Prospective study directed to the synthesis of unsymmetrical linked bis-5-arylidene rhodanine derivatives via "one-pot two steps" reactions under microwave irradiation with their antitumor activity

Article abstract of DOI:10.1007/s00044-014-1186-7

We here report on the synthesis of new unsymmetrical linked bis-5-arylidene rhodanine derivatives with stereocontrolled Z-configuration. The 6 steps synthesis was achieved and the key steps are the construction of the two 5-arylidene rhodanine moieties using an "one-pot two-steps" method under microwave dielectric heating in a closed reactor. The intermediates 6, 7 and desired unsymmetrical compounds 9 have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT116, and NCI-H727 tumoral cell lines). Two of all compounds have shown potent activity against Huh7 D12, Caco2, and MDA-MB 231. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00044-014-1186-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-1186-7
ORIGINAL RESEARCH
Prospective study directed to the synthesis of unsymmetrical
linked bis-5-arylidene rhodanine derivatives via ‘‘one-pot two
steps’’ reactions under microwave irradiation with their
antitumor activity
Wacothon Karime Coulibaly
Yves-Alain B e´ kro R e´ my Le Gu e´ vel
Jean Pierre Bazureau
•
Ludovic Paquin
•
Anoubil e´ B e´ nie
•
•
•
Myriam Ravache
•
Anne Corlu
•
Received: 22 April 2014 / Accepted: 10 July 2014
Ó Springer Science+Business Media New York 2014
Abstract We here report on the synthesis of new
unsymmetrical linked bis-5-arylidene rhodanine deriva-
tives with stereocontrolled Z-configuration. The 6 steps
synthesis was achieved and the key steps are the con-
struction of the two 5-arylidene rhodanine moieties using
an ‘‘one-pot two-steps’’ method under microwave dielectric
heating in a closed reactor. The intermediates 6, 7 and
desired unsymmetrical compounds 9 have been also eval-
uated for their in vitro inhibition of cell proliferation (Huh7
D12, Caco2, MDA-MB 231, HCT116, and NCI-H727
tumoral cell lines). Two of all compounds have shown
potent activity against Huh7 D12, Caco2, and MDA-MB
Keywords Microwave ꢀ Knoevenagel condensation ꢀ
Rhodanine ꢀ 5-Arylidene-2-thioxo-1,3-thiazolidine-4-one ꢀ
Unsymmetrical bis-rhodanine ꢀ Tumoral lines
Introduction
The 5-arylidene-2-thioxo-1,3-thiazolidinine-4-ones or 5-ary-
lidene rhodanines and their 2-amino-5-arylidene-5H-thiazol-
4-one derivatives belong to five-membered heterocyclic rings
(FMHRs) and are considered as ‘‘privileged scaffolds’’ in the
medicinal chemistry community because they presented an
inherent tendency for a large panel of biological activities
2
31.
(Mentgenetal., 2012).Theselow-molecularweightinhibitors
have been previously studied (Singh et al., 1981; Tomasic and
Masic, 2009) and have been subjected to controversies (Lesyk
and Zimenkovsky, 2004) due to the high potential of these
scaffolds to form intermolecular interactions in diverse
receptors. The FMHRs have been known to possesses a wide
range of biological properties such as potent and selective
inhibitors of the ‘‘atypical’’ dual-specificity phosphatase
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-1186-7) contains supplementary
material, which is available to authorized users.
W. K. Coulibaly ꢀ L. Paquin ꢀ J. P. Bazureau (&)
UMR CNRS 6226, Groupe Ing e´ nierie Chimique et Mol e´ cules
Pour le Vivant (ICMV), Institut des Sciences Chimiques de
Rennes (ISCR), Universit e´ de Rennes 1, B aˆ t. 10A, Campus
de Beaulieu, Avenue du G e´ n e´ ral Leclerc, CS 74205,
(DSP) family member-JNK-stimulating phosphatase-1 (JSP-
1
) (Cutshall et al., 2005), as aldose reductase inhibitor on
35042 Rennes Cedex, France
e-mail: jean-pierre.bazureau@univ-rennes1.fr
diabetic peripheral neuropathy (Hotta et al., 2006), as DDX3
inhibitor for HIV replication (Maga et al., 2008).
W. K. Coulibaly ꢀ A. B e´ nie ꢀ Y.-A. B e´ kro
Our research group is mainly invested in the synthesis of
marine alkaloid derivatives as low-molecular weight-inhibi-
tors (Bazureau et al., 2009) of dual specificity, tyrosine phos-
phorylation-regulated kinases (DYRKs) (Debdab et al., 2011;
Tahtouh et al., 2012) and CLKs (cdc2-like kinases) (Aranda
et al., 2011). Recently, we have realized a complete structure
activity relationship (SAR) study and have identified leucettine
L41 (Fig. 1), a synthetic derivative of the marine alkaloid
leucettamine B, as first potent inhibitor of DYRK1A (IC50
Laboratoire de Chimie Bioorganique et de Substances Naturelles
(
LCBSN), Universit e´ Nangui Abrogoua, BP 802, Abidjan 02,
R e´ publique de C oˆ te d’Ivoire
W. K. Coulibaly
UFR des Sciences Biologiques, Universit e´ P e´ l e´ foro Gon
Coulibaly, BP 1328, Korhogo, R e´ publique de C oˆ te d’Ivoire
R. Le Gu e´ vel ꢀ M. Ravache ꢀ A. Corlu
ImPACcell Platform, Universit e´ de Rennes 1, SFR Biosit,
B aˆ t. 8, 2 Avenue du Prof. L e´ on Bernard, CS 34317,
40 nM) and CLKs, two families of kinase involved in various
3
5043 Rennes Cedex, France
123

Med Chem Res
O
O
O
O
O
N
H
N
O
H
N
H N
2
N
N
S
N
N
S
N
N
H
N
H
O
O
O
N
leucettamine B
DYRK1A, IC50: 920 nM
leucettine L41
DYRK1A, IC50: 40 nM
O
N,N'-Bis(5-arylidene-4-oxo-4,5-dihydrothiazolin-2-yl)
aminopropyl piperazine
DYRK1A, IC50: 40 nM
Fig. 1 Inhibitors of the protein kinase DYRK1A identified and developed in our group
diseasesincludingAlzheimer’sdisease (AD),Downsyndrome
Smith et al., 2012), and also cancer (Ionescu et al., 2012; Xiao
described protocol (Radi et al., 2010) involving the
(
‘‘Holmberg method’’ (Holmberg, 1910) (which is based on
the reaction of bis(carboxymethyl)-trithiocarbonate 3 with
primary amine) and Knoevenagel condensation to afford
directly the 5-arylidene rhodanine 6 under microwave
irradiation. This choice was guided by the fact that the
major benefits of performing reaction under microwave
irradiation are higher product yields and significant rate
enhancements compared to reactions which run with con-
ventional heating (i.e., in oil bath). A real advantage of
commercial laboratory microwave apparatus is their ability
to control reaction conditions precisely, by monitoring
reaction times and temperature/pressure (de la Hoz and
Loupy, 2012; Bazureau and Draye, 2011; Krstenansky and
Cotteril, 2000).
et al., 2013; Ling et al., 2013). Encouraged by these pre-
liminary results, we continued to explore the design and the
synthesis of an expanded series of N,N’-bis-(5-arylidene-4-
oxo-3,5-dihydro-4H-imidazol-2-yl)diamines as potential pro-
tein kinase inhibitors from appropriate symmetric alkyldiam-
ines as flexible linkers (Coulibaly et al., 2012a). Starting from
1,4-bis(3-aminopropyl)piperazine, this strategy was also
extended to the synthetic preparation of symmetric N,N’-
disubstituted diamines bearing 5-arylidene-1,3-thiazolidine-4-
one moiety and to our surprise one of these compounds has
shown nanomolar inhibition potency (IC50 40 nM) towards
DYRK1A (Fig. 1) (Coulibaly et al., 2012b). This result
prompted us to explore now the use of symmetric 1,2-diamino
linker grafted on N-3 position of two different 5-arylidene
rhodanine platforms in order to modulate potential biological
activities. The goal of the present study was to develop
unsymmetrical linked bis-5-arylidene rhodanine derivatives,
via ‘‘one-pot two steps’’ reactions under microwave irradiation
to build heterocyclic platforms and evaluate biological activ-
ities on six representative tumoral cell lines.
For the preparation of 4, reaction optimization consisted
in varying the reaction time (5-20 min.), the reaction
temperature (80–100 °C), the ratio of reagents (ratio 2/3:1–
1.3), the use of a polar or no polar solvent (hexane, Et O,
2
1,4-dioxane, dimethoxyethane), and the use of closed or
open vessel mode and the choice of an organic base (pyr-
idine, i-PrN Et, Et N). After all these experiments, the
2
3
optimal reaction conditions were obtained at 90 °C after
0 min; with a stoichiometric mixture of 2 and 3 solubi-
lized in dimethoxyethane with one equivalent of Et N. The
1
3
Results and discussion
reaction is conducted in a closed reactor (in this case, the
reaction under microwave irradiation is realized in com-
mercial glass tube closed with a snap cap). It is noteworthy
that initial attempts to isolate the compound 4 after a time-
consuming chromatographic purification were unsuccess-
ful. In this context, we decided to drop the structural
identification of 4 in this second step and after the first
microwave irradiation period (10 min.), aromatic aldehyde
5 was added directly in the reaction mixture. The resulting
mixture was irradiated at 110 °C for 5 min. For this present
protocol, we have also examined the chemical reactivity of
two commercially available aldehydes 5 (i.e., 4-methoxy-
benzaldehyde 5a and 3,4-methylenedioxybenzaldehyde
5b). After elimination of the volatiles compounds in vacuo,
the desired products 6a–e were isolated after a simple
Chemistry
The overall strategy to the target linked bis-5-arylidene
rhodanine derivatives is outlined in Scheme 1. Starting
from various commercial symmetric diamines 1 as linkers
(
i.e., ethylenediamine 1a, 1,4-diaminobutane 1b, and 1,4-
bis-(3-aminopropyl)piperazine 1c), these diamino building
block 1 was subjected to 0.1–0.2 equivalent of di-tert-bu-
tyldicarbonate (Boc O) to afford mainly the mono-Boc-
2
protected amine 2 (Bonger et al., 2009) in 26–56 % yield
(
Table 1). For the construction of the first 5-arylidene
rhodanine moiety grafted on the mono-Boc-protected dia-
mino linker 2, we decided to test a ‘‘one-pot two-steps’’
1
23

Med Chem Res
O
S
S
i
ii
H
N
iii
H N
NH2
O
N
H
NH2
O
N
2
n
n
3
S
n
O
R1
O
O
v
1
2
4
HO C
S
S
CO H
2
2
5
R1
R1
R1
S
S
S
S
S
S
S
S
H
iv
O
N
N
HCl, H
N
N
N
N
2
3
S
n
O
n
O
O
n
O
O
HO C
S
S
CO H
2
6
7
2
8
R2
R1
S
S
S
S
vi
N
N
N
n = 0, 2 or
R2
O
O
n
O
N
9
5
Scheme 1 Reagents and reaction conditions: (i) (t-BuO C)
2
2
O, 1,4-
1,4-dioxane, 25 °C, 4 h. (v) 3 1 equiv., Et N 2 equiv., DME, 90 °C,
3
dioxane, 25 °C, 24 h. (ii) 3 1 equiv., Et
3
N 1 equiv., DME, 90 °C,
MWI, 10 min. (vi) 5 1 equiv., 110 °C, MWI, 5 min
MWI, 10 min. (iii) 5 1 equiv., 110 °C, MWI, 5 min. (iv) HCl 6 M,
Table 1 Results for the preparation of carbamates 2, 5-arylidene-2-
thioxo-1,3-thiazolidine carbamate 6, the deprotected derivatives 7 and
the bis-N,N’-(5-arylidene rhodanine-3-yl) derivatives 9
2009). Deprotection of compounds 6 into their corre-
sponding salts 7 was conducted in 1,4-dioxane with a
solution of 6 M HCl at room temperature after 4 h of
reaction time. The expected hydrochloride salts 7 were
synthesized in good yields (65–98 %). Finally, for the
installation of the second 5-arylidene-4-oxo-2-thioxo-1,3-
thiazolidine-1-yl moiety, we employed again the ‘‘one-pot
two-steps’’ protocol under microwave irradiation. To a
1
2
a
Yield (%)
Compound
n
R
R
2
2
a
0
2
–
–
–
–
26
28
b
N
2
c
–
–
56
N
solution of bis(carboxymethyl)-trithiocarbonate
3 in
6
6
6
6
a
b
c
0
0
2
2
4-MeO
–
–
–
–
23
59
44
35
dimethoxyethane, was added successively two equivalents
of triethylamine and appropriate quantity of hydrochloride
salt 7. The resulting suspension in a closed reactor was
heated at 90 °C under microwave irradiation for 10 min.
After this first period of irradiation, aromatic aldehyde 5
(4-methoxybenzaldehyde 5a or benzaldehyde 5c) was
added and the mixture was submitted immediately to
microwave dielectric heating at 110 °C for 5 min. The
desired product 9 was obtained as precipitate after addition
of methanol in the solventless crude residue and triturating,
followed by washings with cooled hexane, methylene
chloride and finally was recrystallized in ethanol to
increase the quality of the precipitated product 9. At this
stage, the compounds 9a–c were fully analyzed and char-
acterized before entering the biological tests. The structure
identification of all these new compounds was based on the
3,4-(OCH O)
2
4-MeO
d
3,4-(OCH
2
O)
O)
N
6
e
3,4-(OCH
2
–
36
N
7
7
7
9
9
9
a
a
b
c
0
0
2
0
0
0
4-MeO
–
–
–
91
98
65
47
43
3,4-(OCH
3,4-(OCH
4-MeO
2
O)
O)
2
a
b
c
H
H
3,4-(OCH O)
2
3,4-(OCH O) 4-MeO 27
2
Isolated yields
1
13
precipitation in MeOH followed by washing with methy-
lene chloride. A set of five designed compounds 6 was
prepared in 23–59 % yield (Table 1) and characterized by
H and C assignments and was performed extensive 1D
1
and 2D NMR spectroscopy. Examination of the H NMR
spectrum in DMSO-d for 9a showed two separated signals
6
1
13
H, C NMR, and HRMS. The geometry of the exocyclic
for the two methylene protons (CH=), one appears at d
7.78 ppm and the second shifted to 7.83 ppm and hence
confirmed the unsymmetrical structure of 9a. It is inter-
esting to note that these two methylene protons appear at
lower field values than those expected for the E-isomers,
double bond (=CH) of these new 5-arylidene rhodanine
derivatives 6a–e was performed; the thermodynamically
more stable Z-isomers predominated and Z-configuration
was assigned as previously reported in literature (Xia et al.,
123

Med Chem Res
Table 2 Antiproliferative activity of compounds 6a–e, 7a–c and 9a–c on six representative tumor cell lines
a
b
Compound
% of survival and IC50 (lM) of selected compounds
Huh7 D12
Caco 2
MDA-MB231
HCT 116
PC3
NCI-H727
Fibroblats
6
6
6
6
6
7
7
7
9
9
9
a
b
c
100
92
114
94
95
110
–
76
76
97
ND
94
86
–
108
68
109
97
95
110
–
d
e
108
68
109
97
95
110
–
48 (8)
85 ([25)
75 (17)
109
19 (8)
94 ([25)
71 (20)
105
60 (15)
13 (7)
83 (20)
109
37 (12)
45 (15)
64 (15)
109
92
54 (12)
93 ([25)
94 ([25)
114
33 (15)
94 (40)
74 (18)
97
– ([25)
a
b
c
– ([25)
– ([25)
–
a
b
c
110
106
113
103
119
–
111
111
111
119
115
(7)
143
119
–
122
123
125
110
116
–
Roscovitine
DMSO
(12)
NE
(5)
(12)
NE
(10)
NE
(20)
NE
([25)
NE
NE
NE
ND not determined, NE no effect at 0.25 % (from a solution of DMSO 25 lM)
a
Percentage of survival measured at 25 lM (after 48 h using a single dose, triplicate)
b
IC50 values in brackets are expressed in lM and are the average of three assays, standard error ± 0.5 lM
which strongly indicates that the two 5-arylidene-4-oxo-2-
thioxo-1,3-thiazolidine-1-yl moieties have both the Z-con-
figuration (Guiheneuf et al., 2014). The unsymmetrical
Conclusion
In summary, the synthesis of unsymmetrical linked bis-5-
arylidene rhodanine derivatives was realized in six steps.
The key steps of this sequence involved the construction of
5-arylidene-4-oxo-2-thioxo-1,3-thiazolidine-1-yl moieties
by ‘‘one-pot two-steps’’ protocol under microwave dielec-
tric heating using primary amine (i.e., intermediates 2 and
1
3
structure of 9a was also confirmed in the C NMR spec-
trum because we observed two separated signals for the
two methylene (CH=) carbons (d 133.1 and 133.4 ppm).
Biology
7
), bis(carboxymethyl)-trithiocarbonate 3 and aromatic
To evaluate the potency of selected compounds 6a–e, 7a–c
and 9a–c for their in vitro inhibition of cell proliferation, we
used a panel of 6 representative tumoral cell lines, namely
Huh7 D12 (differential hepatocellular carcinoma), Caco2
aldehydes 5. The intermediates 6, 7 and unsymmetrical
compounds 9 have been built with a Z-geometry and their
in vitro inhibition of cell proliferation was carried out.
None of unsymmetrical compounds showed a significant
activity against the six tumoral cell lines, but the inter-
mediates 6e and 7a exhibit activity against Huh7 D12,
Caco 2, and MDA MB231 cell lines.
(
differentiating colorectal adenocarcinoma), HCT (actively
proliferating colorectal carcinoma), PC3 (prostate carci-
noma), NCI-H2 (lung carcinoma), MDA-MB 231 (breast
carcinoma), and diploid skin fibroblasts as normal cell lines
for control. Roscovitine was also used as a positive control
and it IC50 values were compared with those obtained for the
compounds 6, 7, and 9. Results of the in vitro antiprolifer-
ative data activity are reported in Table 2. The most active
compound was clearly 6e and exhibited antitumor activities
in the Huh7 D12 and Caco2 cell lines with IC50 values lower
than 10 lM (Huh7 D12 IC50 8 lM and Caco2 IC50 8 lM).
In addition, 7a presented also a selective activity in the
MDA MB231 cell line (IC50 7 lM) and did not exhibit the
growth of normal fibroblasts (IC [ 25 lM). On the other
Experimental section
Chemistry
General remarks
Melting points were determined on a Kofler melting point
apparatus and were uncorrected. Thin-layer chromatogra-
phy (TLC) was accomplished on 0.2-mm precoated plates
of silica gel 60 F-254 (Merck). Visualization was made
with ultraviolet light (254 and 365 nM) or with a fluores-
5
0
hand, in the desired unsymmetrical linked bis-5-arylidene
rhodanine derivatives 9a–c, none of these compounds pre-
sented a significant activity against the six representative
tumoral cell lines.
1
cence indicator. H NMR spectra were recorded on
1
3
BRUKER AC 300 P (300 MHz) spectrometer and
C
1
23

Med Chem Res
NMR spectra on BRUKER AC 300 P (75 MHz) spec-
trometer. Chemical shifts are expressed in parts per million
downfield from tetramethylsilane as an internal standard.
Data are given in the following order: d value, multiplicity
J = 5.8 Hz, CH ); 2.96 (t, 2H, J = 4.3 Hz, CH NH); 4.93
2 2
1
(br s, 2H, NH ); 5.71 (br s, 1H, NH). C NMR (DMSO-d6)
3
2
d: 28.2 (CH ); 41.1 (CH ); 66.8 (CH NH); 78.7 (Me CO);
3
2
2
3
156.3 (NHCO). HRMS, m/z: 161.1289 found (calculated
?
for C H N O [M?H] requires 161.1290).
(
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and
7
17 2 2
br, broad), number of protons, coupling constants J is given
in Hertz. The mass spectra (HRMS) were taken, respec-
tively, on a MS/MS ZABSpec Tof Micromass (EBE TOF
geometry) at an ionizing potential of 8 eV and on a
VARIAN MAT 311 at an ionizing potential of 70 eV in the
Centre R e´ gional de Mesures Physiques de l’Ouest
Tert-butyl (4-aminobutyl)carbamate (2b)
In a 250 ml two-necked round-bottomed flask, provided
with magnetic stirrer and condenser, commercial 1,4-di-
aminobutane 1a (14.3 ml, 12.5 g, 0.14 mol.) was solubi-
lized in 1,4-dioxane (69 ml). To this mixture was added
dropwise a solution of di-tert-butyldicarbonate (6.5 g,
30 mmol.) in 85 ml of 1,4-dioxane over a period of 3 h at
room temperature. After vigorous stirring at 25 °C during
12 h, the volatile compounds of the reaction mixture were
eliminated in vacuo and to the crude reaction mixture was
poured 150 ml of deionized water. The mixture was
extracted with methylene chloride (5 9 50 ml), organic
phases were collected and dried over anhydrous magne-
sium sulfate. The filtrate was concentrated in a rotary
evaporator under reduced pressure and was dried under
(
CRMPO, Rennes). Reactions under microwave irradia-
Ò
tions were realized in the Anton Paar Monowave 300
microwave reactor (Anton-Paar France) using borosilicate
glass vials of 10 ml equipped with snap caps (at the end of
the irradiation, cooling reaction was realized by com-
pressed air). The microwave instrument consists of a con-
tinuous focused microwave power output from 0 to 800 W
Ò
for this Monowave 300 apparatus. All the experiments in
the microwave reactor were performed using stirring
option. The target temperature was reached with a ramp of
3
min and the chosen microwave power stay constant to
-
2
hold the mixture at this temperature. The reaction tem-
perature is monitored using calibrated infrared sensor and
the reaction time included the ramp period. The microwave
irradiation parameters (power and temperature) were
monitored by the Monowave software package of the
high vacuum (10 Torr) at 25 °C for 10 min. The desired
carbamate 2b (1.58 g) was obtained as colorless mobile oil
1
in 28 % yield and was further used without purification. H
NMR (DMSO-d ) d: 1.34 (s, 9H; Me CO); 1.40 (m, 4H,
6
3
CH ); 2.61 (t, 2H, J = 6.7 Hz, CH ); 3.02 (m, 2H,
2
2
Ò
13
Monowave 300 microwave reactor. Solvents were evap-
CH NH); 4.93 (br s, 2H, NH ); 5.71 (br s, 1H, NH).
2
C
2
orated with a BUCHI rotary evaporator. All reagents and
solvents were purchased from Acros, Sigma-Aldrich Chi-
mie, TCI France and Fluka France and were used without
further purification.
NMR (DMSO-d ) d: 27.2 (CH ); 28.4 (Me CO); 29.5
6
2
3
(CH ); 40.2 (CH ); 41.1 (CH ); 78.9 (CO); 156.1 (NHCO).
2
2
2
HRMS, m/z: 189.1600 found (calculated for C H N O
9
21
2
2
?
[M?H] requires 189.1603).
Tert-butyl (2-aminoethyl)carbamate (2a)
Tert-butyl {2-[4-(3-aminopropyl)piperazin-1-
yl]propyl}carbamate (2c)
In a 250 ml two-necked round-bottomed flask, provided
with magnetic stirrer and condenser, commercial 1,2-di-
aminoethane 1a (14.42 g, 16.03 ml, 0.24 mol.) was solu-
bilized in 1,4-dioxane (69 ml). To this mixture was added
dropwise a solution of di-tert-butyldicarbonate (6.5 g,
In a 250 ml two-necked round-bottomed flask, provided
with magnetic stirrer and condenser, commercial 1,4-bis-
(3-aminopropyl)piperazine 1c (4.32 ml, 4.21 g, 21 mol.)
was solubilized in 1,4-dioxane (34 ml). To this mixture
was added a solution of di-tert-butyldicarbonate (812 mg.,
37 mmol.) in 16 ml of 1,4-dioxane over a period of 3 h at
room temperature. After vigorous stirring at 25 °C during
12 h, the volatile compounds of the reaction mixture were
eliminated in vacuo and to the crude reaction mixture was
poured 80 ml of deionized water. The mixture was
extracted with methylene chloride (5 9 25 ml), organic
phases were collected and dried over anhydrous magne-
sium sulfate. The filtrate was concentrated in a rotary
evaporator under reduced pressure and was dried under
3
0 mmol.) in 85 ml of 1,4-dioxane over a period of 3 h at
room temperature. After vigorous stirring at 25 °C during
2 h, the volatile compounds of the reaction mixture were
1
removed in vacuo and to the crude reaction mixture was
poured 150 ml of deionized water. The mixture was
extracted with methylene chloride (5 9 50 ml), organic
phases were collected and dried over anhydrous magne-
sium sulfate. The filtrate was concentrated in a rotary
evaporator under reduced pressure and was dried under
-
2
high vacuum (10 Torr) at 25 °C for 10 min. The desired
carbamate 2a (1.25 g) was obtained as colorless mobile oil
-
2
high vacuum (10 Torr) at 25 °C for 10 min. The desired
carbamate 2c (3.52 g) was obtained as colorless mobile oil
in 56 % yield and was further used without purification.
1
in 26 % yield and was further used without purification. H
NMR (DMSO-d ) d: 1.20 (s, 9H, Me C); 2.60 (t, 2H,
6
3
123

Med Chem Res
1
H NMR (DMSO-d ) d: 1.37 (s, 9H, Me C); 1.60 (m, 4H,
(5Z)-Tert-butyl [2-(5-(1,3-benzodioxol-5ylmethylidene)-4-
6
3
CH ); 2.35 (m, 12H, CH ); 2.68 (t, 2H, J = 6.6 Hz,
2
oxo-2-thioxo-1,3-thiazolidin-3-yl)ethyl]carbamate (6b)
2
CH NH ); 3.11 (m, 2H, CH NH); 4.88 (br s, NH ); 5.42 (br
2
2
2
2
1
3
s, 1H, NH). C NMR (DMSO-d ) d: 26.3 (CH ); 28.4
(
Compound 6b was prepared in 59 % yield (212 mg) as
yellow powder from tert-butyl (2-aminoethyl)carbamate 2a
(9 mg., 0.88 mmol.) and 3,4-methylendioxybenzaldehyde
6
2
Me CO); 29.9 (CH ); 39.8 (CH NH ); 40.6 (CH NH);
3 2 2 2 2
5
3.1 (CH N); 56.5 (NCH ); 78.7 (Me CO); 156.1 (NHCO).
2 2 3
HRMS, m/z: 301.2603 found (calculated for C H N O
5 33 4 2
5b (132 mg., 0.88 mmol.) according to the standard pro-
1
1
?
M?H] requires 301.2603).
[
cedure. Mp = 154–156 °C. H NMR (DMSO-d
6
) d: 1.32
s, 9H, Me C); 3.25 (q, 2H, J = 5.1 Hz, 2H, CH NH); 4.10
(
3
2
Standard procedure for the preparation of 5-arylidene-2-
thioxo-1,3-thiazolidine-4-one carbamates 6a-e under
microwave irradiation
(t, 2H, J = 5,3 Hz, 2H, CH
N); 6.15 (s, 2H, OCH O); 6.93
2 2
0
0
(t, 1H, J = 6.1 Hz, 1H, NH); 7.10–7.20 (m, 3H, H-2 , H-3 ,
0
13
H-5 , Ar); 7.70 (s, 1H, CH=). C NMR (DMSO-d
) d: 28.1
6
(
Me C); 36.9 (CH NH); 44.5 (CH N); 77.7 (Me C); 102.1
3
2
2
3
0
O); 109.3 (C-2 , Ar); 109.5 (CH=); 120.1 (C=);
2
In a 10 ml glass tube was placed successively bis(carboxy-
methyl)trithiocarbonate 3 (0.2 g, 0.88 mmol., 1 equiv.),
dimethoxyethane (1 ml), triethylamine (119 ll, 89 mg.,
(OCH
126.7 (C-5 , Ar); 127.3 (C-1 , Ar); 132.5 (C-6 , Ar); 148.3
0
0
0
0
0
(C-4 , Ar); 149.7 (C-3 , Ar); 155.7 (NHCO); 167.2 (C=O);
0
.88 mmol., 1 equiv.), and carbamate 2 (0.88 mmol.,
equiv.). The glass tube was sealed with a snap cap and
193.6 (C=S). HRMS, m/z: 431.0709 found (calculated for
?
Na [M?Na] requires 431.0711).
1
C
18
H
20
N
2
O
5
S
2
Ò
placed in the Monowave 300 Anton Paar microwave cavity
(
P = 800 Watt). The reaction mixture was irradiated at
(5Z)-Tert-butyl [2-(5-(4-methoxybenzylidene)-4-oxo-2-
90 °C for 10 min. under vigorous magnetic stirring. After
microwave dielectric heating, the crude reaction mixture was
thioxo-1,3-thiazolidin-3-yl)butyl]carbamate (6c)
allowed to cool down at room temperature, aldehyde 5
(
Compound 6c was prepared in 44 % yield (163 mg) as yellow
powder from tert-butyl (2-aminobutyl)carbamate 2b (166 mg.,
0.88 mmol.) and 4-methoxybenzaldehyde 5a (120 mg.,
0.88 mol, 1 equiv.) was added to the cooled reaction mix-
ture which was immediately submitted to microwave irra-
diation at 110 °C for 5 min. After cooling, the volatile
compounds of the reaction mixture were eliminated in a
rotary evaporator under reduced pressure. To the crude
reaction mixture was added 2 ml of MeOH and after tritu-
rating, the insoluble product 6 was collected by filtration on a
B u¨ chner funnel (porosity N°4), washed with cooled methy-
lene chloride (2 9 0.5 ml) and was dried under high vacuum
0.88 mmol.) according to the standard procedure. Mp = 142–
1
146 °C. H NMR (DMSO-d
) d: 1.35 (s, 9H, Me
); 2.91 (q, 2H, J = 6.2 Hz,
2
C); 1.61
6
3
(quint, 2H, J = 7.4 Hz, CH
CH NH); 3.83 (s, 3H, OCH
2
); 4.00 (t, 2H, J = 7 Hz, CH N);
2
3
0
6.80 (br s, 1H, NH); 7.12 (d, 2H, J = 9.1 Hz, H-3 , Ar); 7.60 (d,
0
13
2H, J = 8.9 Hz, H-2 , Ar); 7.70 (s, 1H, CH=). C NMR
(DMSO-d
) d: 23.9 (CH
); 26.7 (CH
); 28.1 (Me C); 40.3
3
6
2
2
-
2
0
(
10 Torr) at 25 °C for 1 h. The desired compound 6 was
further used without purification.
(CH N); 55.6 (OCH
2
); 77.4 (Me C); 115.2 (C-3 , Ar); 119.0
3 3
0
0
(C=); 125.5 (C-1 , Ar); 132.9 (C-2 , Ar); 133.2 (CH=); 155.5
0
(
NHCO); 161.5 (C-4 , Ar); 167.0 (C=O); 193.3 (C=S). HRMS,
(
5Z)-Tert-butyl [2-(5-(4-methoxybenzylidene)-4-oxo-2-
m/z: 445.1234 found (calculated for C20H N O S Na
26 2 4 2
?
[M?Na] requires 445.1232).
thioxo-1,3-thiazolidin-3-yl)ethyl]carbamate (6a)
Compound 6a was prepared in 23 % yield (80 mg) as
yellow powder from tert-butyl (2-aminoethyl)carbamate 2a
(5Z)-Tert-butyl [2-(5-(1,3-benzodioxol-5ylmethylidene)-4-
oxo-2-thioxo-1,3-thiazolidin-3-yl)butyl]carbamate (6d)
(
(
9 mg., 0.88 mmol.) and 4-methoxybenzaldehyde 5a
120 mg., 0.88 mmol.) according to the standard proce-
Compound 6d was prepared in 35 % yield (134 mg) as yellow
powder from tert-butyl (2-aminobutyl)carbamate 2b (166 mg.,
0.88 mmol.) and 3,4-methylenedioxybenzaldehyde 5b
1
dure. Mp = 134–136 °C. H NMR (DMSO-d ) d: 1.31 (s,
9
6
H, Me C); 3.25 (q, 2H, J = 5.1 Hz, CH NH); 3.83 (s, 3H,
3 2
OCH ); 4.10 (t, 2H, J = 5.3 Hz, CH ); 6.94 (br t, 1H,
3
(132 mg., 0.88 mmol.) according to the standard procedure.
2
0
1
J = 6.1 Hz, NHCH ); 7.10 (d, 2H, J = 8,8 Hz, H-3 , Ar);
2
Mp = 226–228 °C. H NMR (DMSO-d
6
) d: 1.40 (s, 9H,
); 1.67 (m, 2H, CH ); 2.97 (q, 2H,
NH); 4.07 (t, 2H, J = 7.2 Hz, CH
0
13
7
.60 (d, 2H, J = 8,8 Hz, H-2 , Ar); 7,70 (s, 1H, CH=).
C
Me
J = 6.8 Hz, CH
(s, 2H, OCH
3
C); 1.44 (m, 2H, CH
2
2
NMR (DMSO-d ) d: 28.1 (CMe ); 36.9 (CH NH); 44.5
2
N); 6.13
2
6
3
2
0
0
(
CH N); 55.5 (OCH ); 77.7 (OCMe ); 115.2 (C-3 , Ar);
2
2
O); 6.42 (br s, 1H, NH); 7.07–7.20 (m, 3H, H-2 ,
3
3
0
0
0
0
13
1
19.4 (C-1 , Ar); 125.6 (C=); 132.5 (CH=); 132.7 (C-2 ,
0
H-5 , H-6 , Ar); 7.72 (s, 1H, CH=). C NMR (DMSO-d
6
) d:
C); 44.0 (CH NH); 56.0
2
Ar); 155.7 (NHCO); 161.4 (C-4 , Ar); 167.3 (C=O); 193.7
23.9 (CH ); 26.8 (CH
2
2
); 28.2 (Me
3
0
(
C=S). HRMS, m/z: 417.0921 found (calculated for
(CH N); 77.5 (CMe ); 102.1 (OCH
2
3
2
O); 109.2 (C-2 , Ar); 109.4
0
?
C H N O S Na [M?Na] requires 417.0918).
0
0
(C-5 , Ar); 120.0 (C=); 126.8 (C-6 , Cipso, Ar); 127.3 (C-1 ,
1
8 22 2 4 2
1
23

Med Chem Res
0
0
Cipso, Ar); 133.1 (CH=); 148.4 (C-4 , Ar); 149.8 (C-3 , Ar);
oxo-2-thioxo-1,3-thiazolidin-3-yl)ethyl]carbamate 6a (158 mg.,
0.4 mmol.) according to the standard procedure. Mp = 260–
1
55.5 (NHCO); 166.9 (C=O); 193.1(C=S). HRMS, m/z:
?
59.1023 found (calculated for C H N O S Na [M?Na]
5 2
1
4
262 °C. H NMR (DMSO-d ) d: 3.13 (t, 2H, J = 6 Hz, CH );
20
24
2
6
2
requires 459.1024).
3.84 (s, 3H, OCH ); 4.20 (t, 2H, J = 6 Hz, CH ); 7.13 (d, 2H,
3 2
0
0
J = 8.9 Hz, H-3 , Ar); 7.63 (d, 2H, J = 8.8 Hz, H-2 , Ar); 7.79
13
(
5Z)-Tert-butyl [(4-{[5-(1,3-benzodioxol-5-ylmethylidene)-
(
s, 1H, CH=); 7.94 (br s, 2H, NH ). C NMR (DMSO-d )d:36.2
2
6
4
-oxo-2-thioxo-1,3-thiazolidin-3-yl]propyl}piperazin-1-
0
CH ); 41.7 (CH ); 55.6 (OCH ); 115.2 (C-3 , Ar); 119.4 (C=);
2 2 3
(
yl)propyl]carbamate (6e)
0
0
0
1
25.5 (C-1 , Ar); 132.8 (C-2 , Ar); 132.9 (CH=); 161.5 (C-4 ,Ar);
1
67.5 (C=O); 193.8 (C=S). HRMS, m/z: 295.0577 found (cal-
Compound 6e was prepared in 36 % yield (174 mg) as yellow
powder from tert-butyl {2-[4-(2-aminopropyl)piperazin-1-
yl]propyl}carbamate 2c (263 mg., 0.88 mmol.) and 3,4-
methylenedioxybenzaldehyde 5b (132 mg., 0.88 mmol.)
?
culated for C H N O S [M?H] requires 295.0575);
13 15 2 2 2
?
278.0316 found (calculated for C H NO S [M-NH ?H]
3
13
12
2 2
requires 278.0309).
1
according to the standard procedure. Mp = 132–134 °C. H
NMR (DMSO-d ) d: 1.34 (s, 9H, Me C); 1.41 (m, 2H, CH );
6
3
2
(
5Z)-3-(2-Aminoethyl)-5-(1,3-benzodixol-5-ylmethylidene)-
1.80 (m, 2H, CH ); 2.10 (t, 4H, J = 7.1 Hz, 4H, CH N); 2,25
2 2
2
-thioxo-1,3-thiazolidin-4-one hydrochloride (7b)
(
m, 8H, 4xNCH ); 2.84 (q, 2H, J = 6.1 Hz, CH NH); 4.08 (t,
2
2
2
H, J = 6.9 Hz, CH N); 6.14 (s, 2H, OCH O); 6.73 (s, 1H,
2 2
Compound 7b was prepared in 98 % yield (121 mg) as yellow
powder from (5Z)-tert-butyl [2-(5-(1,3-benzodixol-5-ylmethyli-
dene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)ethyl]carbamate 6b
0
0
0
NH); 7.10–7.21(m, 3H, H-2 ,H-5 ,H-6 ,Ar);7.72(s,1H,CH=).
13
C NMR (DMSO-d ) d: 26.5 (CH ); 28.1 (CMe ); 38.3 (CH );
6
2
3
2
40.0 (CH NH); 43.2 (CH N); 52.8 (CH N); 52.9 (CH N); 55.5
2 2 2 2
(
163 mg., 0.4 mmol.) according to the standard procedure.
1
(
CH N); 77.3 (CMe ); 102.2 (OCH O); 109,3 (CH=); 109.5 (C-
2
0
3
2
Mp = 260–262 °C. H NMR (DMSO-d ) d: 3.13 (t, 2H,
J = 5,9 Hz, CH NH ); 4.26 (t, 2H, J = 5.9 Hz, CH N); 6.15 (s,
6
0
0
2
, Ar); 120,0 (C=); 126.8 (C-5 , Ar); 127.3 (C-1 , Ar); 132.9 (C-
0
2
2
2
0
0
6
, Ar); 148.3 (C-4 , Ar); 149.8 (C-3 , Ar); 155.5 (NHCO); 167.2
0 0 0
H, OCH O); 7.11–7.25 (m, 3H, H-2 , H-5 , H-6 , Ar); 7.75 (s,
2
2
(
C=O); 193.0 (C=S). HRMS, m/z: 549.2195 found (calculated
13
1H, CH=); 7.87 (br s, 2H, NH ). C NMR (DMSO-d ) d: 36.3
2
6
?
for C H N O S [M?H] requires 549.2205).
26 37 4 5 2
(
CH NH); 41.7 (CH N); 102.2 (OCH O); 109.4 (CH=); 109.6
2
2
2
0
0
0
0
(
C-2 , Ar); 120.1 (C=); 126.9 (C-5 , Ar); 127.1 (C-1 , Ar); 133.0
Standard procedure for the preparation of salts 7a–e after
deprotection of the 5-arylidene-2-thioxo-1,3-thiazolidine-
0
0
(
C-6 , Ar); 148.4(C-4 , Ar); 149.9 (C-3 , Ar); 167.5 (C=O); 193.7
C=S). HRMS, m/z: 309.0369 found (calculated for C H
3 12
(
1
4
-one carbamates 6
?
N O S [M?H] requires 309.0367); 292.0109 found (calcu-
3 2
?
lated for C H NO S [M-NH ?H] requires 292.0102).
2
13
10
3 2
3
In a 50 ml two-necked round-bottomed flask provided with a
magnetic stirrer and condenser, carbamate 6 (0.4 mmol.,
1
equiv.) was solubilized in 1,4-dioxane (2 ml) at room
(
5Z)-3-(4-Aminobutyl)-5-(1,3-benzodixol-5-
temperature under vigorous stirring during 10 min. To this
homogeneous solution was added dropwise for 30 min; a
solution of 6 M HCl (2 ml) in 1,4-dioxane (2 ml). The reac-
tion mixture was stirred during 4 h at 25 °C and was con-
centrated in a rotary evaporator under reduced pressure for
elimination of volatile compounds. To the crystallized crude
ylmethylidene)-2-thioxo-1,3-thiazolidin-4-one
hydrochloride (7c)
Compound 7c was prepared in 65 % yield (87 mg) from (5Z)-
tert-butyl [2-(5-(1,3-benzodixol-5-ylmethylidene)-4-oxo-2-
thioxo-1,3-thiazolidin-3-yl)butyl]carbamate 6d (174 mg.,
reaction mixture was added 5 ml of Et O and after triturating,
2
0
.4 mmol.) according to the standard procedure. Mp = 259–
1
the insoluble salt 7 was collected by filtration, then washed
with 2 9 5 ml of Et O. The desired salt 7 was dried under
2
60 °C. H NMR (DMSO-d ) d: 1.16 (m, 2H, CH ); 1.75 (m,
6
2
2
-2
2H, CH ); 2.86 (m, 2H, CH
2
NH ); 4.12 (t, 2H, J = 6.7 Hz,
2 2
high vacuum (10 Torr) at 25 °C for 1 h that gave a yel-
lowish powder and was further used without purification.
0
0
0
CH N); 6.22 (s, 2H, OCH O); 7.17–7.28 (m, H-2 , H-5 , H-6 ,
2
2
1
3
Ar); 7.82 (s, 1H, CH=). C NMR (DMSO-d ) d: 23.7 (CH );
6
2
3
1
1
1
8.3 (CH ); 43.6 (CH NH ); 66.3 (CH N); 102.2 (OCH O);
2 2 2 2 2
(
5Z)-3-(2-Aminoethyl)-5-(4-methoxybenzylidene)-2-thioxo-
,3-thiazolidin-4-one hydrochloride (7a)
0
0
0
09.4 (C-2); 109.6 (C-5 , Ar); 119.6 (C=); 127.1 (C-6 , Ar);
0
1
33.3 (CH=); 148.4 (C-4 , Ar); 149.9 (C-3 , Ar); 167.1 (C=O);
95.3 (C=S). HRMS, m/z: 337.0681 found (calculated for
?
Compound 7a was prepared in 91 % yield (107 mg) as yellow
powder from (5Z)-tert-butyl [2-(5-(4-methoxybenzylidene)-4-
C H N O S [M?H] requires 337.0681).
15 17 2 3 2
123

Med Chem Res
Standard procedure for the preparation of the linked bis-
N,N’-(5-arylidene rhodanin-3-yl) derivatives 9 under
microwave irradiation
2-thioxo-1,3-thiazolidin-4-one hydrochloride 7b (200 mg.,
0.58 mmol.) and benzaldehyde 5c (62 mg., 0.58 mmol.)
1
according to the standard procedure. Mp = 260–262 °C. H
NMR (DMSO-d ) d: 4.43 (t, 4H, J = 3.9 Hz, CH ); 6.15 (s,
6
2
0 0 0
2H, OCH O); 7.10–7.23 (m, 3H, H-2 , H-5 , H-6 , Ar); 7.53
2
In a 10 ml glass tube was placed successively bis(carboxy-
methyl)trithiocarbonate 3 (0.13 g, 0.58 mol., 1 equiv.),
dimethoxyethane (1 ml), triethylamine (155 ll, 116 mg.,
0
0
(d, 3H, J = 7.3 Hz, H-3 , H-4 , Ar); 7.66 (d, 2H, J = 5.7 Hz,
0
13
H-2 , Ar); 7.75 (s, 1H, CH=); 7.83 (s, 1H, CH=). C NMR
1
.16 mmol., 2 equiv.), and hydrochloride salt 7 (0.58 mmol.,
equiv.). The glass tube was sealed with a snap cap and
(DMSO-d ) d: 41.5 (CH ); 102.2 (OCH O); 109.4 (C-2, Ar);
6
2
2
1
109.7 (C-5, Ar); 119.1 (C=); 119.4 (C=); 121.8 (C-6, Ar);
0 0
Ò
placed in the Monowave 300 Anton Paar microwave cavity
121.8 (C-1, Cipso, Ar); 127.2 (C-2 , Ar); 129.5 (C-3 , Ar);
0
0
(
P = 800 Watt). The reaction mixture was irradiated at 90 °C
130.8 (C-4 , Ar); 132.7 (CH=); 133.4 (C-1 , Cipso, Ar); 148.4
(C-3, Cipso, Ar); 150,0 (C-4, Cipso, Ar); 167.2 (C=O); 193.6
(C=S). HRMS, m/z: 513.0070 found (calculated for
for 10 min. under vigorous magnetic stirring. After micro-
wave dielectric heating, the crude reaction mixture was
allowed to cool down at room temperature, aldehyde 5
?
C H N O S [M?H] requires 513.0071).
23 17 2 4 4
(
0.58 mol, 1 equiv.) was added to the cooled reaction mixture
which was immediately submitted to microwave irradiation at
10 °Cfor5 min. Aftercooling, thevolatilecompoundsofthe
1
(5Z)-5-(1,3-Benzodioxol-5-ylmethylidene)-3-{2-[(5Z)-5-(4-
methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-
yl]ethyl}-2-thioxo-1,3-thiazolidin-4-one (9c)
reaction mixture were eliminated in a rotary evaporator under
reduced pressure. To the crude reaction mixture was added
2
ml of MeOH and after triturating, the insoluble product 9
was collected byfiltrationona B u¨ chner funnel (porosity N°4),
washed successively with cooled hexane (5 9 2 ml), meth-
ylene chloride (3 9 1 ml) and was dried under high vacuum
Compound 9c waspreparedin27 %yield(85 mg)from(5Z)-3-
w(2-aminoethyl)-5-(1,3-benzodixol-5-ylmethylidene)-2-thi-
oxo-1,3-thiazolidin-4-one hydrochloride 7b (200 mg.,
0.58 mmol.) and 4-methoxybenzaldehyde 5a (79 mg.,
-2
(10 Torr) at 25 °C for 1 h. The desired compound 9 was
purified by recrystallization in EtOH.
0.58 mmol.) according to the standard procedure. Mp =
1
1
64–166 °C. H NMR (DMSO-d ) d: 3.84 (s, 3H, OCH );
6
3
4
.41 (s, 4H, CH ); 6.15 (s, 2H, OCH O); 7.10 (d, 2H,
0
2
2
(
5Z)-5-Benzylidene-3-{2-[(5Z)-5-(4-methoxybenzylidene)-
-oxo-2-thioxo-1,3-thiazolidin-3-yl]ethyl}-2-thioxo-1,3-
J = 8.8 Hz, H-2 , Ar); 7.09-7.20 (m, 7H, H-2, H-5, H-6, Ar);
0
4
7
.60 (d, 2H, J = 8.8 Hz, H-3 , Ar); 7.74(s, 1H, CH=);7.78 (s,
13
thiazolidin-4-one (9a)
1
H, CH=). C NMR (DMSO-d ) d: 41.6 (CH ); 55.6
6
2
0
OCH ); 99.5 (OCH O); 115.2 (C-3 , C-2, Ar); 118.5 (C=);
3 2
(
Compound 9a was prepared in 47 % yield (136 mg) as
yellow powder from (5Z)-3-(2-aminoethyl)-5-(4-methoxy-
benzylidene)-2-thioxo-1,3-thiazolidin-4-one hydrochloride
0
0
1
1
1
2
19.1(C-1 , Cipso, Ar); 125.4(C-1, Cipso, Ar);127.0(C-6, Ar);
33.1 (C-2 , C-5, Ar); 133.4 (CH=); 148.4 (C-4, Cipso, Ar);
0
50.0 (C-3, Cipso, Ar); 161.6 (C-4 , Cipso, Ar); 167.2 (C=O);
7
a (363 mg., 0.58 mmol.) and benzaldehyde 5c (62 mg.,
.58 mmol.) according to the standard procedure.
13.1 (C=S). HRMS, m/z: 543.0172 found (calculated for
?
C H N O S [M?H] requires 543.0177).
21 19 2 4 4
0
1
Mp = 222–224 °C. H NMR (DMSO-d ) d: 3.84 (s, 3H,
6
OCH ); 4.43 (s, 4H, CH ); 7.11 (d, 2H, J = 8.8 Hz, H-3,
0
3
2
0
0
Ar); 7.53–7.63 (m, 7H, H-2, H-2 , H-3 , H-4 , Ar); 7.78 (s,
Cell culture and survival assays
1
3
1
4
1
H, CH=); 7.83 (s, 1H, CH=). C NMR (DMSO-d ) d:
6
0.4 (CH N); 55.7 (OCH ); 115.1 (C-3, Ar); 118,5 (C=);
2
3
Skin diploid fibroblastic cells were provided by BIOPRE-
DIC International Company (Rennes, France). Caco2 (Ref
ECACC: 86010202), Huh-7D12 (Ref ECACC: 01042712),
MDA-MB-231 (Ref ECACC: 92020424), HCT-116 (Ref
ECACC: 91091005), PC3 (Ref ECACC: 90112714) and
NCI-H727 (Ref ECACC: 94060303) cell lines were
obtained from the ECACC collection. Cells were grown
according to ECACC recommendations (Nakabayashi
et al., 1982). The toxicity test of the compounds on these
0
0
21.8 (C-1, Cipso, Ar); 125.4 (C-1 , C , Ar); 129.5 (C-2 ,
ipso
0
0
Ar); 130.8 (C-3 , C-4 , Ar); 132.8 (C-2, Ar); 133.1 (CH=);
33.4 (CH=); 161.6 (C-4, Cipso, Ar); 167.2 (C=O); 193.7
C=S). HRMS, m/z: 521.0097 found (calculated for
1
(
?
C H N O S Na [M?Na] requires 521.0098).
23 18 2 3 4
(
5Z)-5-(1,3-Benzodioxol-5-ylmethylidene)-3-{2-[(5Z)-5-
benzylidene-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]ethyl}-2-
3
thioxo-1,3-thiazolidin-4-one (9b)
cells was as follows: 2 9 10 cells for HCT-116 cells or 4
3
x 10 for the other cells were seeded in 96 multiwell plates
Compound 9b was prepared in 43 % yield (128 mg) from
(
in triplicate and left for 24 h for attachment, spreading, and
growing. Then, cells were exposed for 48 h to increasing
5Z)-3-(2-aminoethyl)-5-(1,3-benzodixol-5-ylmethylidene)-
1
23

Med Chem Res
concentrations of the compounds, ranging from 0.1 to
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5 lM in a final volume of 120 ll of culture medium. Cells
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(
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Acknowledgments One of us (K.W.C.) wishes to thank the Agence
0
0
Universitaire de la Francophonie AUF, contract N°0486 for a
research fellowship. Financial support of this program carried out
under the French National Cancer Institute ‘‘Canc e´ rop oˆ le Grand
Ouest’’ by contracts PRIR 04-8390 and ACI 04-2254, is gratefully
acknowledged.
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