Optimization of troglitazone derivatives as potent anti-proliferative agents: Towards more active and less toxic compounds

Article abstract of DOI:10.1016/j.ejmech.2014.06.015

Δ2-Troglitazone derivatives were shown to exhibit anti-proliferative activity in a PPARγ-independent manner. We prepared various compounds in order to increase their potency and decrease their toxicity towards non-malignant primary cultured hepatocytes. Many compounds induced viabilities less than 20% at 10 μM on various cancer cell lines. Furthermore, five of them showed hepatocyte viability of 80% or more at 200 μM. In addition, compounds 17 and 18 exhibited promising maximum tolerated doses on a murine model, enabling future investigations.

Full text of DOI:10.1016/j.ejmech.2014.06.015

European Journal of Medicinal Chemistry 83 (2014) 129e140
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Optimization of troglitazone derivatives as potent anti-proliferative
agents: Towards more active and less toxic compounds
,
,
, d
Andrea Bordessa a b, Christelle Colin-Cassin c d, Isabelle Grillier-Vuissoz c
,
Sandra Kuntz c d, Sabine Mazerbourg c d, Gauthier Husson c d, Myriam Vo a
,
,
,
,
, b
Stephane Flament , Helene Martin , Yves Chapleur b, Michel Boisbrun a
c
,
d
e
a,
, b, *
ꢀ
ꢀ ꢁ
a
ꢀ
ꢁ
Universite de Lorraine, SRSMC, UMR 7565, BP 70239, F-54506 Vand
œ
uvre-les-Nancy, France
b CNRS, SRSMC, UMR 7565, BP 70239, F-54506 Vand
œ
uvre-les-Nancy, France
uvre-les-Nancy Cedex, France
uvre-les-Nancy Cedex, France
ꢁ
c
ꢀ
ꢁ
Universite de Lorraine, CRAN, UMR 7039, BP 70239, F-54506 Vand
œ
d CNRS, CRAN, UMR 7039, BP 70239, F-54506 Vand
œ
ꢁ
e
ꢀ
ꢀ
Universite de Franche-Comte, Laboratoire de Toxicologie Cellulaire, EA 4267, 25030 Besançon Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
D
2-Troglitazone derivatives were shown to exhibit anti-proliferative activity in a PPARg-independent
Received 31 January 2014
Received in revised form
16 May 2014
Accepted 9 June 2014
Available online 10 June 2014
manner. We prepared various compounds in order to increase their potency and decrease their toxicity
towards non-malignant primary cultured hepatocytes. Many compounds induced viabilities less than
20% at 10
or more at 200
a murine model, enabling future investigations.
m
M on various cancer cell lines. Furthermore, five of them showed hepatocyte viability of 80%
m
M. In addition, compounds 17 and 18 exhibited promising maximum tolerated doses on
© 2014 Elsevier Masson SAS. All rights reserved.
Keywords:
Troglitazone
Chromane
Cancer
Hepatotoxicity
1. Introduction
structureeactivity and structureetoxicity relationships in this series
of compounds. This study confirmed that the presence of a double
Numerous compounds bearing a thiazolidine-2,4-dione (TZD)
moiety were shown to exhibit outstanding biological activities [1].
Among others, ciglitazone (CGZ) and troglitazone (TGZ) are insulin
bond adjacent to the TZD moiety (D2TGZ series) favors the anti-
proliferative activity (MCF-7 and MDA-MB-231 breast cancer cell
lines), and that such a modification induces less toxicity on primary
cultured human hepatocytes. Furthermore, apolar substituents
linked to the chromane moiety (via an ester linkage) were favorable
on both aspects too. Polar groups were tolerated if they were distant
from the heterocycle thanks to an apolar linker. In addition, simple
removal of the chromane hydroxyl group slightly increased the po-
tency of the parent compound and yielded the least toxic compound
[16]. Thus, in the present study, we intended to obtain a cumulative
sensitizers via peroxisome proliferator-activated receptor g (PPARg)
transactivation and TGZ was used in the United States for the
treatment of type 2 diabetes from 1997 until its withdrawal in 2000
[2]. Furthermore, TZD derivatives showed anti-proliferative activity
and TGZ was envisioned as a therapeutic alternative to treat breast
cancer [3,4]. Many studies have recently shown that this property is
at least partly PPARg-independent [5], with various cellular targets
being involved, such as cyclin D1 [6], androgen receptor [7], estro-
gen receptor [8], AMPK [9,10], Ca2þ intracellular stores [11], ERK1/2
activation [12]. Chen et al. recently proposed that TZD derivatives
activity is mediated by energy restriction [13e15].
Previously, we synthesized [16] new TGZ derivatives bearing
various substituents on the chromane moiety, in order to clarify
effect by linking the deoxygenated D2TGZ template to an apolar
linear alkyl chain via a stable carbonecarbon bond. A terminal amino
group would give interesting solubility propertyand an additional N-
functionalization of the TZD group could also be of value (Fig. 1, Path
A). Furthermore, since a permutational rearrangement of CGZ-based
molecules led to an increased anti-proliferative activity [7], we
intended to follow an analogous strategy starting from
exploring three permutational possibilities (Fig. 1, Path B).
The aim of our study was to synthesize these compounds and
to evaluate their anti-proliferative activity towards various cancer
D2TGZ,
* Corresponding author. CNRS, SRSMC, UMR 7565, BP 70239, F-54506 Vandœu-
ꢁ
vre-les-Nancy, France.
E-mail address: michel.boisbrun@univ-lorraine.fr (M. Boisbrun).
http://dx.doi.org/10.1016/j.ejmech.2014.06.015
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

130
A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
Fig. 1. Structures of
D2-troglitazone and target molecules.
cell lines. Since TGZ itself exhibited serious hepatotoxicity [2]
leading to its withdrawal from the market, the toxicity of the
most active compounds were evaluated on non-malignant primary
cultured human hepatocytes and maximum tolerated dose of the
lead compounds were further evaluated in vivo using a murine
model.
2. Chemistry
In the context of PPARg activation, it was reported that the TZD
moiety is involved in a network of hydrogen bonds in the Ligand
Binding Domain, for which the acidic NH proton plays a major role
[17]. Since the anticancer effects of our molecules are PPARg-in-
dependent, it was challenging to functionalize this position. Thus,
already reported compounds 1 and 6 [16] which showed encour-
aging activity and toxicity profiles were selected for this purpose
(Scheme 1). They afforded benzylated and methylated compounds
2e5 and 7,8.
We intended to prepare deoxygenated
D2TGZ derivatives
Scheme 1. Synthesis of N-alkylated derivatives. Reagents and conditions: (a) PhCH2Br,
K2CO3; (b) CH3I, K2CO3; (c) TFA.
(Scheme 2). For this purpose, FriedeleCrafts reaction on reported
compound 9 [16] using 6-bromohexanoyl chloride afforded keto-
ester 10, which was reduced with LiAlH4/AlCl3 [18] to give 11.
Bromide was substituted by azide to give 12, and simultaneous
reduction to primary amine and Boc protection [19] afforded 13.
Triflate activation of the primary alcohol followed by displacement
with 4-hydroxybenzaldehyde gave 14, then Knoevenagel conden-
sation with TZD yielded target compound 15. The Boc group could
be removed with or without anticipated methylation of TZD,
affording 17 (via 16), and 18.
Other permuted D2TGZ derivatives were obtained as depicted in
Scheme 5. Formylation [22] of 9 [16] gave 38 which was condensed
with TZD, and then benzylated to give 40. Reported 41 [16] was
reduced in one step (instead of the reported two-steps procedure
[23]) to give 42 which was then O-protected. Condensation with
TZD, followed by benzylation and subsequent deprotection affor-
ded permuted compound 46.
As mentioned above, we prepared permuted D2TGZ derivatives.
We started from 40-hydroxy-5-benzilidene-thiazolidinedione [20]
19 (Scheme 3). In a first attempt, we simply N-benzylated this
compound to afford 25, which was immediately tested for its anti-
proliferative activity. We were surprised by its high activity (Table 1,
Fig. 2). Thus, we prepared many derivatives starting from variously
substituted benzaldehydes. We also prepared related compound 31
which was previously reported by Chen and coworkers [7], for
comparison.
We prepared permuted compound 34 by condensing 19 with
already reported [16] triflate 32 and subsequent deprotection of
intermediate 33 (Scheme 4). To explore further structureeactivity
relationships, we also reacted 19 with commercial cinnamyl bro-
mide and with a biphenyl synthon [21], affording 35, 36, and 37.
3. Biological studies and discussion
All the new compounds were tested for their anti-proliferative
activity against 8 cancer cell lines focusing on colon, breast, skin,
pancreas, liver, and prostate cancers (see Supplementary data).
Among these compounds, a few were very hydrophobic and were
prone to precipitate after addition of the DMSO solution into the
culture medium. Thus, we could not evaluate the activities of 2, 4, 7,
and 16. Besides, since the activities of the compounds towards
various cell lines were roughly similar, we extracted from this pool
of results the activities towards hormone-dependent (MCF-7) and
hormone-independent (MDA-MB-231) breast cancer cell lines

A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
131
Scheme 2. Synthesis of deoxygenated derivatives. Reagents and conditions: (a) Br(CH2)5COCl, AlCl3; (b) LiAlH4, AlCl3; (c) NaN3; (d) H2, Pd/C, Boc2O; e) Tf2O, Pyr., then 4-
hydroxybenzaldehyde, K2CO3; (f) TZD, piperidine; (g) CH3I, K2CO3, (h) TFA.
independent cell line, but abolished activity towards MCF-7 cells.
This selectivity would be valuable in order to target hormone non-
responsive tumors. The same chemical modification on reported
active compound 6 [16] was much beneficial towards both cell lines
(compare 6 to 8). Furthermore, deoxygenated
D2TGZ series affor-
ded very active compounds towards both cell lines too, especially
unprotected 17 and 18. It is remarkable that 8, 17, and 18 were very
active since they induced viabilities lower than 10% at 10
mentioned before, it was our surprise to notice that simple N-
benzylated permuted compound 25 was so active (24.5% 1.9
mM. As
Scheme 3. Synthesis of 3-benzyl-5-benzylidenethiazolidine-2,4-dione derivatives and
structure of compound 31. Reagents and conditions: (a) TZD, b-alanine [20]; (b) K2CO3,
PhCH2Br.
viability on MDA-MB-231, see Table 1), but changing the nature of
the substituents on the phenyl ring (26e30) was detrimental to the
activity. Real permuted
D2TGZ derivative 34 was very active on
both cell lines, as cinnamyl 35 (less than 10% viability on MDA-MB-
231), but biphenyl 36 was less active and carboxyl-deprotected 37
was not active. Unfortunately, other permuted derivatives were not
very active.
We investigated the effects of the most active compounds on the
viability of primary cultured non-malignant human hepatocytes,
together with reference compounds (Table 1). N-methylation of
(Fig. 2). TGZ,
comparison.
D2TGZ and compound 31 were also tested for
As expected,
other reference compound, 31, was much more active. N-benzyla-
tion on the 2TGZ core (giving 3) did not change the activity. N-
D2TGZ was slightly more active than TGZ. The
D
methylation (compound 5) had also low impact on the hormone-
D2TGZ gave 5 which exhibited the best viability of the whole series,
showing surprisingly a slight increase of cell number. The same N-
methylation of 6 gave 8 which was finally more toxic towards he-
Table 1
Impact of selected compounds on the viability of two cancerous cell lines and on
non-malignant hepatocytes.
patocytes than 6 at 200
compounds 15, 17, and 18 exhibited 80% (or more) viability on
primary cultured hepatocytes at 100 and 200 M. This might be due
mM. Very interestingly, deoxygenated
Compound
Cancer cells viability
(% of control)a
Hepatocyte viability
(% of control)b
m
to the absence of oxygen atom at the 6-position of the chromane
core, preventing the formation of reported toxic quinone-type de-
rivatives (Fig. 3) [24].
Permuted compounds 25, 33 and reference compounds
exhibited much higher hepatotoxicity, especially at 200 mM, high-
lighting the potential of our best new compounds. Very active
permuted compounds 34 and 35 showed low to very low toxicity
on hepatocytes. This is not easy to rationalize, especially for 34,
which bears a hydroxyl group on the chromane template. Much
work was done to understand the metabolic pathways leading to
TGZ hepatotoxicity, which was not observed with other TZD
[2,24e26]. It is known that TGZ is oxidized in the liver by CYP3A4
and CYP2C8, leading to toxic metabolites which can react with
glutathione whose depletion may also induce toxicity. While
oxidation of the TZD ring (Fig. 3, right side) may occur with other
TZD derivatives, the reactivity of the chromane residue (Fig. 3, left
MDA-MB-231
MCF-7
100
m
M
200 mM
5
6
8
64.3 1.6
42.2 5.0
0.0 0.2
49.3 7.1
0.0 0.3
7.6 1.5
24.5 1.9
57.9 0.8
4.8 0.2
8.7 5.1
88.1 13.9
69.3 4.7
46.9 1.0
100.0 7.0
62.5 5.2
0.0 0.2
75.5 8.0
0.0 0.1
146.7 5.7
79.3 8.2
84.5 4.3
85.1 9.3
82.6 6.0
83.2 19.0
40.8 4.6
65.1 6.5
110.0 5.8
88.8 9.3
52.2 4.9
62.8 4.6
42.1 7.0
127.1 5.9
74.7 2.2
54.4 3.8
80.3 2.0
82.7 8.5
79.9 5.8
18.0 1.2
37.8 1.2
103.4 14.5
62.7 5.9
22.5 5.1
43.1 3.6
30.3 1.0
15
17
18
25
33
34
35
TGZ
2.7 0.4
43.9 9.3
85.7 12.6
5.2 2.1
35.0 2.1
96.7 6.2
84.0 6.6
23.8 7.3
D
31
2TGZ
a
Surviving breast cancer cells SEM at 10 mM concentration, as compared to
non-treated cells.
Surviving non-malignant hepatocytes in primary cultures SEM at two con-
centrations, as compared to non-treated cells.
b

132
A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
Fig. 2. Viability of two breast cancer cell lines subjected to the prepared compounds, evaluated by MTS assays in 10% FCS-containing RPMI medium after 72 h of drug treatment
(10
M). Column, mean; bars SEM (N ¼ 3).
m
side) is assumed to explain the specific hepatotoxicity of TGZ. The
liver injury induced by TGZ is reported to be idiosyncratic and not
reproducible in animals [2].Yokoi [26] assumed it is linked to the
large interindividual variability of CYP3A4 activities. This variability
may explain the very low toxicity we observed for 5 and 34 on
primary cultured human hepatocytes despite the presence of a 6-
hydroxy moiety on the chromane core. These considerations in
mind and in order to avoid the potential risk of liver injury, we
decided to develop only compounds which cannot lead to quinone-
type metabolites i.e. devoid of the 6-hydroxy moiety. Since 17 and
18 are devoid of this moiety and showed a very good activity/he-
patocyte viability profile, they were selected for further studies.
Since the tumor growth relies on the cell ability to proliferate on
limited nutriment conditions, we measured their IC50 in limited
(1%) FCS condition, instead of usual 10%. IC50 of 17 and 18 were
acute toxicity of the compound since they only differ in this moiety.
This could be rationalized by the fact that the TZD moiety of TGZ
was reported to be metabolized into isocyanate derivative which in
turn traps cytoprotective glutathione (Fig. 3) [24]. N-methylation
should prevent the formation of this deleterious intermediate and
this could also account for the high hepatocyte viability of 5,
compared to
4. Conclusion
We prepared a series of new compounds based on a
D2TGZ.
D
2TGZ
template, with alkylation of the thiazolidinedione moiety and/or
alkylation of the chromane template after removal of the hydroxyl
group. Other compounds with a permuted structure were also
synthesized. Many compounds exhibited anti-proliferative activity
towards various cancer cell lines with viabilities less than 20% at
shown to be 6.1 0.4 and 3.6 0.7
mM respectively towards MCF-7
and 6.7 0.7 and 1.5 0.1 M respectively towards MDA-MB-231.
In order to design future in vivo efficacy testing, acute toxicity
was evaluated on a murine model. Compounds 17, 18, and reference
m
10
human non-malignant hepatocytes with viabilities at or over 80% at
200 M. Two compounds displayed low in vivo toxicity in a rodent
mM. Furthermore, many of them exhibited low toxicity towards
m
D
2TGZ were injected intravenously to female BALBc/AnNHsd mice
(see Supplementary data). Maximum Tolerated Dose (MTD) was
inferior to 34.0 mg/kg for 2TGZ. It was equal to this dose for 18 and
model with MTD at 34.0 and 65.5 mg/kg. These promising data let
us envision further studies dealing with these compounds or
related derivatives.
D
to 65.5 mg/kg for 17 (solubility limit of 17 in the mixture of solvents
used). Thus, it appears that N-methylation decreases the in vivo
Scheme 4. Synthesis of permuted 34 and derivatives. Reagents and conditions: (a) 32,
K2CO3; (b) Cinnamyl bromide, K2CO3; (c) 40-Bromomethyl-biphenyl-2-carboxylic acid
tert-butyl ester, K2CO3; (d) TFA.
Scheme 5. Other permuted derivatives. Reagents and conditions: (a) dichlor-
omethoxymethane, TiCl4; (b) TZD, piperidine, benzoic acid; (c) K2CO3, PhCH2Br; (d)
DIBAL-H, hexane, ꢀ78 ꢁC; (e) Boc2O, DMAP; (f) TFA.

A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
133
Fig. 3. Metabolic products generated from TGZ by CYP2C8 and CYP3A4 oxidation [24].
5. Experimental protocols
for 3 h and then stirred at room temperature overnight. It was
diluted with EtOAc (30 mL), then washed with distilled water
(5 ꢂ 20 mL). The solvent was dried (Na2SO4) then evaporated. The
residue was crystallized in EtOAc. The crystals were filtered then
washed with cooled EtOAc (8 mL) and with a 1:1 mixture of EtOAc
and hexane (2 ꢂ 8 mL) to give 266 mg (0.42 mmol, 85% yield) of
5.1. Chemistry
5.1.1. General methods
Solvents and liquid reagents were purified and dried according
to recommended procedures. Chemical reagents were purchased
from SigmaeAldrich, Fluka, Alfa Aesar or TCI Europe and were used
as received. Troglitazone used for anti-proliferative and hepato-
toxicity assays was purchased from SigmaeAldrich. Previously
described starting compounds (1, 6, 9, and 32) were prepared as
already reported [16] from racemic trolox® purchased from Sig-
maeAldrich. Analytical thin-layer chromatography was performed
with silica gel 60 F254, 0.25 mm pre-coated TLC plates (Merck).
Compounds were visualized using UV light (254 nm) and a solution
of cerium sulfate tetrahydrate and phosphomolybdic acid in 10%
aqueous sulfuric acid as developing agent. Column chromatogra-
white crystals. M.p. 188 ꢁC. IR (film)
n
(cmꢀ1): 2980, 2931, 1750,
1683. 1H NMR (CDCl3):
d 1.42 (s, 3H, CH3), 1.55 (s, 9H, tBu), 1.90 (m,
1H, CH2), 2.04 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.12
(m,1H, CH2), 2.63 (m, 2H, CH2), 3.94, 4.04 (AB system, J ¼ 9.3 Hz, 2H,
OCH2), 4.90 (s, 2H, NCH2), 7.00 (d, J ¼ 8.8 Hz, 2H, Harom), 7.33 (m, 3H,
H
arom), 7.44 (m, 4H, Harom), 7.86 (s, 1H, CH]C). 13C NMR (CDCl3):
d
11.9 (CH3), 12.0 (CH3), 12.8 (CH3), 20.3 (CH2), 22.9 (CH3), 27.9 (tBu),
28.5 (CH2), 45.3 (NCH2), 72.9, 74.5, 82.9, 115.7, 117.3, 118.7, 123.3,
125.6, 126.2, 127.6, 128.3, 128.9, 129.0, 132.3, 134.1, 135.4, 141.5,
148.9, 152.4, 161.1, 166.5, 168.9. ESI-MS (pos. mode): m/z ¼ 652.39
[MþNa]þ. Anal. Calcd for C36H39NO7S (629.76): C, 68.66; H, 6.24; N,
2.22. Found: C, 68.67; H, 6.16; N, 2.23.
phies were performed using Merck SI 60 (63e200 mM) silica gel.
NMR spectra were recorded at 303K on a Bruker DPX250 (250 MHz
for 1H and 62.9 MHz for 13C) spectrometer. The chemical shifts are
reported in ppm (d) relative to residual solvent peak [27]. Mass
5.1.3. ( ) 3-Benzyl-(5Z)-[4-(6-hydroxy-2,5,7,8-
tetramethylchroman-2-ylmethoxy)benzylidene]-thiazolidine-2,4-
dione (3)
spectra (MS) were recorded on a micrOTOFq (Bruker) ESI/QqTOF
spectrometer. Melting points (M.p.) were determined with a Kofler
bench and are uncorrected. Infrared spectra (IR) were recorded on a
Perkin Elmer PE 850 spectrophotometer using a thin film deposi-
tion on NaCl window or KBr pellets. Elemental analyses were per-
formed using a Thermofinnigan Flash EA 1112 apparatus.
To a solution of 2 (200 mg, 0.32 mmol) in CH2Cl2 (6 mL) was
added trifluoroacetic acid (2 mL). The solution was stirred at room
temperature for 0.5 h. The solution was concentrated under vac-
uum until dryness. The residue was dissolved in EtOAc (30 mL) and
the solution was washed with a 5% aqueous NaHCO3 solution
(2 ꢂ 10 mL) and distilled water (2 ꢂ 10 mL), dried (Na2SO4) and
concentrated. The residue was recrystallized with a 1:1 mixture of
EtOAc and hexane to give 83 mg (0.16 mmol, 49% yield) of white
5.1.2. ( ) Carbonic acid 2-[4-(3-benzyl-2,4-dioxo-thiazolidin-(5Z)-
ylidenemethyl)phenoxymethyl]-2,5,7,8-tetramethylchroman-6-yl
tert-butyl ester (2)
powder. M.p. 137 ꢁC. IR (film)
NMR (CDCl3): 1.42 (s, 3H, CH3), 1.91 (m, 1H, CH2), 2.08 (s, 3H, CH3),
n
(cmꢀ1): 3497, 2924, 1735, 1678. 1H
To a solution of 1 [16] (270 mg, 0.5 mmol) in DMF (3 mL) were
d
added K2CO3 (90 mg, 0.65 mmol) and benzylbromide (65
mL,
2.10 (m, 1H, CH2), 2.11 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.65 (m, 2H,
CH2), 3.96, 4.04 (AB system, J ¼ 9.5 Hz, 2H, OCH2), 4.23 (s, 1H, OH),
0.55 mmol). The reaction mixture was heated at 80 ꢁC under argon

134
A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
4.89 (s, 2H, NCH2), 7.00 (d, J ¼ 8.6 Hz, 2H, Harom), 7.32 (m, 3H, Harom),
7.43 (m, 4H, Harom), 7.85 (s, 1H, CH]C). 13C NMR (CDCl3):
11.4
(20 mL) and distilled water (20 mL), dried (MgSO4) and the solvent
was removed under vacuum to give a yellowish oil which was
purified by precipitation in cold MeOH to afford 7 (223 mg,
d
(CH3), 12.0 (CH3), 12.4 (CH3), 20.4 (CH2), 22.7 (CH3), 28.9 (CH2), 45.3
(NCH2), 72.9, 74.1, 115.7, 117.3, 118.7, 121.5, 122.9, 126.2, 128.3, 128.9,
129.0,132.3,134.1,135.4,145.1,145.2,161.1,166.5,168.1. ESI-MS (pos.
mode): m/z ¼ 530.32 [MþH]þ, 552.34 [MþNa]þ. Anal. Calcd for
0.32 mmol, 85%) as a colorless solid. M.p. 116e118 ꢁC. IR (film)
n
(cmꢀ1): 2930, 1739, 1684. 1H NMR (CDCl3):
d 1.43 (s, 3H, CH3),
1.29e1.66 (m, 8H, linker-CH2), 1.44 (s, 9H, etBu), 1.68e1.86 (m, 2H,
linker-CH2), 1.86e1.94 (m, 1H, chromane 3-HaHb), 1.96 (s, 3H, CH3),
2.00 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.03e2.17 (m, 1H, chromane 3-
HaHb), 2.52e2.70 (m, 4H, chromane 4-H2, linker-CH2), 3.11 (q, 2H,
J ¼ 6.4 Hz, linker-CH2), 3.24 (s, 3H, NCH3), 3.95, 4.05 (AB system,
J ¼ 9.5 Hz, 2H, CH2O), 4.51 (s, br, 1H, NHBoc), 7.01 (d, J ¼ 8.8 Hz, 2H,
C
31H31NO5S (529.65): C, 70.30; H, 5.90; N, 2.64. Found: C, 70.46; H,
5.94; N, 2.74.
5.1.4. ( ) Carbonic acid tert-butyl ester 2,5,7,8-tetramethyl-2-[4-
(3-methyl-2,4-dioxothiazolidin-(5Z)-ylidenemethyl)
phenoxymethyl]-chroman-6-yl ester (4)
H
arom), 7.45 (d, J ¼ 8.8 Hz, 2H, Harom), 7.86 (s, 1H, CH]C). 13C NMR
To a solution of 1 [16] (270 mg, 0.5 mmol) in DMF (3 mL) was
(CDCl3): d 11.9, 12.2, 13.0, 20.1, 22.7, 25.0, 26.6, 27.9, 28.3, 28.4, 28.9,
added K2CO3 (90 mg, 0.65 mmol) and methyliodide (37
m
L,
29.2, 30.0, 34.0, 40.6, 72.7, 74.4, 77.2, 114.7, 115.5, 117.2, 118.6, 123.1,
125.1,126.1, 127.2,132.2,133.6,141.0,148.7, 160.9,166.6,168.2,172.2.
Anal. Calcd for C38H50N2O8S (694.88): 65.68; H, 7.25; N, 4.03.
Found: C, 65.70; H, 7.11; N, 3.89.
0.6 mmol) and the suspension was heated at 80 ꢁC for 3 h under
argon. The mixture was diluted with EtOAc (30 mL) and washed
with distilled water (5 ꢂ 20 mL). The organic phase was dried
(Na2SO4) and the solvent was evaporated. The residue was purified
by column chromatography (eluent: hexane/CH2Cl2, 50:50 /
20:80) to give an oily compound which was dissolved in Et2O fol-
lowed by apparition of crystals which were filtered and washed
with a 1:1 mixture of hexane and Et2O to give 137 mg (0.25 mmol,
5.1.7. ( ) 8-Amino-octanoic acid 2,5,7,8-tetramethyl-2-[4-(3-
methyl-2,4-dioxothiazolidin-(5Z)-ylidenemethyl)phenoxymethyl]
chroman-6-yl ester trifluoroacetic acid salt (8)
To an ice-cooled solution of 7 (157 mg, 0.226 mmol) in dry
CH2Cl2 (2 mL) was added trifluoroacetic acid (1 mL). The reaction
was allowed to come at room temperature and stirred for 3 h. The
solvent was evaporated and the excess of TFA was driven off by co-
evaporation with MeOH (5 times). The yellowish solid so obtained
was washed with Et2O to afford 8 (95 mg, 0.13 mmol, 59%) as a
50% yield) of white crystals. M.p. 166 ꢁC. IR (film)
n
(cmꢀ1): 2980,
2933, 1751, 1686. 1H NMR (CDCl3):
d
1.43 (s, 3H, CH3), 1.55 (s, 9H,
tBu), 1.90 (m, 1H, CH2), 2.04 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.08 (s,
3H, CH3), 2.11 (m, 1H, CH2), 2.64 (m, 2H, CH2), 3.24 (s, 3H, NCH3),
3.95,4.05 (AB system, J ¼ 9.4 Hz, 2H, OCH2), 7.01 (d, J ¼ 8.8 Hz, 2H,
H
arom), 7.46 (d, J ¼ 8.8 Hz, 2H, Harom), 7.86 (s, 1H, CH]C). 13C NMR
slightly yellow solid. M.p.144e146 ꢁC. IR (film)
n
(cmꢀ1): 2933, 1741,
(CDCl3):
d
11.9 (CH3), 12.0 (CH3), 12.8 (CH3), 20.2 (CH2), 22.9 (CH3),
1681. 1H NMR (CDCl3):
d
1.29e1.40 (m, 4H, linker-CH2), 1.42 (s, 3H,
27.8 (tBu), 28.0 (NCH3), 28.4 (CH2), 72.8, 74.5, 82.9,115.7,117.3,118.7,
123.3, 125.5, 126.2, 127.6, 132.3, 133.8, 141.5, 148.9, 152.4, 161.0,
166.8, 168.3. ESI-MS (pos. mode): m/z ¼ 576.28 [MþNa]þ. Anal.
Calcd for C30H35NO7S (553.67): C, 65.08; H, 6.37; N, 2.53. Found: C,
65.10; H, 6.37; N, 2.53.
CH3), 1.55e1.83 (m, 4H, linker-CH2), 1.84e1.94 (m, 1H, chromane 3-
HaHb), 1.95 (s, 3H, CH3), 1.99 (s, 3H, CH3), 2.05 (s, 3H, CH3),
2.00e2.24 (m, 3H, chromane 3-HaHb, linker-CH2), 2.50e2.70 (m,
4H, chromane 4-H2, linker-CH2), 2.79e2.97 (m, 2H, linker-CH2),
3.23 (s, 3H, NCH3), 3.95, 4.05 (AB system, J ¼ 9.3 Hz, 2H, CH2O), 7.00
(d, J ¼ 8.7 Hz, 2H, Harom), 7.44 (d, J ¼ 8.7 Hz, 2H, Harom), 7.85 (br s,
5.1.5. ( ) (5Z)-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-
ylmethoxy)benzylidene]-3-methyl-thiazolidine-2,4-dione (5)
4H, NHþ3 , CH]C). 13C NMR (CDCl3):
d 11.8, 12.1, 12.9, 20.1, 22.6, 24.7,
25.9, 27.3, 27.8, 28.3, 28.5, 28.8, 33.8, 72.8, 74.4, 115.5, 117.2, 118.6,
123.1, 125.1, 126.1, 127.1, 130.9, 132.1, 133.6, 141.0, 148.7, 160.9, 166.6,
168.1, 172.4. ESI-MS (pos. mode): m/z ¼ 595.14 [MþH]þ. Anal. Calcd
for C35H43F3N2O8S (708.78): C, 59.31; H, 6.11; N, 3.95. Found: C,
58.93; H, 6.06; N, 3.81.
To a solution of 4 (60 mg, 0.11 mmol) in CH2Cl2 (6 mL) was added
trifluoroacetic acid (2 mL) and the solution was stirred at room
temperature for 1 h. The mixture was concentrated to dryness. The
residue was dissolved in EtOAC (30 mL) and the solution was
washed with a 5% aqueous NaHCO3 solution (2 ꢂ 10 mL) and
distilled water (2 ꢂ 10 mL), dried (Na2SO4) and concentrated. The
residue was purified by column chromatography (eluent: hexane/
EtOAc, 8:2) to give a residue which after recrystallization in EtOAc
afforded 33 mg (0.07 mmol, 67% yield) of yellow crystals. M.p.
5.1.8. ( ) 6-(6-Bromohexanoyl)-2,5,7,8-tetramethylchroman-2-
carboxylic acid ethyl ester (10)
Preparation of the intermediate acyl chloride: a solution of 1-
Bromohexanoic acid (2.02 g, 10.3 mmol) and thionyl chloride
(2.2 mL, 30.3 mmol) in dry CH2Cl2 (10 mL) was refluxed under
argon for 4 h. The solvent was removed under vacuum for several
hours to remove the excess of thionyl chloride. The colorless oil
obtained was directly used in the next step without further
purification.
FideleCraft reaction: to a suspension of the above acyl chloride
and AlCl3 (1.44 g,10.8 mmol) at 0 ꢁC in dry CH2Cl2 (3 mL) was slowly
added a solution of 9 [16] (586 mg, 2.23 mmol) in dry CH2Cl2 (4 mL).
The reaction was stirred under argon at 0 ꢁC for 1 h and then at
room temperature overnight. The flask was periodically purged
with argon to drive off the HCl. The reaction was cautiously
quenched with cold distilled water (6 mL) and concentrated HCl
(2 mL). The organic phase was separated and washed with 5%
aqueous NaHCO3 solution (10 mL), dried (MgSO4) and the solvent
was removed under vacuum to give a yellowish oil which was
purified by column chromatography (eluent: hexane/EtOAc, 95:5)
154 ꢁC. IR (film)
1.42 (s, 3H, CH3), 1.93 (m, 2H, CH2), 2.08 (s, 3H, CH3), 2.12 (s, 3H,
n
(cmꢀ1): 3446, 2924, 1735, 1681. 1H NMR (CDCl3):
d
CH3), 2.16 (s, 3H, CH3), 2.66 (m, 2H, CH2), 3.24 (s, 3H, NCH3),
3.96,4.04 (AB system, J ¼ 9.2 Hz, 2H, OCH2), 7.01 (d, J ¼ 8.8 Hz, 2H,
H
arom), 7.45 (d, J ¼ 8.8 Hz, 2H, Harom), 7.87 (s, 1H, CH]C). 13C NMR
(CDCl3):
d
11.4 (CH3), 12.0 (CH3), 12.4 (CH3), 20.4 (CH2), 22.7 (CH3),
28.0 (NCH3), 28.9 (CH2), 73.0, 74.1, 115.7, 117.3, 118.7, 118.8, 121.5,
122.9, 126.2, 132.3, 133.8, 145.1, 145.2, 161.1, 166.8, 168.3. ESI-MS
(pos. mode): m/z ¼ 454.03 [MþH]þ, 476.00 [MþNa]þ. Anal. Calcd
for C25H27NO5S (453.55): C, 66.20; H, 6.00; N, 3.09. Found: C, 65.85;
H, 6.13; N, 3.24.
5.1.6. ( ) 8-tert-Butoxycarbonylamino-octanoic acid 2,5,7,8-
tetramethyl-2-[4-(3-methyl-2,4-dioxo-thiazolidin-(5Z)-
ylidenemethyl)phenoxymethyl]chroman-6-yl ester (7)
To a solution of 6 [16] (259 mg, 0.38 mmol) in dry DMF (4 mL)
were added K2CO3 (68 mg, 0.49 mmol) and methyliodide (28
mL,
to afford 10 (690 mg,1.57 mmol, 70%) as a colorless liquid. IR (film)
(cmꢀ1): 2976, 2934, 2862, 1749, 1730, 1697. 1H NMR (CDCl3):
1.19
(t, J ¼ 7.1 Hz, 3H, COOCH2CH3),1.47e1.58 (m, 2H, linker-CH2),1.61 (s,
n
0.45 mmol). The mixture was reacted under argon at 80 ꢁC for 4 h.
The mixture was diluted with EtOAc (30 mL), washed with brine
d

A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
135
3H, CH3), 1.65e1.78 (m, 2H, linker-CH2), 1.82e1.95 (m, 3H, chro-
mane 3-HaHb, linker-CH2), 1.98 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.15 (s,
3H, CH3), 2.36e2.62 (m, 3H, chromane 4-H2, chromane 3-HaHb),
2.67 (t, J ¼ 7.2 Hz, 2H, linker-CH2C]O), 3.42 (t, J ¼ 6.7 Hz, 2H, linker-
CH2Br), 4.12 (dq, Ja ¼ 7.1 Hz, Jb ¼ 1.3 Hz, 2H, COOCH2CH3). 13C NMR
d 1.23 (s, 3H, CH3), 1.33e1.58 (m, 6H, linker-CH2), 1.45 (s, 9H, etBu),
1.56e1.80 (m, 4H, chromane 3-HaHb, linker-CH2, CH2OH), 1.92e2.08
(m, 1H, chromane 3-HaHb), 2.12 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.20
(s, 3H, CH3), 2.54e2.73 (m, 4H, chromane 4-H2, linker-CH2),
3.07e3.16 (m, 2H, linker-CH2), 3.55e3.70 (m, CH2OH), 4.46 (br s,1H,
(CDCl3):
d
11.5, 14.2, 15.7, 16.8, 20.6, 22.8, 25.4, 27.9, 30.4, 32.9, 33.7,
NHBoc). 13C NMR (CDCl3):
d 12.2, 15.1, 16.0, 20.6, 20.7, 26.8, 28.0,
45.6, 61.3, 77.5, 117.2, 123.0, 128.0, 129.6, 135.6, 151.8, 173.5, 211.5.
28.6, 30.0, 30.1, 30.2, 30.3, 40.8, 69.5, 75.3, 79.2, 117.0, 122.2, 131.1,
131.7, 133.4, 149.0, 156.1. ESI-MS (pos. mode): m/z ¼ 442.30
[MþNa]þ. Anal. Calcd for C25H41NO4 (419.60): C, 71.56; H, 9.85; N,
3.34. Found: C, 71.49; H, 10.20; N, 3.36.
ESI-MS (pos. mode): m/z ¼ 461.13 [MþNa]þ. Anal. Calcd for
C
22H31BrO4 (439.38): 60.14; H, 7.11. Found: C, 60.21; H, 7.13.
5.1.9. ( ) [6-(6-Bromohexyl)-2,5,7,8-tetramethylchroman-2-yl]
methanol (11)
5.1.12. ( ) {6-[2-(4-Formyl-phenoxymethyl)-2,5,7,8-
To a suspension of LiAlH4 (176 mg, 4.64 mmol) in dry Et2O
(9 mL) under argon was slowly added a solution of AlCl3 (413 mg,
3.10 mmol) in dry Et2O (6 mL). Five minutes later, a solution con-
taining 10 (680 mg, 1.55 mmol) and AlCl3 (206 mg, 1.55 mmol) in
dry Et2O (12 mL) was added. The mixture was stirred under argon
at room temperature for 2 h and then quenched with cold water
(24 mL) and 6 M aqueous H2SO4 solution. The organic layer was
separated and the aqueous phase was extracted with EtOAc
(2 ꢂ 15 mL). The combined organic layers were washed with 2 M
aqueous Na2CO3 solution (10 mL), dried (MgSO4) and the solvent
was removed under vacuum to give 11 (592 mg, 1.54 mmol, 98%
yield) as a colorless liquid which was directly used in the next step
tetramethylchroman-6-yl]hexyl}carbamic acid tert-butyl ester (14)
Preparation of the triflate intermediate: to an ice-cooled solution
of anhydrous pyridine (430
mL, 5.39 mmol) in dry CH2Cl2 (5 mL),
was added dropwise trifluoromethanesulfonic anhydride (210
mL,
1.26 mmol) under argon. A solution of 13 (377 mg, 0.90 mmol) in
dry CH2Cl2 (5 mL) was added to the reaction mixture. The solution
was stirred at 0 ꢁC for 20 min and the solvent was evaporated. The
excess of pyridine was co-evaporated twice with toluene and the
residue so obtained was dissolved in EtOAc (25 mL). The organic
layer was washed with 5% aqueous NaHCO3 solution (2 ꢂ 15 mL)
and brine (20 mL), dried (MgSO4) and the solvent was removed
under vacuum to give a brown oily residue.
without further purification. 1H NMR (CDCl3):
d
1.24 (s, 3H, CH3),
Condensation with 4-hydroxybenzaldehyde: to a solution of the
above triflate in dry DMF (3 mL)were added4-hydroxybenzaldehyde
(164 mg, 1.35 mmol) and K2CO3 (232 mg, 1.68 mmol). The reaction
mixture was stirred under argon at room temperature for two days,
and then water (8 mL) was added. The resulting suspension was
extracted with EtOAc (2 ꢂ 20 mL). The organic layer was washed 5%
aqueous NaHCO3 solution (2 ꢂ 15 mL) and brine (20 mL), dried
(MgSO4) and the solvent was removed under vacuum to give a
yellowish oilwhich waspurifiedbycolumn chromatography (eluent:
hexane/EtOAc, 9:1) to afford 14 (316 mg, 0.60 mmol, 67% yield) as a
1.38e1.57 (m, 6H, linker-CH2),1.68e1.80 (m,1H, chromane 3-HaHb),
1.81e2.09 (m, 4H, linker-CH2, chromane 3-HaHb, CH2OH), 2.13 (s,
3H, CH3), 2.17 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.56e2.74 (m, 4H,
chromane 4-H2, linker-CH2), 3.43 (t, J ¼ 6.8 Hz, 2H, linker-CH2), 3.63
(m, CH2OH). 13C NMR (CDCl3):
d 12.2, 15.1, 16.0, 20.68, 20.70, 28.0,
28.2, 39.4, 30.07, 30.10, 33.0, 34.1, 69.6, 75.3, 117.0, 122.2, 130.9,
131.7, 133.4, 149.0. ESI-MS (pos. mode): m/z ¼ 301.10 [MþNa]þ.
5.1.10. ( ) [6-(6-Azidohexyl)-2,5,7,8-tetramethylchroman-2-yl]
methanol (12)
white foam. M.p. 84e85 ꢁC. IR (film)
n
(cmꢀ1):3409, 2929, 2857,1686.
A suspension of 11 (592 mg, 1.54 mmol) and NaN3 (1.00 g,
15.4 mmol) in dry DMF (15 mL) was heated at 80 ꢁC for 6 h. The
mixture was cooled to room temperature, then diluted with EtOAc
(60 mL) and washed with brine (2 ꢂ 50 mL) and distilled water
(50 mL), dried (MgSO4) and the solvent was removed under vac-
uum to give 12 (532 mg, 1.54 mmol, 98%) as a colorless oil, which
1H NMR (CDCl3):
d
1.43 (s, 3H, CH3), 1.33e1.44 (m, 4H, linker-CH2),
1.44 (s, 9H, etBu), 1.50e1.62 (m, 4H, linker-CH2), 1.84e1.97 (m, 1H,
chromane 3-HaHb), 2.07e2.17 (m,1H, chromane 3-HaHb), 2.09 (s, 3H,
CH3), 2.15 (s, 3H, CH3), 2.20 (s, 3H, CH3), 2.52e2.72 (m, 4H, chromane
4-H2, linker-CH2), 3.10 (m, 2H, linker-CH2), 3.98, 4.08 (AB system,
J ¼ 9.3 Hz, 2H, CH2O), 4.50 (br s, 1H, NHBoc), 7.03 (d, J ¼ 8.8 Hz, 2H,
was used in the next step without further purification. IR (film)
n
H
arom), 7.82 (d, J ¼ 8.8 Hz, 2H, Harom), 9.88 (s, 1H, CHO). 13C NMR
(cmꢀ1): 2931, 2857, 2095. 1H NMR (CDCl3):
d
1.23 (s, 3H, CH3),
(CDCl3): d 12.0, 14.9, 15.8, 20.6, 22.7, 26.7, 28.4, 28.7, 29.8, 30.0, 30.1,
1.37e1.52 (m, 6H, linker-CH2), 1.56e1.80 (m, 3H, chromane 3-HaHb,
linker-CH2), 1.82 (br s, CH2OH), 1.81e2.09 (m, 1H, chromane 3-
HaHb), 2.12 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.21 (s, 3H, CH3),
2.56e2.74 (m, 4H, chromane 4-H2, linker-CH2), 3.28 (t, J ¼ 7.5 Hz,
30.2, 40.6, 72.9, 74.0, 79.1, 115.0, 116.7, 122.2, 130.1, 131.0, 131.5, 131.9,
133.4, 148.9, 156.0, 164.1, 190.8. ESI-MS (pos. mode): m/z ¼ 546.33
[MþNa]þ. Anal. Calcd for C32H45NO5 (523.70): C, 73.39; H, 8.66; N,
2.67. Found: C, 73.49; H, 8.67; N, 2.78.
2H, linker-CH2), 3.55e3.69 (m, CH2OH). 13C NMR (CDCl3):
d 12.1,
14.9, 15.9, 20.6, 26.7, 27.9, 28.9, 29.7, 29.9, 30.0, 51.5, 69.4, 75.2,
116.9, 122.1, 130.8, 131.6, 133.3, 149.0. ESI-MS (pos. mode): m/
z ¼ 368.23 [MþNa]þ.
5.1.13. ( ) (6-{2-[4-(2,4-Dioxothiazolidin-(5Z)-ylidenemethyl)-
phenoxymethyl]-2,5,7,8-tetra-methylchroman-6-yl}-hexyl)
carbamic acid tert-butyl ester (15)
A solution of 14 (68 mg, 0.13 mmol), thiazolidinedione (31 mg,
5.1.11. ( ) [6-(2-Hydroxymethyl-2,5,7,8-tetramethylchroman-6-yl)
hexyl]carbamic acid tert-butyl ester (13)
0.26 mmol), piperidine (70 mL, 0.07 mmol), and benzoic acid
(80 mg, 0.07 mmol) in dry toluene (3 mL) was refluxed overnight
under argon. The reaction mixture was cooled to room tempera-
ture, diluted with EtOAc (10 mL), washed with 1 N HCl solution
(5 mL), 5% aqueous NaHCO3 solution (5 mL) and brine (5 mL), dried
(MgSO4), and the solvent was removed under vacuum to give a
yellowish oil which was purified by precipitation in cold MeOH to
afford 15 (66 mg, 0.10 mmol, 81%) as a slightly yellow solid. M.p.
A suspension of 12 (532 mg,1.54 mmol), Pd/C (53 mg) and Boc2O
(403 mg, 1.85 mmol) in dry MeOH (10 mL) was reacted overnight
under H2. The mixture was filtered on Celite® and the MeOH was
removed under vacuum. The mixture was dissolved with EtOAc
(20 mL) and washed with 5% aqueous citric acid solution
(2 ꢂ 15 mL), 5% aqueous NaHCO3 solution (2 ꢂ 15 mL), distilled
water (20 mL), dried (MgSO4), and the solvent was removed under
vacuum to give a yellowish oil which was purified by column
chromatography (eluent:hexane/EtOAc, 8:2) to afford 13 (452 mg,
1.08 mmol, 70% yield) as an amorphous solid. M.p. 64e65 ꢁC. IR
116e118 ꢁC. IR (film)
(CDCl3): 1.43 (s, 3H, CH3), 1.36e1.44 (m, 4H, linker-CH2), 1.45 (s,
n
(cmꢀ1): 2930, 2762, 1741, 1697, 1596. 1H NMR
d
9H, etBu), 1.55e1.69 (m, 4H, linker-CH2), 1.82e1.98 (m, 1H, chro-
mane 3-HaHb), 2.10e2.14 (m, 1H, chromane 3-HaHb), 2.09 (s, 3H,
CH3), 2.15 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.52e2.74 (m, 4H,
(film)
n
(cmꢀ1): 3394, 2971, 2930, 2857, 1693. 1H NMR (CDCl3):

136
A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
chromane 4-H2, linker-CH2), 3.06e3.18 (m, 2H, linker-CH2), 3.96,
4.06 (AB system, J ¼ 9.4 Hz, 2H, CH2O), 4.50 (br s, 1H, NHBoc), 7.01
(d, J ¼ 9.0 Hz, 2H, Harom), 7.43 (d, J ¼ 9.0 Hz, 2H, Harom), 7.80 (s, 1H,
evaporation with MeOH (5 times). The yellowish solid so obtained
was filtered and washed with Et2O to afford 18 (24 mg, 37.7 mol,
53% yield) as a light yellow solid. M.p. 146 ꢁC. IR (KBr) (cmꢀ1):
2927, 2857, 1736, 1686. 1H NMR (MeOD-d4):
1.40 (s, 3H, CH3),
m
n
CH]C), 8.41 (br s, 1H, NH). 13C (62.5 MHz in CDCl3):
d
12.0, 14.9,
d
15.8, 20.6, 22.7, 25.3, 26.7, 28.4, 28.7, 29.9, 30.0, 30.1, 30.2, 40.6, 72.9,
74.0, 115.6, 116.7, 119.4, 122.2, 125.8, 131.0, 131.6, 132.2, 133.4, 134.2,
148.9, 161.2, 166.7, 167.2. ESI-MS (pos. mode): m/z ¼ 645.30
[(MþNa)þ]. Anal. Calcd for C35H46N2O6S, 0.3H2O (523.70): C, 66.85;
H, 7.48; N, 4.45. Found: C, 66.83; H, 7.27; N, 4.47.
1.42e1.51 (m, 6H, linker-CH2), 1.60e1.73 (m, 2H, linker-CH2), 1.91
(m, 1H, chromane 3-HaHb), 2.01 (s, 3H, CH3), 2.03e2.13 (m, 1H,
chromane 3-HaHb), 2.15 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.58e2.73 (m,
4H, chromane 4-H2, linker-CH2), 2.92 (t, J ¼ 7.3 Hz, 2H, linker-CH2),
4.07 (s, 2H, CH2O), 7.06 (d, J ¼ 8.8 Hz, 2H, Harom), 7.48 (d, J ¼ 8.8 Hz,
2H, Harom), 7.73 (s, 1H, CH]C). 13C NMR (MeOD-d4):
d 12.2, 15.1,
5.1.14. ( ) (6-{2,5,7,8-Tetramethyl-2-[4-(3-methyl-2,4-
dioxothiazolidin-(5Z)-ylidenemethyl)-phenoxymethyl]chroman-6-
yl}-hexyl)carbamic acid tert-butyl ester (16)
To a solution of 15 (230 mg, 0.37 mmol) in dry DMF (3 mL) were
added K2CO3 (66 mg, 0.48 mmol) and methyliodide (28
16.0, 21.6, 22.6, 27.4, 28.7, 30.0, 30.6, 30.7, 31.1, 40.8, 74.0, 75.3,116.6,
118.0, 121.7, 123.1, 127.4, 131.7, 132.3, 133.3, 133.7, 134.0, 150.2, 162.5,
169.2,169.6. ESI-MS (pos. mode): m/z ¼ 523.27 [MþH]þ. Anal. Calcd
for C32H39F3N2O6S, 0.5H2O (645.73): C, 59.52; H, 6.24; N, 4.34.
Found: C, 59.26; H, 6.11; N, 4.26.
mL,
0.44 mmol). The mixture was reacted underargon at 80 ꢁC for 3 h. The
mixture was diluted with EtOAc (30 mL), washed with brine (20 mL)
and distilled water (20 mL), dried (MgSO4) and the solvent was
removed under vacuum to give a yellowish oil which was purified by
precipitation in cold MeOH to afford 16 (154 mg, 0.24 mmol, 65%
5.1.17. General procedure for the synthesis of compounds 19-24
Compounds 19 to 24 were prepared by a procedure reported by
Chen et al. [20]: A solution of benzaldehyde derivative (2.0 mmol),
2,4-thiazolidinedione (2.0 mmol) and
b-alanine (2.6 mmol) in
yield) as a colorless solid. M.p. 112e114 ꢁC. IR (film)
n
(cmꢀ1): 2930,
acetic acid (7 mL) was refluxed for three hours. The solution was
cooled to room temperature and distilled water (10 mL) was added.
The resulted precipitate was filtered, washed with cold acetic acid
and water, dried under vacuum to give the desired benzylidene-
thiazolidine-2,4-dione derivative which was used in the next step
without further purification.
Compounds 19, 20, 21, and 23 were already described by Chen
team [20]. Compounds 22 [28] and 24 [29] were previously ob-
tained by closely related procedures.
1736, 1685, 1597. 1H NMR (CDCl3):
d
1.43 (s, 3H, CH3), 1.36e1.44 (m,
4H, linker-CH2), 1.44 (s, 9H, etBu), 1.47e1.54 (m, 2H, linker-CH2),
1.55e1.65 (m, 2H, linker-CH2), 1.83e1.98 (m, 1H, chromane 3-HaHb),
2.05e2.17 (m, 1H, chromane 3-HaHb), 2.09 (s, 3H, CH3), 2.15 (s, 3H,
CH3), 2.19 (s, 3H, CH3), 2.54e2.71 (m, 4H, chromane 4-H2, linker-CH2),
3.12 (m, 2H, linker-CH2), 3.24 (s, 3H, NCH3), 3.95, 4.05 (AB system,
J ¼ 9.4 Hz, 2H, CH2O), 4.49 (br s, 1H, NHBoc), 7.01 (d, J ¼ 8.8 Hz, 2H,
H
arom), 7.45 (d, J ¼ 8.8 Hz, 2H, Harom), 7.86 (s, 1H, CH]C). 13C NMR
(CDCl3):
d 12.0, 14.9, 15.8, 20.6, 22.7, 26.7, 27.9, 28.4, 28.7, 29.8, 30.0,
30.1, 30.2, 40.6, 72.9, 74.0, 77.2, 115.5, 116.7, 118.6, 122.2, 126.0, 130.9,
131.5, 132.2, 133.4, 133.7, 148.9, 155.9, 161.0, 166.7, 168.1. ESI-MS (pos.
mode): m/z ¼ 659.32[MþNa]þ. Anal. Calcd for C36H48N2O6S (636.84):
C, 67.90; H, 7.60; N, 4.40. Found: C, 67.54; H, 7.54; N, 4.51.
5.1.18. General procedure for the synthesis of compounds 25e30
To a solution of the corresponding 5-benzylidene-thiazolidin-
2,4-dione (1.0 mmol) in dry DMF (3 mL) were added K2CO3
(1.3 mmol) and benzylbromide (1.1 mmol). The reaction was stirred
under argon at 80 ꢁC for 4 h and then allowed to come at room
temperature. Water (10 mL) was added and the solution was
extracted with EtOAc (3 ꢂ 15 mL). The combined organic layers
were dried (MgSO4) and the solvent was removed under vacuum to
give a yellowish oil which was purified by precipitation in Et2O to
give the desired compound as a colorless solid.
5.1.15. ( ) (5Z)-{4-[6-(6-Aminohexyl)-2,5,7,8-tetramethylchroman-
2-ylmethoxy]benzylidene}-3-methylthiazolidine-2,4-dione
trifluoroacetic acid salt (17)
To an ice-cooled solution of 16 (30 mg, 48.2 mmol) in dry CH2Cl2
(2 mL) was added trifluoroacetic acid (1 mL). The reaction was
allowed to come at roomtemperature and stirred for 3 h. The solvent
was evaporated and the excess of TFA was driven off by co-
evaporation with MeOH (5 times). The solid so obtained was
The syntheses of compounds 25e29 have been reported, using
similar protocols.
filtered and washed with Et2O to afford 17 (17 mg, 26.1
a colorless solid. M.p.164e165 ꢁC. IR (KBr) (cmꢀ1): 2931,1741,1679.
1H NMR (CDCl3):
1.42 (s, 3H, CH3), 1.28e1.57 (m, 6H, linker-CH2),
mmol, 54%) as
5.1.18.1. 3-Benzyl-(5Z)-(4-hydroxybenzylidene)thiazolidine-2,4-
n
dione (25) [30]. 1H NMR (DMSO-d6):
d
4.83 (s, 2H, CH2), 6.93 (d,
J ¼ 8.4 Hz, 2H, Harom), 7.33 (m, 5H, Harom), 7.50 (d, J ¼ 8.4 Hz, 2H,
arom), 7.87 (s, 1H, CH]C), 10.38 (s, 1H, OH). Anal. Calcd for
17H13NO3S (311.36): C, 65.58; H, 4.21; N, 4.50. Found: C, 65.53; H,
d
1.57e1.80 (m, 2H, linker-CH2), 1.91 (m, 1H, chromane 3-HaHb),
2.08e2.17 (m, 1H, chromane 3-HaHb), 2.08 (s, 3H, CH3), 2.13 (s, 3H,
CH3), 2.17 (s, 3H, CH3), 2.44e2.75 (m, 4H, chromane 4-H2, linker-
CH2), 2.95 (m, 2H, linker-CH2), 3.23 (s, 3H, NCH3), 3.95, 4.05 (AB
system, J ¼ 9.4 Hz, 2H, CH2O), 6.99 (d, J ¼ 8.0 Hz, 2H, Harom), 7.43 (d,
J ¼ 8.0 Hz, 2H, Harom), 7.85 (br s, 3H, CH]C, NH2). 13C NMR (DMSO-
H
C
4.21; N, 4.50.
5.1.18.2. 3-Benzyl-(5Z)-benzylidenethiazolidine-2,4-dione (26) [31,32].
1H NMR (CDCl3):
d
4.91 (s, 2H, CH2), 7.32 (m, 2H, Harom), 7.44 (m, 5H,
d6): d 11.9, 14.6, 15.5, 19.9, 21.5, 25.6, 27.0, 27.7, 27.8, 28.1, 28.9, 29.2,
Harom), 7.91 (s, 1H, CH]C). Anal. Calcd for C17H13NO2S (295.36): C,
29.5, 72.6, 73.9, 115.7, 116.5, 118.3, 120.9, 125.6, 130.0, 130.9, 132.1,
132.4, 132.5, 148.4, 160.6, 165.9, 167.4. ESI-MS (pos. mode): m/
z ¼ 537.29 [MþH]þ. Anal. Calcd for C33H41F3N2O6S, 0.5H2O (659.76):
C, 60.08; H, 6.42; N, 4.25. Found: C, 60.35; H, 6.38; N, 4.25.
69.13; H, 4.44; N, 4.74. Found: C, 68.90; H, 4.24; N, 4.78.
5.1.18.3. 3-Benzyl-(5Z)-(4-chlorobenzylidene)thiazolidine-2,4-dione
(27) [33]. 1H NMR (CDCl3):
H
C
d
4.90 (s, 2H, CH2), 7.28e7.38 (m, 3H,
arom), 7.39e7.49 (m, 6H, Harom), 7.84 (s, 1H, CH]C). Anal. Calcd for
17H12ClNO2S (329.80): C, 61.91; H, 3.67; N, 4.25. Found: C, 61.93; H,
5.1.16. ( ) (5Z)-{4-[6-(6-Aminohexyl)-2,5,7,8-tetramethylchroman-
2-ylmethoxy]benzylidene}-thiazolidine-2,4-dione trifluoroacetic
acid salt (18)
3.76; N, 4.27.
To an ice-cooled solution of 15 (44 mg, 70.6 mmol) in dry CH2Cl2
(2 mL) was added trifluoroacetic acid (1 mL). The reaction was
allowed to come at room temperature and stirred for 3 h. The
solvent was evaporated and the excess of TFA was driven off by co-
5.1.18.4. 3-Benzyl-(5Z)-(4-nitrobenzylidene)thiazolidine-2,4-dione
(28) [32]. 1H NMR (CDCl3):
d
3.86 (s, 3H, CH3), 4.90 (s, 2H, CH2), 6.98
(d, J ¼ 10.0 Hz, 2H, Harom), 7.34 (m, 3H, Harom), 7.44 (m, 4H, Harom),

A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
137
7.86 (s, 1H, CH]C). Anal. Calcd for C17H12N2O4S (340.35): C, 59.99;
H, 3.55; N, 8.23. Found: C, 59.94; H, 3.55; N, 8.14.
(30 mL). The solution was washed with 5% aqueous NaHCO3 solu-
tion (2 ꢂ 10 mL) and brine (2 ꢂ 10 mL), dried (MgSO4) and the
solvent was removed under vacuum to give a yellow matter which
was suspended in Et2O, and then sonicated. Resulting material was
filtered and washed with the same solvent to afford 34 (221 mg,
5.1.18.5. 3-Benzyl-(5Z)-(4-methoxybenzylidene)thiazolidine-2,4-
dione (29) [32]. 1H NMR (CDCl3):
d 3.86 (s, 3H, CH3), 4.90 (s, 2H,
CH2), 6.98 (d, J ¼ 10.0 Hz, 2H, Harom), 7.34 (m, 3H, Harom), 7.44 (m,
4H, Harom), 7.86 (s, 1H, CH]C). Anal. Calcd for C18H15NO3S (325.38):
C, 66.44; H, 4.65; N, 4.30. Found: C, 66.32; H, 4.73; N, 4.37.
0.50 mmol, 90% yield) as a yellow powder. M.p. 215 ꢁC. IR (KBr)
n
(cmꢀ1): 3448, 2933, 1736, 1677. 1H NMR (DMSO-d6):
d
1.14 (s, 3H,
CH3), 1.78 (m, 2H, CH2), 1.92 (s, 3H, CH3), 2.01 (s, 3H, CH3), 2.02 (s,
3H, CH3), 2.59 (m, 2H, CH2), 3.84 (s, 2H, CH2N), 6.92 (d, J ¼ 8.8 Hz,
2H, Harom), 7.40 (s,1H, OH), 7.50 (d, J ¼ 8.8 Hz, 2H, Harom), 7.85 (s,1H,
5.1.18.6. 3-Benzyl-(5Z)-(3,4,5-trimethoxybenzylidene)thiazolidine-
2,4-dione (30). M.p. 120e122 ꢁC. IR (film)
n
(cmꢀ1): 3002, 2940,
CH]C), 10.33 (br s, 1H, OH). 13C NMR (DMSO-d6):
d 11.6, 11.8, 12.7,
2838, 1740, 1683. 1H NMR (CDCl3):
CH2), 6.72 (s, 2H, Harom), 7.33 (m, 3H, Harom), 7.43 (m, 2H, Harom),
7.82 (s, 1H, CH]C). 13C NMR (CDCl3):
45.3, 56.2, 61.0, 107.5, 120.4,
d
3.90 (s, 9H, OCH3), 4.91 (s, 2H,
19.7, 21.9, 29.5, 48.8, 74.4, 116.0, 116.4, 116.6, 120.1, 121.3, 122.7,
123.9, 132.5, 133.3, 143.9, 145.4, 160.0, 166.1, 167.4. ESI-MS (pos.
mode): m/z ¼ 462.03 [MþNa]þ. Anal. Calcd for C24H25NO5S,
0.25H2O (444.02): C, 64.92; H, 5.79; N, 3.15. Found: C, 65.13; H,
5.85; N, 3.28.
d
128.3, 128.6, 128.7, 128.8, 134.1, 135.1, 140.3, 153.6, 166.0, 167.6. ESI-
MS (pos. mode): m/z
¼
408.09 [MþNa]þ. Anal. Calcd for
C
20H19NO5S (385.43): C, 62.32; H, 4.97; N, 3.63. Found: C, 62.40; H,
4.99; N, 3.67.
5.1.21. (5Z)-(4-hydroxybenzylidene)-3-(3-phenylallyl)thiazolidine-
2,4-dione (35)
5.1.19. ( ) Carbonic acid tert-butyl ester 2-[(5Z)-(4-
hydroxybenzylidene)-2,4-dioxothiazolidin-3-ylmethyl]-2,5,7,8-
tetramethylchroman-6-yl ester (33)
Preparation of triflate 32: to an ice-cooled solution of anhydrous
pyridine (1.4 mL, 12.80 mmol) in dry CH2Cl2 (10 mL), was added
A suspension of 19 (305 mg, 1.38 mmol), cinnamyl bromide
(287 mg, 1.51 mmol) and K2CO3 (247 mg, 1.79 mmol) in dry DMF
(6 mL) was stirred at 80 ꢁC overnight. The mixture was diluted with
EtOAc (30 mL), washed with distilled water (3 ꢂ 20 mL), dried
(MgSO4) and the solvent was removed under vacuum to give a
yellowish oil which was purified by precipitation in CH2Cl2 to afford
35 (137 mg, 0.41 mmol, 29% yield) as a colorless solid. M.p.
dropwise trifluoromethanesulfonic anhydride (522
under argon. A solution of Carbonic acid tert-butyl ester 2-
hydroxymethyl-2,5,7,8-tetramethylchroman-6-yl ester [16]
mL, 3.15 mmol)
114e116 ꢁC. IR (KBr) (cmꢀ1): 2950,1734,1681. 1H NMR (DMSO-d6):
n
(730 mg, 2.17 mmol) in dry CH2Cl2 (5 mL) was added to the reac-
tion mixture. The solution was stirred at 0 ꢁC for 20 min and the
solvent was evaporated. The excess of pyridine was co-evaporated
twice with toluene and the residue so obtained was dissolved in
EtOAc (50 mL). The organic layer was washed with 5% aqueous
NaHCO3 solution (2 ꢂ 30 mL) and brine (20 mL), dried (MgSO4) and
the solvent was removed under vacuum to give a yellow oily
residue.
d
4.43 (d, J ¼ 5.6 Hz, 2H, eCH2), 6.23e6.37 (m,1H, CH2CH]), 6.60 (d,
J ¼ 16.0 Hz,1H, PhCH]), 6.95 (d, J ¼ 8.5 Hz, 2H, Harom), 7.19e7.40 (m,
3H, Harom), 7.41e7.59 (m, 4H, Harom), 7.88 (s, 1H, CH]C).13C NMR
(DMSO-d6): d 43.4,115.5, 117.2, 122.5, 123.1, 124.3,128.3,131.1, 132.4,
132.9, 134.0, 136.3, 160.6, 166.0, 167.7. ESI-MS (neg. mode): m/
z ¼ 336.07 [MꢀH]ꢀ. Anal. Calcd for C19H15NO3S (337.39): C, 67.64; H,
4.48; N, 4.15. Found: C, 67.25; H, 4.55; N, 4.03.
Condensation with 19: to a solution of the above triflate in dry
DMF (6 mL) were added 19 (456 mg, 2.06 mmol) and K2CO3
(378 mg, 2.39 mmol). The reaction mixture was stirred under argon
at room temperature for two days, and then water (30 mL) was
added. The resulting suspension was extracted with EtOAc
(2 ꢂ 50 mL). The organic layer was washed with 5% aqueous
NaHCO3 solution (2 ꢂ 30 mL) and brine (20 mL), dried (MgSO4) and
the solvent was removed under vacuum to give an orange foam
which was purified by column chromatography (eluent: hexane/
EtOAc, 9:1 /8:2) to give a yellow foam which was suspended in an
8:2 mixture of hexane and EtOAc, and then sonicated. Resulting
material was filtered and washed with the same mixture of solvent
to afford 33 (462 mg, 0.86 mmol, 42% yield) as colorless crystals.
5.1.22. 40-[(5Z)-(4-hydroxybenzylidene)-2,4-dioxothiazolidin-3-
ylmethyl]biphenyl-2-carboxylic acid tert-butyl ester (36)
To a solution of 19 (519 mg, 2.20 mmol) in dry DMF (10 mL) were
added K2CO3 (383 mg, 2.8 mmol) and 40-Bromomethyl-biphenyl-2-
carboxylic acid tert-butyl ester [21] (741 mg, 2.1 mmol). The reac-
tion was stirred under argon at 80 ꢁC for 5 h and then allowed to
come at room temperature. Distilled water (10 mL) was added and
the solution was extracted with EtOAc (3 ꢂ 15 mL). The combined
organic layers were dried (MgSO4) and the solvent was removed
under vacuum to give a yellowish oil which was purified by column
chromatography (eluent: hexane/EtOAc, 7:3) to give 36 (528 mg,
1.08 mmol, 52% yield) as a colorless solid. M.p. 118e120 ꢁC. IR (film)
n
(cmꢀ1): 3374, 2971, 1733, 1681. 1H NMR (CDCl3):
d 1.21 (s, 9H, t-
M.p.174 ꢁC. IR (film)
(CDCl3): 1.24 (s, 3H, CH3), 1.56 (s, 9H, tBu), 1.83 (m, 2H, CH2), 2.04
n
(cmꢀ1): 3394, 2982, 2934,1744,1686. 1H NMR
Bu), 4.95 (s, 2H, CH2), 5.40 (s, 1H, OH), 6.91 (d, J ¼ 8.7 Hz, 2H, Harom),
d
7.24e7.32 (m, 3H, Harom), 7.34e7.52 (m, 6H, Harom), 7.78 (d,
(s, 3H, CH3), 2.07 (s, 6H, CH3 ꢂ 2), 2.66 (m, 2H, CH2), 3.81 (br s, 2H,
J ¼ 7.2 Hz, 1H, Harom), 7.85 (s, 1H, CH]C). 13C NMR (CDCl3):
d 27.7,
CH2N), 6.09 (br s, 1H, OH), 6.81 (d, J ¼ 8.0 Hz, 2H, Harom), 7.36 (d,
45.2, 81.7, 116.5, 118.4, 126.0, 127.4, 128.7, 129.1, 129.9, 130.6, 131.0,
132.6, 132.9,134.2 (2 pics), 141.7, 142.1, 158.3, 166.5, 168.1, 168.3. ESI-
J ¼ 8.0 Hz, 2H, Harom), 7.80 (s, 1H, CH]C). 13C NMR (CDCl3):
d 12.0
(CH3, 2 pics), 12.8 (CH3), 20.2 (CH2), 22.6 (CH3), 27.9 (tBu), 29.7
(CH2), 48.9 (NCH2), 75.5, 83.3, 116.4, 116.9, 118.1, 123.8, 125.3, 125.8,
127.5, 132.6, 133.9, 141.3, 148.8, 152.9, 158.4, 166.9, 168.3. ESI-MS
(pos. mode): m/z ¼ 562.22 [MþNa]þ. Anal. Calcd for C29H33NO7S
(539.64): C, 64.54; H, 6.16; N, 2.60. Found: C, 64.31; H, 6.10; N, 2.65.
MS (pos. mode): m/z
C
67.68; H, 5.15; N, 2.81.
¼
510.14 [MþNa]þ. Anal. Calcd for
28H25NO5S, 0.5H2O (496.58): C, 67.72; H, 5.28; N, 2.82. Found: C,
5.1.23. 40-[(5Z)-(4-hydroxybenzylidene)-2,4-dioxothiazolidin-3-
ylmethyl]biphenyl-2-carboxylic acid (37)
5.1.20. ( ) (5Z)-(4-hydroxybenzylidene)-3-(6-hydroxy-2,5,7,8-
tetramethylchroman-2-ylmethyl)-thiazolidine-2,4-dione (34)
To a suspension of 33 (300 mg, 0.56 mmol) in CH2Cl2 (8 mL) was
added trifluoroacetic acid (2 mL) and the resulting yellow solution
was stirred at room temperature for 1 h. The mixture was
concentrated to dryness and the residue was dissolved in EtOAc
To a solution of 36 (294 mg, 0.60 mmol) in CH2Cl2 (6 mL) was
added TFA (2 mL) and the mixture was stirred at 0 ꢁC for 2 h. The
solvent was evaporated under vacuum and the excess of TFA was
driven off by co-evaporation with MeOH (5 times). The mixture was
dissolved in EtOAc (10 mL) and extracted with a 5% NaHCO3 solu-
tion (3 ꢂ 15 mL). The aqueous phase was washed with Et2O,

138
A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
acidified at pH ¼ 1 with a 1 M HCl solution, and extracted with
EtOAc (3 ꢂ 30 mL) and CH2Cl2 (2 ꢂ 20 mL). The organic phases were
gathered, dried (MgSO4) and concentrated to dryness to give a
yellowish solid which was precipitated in a 1:1 mixture of hexane
and Et2O to afford 37 (166 mg, 0.39 mmol, 64% yield) as a light
(30 mL) and washed with brine (2 ꢂ 20 mL), dried (MgSO4) and the
solvent was removed under vacuum to give a sticky yellowish solid
which was purified by column chromatography (eluent: hexane/
EtOAc, 8:2) to afford 40 (597 mg, 1.24 mmol, 90% yield) as a white
solid. M.p. 144e146 ꢁC. IR (film)
NMR (CDCl3):
n
(cmꢀ1): 2982, 2935, 1747, 1686. 1H
yellow solid. M.p. 128e130 ꢁC. IR (KBr)
1709, 1662. 1H NMR (DMSO-d6):
4.88 (s, 2H, CH2), 6.94 (d,
J ¼ 8.4 Hz, 2H, Harom), 7.29e7.41 (m, 5H, Harom), 7.42e7.62 (m, 4H,
arom), 7.72 (d, J ¼ 7.4 Hz, 1H, Harom), 7.91 (s, 1H, CH]C), 10.43 (br s,
1H, OH), 12.65 (br s, 1H, COOH). 13C NMR (DMSO-d6):
44.2, 116.4,
n
(cmꢀ1): 3400, 2924, 1730,
d
1.17 (t, J ¼ 6.2 Hz, 3H, CH2CH3), 1.63 (s, 3H, CH3), 1.90
d
(m, 1H, chromane 3-HaHb), 2.03 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.17
(s, 3H, CH3), 2.38e2.70 (m, 3H, chromane 4-H2, chromane 3-HaHb),
4.14 (br q, J ¼ 7.2 Hz, 2H, CH2CH3), 4.88 (s, 2H, CH2Ph), 7.35 (m, 3H,
H
d
H
arom), 7.46 (m, 2H, Harom), 8.01 (s, 1H, CH]C). 13C NMR (CDCl3):
116.5, 123.8, 127.3 (2 pics), 128.6, 129.1, 130.4, 130.8, 132.2, 132.6,
134.0, 134.4, 140.3, 140.4, 160.2, 165.7, 167.5, 169.4. ESI-MS (pos.
mode): m/z ¼ 454.08 [MþNa]þ. Anal. Calcd for C28H25NO5S, H2O
(449.48): C, 64.13; H, 4.26; N, 3.12. Found: C, 64.16; H, 4.02; N, 3.04.
d
11.8, 14.2, 16.4, 17.3, 20.9, 25.4, 30.4, 45.3, 61.3, 77.6, 117.4, 123.1,
125.6, 127.8, 128.4, 128.9, 129.2, 131.3, 132.9, 135.4, 137.2, 152.5,
165.1, 168.5, 173.4. ESI-MS (pos. mode): m/z ¼ 502.16 [MþNa]þ.
Anal. Calcd for C20H23NO5S (389.47): C, 67.62; H, 6.09; N, 2.92.
Found: C, 67.73; H, 6.05; N, 2.92.
5.1.24. ( ) 6-Formyl-2,5,7,8-tetramethylchroman-2-carboxylic acid
ethyl ester (38)
5.1.27. ( ) 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carbaldehyde
(42) [23,34]
A solution of 9 [16] (2.48 g, 9.45 mmol) in dry CH2Cl2 (70 mL)
was purged with nitrogen and dichloromethoxymethane (1.71 mL,
18.90 mmol) was added. The reaction was stirred at room tem-
perature for 5 min and TiCl4 (2.59 mL, 23.63 mmol) was added. The
reaction was stirred for 1.5 h and then carefully quenched with a
saturated aqueous NH4Cl solution (100 mL). The mixture was
vigorously stirred for 2 h and the organic layer was separated. The
aqueous phase was extracted with CH2Cl2 (3 ꢂ 50 mL). The com-
To a cold (ꢀ78 ꢁC) solution of 41 [16] (2.94 g, 10.56 mmol) in dry
hexane (50 mL) was added dropwise a 1.2 M DIBAL-H solution in
toluene (26.6 mL, 31.92 mmol) under nitrogen. The reaction was
stirred until the total consumption of the starting material (TLC)
and quenched with MeOH (10 mL) and distilled water (30 mL). The
mixture was progressively brought to room temperature, the
organic layer was separated and the aqueous phase was extracted
with CH2Cl2 (2 ꢂ 30 mL). The organic phases were gathered and
evaporated. The residue was dissolved in EtOAc (100 mL), washed
with 1 M HCl solution (30 mL) and brine (50 mL), dried (MgSO4)
and the solvent was removed under vacuum to give a yellowish
solid which was purified by column chromatography (eluent:
hexane/EtOAc, 8:2) to afford 42 (1.81 g, 7.80 mmol, 73% yield) as a
bined organic layers were washed with
1 M HCl solution
(3 ꢂ 50 mL), a saturated aqueous NaHCO3 solution (50 mL) and
brine (50 mL), dried (MgSO4) and the solvent was removed under
vacuum to give 38 (2.69 g, 9.26 mmol, 98% yield) as a colorless
liquid which was used in the next step without further purification.
1H NMR (CDCl3):
d
1.19 (t, J ¼ 7.5 Hz, 3H, eCH2CH3),1.64 (s, 3H, CH3),
1.90 (m, 1H, 3-HaHb), 2.21 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.48 (s, 3H,
CH3), 2.43e2.55 (m, 2H, chromane 4-H2), 2.72 (m, 1H, chromane 3-
HaHb), 4.14 (q, J ¼ 7.5 Hz, 2H, CH2CH3), 10.55 (s, 3H, CHO). 13C NMR
white solid. 1H NMR (CDCl3):
d 1.39 (s, 3H, CH3), 1.83 (m, 1H,
chromane 3-HaHb), 2.07 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.21 (s, 3H,
CH3), 2.29 (m, 1H, chromane 3-HaHb), 2.59 (m, 2H, chromane 4-H2),
4.29 (br s, 1H, OH), 9.61 (s, 1H, CHO).
(CDCl3): d 11.4, 14.1, 14.8, 15.6, 20.6, 25.1, 30.3, 61.3, 77.8, 117.5, 123.4,
127.0, 137.7, 138.6, 155.3, 172.9, 194.0.
5.1.28. ( ) Carbonic acid tert-butyl ester 2-formyl-2,5,7,8-
5.1.25. ( ) 6-(2,4-Dioxothiazolidin-(5Z)-ylidenemethyl)-2,5,7,8-
tetramethylchroman-2-carboxylic acid ethyl ester (39)
To a solution of 38 (594 mg, 2.05 mmol) in dry toluene (8 mL)
were successively added 2,4-thiazolidinedione (479 mg,
tetramethylchroman-6-yl ester (43)
To a solution of 42 (1.12 g, 4.82 mmol) in CH2Cl2 (15 mL) were
added Boc2O (1.16 g, 5.30 mmol) and DMAP (59 mg, 0.48 mmol).
The reaction mixture was stirred at room temperature for 3 h, the
solvent was evaporated under vacuum and the residue was dis-
solved in EtOAc (20 mL). The organic phase was washed with 5%
aqueous citric acid solution (2 ꢂ 20 mL) and 5% aqueous NaHCO3
solution (2 ꢂ 20 mL), dried (MgSO4) and the solvent was removed
under vacuum to give a yellowish solid which was purified by
column chromatography (eluent: hexane/EtOAc, 8:2) to afford 43
4.09 mmol), piperidine (100
mL, 1.02 mmol), and benzoic acid
(124 mg, 1.02 mmol). The reaction was reflux overnight under ni-
trogen, then cooled to room temperature, diluted with EtOAc
(30 mL), washed with 5% aqueous NaHCO3 solution (2 ꢂ 15 mL) and
brine (20 mL), dried (MgSO4) and the solvent was removed under
vacuum to afford a yellowish solid which was purified by column
chromatography (eluent: hexane/EtOAc, 8:2) to give 39 (740 mg,
(1.22 g, 3.67 mmol, 76% yield) as a white solid. M.p. 62 ꢁC. IR (film)
n
1.90 mmol, 92% yield) as a white solid. M.p. 176e178 ꢁC. IR (film)
n
(cmꢀ1): 2980, 2932, 2360, 2341, 1753. 1H NMR (CDCl3):
d
1.39 (s, 3H,
(cmꢀ1): 3221, 2982, 1748, 1704. 1H NMR (CDCl3):
d
1.20 (t, J ¼ 7.5 Hz,
CH3), 1.55 (s, 9H, t-Bu), 1.82 (m, 1H, chromane 3-HaHb), 2.00 (s, 3H,
CH3), 2.10 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.25 (m, 1H, chromane 3-
HaHb), 2.58 (m, 2H, chromane 4-H2), 9.62 (s, 1H, CHO). 13C NMR
3H, CH2CH3), 1.65 (s, 3H, CH3), 1.90 (m, 1H, chromane 3-HaHb), 2.06
(s, 3H, CH3), 2.15 (s, 3H, CH3), 2.19 (s, 3H, CH3), 2.40e2.72 (m, 3H,
chromane 4-H2, chromane 3-HaHb), 4.14 (br q, J ¼ 7.5 Hz, 2H,
CH2CH3), 7.96 (s, 1H, CH]C), 8.26 (s, 1H, NH). 13C NMR (CDCl3):
(CDCl3): d 11.7, 11.8, 12.7, 20.1, 21.5, 27.5, 27.7, 80.5, 82.8, 117.5, 123.2,
125.6, 127.7, 141.8, 148.8, 152.1, 204.0. ESI-MS (pos. mode): m/
z ¼ 357.17 [MþNa]þ. Anal. Calcd for C19H26O5, 0.25H2O (334.41): C,
67.33; H, 7.88. Found: C, 67.36; H, 8.06.
d
11.7, 14.1, 16.2, 17.1, 20.8, 25.2, 30.2, 61.2, 77.5, 117.3, 123.0, 125.3,
128.6, 131.1, 132.7, 137.6, 152.5, 165.3, 167.7, 173.3. ESI-MS (pos.
mode): m/z
¼
412.11 [MþNa]þ. Anal. Calcd for C20H23NO5S
(389.47): C, 61.68; H, 5.95; N, 3.60. Found: C, 61.33; H, 5.83; N, 3.39.
5.1.29. ( ) Carbonic acid tert-butyl ester 2-(2,4-dioxothiazolidin-
(5Z)-ylidenemethyl)-2,5,7,8-tetramethylchroman-6-yl ester (44)
To a solution of 43 (494 mg, 1.47 mmol) in dry toluene (5 mL)
were added 2,4-thiazolidinedione (498 mg, 4.26 mmol), piperidine
5.1.26. ( ) 6-(3-Benzyl-2,4-dioxothiazolidin-(5Z)-ylidenemethyl)-
2,5,7,8-tetramethylchroman-2-carboxylic acid ethyl ester (40)
To a solution of 39 (539 mg, 1.39 mmol) in dry DMF (10 mL),
were added K2CO3 (250 mg, 1.81 mmol) and benzylbromide
(105 mL, 1.07 mmol) and benzoic acid (130 mg, 1.07 mmol). The
reaction was refluxed overnight and then cooled to room temper-
ature, diluted with EtOAc (20 mL) and washed with 5% aqueous
citric acid solution (2 ꢂ 20 mL), 5% aqueous NaHCO3 solution
(180
nitrogen, then cooled at room temperature, diluted with EtOAc
m
L, 1.52 mmol). The mixture was stirred at 80 ꢁC for 6 h under

A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
139
(2 ꢂ 20 mL) and brine (20 mL), dried (MgSO4) and the solvent was
removed under vacuum to give a yellowish solid which was puri-
fied by column chromatography (eluent: hexane/EtOAc, 8:2) to
afford 44 (386 mg, 0.89 mmol, 60% yield) as a white solid. M.p.
which were added
L
-glutamine, 10% fetal calf serum (v/v), 100 UI of
penicillin, 100 g/mL of streptomycin, and 1.5
m
m
g/mL of fungizone.
5.2.1.2. Cell proliferation assay. 96-wells plates were seeded with
the requisite number of cells (1900 cells per well for MCF-7, 1300
for MDA-MB-231) in 200 mL of medium. 24 h later, 10 mM DMSO
solution of the compounds were added and the mixture was kept
under these conditions for 72 h, with a final concentration of DMSO
of 1%. Control wells were treated with an equal volume of DMSO.
The number of viable cells was evaluated at 490 nm with the MTS
reagent (Promega, Madison, WI).
124e125 ꢁC. IR (film)
(CDCl3):
n
(cmꢀ1): 2979, 2930,1751,1706,1637. 1H NMR
d
1.48 (s, 3H, CH3), 1.56 (s, 9H, t-Bu), 1.90 (m, 1H, chromane
3-HaHb), 1.99e2.07 (m, 1H, chromane 3-HaHb), 2.03 (s, 3H, CH3),
2.10 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.64 (m, 2H, chromane 4-H2),
7.00 (s, 1H, CH]C), 8.41 (s, 1H, NH). 13C NMR (CDCl3):
d 11.9, 12.7,
12.8, 20.5, 24.3, 27.7, 31.5, 75.7, 83.1, 117.3, 123.4, 125.1, 125.6, 128.2,
140.3, 141.9, 148.1, 152.4, 166.0, 168.9. ESI-MS (pos. mode): m/
z ¼ 456.15 [MþNa]þ. Anal. Calcd for C22H27NO6S (433.52): C, 60.95;
H, 6.28; N, 3.23. Found: C, 61.28; H, 6.63; N, 3.10.
5.2.2. Determination of the IC50 of the two lead compounds on
MCF-7 and MDA-MB-231
5.1.30. ( ) Carbonic acid 2-(3-benzyl-2,4-dioxothiazolidin-(5Z)-
ylidenemethyl)-2,5,7,8-tetramethyl-chroman-6-yl-tert-butyl ester
(45)
5.2.2.1. Cell culture and reagents. MCF-7 and MDA-MB-231 human
breast cancer cell lines were obtained from American Type Culture
Collection (Rockville, MD). Both cell lines were grown at 37 ꢁC,
according to American Type Culture Collection recommendations,
in phenol red Dulbecco's modified Eagle medium (DMEM, Invi-
trogen, Cergy Pontoise, France) for MCF-7 and in L-15 medium
(Invitrogen) for MDA-MB-231. These media were supplemented
with 10% fetal calf serum (FCS, SigmaeAldrich, Lyon, France) and
To a solution of 44 (345 mg, 0.80 mmol) in dry DMF (5 mL), were
added K2CO3 (144 mg, 1.04 mmol) and benzylbromide (100
mL,
0.89 mmol). The mixture was heated to 80 ꢁC for 6 h under nitro-
gen, then cooled to room temperature. The suspension was diluted
with EtOAc (20 mL) and washed with brine (2 ꢂ 20 mL), dried
(MgSO4) and the solvent was removed under vacuum to give a
sticky yellowish solid which was purified by column chromatog-
raphy (eluent: hexane/EtOAc, 8:2) to afford 45 (383 mg, 0.73 mmol,
2 mM L-glutamine (Invitrogen).
5.2.2.2. Cell proliferation assay. Cells were seeded in 6-well plates
91% yield) as a white solid. M.p.110e112 ꢁC. IR (film)
n
(cmꢀ1): 2979,
at the density of 8.104 cells/well in 2 mL of medium supplemented
2929, 1752, 1686. 1H NMR (CDCl3):
d
1.48 (s, 3H, CH3), 1.55 (s, 9H, t-
with 10% FCS and 2 mM
the medium was replaced by fresh medium supplemented with 1%
FCS and 2 mM -glutamine. Cell proliferation was studied after 24 h
L-glutamine. After 24 h of cell attachment,
Bu), 1.88 (m, 1H, chromane 3-HaHb), 1.99e2.06 (m, 1H, chromane 3-
HaHb), 2.02 (s, 3H, CH3), 2.09 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.63 (m,
2H, chromane 4-H2), 4.80 (s, 2H, CH2Ph), 7.00 (s, 1H, CH]C),
7.28e7.36 (m, 3H, Harom), 7.37e7.44 (m, 2H, Harom). 13C NMR
L
of treatment. Control wells received 0.1% DMSO. At the end of the
treatment, cells were washed with PBS, trypsinized and counted
with the CellTiter-GloTM Luminescent Cell Viability Assay (Promega,
Charbonnieres, France). Each treatment was performed in tripli-
cate. For the different compounds, the concentration leading to a
decrease of 50% in the number of viable cells (IC50) was measured.
(CDCl3): d 12.0, 12.7, 12.9, 20.7, 24.9, 27.8, 31.8, 45.0, 76.0, 83.0, 117.4,
123.5, 124.3, 125.6, 128.2, 128.3, 128.8, 129.1, 135.3, 140.3, 142.0,
148.2, 152.2, 165.9, 169.7. ESI-MS (pos. mode): m/z ¼ 546.18
[MþH]þ. Anal. Calcd for C29H33NO6S (523.64): C, 66.52; H, 6.35; N,
2.67. Found: C, 66.23; H, 6.50; N, 2.59.
5.2.3. Hepatocyte viability
5.1.31. ( ) 3-Benzyl-(5Z)-(6-hydroxy-2,5,7,8-tetramethylchroman-
2-ylmethylene)thiazolidine-2,4-dione (46)
5.2.3.1. Cell culture and reagents. Cryopreserved human hepato-
cytes were provided by Kaly-cell (Illkirch, France). They were
distributed in 96-well plates at the density of 0.1 ꢂ106 cells/well in
To a solution of 45 (236 mg, 0.45 mmol) in CH2Cl2 (6 mL) was
slowly added trifluoroacetic acid (2 mL). The solution was stirred at
room temperature for 3 h, then the solvent was removed under
vacuum. Excess trifluoroacetic acid was removed by co-evaporation
with MeOH (5 times) to afford a slightly yellow solid which was
purified by column chromatography (eluent: hexane/EtOAc 9:1) to
afford 46 (168 mg, 0.40 mmol, 88% yield) as a white solid. M.p.
50 ml of DMEM (Gibco, Invitrogen, UK) supplemented with genta-
mycin (50 mg/L, Sigma Aldrich, France), insulin (4 mg/L, Sigma
Aldrich, France) and dexamethasone (1 M, Sigma Aldrich, France)
and were kept under a CO2/air (5%/95%) humidified atmosphere at
37 ꢁC. After 30 min of equilibration, under stirring at 900 rpm, 50
of test compounds or DMSO (0.1%) were added. Compounds were
tested at 2 concentrations (100 and 200 M) in triplicate.
m
mL
120e122 ꢁC. IR (film)
n
(cmꢀ1): 3504, 2928, 1739, 1682, 1635.
1H NMR (CDCl3):
d
1.49 (s, 3H, CH3), 1.88 (m, 1H, chromane 3-HaHb),
m
2.01e2.13 (m, 1H, chromane 3-HaHb), 2.09 (s, 3H, CH3), 2.17 (s, 3H,
CH3), 2.23 (s, 3H, CH3), 2.64 (m, 2H, chromane 4-H2), 4.79 (s, 2H,
CH2Ph), 7.06 (s, 1H, CH]C), 7.28e7.35 (m, 3H, Harom), 7.37e7.45 (m,
5.2.3.2. Cytotoxicity assay (MTT assay). After 90 min of treatment,
MTT (10 L/well at 10 mg/mL, Sigma Aldrich, France) was added
and incubated during 30 min at 37 ꢁC. Plates were centrifuged, MTT
was removed and 100 L DMSO was distributed per well. The
absorbance was read at 595 nm by microplate spectrophotometry.
Cell viability was expressed as percentage over controls (DMSO,
0.1%).
m
2H, Harom). 13C NMR (CDCl3):
d 11.5, 12.4, 12.8, 20.9, 25.1, 32.1, 45.0,
m
75.7, 117.3, 118.7, 121.9, 122.9, 124.2, 128.3, 128.8, 129.2, 135.3, 140.7,
144.5, 145.7, 165.9, 169.9. ESI-MS (pos. mode): m/z ¼ 446.14
[MþNa]þ. Anal. Calcd for C24H25NO4S (423.52): C, 68.06; H, 5.95; N,
3.31. Found: C, 67.87; H, 6.20; N, 3.12.
5.2. Biological evaluation
Acknowledgments
5.2.1. Inhibition of growth of MCF-7 and MDA-MB-231 at 10
concentration
5.2.1.1. Cell culture and reagents. MCF-7 and MDA-MB-231 human
breast cancer cell lines were obtained from American Type Culture
Collection (Rockville, MD). Both cell lines were grown at 37 ꢁC and
kept under 5% CO2. Cells were grown in RPMI culture medium to
m
M
The authors thank Kaly-Cell (Illkirch) for providing human he-
patocytes and for viability measurements, T. Cresteil and G. Aubert
(ICSN, Gif sur Yvette) for viability measurements and J.-F. Bisson
ꢁ
(ETAP, Vandœuvre-les-Nancy) for evaluation of MTD on mice. We
also acknowledge A. Kleinclauss, F. Dupire, S. Adach and B. Fernette
for technical assistance.

140
A. Bordessa et al. / European Journal of Medicinal Chemistry 83 (2014) 129e140
derivatives: anti-proliferative activity in breast cancer cell lines and pre-
Appendix A. Supplementary data
liminary toxicological study, Eur. J. Med. Chem. 51 (2012) 206e215.
[17] V. Zoete, A. Grosdidier, O. Michielin, Peroxisome proliferator-activated re-
ceptor structures: ligand specificity, molecular switch and interactions with
regulators, Biochim. Biophys. Acta 1771 (2007) 915e925.
[18] P. Kiprof, J. Li, C.L. Renish, E.K. Kalombo, V.G. Young, The effect of solubility on
the stability of titanium(IV) arene complexes derived from hexasubstituted
arenes and TiCl4, J. Organomet. Chem. 620 (2001) 113e118.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.06.015. These data include NMR
spectra of tested compounds and in vitro and in vivo detailed
biological results.
[19] P.G. Reddy, T.V. Pratap, G.D.K. Kumar, S.K. Mohanty, S. Baskaran, The Lindlar
catalyst revitalized: a highly chemoselective method for the direct conversion
of azides to N-(tert-butoxycarbonyl)amines, Eur. J. Org. Chem. 2002 (2002)
3740e3743.
[20] Y. Luo, L. Ma, H. Zheng, L. Chen, R. Li, C. He, S. Yang, X. Ye, Z. Chen, Z. Li, Y. Gao,
J. Han, G. He, L. Yang, Y. Wei, Discovery of (Z)-5-(4-Methoxybenzylidene)
thiazolidine-2,4-dione, a readily available and orally active glitazone for the
treatment of concanavalin a-induced acute liver injury of BALB/c mice, J. Med.
Chem. 53 (2010) 273e281.
[21] W.R. Schoen, J.M. Pisano, K. Prendergast, M.J. Wyvratt, M.H. Fisher, K. Cheng,
W.W.-S. Chan, B. Butler, R.G. Smith, R.G. Ball, A novel 3-substituted benza-
zepinone growth hormone secretagogue (L-692,429), J. Med. Chem. 37 (1994)
897e906.
[22] O. Garcia, J.M. Bofill, E. Nicolas, F. Albericio, 2,2,4,6,7-Pentamethyl-2,3-
dihydrobenzofuran-5-methyl (Pbfm) as an alternative to the trityl group for
the side-chain protection of cysteine and asparagine/glutamine, Eur. J. Org.
Chem. 2010 (2010) 3631e3640.
References
[1] V.S. Jain, D.K. Vora, C.S. Ramaa, Thiazolidine-2,4-diones: progress towards
multifarious applications, Bioorg. Med. Chem. 21 (2013) 1599e1620.
[2] M. Chojkier, Troglitazone and liver injury: in search for answers, Hepatology
41 (2005) 237e246.
[3] A. Baranova, PPAR ligands as potential modifiers of breast carcinoma out-
comes, PPAR Res. 2008 (2008) 1e10.
[4] H.J. Burstein, G.D. Demetri, E. Mueller, P. Sarraf, B.M. Spie-Gelman, E.P. Winer,
Use of the peroxisome proliferator-activated receptor (PPAR)g ligand trogli-
tazone as treatment for refractory breast cancer: a phase II study, Breast
Cancer Res. Treat. 79 (2003) 391e397.
[5] I. Grillier-Vuissoz, S. Mazerbourg, M. Boisbrun, S. Kuntz, Y. Chapleur,
S. Flament, PPARg-independant activity of thiazolidinediones : a promising
mechanism of action for new anticancer drugs ? J. Carcinog. Mutagen. (2014).
http://dx.doi.org/4172/2157-2518.S8-002 (in press).
[23] M. Koufaki, C. Kiziridi, X. Alexi, M.N. Alexis, Design and synthesis of novel
neuroprotective 1,2-dithiolane/chroman hybrids, Bioorg. Med. Chem. 17
(2009) 6432e6441.
[24] V.A. Dixit, P.V. Bharatam, Toxic metabolite formation from troglitazone (TGZ):
new insights from a DFT study, Chem. Res. Toxicol. 24 (2011) 1113e1122.
[6] J.-W. Huang, C.-W. Shiau, J. Yang, D.-S. Wang, H.-C. Chiu, C.-Y. Chen, C.-S. Chen,
Development of small-molecule cyclin D1-ablative agents, J. Med. Chem. 49
(2006) 4684e4689.
[7] J. Yang, S. Wei, D.-S. Wang, Y.-C. Wang, S.K. Kulp, C.-S. Chen, Pharmacological
exploitation of the peroxisome proliferator-activated receptor
ciglitazone to develop a novel class of androgen receptor-ablative agents,
J. Med. Chem. 51 (2008) 2100e2107.
g agonist
ꢀ
€
[25] R. Alvarez-Sanchez, F. Montavon, T. Hartung, A. Pahler, Thiazolidinedione
bioactivation: a comparison of the bioactivation potentials of troglitazone,
rosiglitazone, and pioglitazone using stable isotope-labeled analogues and
liquid chromatography tandem mass spectrometry, Chem. Res. Toxicol. 19
(2006) 1106e1116.
[8] J. Lecomte, S. Flament, S. Salamone, M. Boisbrun, S. Mazerbourg, Y. Chapleur,
I. Griller-Vuissoz, Disruption of ER
evidences of PPAR -independent events in two hormone-dependent breast
cancer cell lines, Breast Cancer Res. Treat. 112 (2008) 437e451.
[9] J.H. Guh, W.-L. Chang, J. Yang, S.-L. Lee, S. Wei, D. Wang, S.K. Kulp, C.-S. Chen,
Development of novel adenosine monophosphate-activated protein kinase
activators, J. Med. Chem. 53 (2010) 2552e2561.
a signalling pathway by PPARg agonists:
g
[26] T. Yokoi, Troglitazone, Handb. Exp. Pharmacol. 196 (2010) 419e435.
[27] H.E. Gottlieb, V. Kotlyar, A. Nudelman, NMR chemical shifts of common lab-
oratory solvents as trace impurities, J. Org. Chem. 62 (1997) 7512e7515.
[28] N. Zidar, T. Tomasic, R. Sink, V. Rupnik, A. Kovac, S. Turk, D. Patin, D. Blanot,
}
C. Contreras Martel, A. Dessen, M. Muller Premru, A. Zega, S. Gobec, L. Peterlin
[10] K.-H. Lee, E.-C. Hsu, J.-H. Guh, H.-C. Yang, D. Wang, S.K. Kulp, C.L. Shapiro, C.-
S. Chen, Targeting energy metabolic and oncogenic signaling pathways in
triple-negative breast cancer by a novel adenosine monophosphate-activated
protein kinase (AMPK) activator, J. Biol. Chem. 286 (2011) 39247e39258.
[11] Y.-H. Fan, H. Chen, A. Natarajan, Y. Guo, F. Harbinski, J. Lyasere, W. Christ,
H. Aktas, J.A. Halperin, Structure-activity requirements for the anti-
proliferative effect of troglitazone derivatives mediated by depletion of
intracellular calcium, Bioorg. Med. Chem. Lett. 14 (2004) 2547e2550.
[12] S. Chbicheb, X. Yao, J.-L. Rodeau, S. Salamone, M. Boisbrun, G. Thield,
D. Spohnd, I. Grillier-Vuissoz, Y. Chapleur, S. Flament, S. Mazerbourg, EGR1
Masic, D. Kikelj, Discovery of novel 5-benzylidenerhodanine and 5-
benzylidenethiazolidine-2,4-dione inhibitors of MurD ligase, J. Med. Chem.
53 (2010) 6584e6594.
[29] T. Tomasic, N. Zidar, M. Muller-Premru, D. Kikelj, L. Peterlin Masic, Synthesis
and antibacterial activity of 5-ylidenethiazolidin-4-ones and 5-benzylidene-
4,6-pyrimidinediones, Eur. J. Med. Chem. 45 (2010) 1667e1672.
[30] S.S. Purohit, A. Alman, J. Shewale, Synthesis and antimicrobial activity of a
new series of 3,5-disubstituted thiazolidine-2,4-diones, Int. J. Pharm. Pharm.
Sci. 4 (2012) 273e276.
[31] H.M.H.G. Albers, L.A. Van Meeteren, D.A. Egan, E.W. Van Tilburg,
W.H. Moolenaar, H. Ovaa, Discovery and optimization of boronic acid based
inhibitors of autotaxin, J. Med. Chem. 53 (2010) 4958e4967.
[32] D.-H. Yang, Z.-C. Chen, S.-Y. Chen, Q.-G. Zheng, Organic reactions in ionic
liquids; ionic liquid-accelerated three-component reaction: a rapid one-pot
synthesis of 3-alkyl-5-[(Z)-arylmethylidene]-1,3-thiazolidine-2,4-diones,
Synthesis 2003 (2003) 1891e1894.
expression
:
a
calcium and ERK1/2 mediated PPAR
g-independent event
involved in the antiproliferative effect of 15-deoxy-
D
12,14-prostaglandin J2
and thiazolidinediones in breast cancer cells, Biochem. Pharmacol. 81 (2011)
1087e1097.
[13] S. Wei, H.-C. Chuang, W.-C. Tsai, H.-C. Yang, S.-R. Ho, A.J. Paterson, S.K. Kulp,
C.-S. Chen, Thiazolidinediones mimic glucose starvation in facilitating Sp1
degradation through the up-regulation of
b-transducin repeat-containing
[33] M.T. Omar, M.M. Habashy, A.M. Youssef, F.A. Sherif, 4-Thiazolidinones VIII.
The role of substituents at position-3 on the mode of cleavage of 5-(aryl-
methylene)-2,4-dioxothiazolidines, J. Prakt. Chem. 331 (1989) 393e398.
protein, Mol. Pharmacol. 76 (2009) 47e57.
[14] S. Wei, S.K. Kulp, C.-S. Chen, Energy restriction as an antitumor target of
thiazolidinediones, J. Biol. Chem. 285 (2010) 9780e9791.
[15] D. Wang, P.-C. Chu, C.-N. Yang, R. Yan, Y.-C. Chuang, S.K. Kulp, C.-S. Chen,
Development of a novel class of glucose transporter inhibitors, J. Med. Chem.
55 (2012) 3827e3836.
ꢀ
ꢀ
€
€
[34] G.T. Balogh, K. Vukics, A. Konczol, A. Kis-Varga, A. Gere, J. Fischer, Nitrone
derivatives of trolox as neuroprotective agents, Bioorg. Med. Chem. Lett. 15
(2005) 3012e3015.
[16] S. Salamone, C. Colin, I. Grillier-Vuissoz, S. Kuntz, S. Mazerbourg, S. Flament,
H. Martin, L. Richert, Y. Chapleur, M. Boisbrun, Synthesis of new troglitazone