study, and evaluation of the antiproliferative action of a new group of propargylthio- and propargylselenoquinolines

Article abstract of DOI:10.1007/s00044-014-0922-3

This study describes the synthesis of a new group of halogenopropargylthio- , dipropargylthio-, and halogenopropargylseleno-quinoline derivatives. The ability of all of the synthesized compounds to inhibit the proliferation of the T-47D, MCF-7, MDA-MB-231, and SNB-19 cell lines was determined with the WST-1 assay. The normal fibroblast cell line (HFF-1) was used as a control. The cytotoxic properties of these new, modified propargylquinoline derivatives were comparable to those of cisplatin. The most active compounds, 4,7-dipropargylthiquinoline (8b) and 7-chloro-4-propargylselenoquinoline (5b), were docked into the binding site of human CYP1A1 and CYP1B1. Our data indicate that these derivatives may present promising chemotherapeutic agents, possibly targeting CYP1s pathway.

Full text of DOI:10.1007/s00044-014-0922-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-0922-3
ORIGINAL RESEARCH
Synthesis, molecular docking study, and evaluation
of the antiproliferative action of a new group
of propargylthio- and propargylselenoquinolines
Krzysztof Marciniec
Stanisław Boryczka
•
Małgorzata Latocha
Rafał Kurczab
•
•
Received: 24 September 2013 / Accepted: 16 January 2014
Springer Science+Business Media New York 2014
ꢀ
Abstract This study describes the synthesis of a new
group of halogenopropargylthio-, dipropargylthio-, and
halogenopropargylseleno-quinoline derivatives. The ability
of all of the synthesized compounds to inhibit the prolifer-
ation of the T-47D, MCF-7, MDA-MB-231, and SNB-19
cell lines was determined with the WST-1 assay. The normal
fibroblast cell line (HFF-1) was used as a control. The
cytotoxic properties of these new, modified propargylquin-
oline derivatives were comparable to those of cisplatin. The
most active compounds, 4,7-dipropargylthiquinoline (8b)
and 7-chloro-4-propargylselenoquinoline (5b), were docked
into the binding site of human CYP1A1 and CYP1B1. Our
data indicate that these derivatives may present promising
chemotherapeutic agents, possibly targeting CYP1s
pathway.
Introduction
Interest in cancer has grown during the past century as
infectious diseases have increasingly been controlled as the
result of improved sanitation, vaccination, and antibiotics.
Moreover, the incidence of cancer is still rising, and in
many cases, the applied treatment is ineffective (Clegg
et al., 2002; Silva, 1999). Thus, many research studies are
performed with the goal of identifying new medicines and
treatment options.
Acetylenic derivatives are an important class of com-
pounds, since many of them have anticancer properties.
This class of compounds includes both naturally occurring
antitumor drugs, such as gummiferol (Fullas et al., 1995),
repandiol (Takahashi et al., 1992), and enediyne, as well as
synthetic ones, such as erlotinib (Sos et al., 2009). Natural
enediynes, such as calicheamicin, esperamicin, dynemicin,
and namenamicin (Gredicak and Jeric, 2007; Grissom
et al., 1996; Nicolaou and Dai, 1991), are the most potent
anticancer agents discovered to date. Some members of this
class are three orders of magnitude more potent than other
anticancer drugs, but their clinical use has been limited due
to their toxicity and modest selectivity for cancer cells.
This has prompted several research groups to design,
synthesize, and test new simplified acetylenic analogs,
characterized by a similar mode of action. Several cyclic
and acyclic derivatives, some including pyridine or quin-
oline units, have recently been developed (Boryczka et al.,
Keywords Propargylthioquinolines Á
Propargylselenoquinolines Á Dipropargylthioquinolines Á
Anticancer activity Á Molecular docking
K. Marciniec (&) Á S. Boryczka
Department of Organic Chemistry, The Medical University
of Silesia, 41-200 Sosnowiec, Poland
e-mail: kmarciniec@sum.edu.pl
2
002, 2011; Lo et al., 2007; M o´ l et al., 2008; Rawat et al.,
001; Wu et al., 1996).
2
M. Latocha
Department of Cell Biology, The Medical University of Silesia,
The arylhydrocarbon receptor (AhR) is a ligand-acti-
4
1-200 Sosnowiec, Poland
vated transcription factor that mediates cellular responses
to numerous environmental contaminants (Pohjanvirta and
Tuomisto, 1994). Molecular mechanism and biological
consequences of AhR-mediated regulation of mammalian
R. Kurczab
Institute of Pharmacology, Polish Academy of Sciences,
3
1-343 Krak o´ w, Poland
123

Med Chem Res
cytochrome P450 enzymes by foreign chemicals [e.g.,
polycyclic aromatic hydrocarbons (PAHs), aza-polycyclic
aromatic hydrocarbons (aza-PAHs), and aryl acetylenes]
have been studied extensively (Shimada et al., 2008; Saeki
et al., 2003). Several forms of Cytochrome P450 are con-
sidered to have an important role in tumor development,
because they can metabolize many potential carcinogens
and mutagens (Gonzalez and Gelboin, 1994; Kawajiri and
Fujii-Kuriyama, 1991). Moreover, cytochrome P450
activity may influence the response of established tumors
to anticancer drugs (Guengerich, 1988; Kivist o¨ et al.,
1
995). High expression levels of some forms of Cyto-
chrome P450 have been found in peri-tumor or tumor tis-
sues in estrogen-associated cancers, such as breast and
endometrial cancers (Gajjar et al., 2012; Hevir et al.,
Fig. 1 Structures of representative synthetic aryl acetylenic CYP1
inhibitors
2
011), although the presence of individual forms of Cyto-
evaluated on human CYP1A1 and 1B1 (Fig. 1) (Shimada
et al., 2008).
chrome P450 has previously been investigated in different
types of cancer, including brain, lung, and colon cancer
The generally accepted mechanism of inhibition by the
acetylenes involves two possible pathways. First pathway
involves the oxidation of the internal carbon of the triple bond
which leads to heme destruction and enzyme deactivation
through the formation of an Fe–O–CR=C(•/?)–Heme com-
plex where a radical or positive charge is localized on the
terminal carbon. Second pathway involves the oxidation of the
terminal carbon of the triple bond which results in the forma-
tion ofa reactive ketene intermediate. This ketene intermediate
can covalently bind to a nucleophilic amino acid residue in the
enzyme’s active site leading to irreversible inhibition without
destruction of the heme (Shimada et al., 1998).
(
Murray et al., 1997).
Cytochrome P450 (CYP) enzymes are superfamily of
hemoprotein monoxygenase. In humans, 18 CYP gene fami-
lies, comprising over 50 enzymes, have been identified. The
human CYP1 family is containing three members, CYP1A1,
CYP1A2, and CYP1B1. CYP1A1 is well known as an aryl
hydrocarbon hydroxylase and is capable of catalyzing a
number of oxidations of PAHs. CYP1A1 is expressed, only in
trace amounts, in the human liver, and mainly in extrahepatic
tissues and is controlled by the AhR receptor. Human
CYP1A2 is constitutively expressed in human liver but not in
extrahepatic tissues. CYP1A2 gene expression is also regu-
lated by the AhR-mediated signal pathway. CYP1B1, as well
as CYP1A1, is primarily localized in the extrahepatic tissues
and is characterized by its ability to metabolically activate
PAHs (Chun and Kim, 2003).
The expression of CYP1 family in different types of
malignant tumors has important consequences for treat-
ment of cancer. The expression of CYP1, especially
extrahepatic CYPs 1A1 and 1B1 in tumor cells provides a
molecular target for development of new anticancer drugs.
Keeping the above facts in mind, we have now synthesized
halogenopropargylthio-quinolines 4, halogenopropargylse-
leno-quinolines 5, and dipropargylthio-quinolines 8 and
evaluated their antiproliferative activity against different
cancer cell lines with the WST-1 assay.
P450s 1A1 and 1B1 have been shown, as mentioned
above, to be induced in vivo by chemicals inducers, (e.g.,
PAHs, dioxins), and inhibited in vitro by many types of
chemicals [e.g., synthetic organoselenum compounds such
as 1,2-, 1,3-, and 1,4-phenylenebis(methylene)selenocya-
nate, and synthetic acetylenic PAHs such as 4-etynylbi-
phenyl] (Shimada et al., 2008). Moreover, the aza-PAHs
(
quinoline, benzo[f]quinoline, benzo[h]quinoline, 1,7-phe-
Results and discussion
nantroline) showed similar or more potent AhR ligand
activities than the corresponding parent PAHs. Significant
enhancement of ligand activity was observed in chlorinated
quinolines (3- to 783-fold). When the enhancing effect of
the halogen substituent of quinoline on the AhR ligand
activity was compared, chlorine and bromine atoms were
more effective than the fluorine atom (Saeki et al., 2003).
Aromatic compounds containing acetylene functional
group have long been recognized as mechanism-based
inhibitors of CYPs. Various acetylenic aromatic com-
pounds have been prepared, and their inhibitory activities
Chemistry
Propargylthio- and propargylselenoquinolines 4a–e and
5a–e were synthesized using dihalogenoquinolines 1a–e as
the starting compounds, as shown in Scheme 1. Dihalo-
genoquinolines 1 were converted into uronium salts 2 by
nucleophilic displacement of the chlorine atom by thiourea
or selenourea in ethanol according to our previously
reported methods (M o´ l et al., 2008, Marciniec and Mas-
lankiewicz, 2010). Hydrolysis of the salts 2 and subsequent
1
23

Med Chem Res
Scheme 1 Synthesis of propargylthioquinolines 4a–e and propargylselenoquinolines 5a–e
Scheme 2 Synthesis of dipropargylthioquinolines 8a–e
S- or Se-alkylation of sodium thiolates 3 with propargyl
bromide resulted in the synthesis of compounds 4 and 5.
The crude products were isolated from aqueous sodium
hydroxide by filtration.
signals for the propargyl group at 2.21–2.32 ppm (triplet)
and 3.68–4.16 (doublet) with a coupling constant of
4
13
J = *2.7 Hz. In C NMR spectra of compounds 4, 5,
and 8, the signals at 10–20, 71–73, and 77–81 ppm also are
attributed to the propargyl group.
A high yield of dipropragylthioquinolines 8a–e were
produced from respective dihalogenoquinolines 1a–e in a
one-pot process performed with an excess of sodium
methanethiolate (Maslankiewicz and Marciniec, 2009;
Marciniec and Maslankiewicz, 2010). This process pro-
ceeds stepwise by halogen ipso-substitution resulting in
dimethylthioquinolines 6, which are then S-dealkylated to
respective azinedithiolates 7. They can be trapped by
alkylation with propargyl bromide to produce dipro-
pargylthioquinolines 8a–e (Scheme 2).
In disubstituted quinolines 4, 5, and 8, protons of the pyr-
idine ring of the quinoline moiety formed an AX spin system,
and protons of the benzene ring formed an AMX spin system.
1
13
The assignments of both the H and C NMR spectra of the
quinoline were based on the analysis of coupling patterns and
2D NMR experiments (COSY, HMQC, and HMBC).
Biological study
All final compounds were pure and stable. The com-
The antiproliferative activity of all fifteen compounds was
tested in T-47D (human ductal carcinoma), MCF-7 (human
adenocarcinoma), MDA-MB-231 (human adenocarci-
noma), and SNB-19 (human glioblastoma) cells using the
1
pounds were characterized by H- and C-nuclear mag-
13
1
netic resonance, IR, and CHN analysis. H NMR spectra of
propargylquinolines 4, 5, and 8 show a typical proton
123

Med Chem Res
WST-1 assay. Normal human fibroblasts (HFF-1) were
used as a control when examining the cytotoxic properties
of the new propargylquinoline derivatives. The in vitro
cytotoxic activity results were expressed as the concen-
tration of compound (nM/mL), which inhibits the prolif-
eration of 50 % of tumor cells, as compared to the control
untreated cells (IC ). Cisplatin was used as a reference for
It is important to note that 4,7-dipropargylthioquinoline 8b
and 7-chloro-4-propargylselenoquinoline 5b were more
cytotoxic than cisplatin in MCF-7 cells. Moreover, com-
pound 5b was also more active than cisplatin in MDA-MB-
231. Considering the overall activities of synthesized com-
pounds, 6-chloro-4-propargylthioquinoline 4a and 7-chloro-
4-propargylthioquinoline 4b exhibited a potent antiprolif-
erative activity in SNB-19 cells. The substitution of chlo-
rine atom in the 6- or 7-quinoline position with another thio-
propargyl group in compounds 8a and 8b increased their
anticancer activity in the T-47 and MCF-7 cell lines. In all
types of cell lines, antiproliferative activity seems to be
inherent to compounds 8b, 5b, and 4b. These compounds
seem to be good candidates for further in vitro anticancer
activity studies using a broad panel cell lines with the aim
of selecting compounds for in vivo studies.
50
cytotoxicity (positive control). The results of the cytotox-
icity studies are summarized in Table 1. Among the tested
compounds, only compounds 4b, 5b and 8b exhibited
promising activity against the different cell lines used.
In this study, the obtained data indicated that the most
active compounds against T-47D cell line were in the
following order: 8b [ 8c [ 8d [ 5a [5b [ 4c. As shown
in Table 1, dipropargylthioquinoline 8b had the highest
antiproliferative activity that could be due to the presence
of thiopropargyl groups in the 4- and 7-quinoline position.
On the other hand, compounds 4a, 4b, 4e, and 5a proved
to be effective against SNB-19 cell line. As shown in
Table 1, 6-chloro-4-propargylthioquinoline 4a, 6-chloro-2-
propargylthioquinoline 4e, and 7-chloro-4-propargylthio-
quinoline 4b had higher antiproliferative activity that could
be due to the presence of chlorine atom in the 6- or
Molecular docking
All synthesized compounds were docked to the active site
of CYP1A1 and CYP1B1 and showed binding mode con-
sistent with other docking studies (Mikstacka et al., 2012;
Sheng-Nan et al., 2013). As exemplified in Figs. 2 and 3
(compounds 5b and 8b), quinoline ring formed p–p
stacking interaction with Phe231 in CYP1B1 and Phe224
in CYP1A1. Additionally, edge-to-face interaction with
Phe134 and Phe123 in CYP1B1 and CYP1A1, respec-
tively, was observed. The propargyl moiety in compounds
5b and 8b was located in hydrophobic cavity formed by
7
-quinoline position of the quinoline units. It is also
noteworthy that compounds 4a, 4e, and 4b showed higher
cytotoxic activity than cisplatin in tested cancer cell line,
while their toxicity in normal human fibroblasts was low.
Moreover, MCF-7 cell line was found to be sensitive
toward 4,6- or 4,7-disubstituted quinolines 8b, 5b, and 5a.
Table 1 IC50 values (nM/mL) for the antiproliferative activity of compounds 4a–e, 5a–e and 8a–e
Compound
IC50 (nM/ml)
T-47D
MCF-7
MDA-MB-231
SNB-19
HFF-1
4
4
4
4
4
5
5
5
5
5
8
8
8
8
8
a
b
c
Neg
Neg
299.6 ± 13.5
84.74 ± 2.69
75.6 ± 2.16
Neg
2.52 ± 0.64
3.0 ± 0.90
113.04 ± 11.4
303.78 ± 9.24
2.52 ± 0.59
3.24 ± 0.60
20.29 ± 1.07
89.93 ± 4.21
44.86 ± 4.27
57.32 ± 5.3
Neg
Neg
107.0 ± 6.07
64.8 ± 3.49
132.68 ± 5.35
Neg
192.17 ± 9.75
Neg
206.30 ± 9.45
80.64 ± 1.62
366.79 ± 11.28
Neg
d
e
248.24 ± 10.6
214.0 ± 11.3
29.37 ± 4.70
24.20 ± 1.63
123.75 ± 8.8
178.0 ± 17.7
Neg
197.73 ± 2.43
284.97 ± 6.50
26.17 ± 2.06
192.50 ± 6.37
Neg
a
b
c
32.39 ± 6.4
36.31 ± 4.16
123.66 ± 10.1
Neg
35.6 ± 3.20
58.03 ± 4.27
Neg
d
e
Neg
Neg
Neg
Neg
a
b
c
192.92 ± 2.70
2.96 ± 0.33
9.83 ± 0.59
24.86 ± 0.66
222.60 ± 10.45
108.22 ± 7.65
63.80 ± 5.19
14.84 ± 1.3
167.32 ± 8.93
95.71 ± 2.33
Neg
106.11 ± 2.15
172.51 ± 8.73
204.05 ± 5.50
126.14 ± 3.59
185.50 ± 9.84
28.47 ± 3.53
304.6 ± 2.59
84.59 ± 1.7
293.83 ± 8.60
167.32 ± 7.80
Neg
185.50 ± 9.3
322.77 ± 12.2
Neg
d
e
Neg
Cisplatin
26.14 ± 0.73
2.83 ± 0.26
–
Neg negative in the concentration used
1
23

Med Chem Res
Phe258/Phe224/Leu264 in CYP1A1 and Phe268/Phe231/
Phe256 for CYP1B1. No significant difference between
studied CYP1 members in forming hydrophobic interac-
tions with propargyloquinoline analogs was observed.
The docking results stay in line with cytotoxicity binding
assay findings. The most potent compound 8b (Fig. 2) was
highly ranked by Glide scoring function in both CYPs. It is
worth noting that Glide scoring function correctly predicted
that 8b is more potent than this sulfur analog 5b (Fig. 3).
Although the WST-1 screening protocol did not con-
clude of any possible mechanism for the observed anti-
proliferative activity of the tested compounds, activity of
2,6- and 4,6-dichloroquinolines (le and 1a) were pre-
pared from 6-chloroquinoline N-oxide and phosphoryl
chloride as reported previously (Bachman and Cooper,
1944). The same experimental protocol was applied for the
preparation of 2,3-dichloroquinoline (ld) from 3-chloro-
quinoline N-oxide and 8-bromo-4-chloroquinoline (1c)
from 8-bromoquinoline N-oxide. All other reagents were
from Sigma Aldrich and Alfa Aesar.
Purity of the synthesized compounds was confirmed by
TLC performed on Merck silica gel 60 F254 aluminum
sheets and an ethyl acetate as an eluent. Spots were
detected by their absorption under UV light (k = 254 nm).
Melting points (mp) were determined with a KSP–1N
8b and 5b may be attributed due to the inhibition of CYPs
route that requires to the further studies.
¨
KRUSS apparatus and are uncorrected.
IR spectra in KBr disks were recorded on Shimadzu
IRAffinity-1 FTIR spectrophotometer.
Materials and methods
All NMR spectra were recorded on a Bruker AVANS
3
00 spectrometer operating at 300.18 MHz and 75.48 MHz
13
1
General
for H and C nuclei, respectively, in deuterochloroform
CDCl ) solution. Coupling constant (J) values are pre-
(
3
Organic solvents (from Sigma-Aldrich and Chempur) were
of reagent grade and were used without purification.
sented in hertz (Hz), and spin multiples are given as s
(singlet), d (double), t (triple), and m (multiple).
Fig. 2 Orientation of 4,7-
dipropargylthioquinoline (8b) in
the active site of CYP1A1 and
1
B1
Fig. 3 Orientation of 7-chloro-
-propargylselenoquinoline (5b)
4
in the active site of CYP1A1
and 1B1
123

Med Chem Res
1
Mass spectrometry analyses: samples were prepared in
acetonitrile/water (10/90 v/v) mixture. The LC/MS system
consisted of a Waters Acquity UPLC, coupled to Waters
TQD mass spectrometer. All the analyses were carried out
using an Acquity UPLC BEH C ,50 9 2.1 mm reversed-
H NMR (CDCl , 300 MHz): d = 2.32 (1H, t, J = 2.7 Hz,
3
SCH CCH), 3.85 (2H, d, J = 2.7 Hz, SCH CCH), 7.38
2
2
(1H, d, J = 4.8 Hz, H-3), 7.52 (1H, dd, J = 9.0 Hz, J = 1.
8 Hz, H-6), 8.02 (1H, d, J = 9.0 Hz, H-5), 8.09 (1H, d,
1
J = 1.8 Hz, H-8), 8.78 (1H, d, J = 4.8 Hz, H-2);
3
C
1
8
phase column. A flow rate of 0.3 mL/min and a gradient of
5–95) % B over 5 min was used. Eluent A: water/0.1 %
HCO H; eluent B: acetonitrile/0.1 % HCO H.
NMR (CDCl , 75 MHz): d = 19.8 (CH , SCH CCH), 72.6
(C, SCH CCH), 77.8 (CH, SCH CCH), 116.8 (CH, C-3),
2 2
3
2
2
(
124.8 (CH, C-5), 127.5 (CH, C-6), 128.9 (C, C-4a), 129.0
(CH, C-8), 135.8 (C, C-7), 145.8 (C, C-4), 148.0 (C, C-8a),
150.4 (CH, C-2); tR = 5.44 min, monoisotopic mass 233.
2
2
Elemental analysis (C, H, and N) was obtained on a
EuroVector model 3018 analyzer, and the data were within
?
±
0.4 % of the theoretical values.
0, [M?H] 234.0; Anal. Calc. for C H ClNS: C 61.67; H
12 8
Column chromatography separations were carried out
3.45; N 5.99. Found: 61.76; H 3.35; N 6.01.
on column with Merck Kieselgel 60 using ethyl acetate as
an eluent.
8-Bromo-4-(3-propynylthio)quinoline (4c) White solid
(EtOH); yield 90 %; mp 150–151 ꢁC. IR (KBr) mmax 3216
Chemistry
(:C–H), 2102 (–C:C–), 1567, 1484, 1373, 1280, 824,
-
1 1
7
48 cm ; H NMR (CDCl , 300 MHz): d = 2.32 (1H, t,
3
General procedure for synthesis of propargylthio-
J = 2.7 Hz, SCH CCH), 3.87 (2H, d, J = 2.7 Hz,
2
and propargylselenoquinolines 4a–e and 5a–e
SCH CCH), 7.40–7.46 (2H, m, H-3 and H-6), 8.07–8.10
2
1
3
(2H, m, H-5 and H-7), 8.92 (1H, d, J = 4.8 Hz, H-2);
C
A mixture of the dihalogenoquinoline (1a–e) with 1.1
molar eqvs. of thiourea or selenourea in ethanol (1 mL/
NMR (CDCl , 75 MHz): d = 20.0 (CH , SCH CCH), 72.6
(C, SCH CCH), 77.7 (CH, SCH CCH), 117.4 (CH, C-3),
2 2
3
2
2
1
mmol of 1a–e) was stirred at 50 ꢁC for 45 min under
argon atmosphere. The mixture was then transferred to cold
% aqueous NaOH (10 mL/1 mmol of 1a–e), and prop-
123.3 (CH, C-5), 125.4 (C, C-4a), 126.9 (CH, C-6), 127.5
(C, C-8), 133.7 (CH, C-7), 144.7 (C, C-4), 146.4 (C, C-8a),
150.0 (CH, C-2); tR = 6.23 min, monoisotopic mass 276.
5
?
argyl bromide (1.1 mmol/1 mmol of 1a–e) was added
dropwise to the aqueous layer. The mixture was stirred for
95, [M?H] 278.0; Anal. Calc. for C H BrNS: C 51.82;
12 8
H 2.90; N 5.04. Found: C 51.80; H 2.99; N 5.14.
3
0 min, and resultant solid was filtered off, washed with
water, and air-dried to give crude products 4a–e and 5a–
e. Obtained crude products were crystallized from ethanol
to give pure propargylthio- and propargylselenoquinolines
3-Chloro-2-(3-propynylthio)quinoline (4d) White solid
(EtOH); yield 89 %; mp 95–96 ꢁC; IR (KBr) mmax 3305 (:
C–H), 2121 (–C:C–), 1576, 1488, 1371, 1195, 1150,
-
1 1
4
a–e and 5a–e.
739 cm ; H NMR (CDCl , 300 MHz): d = 2.21 (1H, t,
3
J = 2.7 Hz, SCH CCH), 4.16 (2H, d, J = 2.7 Hz,
2
6
-Chloro-4-(3-propynylthio)quinoline (4a) White solid
EtOH); yield 82 %; mp 144–145 ꢁC; IR (KBr) mmax 3268
:C–H), 2107 (–C:C–), 1559, 1490, 1347, 1286, 861,
SCH CCH), 7.49 (1H, ddd, J = 9.0 Hz, J = 9.0, Hz, J =
2
(
0.9 Hz, H-6), 7.72–7.66 (2H, m, H-5 and H-7), 7.99 (1H,
1
3
(
dd, J = 9.0 Hz, J = 0.9 Hz, H-8), 8.03 (1H, s, H-4);
C
-
1 1
8
32 cm ; H NMR (CDCl , 300 MHz): d = 2.32 (1H, t,
NMR (CDCl , 75 MHz): d = 18.9 (CH , SCH CCH), 70.7
3
3
2
2
J = 2.7 Hz, SCH CCH), 3.85 (2H, d, J = 2.7 Hz,
2
(C, SCH CCH), 79.7 (CH, SCH CCH), 126.3 (CH, C-6),
2 2
SCH CCH), 7.41 (1H, d, J = 4.8 Hz, H-3), 7.68 (1H, dd,
2
126.5 (C, C-3), 126.6 (C, C-4a), 126.8 (CH, C-5), 128.1
(CH, C-8), 129.9 (CH, C-7), 134.1 (CH, C-4), 146.2 (C,
C-8a), 155.7 (C, C-2); tR = 7.17 min, monoisotopic mass
J = 9.0 Hz, J = 2.1 Hz, H-7), 8.04 (1H, d, J = 9.0 Hz,
H-8), 8.08 (1H, d, J = 2.1 Hz, H-5), 8.78 (1H, d, J = 4.
1
3
?
8
Hz, H-2); C NMR (CDCl , 75 MHz): d = 19.9 (CH ,
233.0, [M?H] 234.0; Anal. Calc. for C H ClNS: C 61.
12 8
3
2
SCH CCH), 72.6 (C, SCH CCH), 77.8 (CH, SCH CCH),
2
67; H 3.45; N 5.99. Found: 61.59; H 3.33; N 6.12.
2
2
1
17.6 (CH, C-3), 122.6 (CH, C-5), 127.1 (C, C-4a), 130.8
CH, C-7), 131.7 (CH, C-8), 132.6 (C, C-6), 144.7 (C, C-4),
45.9 (C, C-8a), 149.5 (CH, C-2); tR = 5.47 min, mono-
(
6-Chloro-2-(3-propynylthio)quinoline (4e) White solid
1
(EtOH); yield 93 %; mp 87–88 ꢁC; IR (KBr) m
3289 (:
max
-1 1
?
isotopic mass 233.0, [M?H] 234.0; Anal. Calc. for
C–H), 1592, 1486, 1382, 1290, 1091, 893 cm . H NMR
(CDCl3, 300 MHz): d = 2.22 (1H, t, J = 2.7 Hz,
SCH CCH), 4.16 (2H, d, J = 2.7 Hz, SCH CCH), 7.24
C H ClNS: C 61.67; H 3.45; N 5.99. Found: 61.82; H 3.
12 8
6
5; N 5.90.
2
2
(1H, d, J = 9.0 Hz, H-3), 7.61 (1H, dd, J = 9.0 Hz, J = 2.
7
-Chloro-4-(3-propynylthio)quinoline (4b) White solid
EtOH); yield 71 %; mp 110–111 ꢁC. IR (KBr) mmax 3295
4 Hz, H-7), 7.71 (1H, d, J = 2.4 Hz, H-5), 7.85, (1H, d,
1
3
(
J = 9.0 Hz, H-4), 7.91 (1H, d, J = 9.0 Hz, H-8);
C
-
1
(
:C–H), 1603, 1560, 1488, 1289, 1077, 884, 812 cm
.
NMR (CDCl , 75 MHz): d = 18.0 (CH , SCH CCH), 70.7
3
2
2
1
23

Med Chem Res
?
(
C, SCH CCH), 79.8 (CH, SCH CCH), 121.3 (CH, C-3),
2
mass 324.90, [M?H] 326.0; Anal. Calc. for C H BrNSe:
12 8
2
1
26.4 (CH, C-5), 126.7 (C, C-4a), 129.7 (CH, C-8), 130.6
C 44.34; H 2.4; N 4.31. Found: C 44.45; H 2.51; N 4.41.
(
CH, C-7), 131.1 (C, C-6), 134.8 (CH, C-4), 146.6 (C,
C-8a), 157.7 (C, C-2); tR = 8.03 min, monoisotopic mass
?
3-Chloro-2-(3-propynylseleno)quinoline (5d) White solid
(EtOH); yield 90 %; mp 89–90 ꢁC; IR (KBr) mmax 3288 (:
C–H), 1576, 1487, 1365, 1327, 1290, 1133, 1110, 895,
2
33.0, [M?H] 234.0; Anal. Calc. for C H ClNS: C 61.
12 8
6
7; H 3.45; N 5.99. Found: C 61.37; H 3.25; N 5.89.
-
1 1
7
75 cm ; H NMR (CDCl , 300 MHz): d = 2.23 (1H, t,
3
6
-Chloro-4-(3-propynylseleno)quinoline (5a) White solid
EtOH); yield 86 %; mp 127–128 ꢁC; IR (KBr) mmax 3283
:C–H), 1554, 1488, 1399, 1345, 1281, 1152, 1076, 862,
J = 2.7 Hz, SeCH CCH), 4.06 (2H, d, J = 2.7 Hz,
2
(
SeCH CCH), 7.49 (1H, ddd, J = 9.0 Hz, J = 9.0 Hz, J =
2
(
0.9 Hz, H-6), 7.72–7.68 (2H, m, H-5 and H-7), 7.99 (1H,
13
-
1
1
8
36 cm ; H NMR (CDCl , 300 MHz): d = 2.32 (1H, t,
dd, J = 9.0 Hz, J = 0.9 Hz, H-8), 8.17 (1H, s, H-4);
C
3
J = 2.7 Hz, SeCH CCH), 3.85 (2H, d, J = 2.7 Hz,
2
NMR (CDCl , 75 MHz): d = 12.7 (CH , SeCH CCH), 70.
3
2
2
SeCH CCH), 7.63 (1H, d, J = 4.8 Hz, H-3), 7.69 (1H, dd,
2
8 (C, SeCH CCH), 80.9 (CH, SeCH CCH), 118.8 (C, C-3),
2 2
J = 9.0 Hz, J = 2.1 Hz, H-7), 8.04-8.07 (2H, m, H-5 and
126.4 (CH, C-6), 126.8 (CH, C-5), 127.4 (C, C-4a), 128.3
(CH, C-8), 130.0 (CH, C-7), 137.3 (CH, C-4), 147.0 (C,
C-8a), 155.9 (C, C-2); tR = 8.04 min, monoisotopic mass
1
3
H-8), 8.74 (1H, d, J = 4.8 Hz, H-2); C NMR (CDCl3,
7
5 MHz): d = 11.5 (CH2, SeCH CCH), 72.8 (C,
2
?
SeCH CCH), 79.2 (CH, SeCH CCH), 123.4 (CH, C-3),
2
280.95, [M?H] 282.0; Anal. Calc. for C H ClNSe: C
12 8
2
1
24.8 (CH, C-5), 129.3 (C, C-4a), 130.9 (CH, C-7), 131.8
61.67; H 3.45; N 5.99. Found: C 61.62; H 3.43; N 5.89.
(
CH, C-8), 132.9 (C, C-6), 141.4 (C, C-4), 146.2 (C, C-8a),
1
9
3
49.6 (CH, C-2); tR = 5.98 min, monoisotopic mass 280.
?
5, [M?H] 282.0; Anal. Calc. for C H ClNSe: C 61.6; H
6-Chloro-2-(3-propynylseleno)quinoline (5e) White solid
(EtOH); yield 94 %;mp72–73 ꢁC; IR (KBr)mmax 3287(:C–
H), 1588, 1482, 1386, 1329, 1284, 1134, 1083, 879,
1
2 8
.45; N 5.99. Found: C 61.57; H 3.34; N 5.79.
-1 1
8
29 cm ; H NMR (CDCl , 300 MHz): d = 2.24 (1H, t,
3
7
-Chloro-4-(3-propynylseleno)quinoline (5b) White solid
EtOH); yield 70 %; mp 105–106 ꢁC; IR (KBr) mmax 3299
J = 2.7 Hz, SeCH CCH), 4.07 (2H, d, J = 2.7 Hz,
2
(
SCH CCH), 7.38 (1H, d, J = 9.0 Hz, H-3), 7.62 (1H, dd,
2
-
1
(
1
:C–H), 1554, 1486, 1288, 1185, 1079, 879, 825 cm
H NMR (CDCl , 300 MHz): d = 2.32 (1H, t, J = 2.7 Hz,
;
J = 9.0 Hz,J = 2.4 Hz, H-7), 7.74(1H,d,J = 2.4 Hz, H-5),
7.84 (1H, d, J = 9.0 Hz, H-8), 7.93 (1H, d, J = 9.0 Hz, H-4);
3
1
3
SeCH CCH), 3.85 (2H, d, J = 2.7 Hz, SeCH CCH), 7.54
2
C NMR (CDCl , 75 MHz): d = 10.3 (CH , SeCH CCH),
2
3
2
2
(
1H, dd, J = 9.0 Hz, J = 1.8 Hz, H-6) 7.58 (1H, d, J = 4.
71.0 (C, SeCH CCH), 81.0 (CH, SeCH CCH), 123.6 (CH,
2 2
5
Hz, H-3), 7.99 (1H, d, J = 9.0 Hz, H-5), 8.10 (1H, d,
1
C-3), 126.5 (CH, C-5), 127.0 (C, C-4a), 129.9 (CH, C-4), 130.
6 (CH, C-7), 131.4 (C, C-6), 134.5 (CH, C-8), 147.2 (C, C-8a),
155.4 (C, C-2); tR = 8.01 min, monoisotopic mass 280.95,
3
J = 1.8 Hz, H-8), 8.74 (1H, d, J = 4.5 Hz, H-2);
C
NMR (CDCl , 75 MHz); d = 11.3 (CH , SeCH CCH), 72.
8
3
2
2
?
(C, SeCH CCH), 79.0 (CH, SeCH CCH), 122.2 (CH,
2
[M?H] 282.0; Anal. Calc. for C H ClNSe: C 61.67; H 3.
12 8
2
C-3), 126.9 (C, C-4a), 127.0 (CH, C-5), 127.9 (CH, C-6),
28.8 (CH, C-8), 136.0 (C, C-7), 143.3 (C, C-4), 147.8 (C,
45; N 5.99. Found: C 61.58; H 3.38; N 5.71.
1
C-8a), 150.0 (CH, C-2); tR = 6.04 min, monoisotopic
?
mass 280.95, [M?H] 282.0; Anal. Calc. for C H ClNSe:
General procedure for synthesis
of dipropargylthioquinolines 8a–e
1
2 8
C 61.67; H 3.45; N 5.99. Found: C 61.76; H 3.55; N 5.80.
A mixture of dihalogenoquinoline (1a–e) with 10 molar
eqvs. of sodium methanethiolate and dry DMF (6 mL/
1 mmol of 1a–e) was boiled with stirring under argon
atmosphere for 4 h (the reaction must be carried out in
hood as it proceeds with strong evolution of dimethyl
sulfide). This mixture was then cooled to 70 ꢁC, and the
volatile components were evaporated under vacuum from
water bath. The residue was cooled down in an ice-water
bath, (under argon atmosphere) carefully acidified with
20 % hydrochloric acid (1.5 mL/1 mmol of 1a–e), and
then kept at vacuum to remove methanethiol. This residue
contains crude (non-isolated) dimercaptoquinolines 7 was
added to a solution of 8 % aqueous sodium hydroxide
(4 mL/1 mmol of 1a–e), and then propargyl bromide
(2.2 mmol/1 mmol of 1a–e) was added dropwise on
8
-Bromo-4-(3-propynylseleno)quinoline (5c) White solid
EtOH); yield 94 %; mp 139–140 ꢁC; IR (KBr) mmax 3184
:C–H), 2137 (–C:C–), 1565, 1479, 1376, 1279, 1183,
(
(
-
1 1
1
3
7
091, 826, 752 cm ; H NMR (CDCl , 300 MHz): d = 2.
2 (1H, t, J = 2.7 Hz, SeCH CCH), 3.73 (2H, d, J = 2.
2
3
Hz, SeCH CCH), 7.45 (1H, dd, J = 9.0 Hz, J = 9.0 Hz,
2
H-6), 7.65 (1H, d, J = 4.5 Hz, H-3), 8.02 (1H, dd, J = 9.
0
8
Hz, J = 1.8 Hz, H-7), 8.10 (1H, d, J = 9.0 Hz, J = 1.
1
Hz, H-5), 8.87 (1H, d, J = 4.5 Hz, H-2); C NMR
3
(
CDCl , 75 MHz): d = 11.5 (CH , SeCH CCH), 72.8 (C,
3
2
2
SeCH CCH), 79.0 (CH, SeCH CCH), 122.7 (CH, C-3),
2
2
1
25.3 (C, C-8), 125.4 (CH, C-5), 127.2 (CH, C-6), 129.5
C, C-4a), 133.8 (CH, C-7), 143.9 (C, C-4), 144.7 (C,
C-8a), 149.9 (CH, C-2); tR = 6.51 min, monoisotopic
(
123

Med Chem Res
stirring. The stirring was continued at rt for 1 h. The solid
was filtered off, washed with water, and dried on air.
Obtained crude compounds 8a–e were separated by column
chromatography and finely were crystallized from ethanol
to give pure dipropargylthioquinolines 8a–e.
J = 9.0 Hz, J = 0.9 Hz, H-5), 8.80 (1H, d, J = 4.8 Hz,
1
3
H-2);
C NMR (CDCl , 75 MHz): d = 19.8 (CH ,
3
2
SCH CCH), 19.9 (CH , SCH CCH), 71.3 (C, SCH CCH),
2
2
2
2
72.5 (C, SCH CCH), 77.9 (CH, SCH CCH), 79.5 (CH,
2
2
SCH CCH), 117.3 (CH, C-3), 120.4 (CH, C-5), 125.8 (CH,
2
C-7), 126.3 (C, C-4a), 126.5 (CH, C-6), 137.4 (C, C-8),
4
,6-Di(3-propynylthio)quinoline (8a) Yellow solid (EtOH);
144.8 (C, C-4), 146.1 (C, C-8a), 148.2 (CH, C-2); tR = 6.
?
31 min, monoisotopic mass 269.03, [M?H] 270.0; Anal.
yield 89 %; mp 114–115 ꢁC; IR (KBr) mmax 3285 (:C–H),
3185 (:C–H), 2108 (–C:C–), 1601, 1552, 1495, 1401,
1352, 1283, 1189, 829 cm ; H NMR (CDCl , 300 MHz):
Calc. for C H NS : C 66.88; H 4.12; N 5.20. Found: C
1
5
11
2
-
1 1
66.92; H 4.25; N 5.33.
3
d = 2.30–2.33 (2H, m, 29 SCH CCH), 3.76 (2H, d, J = 2.
2
4
4
0
Hz, SCH CCH), 3.86 (2H, d, J = 2.4 Hz, SCH CCH), 7.
2
2,3-Di(3-propynylthio)quinoline (8d) Yellow solid (EtOH);
yield 89 %; mp 98–99 ꢁC IR (KBr) mmax 3288 (:C–H),
3272 (:C–H), 1570, 1546, 1380, 1360, 1136, 1114, 988,
2
2 (1H, d, J = 4.8 Hz, H-3), 7.45 (1H, dd, J = 9.0 Hz, J =
.9 Hz, H-7), 8.06-8.11 (2H, m, H-5 and H-8), 8.74 (1H, d,
3
1
-1 1
J = 4.8 Hz, H-2); C NMR (CDCl , 75 MHz): d = 19.9
776, 751 cm ; H NMR (CDCl , 300 MHz): d = 2.23–2.
3
3
(
CH , SCH CCH), 22.1 (CH , SCH CCH), 72.1 (C,
2
25 (2H, m, 29 SCH CCH), 3.68 (2H, d, J = 2.4 Hz,
2
2
2
2
SCH CCH), 72.7 (C, SCH CCH), 77.7 (CH, SCH CCH),
2
SCH CCH), 4.14 (2H, d, J = 2.4 Hz, SCH CCH), 7.46
2
2
2
2
7
1
9.0 (CH, SCH CCH), 117.3 (CH, C-3), 122.6 (CH, C-5),
2
(1H, ddd, J = 7.8 Hz, J = 7.6 Hz, J = 1.2 Hz, H-6), 7.67
(1H, ddd, J = 8.4 Hz, J = 7.8 Hz, J = 0.8 Hz, H-7), 7.75
(1H, dd, J = 7.6 Hz, J = 0.8 Hz, H-5), 7.96 (1H, dd, J =
26.7 (C, C-4a), 129.9 (CH, C-8), 131.4 (CH, C-7), 134.7 (C,
C-6), 145.3 (C, C-4), 145.8 (C, C-8a), 148.3 (CH, C-2;. tR =
?
.76 min, monoisotopic mass 269.03, [M?H] 270.0; Anal.
13
4
8.4 Hz, J = 1.2 Hz, H-8), 8.23 (1H, s, H-4); C NMR
Calc. for C H NS : C 66.88; H 4.1; N 5.20. Found: C 66.
1
(CDCl , 75 MHz): d = 19.2 (CH , SCH CCH), 22.9 (CH ,
5
11
2
3
2
2
2
7
8; H 4.10; N 5.24.
SCH CCH), 70.6 (C, SCH CCH), 72.6 (C, SCH CCH), 79.
2 2 2
1
(CH, SCH CCH), 80.0 (CH, SCH CCH), 125.6 (C, C-3),
2 2
4
,7-Di(3-propynylthio)quinoline (8b) White solid (EtOH);
125.9 (CH, C-6), 126.2 (C, C-4a), 127.5 (CH, C-5), 128.0
(CH, C-8), 130.4 (CH, C-7), 141.1 (CH, C-4), 147.3 (C,
C-8a), 159.9 (C, C-2); tR = 7.64 min, monoisotopic mass
yield 82 %; mp 107–108 ꢁC; IR (KBr) mmax 3278 (:C–H),
3
1
3
266 (:C–H), 2016 (–C:C–), 1602, 1559, 1485, 1415,
-1 1
;
?
339, 1293, 1072, 861, 820 cm
H NMR (CDCl3,
269.03, [M?H] 270.0; Anal. Calc. for C H NS : C 66.
15
11
2
00 MHz): d = 2.28 (1H, t, J = 2.7 Hz, SCH CCH), 2.32
88; H 4.12; N 5.20. Found: C 66.92; H 4.35; N 5.16.
2
(
1H, t, J = 2.7 Hz, SCH CCH), 3.79 (2H, d, J = 2.7 Hz,
2
SCH CCH), 3.85 (2H, d, J = 2.7 Hz, SCH CCH), 7.35
2
2,6-Di(3-propynylthio)quinoline (8e) Yellow solid (EtOH);
yield 91 %; mp 109–110 ꢁC; IR (KBr) mmax 3253 (:C–H),
2124 (–C:C–), 1584, 1576, 1482, 1383, 1295, 1145,
2
(
1H, d, J = 4.8 Hz, H-3), 7.52 (1H, dd, J = 9.0 Hz, J = 1.
8
Hz, H-6), 8.00 (1H, d, J = 9.0 Hz, H-5), 8.07 (1H, d,
1
3
-1 1
J = 1.8 Hz, H-8), 8.75 (1H, d, J = 4.8 Hz, H-2);
C
1066, 899, 821 cm ; H NMR (CDCl , 300 MHz): d = 2.
3
NMR (CDCl , 75 MHz): d = 19.8 (CH , SCH CCH), 21.2
21 (1H, t, J = 2.7 Hz, SCH CCH), 2.25 (1H, t, J = 2.
2
3
2
2
(
CH2, SCH CCH), 72.1 (C, SCH CCH), 72.5 (C,
2
7 Hz, SCH CCH), 3.71 (2H, d, J = 2.7 Hz, SCH CCH), 4.
2
2
2
SCH CCH), 78.0 (CH, SCH CCH), 78.9 (CH, SCH CCH),
2
17 (2H, d, J = 2.7 Hz, SCH CCH), 7.25 (1H, d, J = 9.
2
2
2
1
16.4 (CH, C-3), 123.7 (CH, C-5), 124.6 (C, C-4a), 126.9
CH, C-6), 127.1 (CH, C-8), 138.4 (C, C-7), 145.6 (C, C-4),
47.7 (C, C-8a), 149.9 (CH, C-2), tR = 4.68 min, monoi-
0 Hz, H-3), 7.71 (1H, dd, J = 9.0 Hz, J = 2.1 Hz, H-7), 7.
80 (1H, d, J = 2.1 Hz, H-5), 7.78–7.93 (2H, m, H-4 and
(
1
3
1
H-8);
C NMR (CDCl , 75 MHz): d = 18.0 (CH ,
3
2
?
sotopic mass 269.03, [M?H] 270.0; Anal. Calc. for
SCH CCH), 22.6 (CH , SCH CCH), 70.6 (C, SCH CCH),
2
2
2
2
C H NS : C 66.88; H 4.12; N 5.20. Found: C 66.75; H 4.
2
71.9 (C, SCH CCH), 79.6 (CH, SCH CCH), 80.0 (CH,
2 2
1
5
11
2
2; N 5.29.
SCH CCH), 121.0 (CH, C-3), 126.4 (C, C-4a), 128.1 (CH,
2
C-5), 128.7 (CH, C-8), 131.7 (CH, C-7), 132.2 (C, C-6),
4
,8-Di(3-propynylthio)quinoline (8c) Yellow solid (EtOH);
135.1 (CH, C-4), 147.2 (C, C-8a), 157.4 (C, C-2); tR = 8.
?
46 min, monoisotopic mass 269.03, [M?H] 270.0; Anal.
yield 90 %; mp 177–178 ꢁC; IR (KBr) mmax 3271 (:C–H),
3
1
2
7
8
8
7
235 (:C–H), 2018 (–C:C–), 1568, 1484, 1378, 1262,
Calc. for C H NS : C 66.88; H 4.12; N 5.20. Found: C
1
5
11
2
-
1 1
168, 822, 748 cm ; H NMR (CDCl , 300 MHz): d = 2.
3 (1H, t, J = 2.7 Hz, SCH CCH), 2.31 (1H, t, J = 2.
2
66.93; H 4.19; N 5.22.
3
Hz, SCH CCH), 3.82 (2H, d, J = 2.7 Hz, SCH CCH), 3.
2
Docking study
2
5 (2H, d, J = 2.7 Hz, SCH CCH), 7.43 (1H, d, J = 4.
2
Hz, H-3), 7.45, (1H, dd, J = 9.0 Hz, J = 9.0 Hz, H-6),
.54 (1H, dd, J = 9.0 Hz, J = 0.9 Hz, H-7), 7.90 (1H, dd,
The structures of all the synthesized molecules were pre-
pared using LigPrep v. 2.5 (Schr o¨ dinger, LLC, New York,
1
23

Med Chem Res
NY, USA), and the appropriate ionization states at
pH = 7.4 were assigned using Epik v. 2.3 (Schr o¨ dinger,
LLC, New York, USA). The crystal structure of human
cytochrome P450 1B1 (PDB ID: 3PM0) (Wang et al.,
to tested compounds at various concentrations of each
compound (0.4–400 nM/ml), cell viability was quantified
by a cell proliferation assay. The amount of WST-1-for-
mazan produced was measured at 450 nm, and appropriate
calculations were performed as described previously. The
cytotoxic activity of the test compound compared to cis-
platin (positive control). The experiments were repeated in
triplicate for each tested compound concentration. Test
compounds were prepared initially at concentration of
1 mg/ml DMSO. Solvent control (DMSO) was included to
check that the DMSO had no effect at the concentration
used.
2
011) and 1A1 (PDB ID: 4I8V) (Walsh et al., 2013) in
complex with a-naphthoflavone (ANF) was retrieved from
Brookhaven Protein Data Bank (http://www.rcsb.org/pdb/
home/home.do). The Protein Preparation Wizard was used
to assign the bond orders, check the steric clashes, and
assign appropriate amino acid ionization states. The
receptor grids were generated (the OPLS_2005 force field)
by set up the grid box on the center of co-crystalized
ligand. Automated docking was performed by using Glide
v. 5.8 (Schr o¨ dinger, LLC, New York, USA) at SP level
with the flexible docking option turned on. The docking
procedure was validated by re-docking of the ANF mole-
cule to the active site of selected CYPs which resulted in
Calculations of the IC50 values were performed using
GraphPad Prism 6 (GraphPad Software, San Diego, USA).
Acknowledgments This research was supported by the Medical
University of Silesia, Grant No. KNW-1-032/K/3/0.
˚
predicted docking pose with RMSD lower than 1 A, cal-
culated for the best scored pose. The ligand-receptor
complexes were visualized by the means of PyMOL
Molecular Graphics System, v. 1.5.0.4 (Schr o¨ dinger, LLC,
New York, USA).
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