Cycloalkyl-substituted aryl chloroethylureas inhibiting cell cycle progression in G0/G1 phase and thioredoxin-1 nuclear translocation

Article abstract of DOI:10.1016/j.bmcl.2008.05.028

1-(2-Chloroethyl)-3-(4-cyclohexylphenyl)urea (cHCEU) has been shown to abrogate the presence of thioredoxin-1 into the nucleus through its selective covalent alkylation. In the present letter we have evaluated the structure-activity relationships of the s

Full text of DOI:10.1016/j.bmcl.2008.05.028

Bioorganic & Medicinal Chemistry Letters 18 (2008) 3526–3531
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Cycloalkyl-substituted aryl chloroethylureas inhibiting cell cycle progression
in G0/G1 phase and thioredoxin-1 nuclear translocation
a
a
a,c,
Jessica S. Fortin a,b, , Marie-France Côté , Jacques Lacroix , Alexandre Patenaude
, Éric Petitclerc a,c
,
*
René C.-Gaudreault a,c,
*
a Unité des Biotechnologies et de Bioingénierie, CRCHUQ, Hôpital Saint-Francßois d’Assise, Québec, QC, Canada G1L 3L5
b Faculté de Pharmacie, Université Laval, Québec, QC, Canada G1K 7P4
c Faculté de Médecine, Université Laval, Québec, QC, Canada G1K 7P4
a r t i c l e i n f o
a b s t r a c t
Article history:
1-(2-Chloroethyl)-3-(4-cyclohexylphenyl)urea (cHCEU) has been shown to abrogate the presence of thi-
oredoxin-1 into the nucleus through its selective covalent alkylation. In the present letter we have eval-
uated the structure–activity relationships of the substituents at positions 3 and 4 of the phenyl ring of
cHCEU derivatives on cell cycle progression and thioredoxin-1 nuclear translocation. Active CEU deriva-
tives exhibited GI50 ranging from 1.9 to 49 lM on breast carcinoma MCF-7, skin melanoma M21, and
colon carcinoma HT-29 cells. On one hand, compounds 1, 2, 9c, 10c, 13, and 14 arrested the cell cycle
in G2/M phase while CEUs 3, 4, 5c, 6c, 11c, and 12c blocked the cell division in G0/G1 phase. On the other
hand, CEUs 2–4, 5c, 7c, 8c, 11c, and 12c abrogated the translocation of thioredoxin-1 while the other CEU
derivatives were inactive in that respect. Our results suggest that CEU substituted on the phenyl ring at
position 3 or 4 by lower cycloalkyl or cycloalkoxy groups arrest cell progression in G0/G1 phase through
mechanism of action different from their antimicrotubule counterparts, presumably via thioredoxin-1
alkylation and modulation of its activity. The mechanism of action of these new molecules is still unde-
termined. However, the significant accumulation of cells in G0/G1 phase suggests that these molecules
may act similarly to known chemopreventive agents against cancers. In addition, the inhibition of Trx-
1 nuclear localization also suggests the abrogation of an important chemoresistance mechanism towards
a variety of chemotherapeutic agents.
Received 15 March 2008
Revised 2 May 2008
Accepted 6 May 2008
Available online 10 May 2008
Keywords:
Phenyl chloroethylurea
Thioredoxin-1
Alkylating agents
Anticancer drugs
Ó 2008 Elsevier Ltd. All rights reserved.
In the past two decades, we have focused our research program
on the development of new ‘soft’ alkylating agents designated as
aryl chloroethylureas (CEU).1–10 CEU derivatives such as 4-tert-bu-
tyl-3-[(2-chloroethyl)]ureido]benzene (tBCEU, 13) and its bioiso-
stere 4-iodo-3-[(2-chloroethyl)]ureido]benzene (ICEU, 14) were
shown to bind irreversibly to the colchicine-binding site (C-BS)
on bII-tubulin (Fig. 1).3–5 The covalent binding of tBCEU, ICEU,
and several other CEU derivatives to the C-BS led to the arrest of
the cell division in G2/M phase, cytoskeleton disruption, and apop-
tosis.3–5,10 Recently, ICEU was shown to be specifically biodistrib-
uted into the gastrointestinal tract and to inhibit efficiently
mouse colon carcinoma (CT-26) tumors grafted onto mice.11,12
Screening assays were performed to evaluate the antiproliferative
properties of closely related CEU derivatives and their effects on
cell division, and on C-BS alkylation. Our results showed that 4-
cyclohexyl-[3-(2-chloroethyl)ureido]benzene (cHCEU, 4)7,13,14
inhibits the cell division in G0/G1 phase instead of G2/M phase
and that cHCEU does not bind covalently to bII-tubulin when tested
at concentrations inhibiting tumor cell growth by 50%.12,13 The use
of [14C-carbonyl]-cHCEU clearly showed that the drug was not
binding to C-BS13 but instead to a few other proteins, notably,
the mitochondrial voltage-dependent anion channel isoform-
1(VDAC-1),13 and more recently, the thioredoxin isoform-1 (Trx-
1).14 Noteworthy, cHCEU binding to Trx-1 was shown to inhibit
its presence into the cell nucleus.
Trx-1 is a 12 kDa protein located in the cytoplasm and trans-
located into the nucleus under a number of physiological and
stress conditions.15–17 Trx-1 is an electron donor for Trx peroxi-
dase, thioredoxin reductase, and ribonucleotide reductase.16,17
Through its unique redox-mediating properties, Trx-1 controls
the activity of several proteins such as AP-1 and NFjB, which
are essential for cell cycle progression.15–17 It was shown that
Trx-1 could control cell cycle movement through G1, S, and G2/
M phases in cells stimulated to exit quiescence and to enter
G1 phase. The intranuclear Trx-1 controls the activity of the
AP-1 c-fos/c-jun heterodimer by reducing the nuclear redox fac-
tor, Ref-1/Hap-1.14–20 AP-1 is important for the control of G0/G1
* Corresponding authors. Tel.: +1 418 525 4485; fax: +1 418 525 4372 (J.S.F.); tel.:
+1 418 525 4444x52363; fax: +1 418 525 4372 (R.C.-G.).
E-mail addresses: jessica.fortin.1@ulaval.ca (J.S. Fortin), rene.c-gaudreault@
crsfa.ulaval.ca (R. C.-Gaudreault).
Present address: Medical Biophysics Department, BC Cancer Research Centre, 675
West 10th Avenue, Vancouver, BC, Canada V5Z 1L3.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.028

J. S. Fortin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3526–3531
3527
Figure 1. (A) Chemical structures of 1-(2-chloroethyl)-3-(4-cyclohexylphenyl)urea (cHCEU), 4-tert-butyl-[3-(2-chloroethyl)ureido]benzene (tBCEU) and 4-iodo-3-[(2-chlo-
roethyl)]ureido]benzene (ICEU). (B) Alkylation of tubulin isoform-bII, which was performed as reported earlier.3–5,13,14 The alkylated bII-tubulin by-product appears as a
higher molecular weight band reacting with the monoclonal anti-bII-tubulin antibody. A supplementary band indicates that tubulin isoform-bII is alkylated by the drug. (C)
Cell cycle progression was evaluated by flow cytometry using propidium iodide staining.3–5,13,14 (D) Intracellular localization of thioredoxin-1.
transition involving AP-1-responsive cyclin D1 gene. In addition,
Trx-1 is also required to maintain the deoxyribonucleotide pool
during the S phase of the cell division.12,21 Of interest, Trx-1 is
overexpressed in cancers such as colon, pancreas, and breast
and correlates with poor prognosis.17–20 Increased Trx expression
protects cells from apoptosis induced by a variety of agents, such
as etoposide, doxorubicin, docetaxel, and cisplatin.21–24 Trx-1 is
therefore a recognized target for the development of new anti-
neoplastic and chemopreventive agents and in that context sev-
eral molecules derived from alkyl 2-amidazolyl disulfides,
quinols, napthoquinone spiroketals, and selenium derivatives
have been developed already.25–29 However, it seems that so
far only 1-methylpropyl 2-imidazolyl disulfide (PX-12Ò) is cur-
rently undergoing clinical trials.30
their efficacy to block nuclear translocation of Trx-1, cell cycle pro-
gression, and tumor cell proliferation.
Scheme 1 illustrates the synthesis of CEU and EU derivatives
using the nucleophilic addition of either 2-chloroethylisocyanate
or ethylisocyanate to the corresponding anilines.6–10 Anilines
substituted by a cycloalkyloxy moiety were prepared using a Wil-
liamson-type reaction followed by the reduction of the aromatic
nitro group with SnCl2.11,31
Tumor cell growth inhibition activity of CEU derivatives and
antineoplastics such as PX-12, cisplatin, colchicine, and paclitaxel
was evaluated on three human cell lines, namely, MCF-7 breast
carcinoma, M21 skin melanoma, and HT-29 colon carcinoma cells.
Cell growth inhibition was assessed according to the NCI/NIH
Developmental Therapeutics Program.33 The results are summa-
rized in Table 1 and expressed as the concentration of drug inhib-
iting the cell growth by 50% (GI50).
In the present study, we have studied the effect of various sub-
stituents of the aromatic ring of a series of cHCEU derivatives and
OH
O
O
b
a
Br
(CH2)n
+
(CH2)n
(CH2)n
NO2
NH2
NO2
n= 1 to 3
5-12a
5-8b
c
d
11b, 12b
O
O
O
O
Cl
(CH2)n
(CH2)n
N
H
N
N
N
H
H
H
1-4, 5-8c, 9-12c
15
Scheme 1. Synthesis of aryl chloroethylureas. Reagents: (a) NaOH, DMF, reflux; (b) SnCl2Á2H2O, EtOH, reflux; (c) 2-chloroethylisocyanate or; (d) ethylisocyanate, CH2Cl2.

3528
J. S. Fortin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3526–3531
Table 1
Antiproliferative activity of compounds 1–4, 5–12c, and 13–15; PX-12; cisplatin; and paclitaxel was performed on MCF-7, M21, and HT-29 cells, flow cytometry analysis was
realized using MCF-7 cells, and immunocytochemistry was performed on M21 cells using a monoclonal anti-thioredoxin-1 antibody
O
R
Cl
N
H
N
H
Compound
R
GI50 (lM)
FACS (%) MCF-7
S
Trx-1 location M21
HT-29
3.6
M21
MCF-7
14.1
G0/G1
31
G2/M
40
16,7,10
8.0
4.1
27
29
38
29
16
19
24
29
33
20
26
19
26,7
1.9
5.6
22
21
49
35
45
25
9.1
24
19
17
63
71
72
64
57
59
15
44
75
45
8
310
19
4 (cHCEU)7
12.6
31
21
13
9
5c
38
6c
9.9
22
12
14
8
7c
23
36
8c
7.9
2.4
5.6
12.5
20
9c
5.2
65
30
6
10c
11c
16
18
(continued on next page)

J. S. Fortin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3526–3531
3529
Table 1 (continued)
Compound
R
GI50 (lM)
FACS (%) MCF-7
S G2/M
Trx-1 location M21
HT-29
10.7
M21
MCF-7
21
G0/G1
72
12c
20
22
24
33
13
27
19
11
23
22
6
136,7,10 (tBCEU)
146,7,10 (ICEU)
PX-12a
2.3
1.9
4.3
3.9
6.2
17
25
29
53
19
9
58
42
58
20
62
80
22
19
6.0
25
8.3
8.3
Cisplatin
Colchicine
Paclitaxel
15
10.1
0.004
0.015
n.e.
12.9
6.4
0.015
0.009
0.054
n.e.
n.e.
0.037
n.e.
55
59
DMSO
n.e.
n.e.
For FACS and immunocytochemistry analysis, exponentially growing MCF-7 or M21 cells were incubated for 16 h, in absence or in presence of CEUs (1, 9c, 13, 14 at 25 lM; 2–
4, 5–8c, 10–12c, 15 at 50 lM), cisplatin (30 lM), colchicine (0.1 lM), paclitaxel (0.1 lM), PX-12 (25 lM). The concentration of DMSO was maintained at 0.1%.
a
Prepared according to Kirkpatrick.32
The results show that the antiproliferative activity of the new
compounds is related, notably, to the presence of an electrophilic
group on the urea moiety of the molecules.10 Accordingly, 4-
cyclohexyl-[3-(ethyl)ureido]benzene 15, an ethylurea derivative
that is devoid of electrophilicity did not inhibit the proliferation
of the cell lines tested in this study even at 100 lM. However,
CEU derivatives 1–4, 5–12c, tBCEU, and ICEU displayed signifi-
cant antiproliferative activity on all tumor cell lines tested,
exhibiting GI50 values ranging from 2 to 49 lM. It is of interest
to point out that the substitution at position 3 (6c, 8c, 12c) sig-
nificantly improved the antiproliferative activity when compared
to molecules substituted on position 4 (4, 5c, 7c, 11c).
phase; phenomenon most likely related to the covalent binding
of the drugs to the C-BS of bII-tubulin.3–5,10 Unexpectedly, the
prototypical compound 4 blocked the cell cycle in G0/G1 phase.14
In that context, we have evaluated using flow cytometry analysis
whether the new cHCEU derivatives inhibit the cell cycle in G0/
G1 or in G2/M phase. The experiments were conducted on MCF-7
cells using 50 lM for 2-times the GI50 of the drug for 24 h. Table
1 shows for each drug the percentage of the cell arrested in the
various phases of the cell cycle. As reported previously, tBCEU,
ICEU, and the Trx-1 thioalkylating agent PX-12 blocked the cell
cycle progression in G2/M phase (Table 1). Compounds 1, 2, 9c
and 10c also induce the accumulation of cells in G2/M phase.
All other CEU derivatives (3, 4, 5c, 6c, 11c, 12c) clearly arrested
the cell cycle in G0/G1 phase.
Previous studies have shown that prototypical CEU deriva-
tives such as tBCEU and ICEU arrested the cell cycle in G2/M

3530
J. S. Fortin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3526–3531
Figure 2. Effect of compounds 1 and 4 on cell cycle progression. Exponentially growing MCF-7 cells were incubated for 24 h in absence or presence at 1-, 2-, and 4-times their
respective GI50. The concentration of DMSO used as an excipient was maintained at 0.1%. The cell cycle was evaluated by flow cytometry using propidium iodide staining.
cisplatin treatment is part of the mechanism of chemoresistance
Cytoplasm
4
Nucleus
4
to that drug, probably through p53, an anti-apoptotic gene, up-
regulation.21,35 Trx-1 confined into the nucleus compartment
has been shown to induce cell transcription and proliferation
to promote cell survival16,21,28 through
a signaling pathway
13
13
involving the reduction of Ref-1 and the induction of AP-1 activ-
ity.15–17 The latter is a powerful transcription factor promoting
cell growth and survival and controlling also the G0/G1 transition
via the AP-1-responsive cyclin D1.15–17,35
Figure 3. Effect of compounds 4, 13, and cisplatin on cytosolic and nuclear fractions
of thioredoxin-1. M21 cells were treated for 24 h with 25 lM of cisplatin (cDDP) and
compound 13, or 50 lM of compound 4, prior to cell fractionation. The resulting
nuclear and cytoplasmic proteins extracts were next separated on SDS–PAGE 15%
and then analyzed by Western blot using a polyclonal anti-Trx-1. Results are rep-
resentative of two separate experiments.
This study was designed to assess, at least partly, the impor-
tance of the nature and the position of the substituting moieties
on the aromatic ring of cHCEU derivatives on cell cycle progres-
sion, the presence of Trx-1 into the nucleus, and cell prolifera-
tion. Interestingly, all new CEU derivatives of the prototypical
compound 4 synthesized in this study exhibited antiproliferative
activity between 2 and 49 lM. However, these results should be
interpreted cautiously since the arrest of the cell cycle in G0/G1
transition phase suggests that the cells are entering into a ‘qui-
escent-like’ state where the cells do not divide actively and are
partly protected against cytotoxic agents, while drug arresting
the cell cycle in G2/M phase may normally initiate the apoptotic
program.36–38 Of note, our study shows that alicyclic substitution
on position 4 of the aliphatic ring with cycloalkyl or a cyclo-
alkyloxy moiety increases the efficacy of CEUs to inhibit Trx-1
nuclear translocation. The present study expands the family of
CEU that inhibit the cell cycle in G0/G1 phase, a unique property
that has been observed so far only with compound 4. Similarly
to cHCEU, the new inhibitors of the cell cycle progression in
G0/G1 phase do not inhibit cell growth through alkylation of
the C-BS on bII-tubulin. The precise mechanisms of action under-
lying both the accumulation of the cells in G0/G1 phase and the
Trx-1 nuclear translocation inhibition in response to cHCEU and
several of its derivatives are still under investigation. However,
they suggest that these new compounds might act as modulators
of chemoresistance to a variety of anticancer drugs such as cis-
platin and 5,12 anthracyclinediones.
Figure 2 depicts the cell cycle analysis of compounds 1 and 4
that are targeting b-tubulin and Trx-1, respectively. The experi-
ments were performed on MCF-7 tumor cells using 1-, 2-, and 4-
times their respective GI50 for 24 h and they clearly show that 1
and 4 block the cell cycle progression in G2/M and G0/G1 phase,
respectively.
As shown in Table 1, compound 4 abrogated the presence of
Trx-1 into the nucleus in contrast to DMSO used as an excipient.
That unexpected and important pharmacological phenomena
prompted us to assess the effect of the new cHCEU derivatives
on the cellular location of Trx-1 using immunocytochemistry
analysis. The results shown in Table 1 illustrate that the oxophe-
nyl derivatives 9c, and 10c do not significantly affect the intra-
cellular location of Trx-1. In contrast, the alicyclic compounds
4, 5c, 7c, 11c, and 12c abrogated the presence of Trx-1 into
the nucleus. The naphthyl and the fluorenyl compounds 2 and
3, together with compounds 6c and 8c, and 14 exhibited a mit-
igated effect on nuclear Trx-1 and unexpectedly, compound 1
seems to increase the presence of Trx-1 into the nucleus as ob-
served with cisplatin, which is known to trigger such a phenom-
enon.21,34 Interestingly, alicyclic compounds substituted at
position 4 (e.g., 5c and 7c) were more potent to inhibit Trx-1 nu-
clear translocation than their 3-substituted counterparts (e.g., 6c
and 8c). Nuclear extraction and Western blot analysis (Fig. 3)
confirmed the results obtained using immunocytochemistry
analysis and clearly show that the Trx-1 nuclear translocation
is repressed by compound 4 but not by the antimicrotubule
compound 13. In contrast to DMSO, 1, cisplatin, and PX-12 in-
creased Trx-1 localization into the nucleus. Trx-1 translocation
into the nucleus is associated to stress following H2O2 exposi-
tion, UV radiation, cisplatin treatment, and hypoxia.16,21,28 Inter-
estingly, the extended nuclear translocation of Trx-1 following
Acknowledgments
This work was supported by grants from le Fonds de la Recher-
che en Santé du Québec, Junior II (E.P.) and Canadian Institute for
Health Research (R.C.-G., E.P.; Grant #MOP-79334). Jessica S. Fortin
is recipient of a studentship from the Fonds de la Recherche en
Santé du Québec. We thank the Proteomic and Mass Spectrometry
Centre of the University of Toronto for its professional services. We
are very grateful to Mr. Maurice Dufour for the FACS analysis and
technical advices.

J. S. Fortin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3526–3531
3531
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.05.028.
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