2,6-Diphenylthiazolo[3,2-b][1,2,4]triazoles as telomeric G-quadruplex stabilizers

Article abstract of DOI:10.1016/j.bmcl.2009.05.025

The design and synthesis of 2,6-diphenylthiazolo[3,2-b][1,2,4]triazoles characterized by a large aromatic building block bearing cationic side chains are reported. These molecules are evaluated as telomeric G-quadruplex stabilizers and for their selectivi

Full text of DOI:10.1016/j.bmcl.2009.05.025

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3434–3438
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Bioorganic & Medicinal Chemistry Letters
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2,6-Diphenylthiazolo[3,2-b][1,2,4]triazoles as telomeric G-quadruplex stabilizers
Jamal El Bakali a, Frédérique Klupsch a, Aurore Guédin b, Bertrand Brassart c, Gaëlle Fontaine d,
Amaury Farce e, Pascal Roussel f, Raymond Houssin a, Jean-Luc Bernier d, Philippe Chavatte e,
a
Jean-Louis Mergny b, Jean-François Riou b, , Jean-Pierre Hénichart
*
a Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, IFR 114, Université de Lille 2, 3 rue du Professeur Laguesse, BP 83, 59006 Lille, France
b INSERM U565, CNRS UMR 7196, USM 503, Muséum National d’Histoire Naturelle, Case Postale 26, 43 rue Cuvier, 75005 Paris, France
c Laboratoire d’Onco-Pharmacologie, JE 2428, Université de Reims Champagne-Ardenne, 51096 Reims, France
d Laboratoire de Chimie Organique Physique, CNRS UMR 8009, Université des Sciences et Technologies de Lille, 59655 Villeneuve d’Ascq, France
e Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, EA 1643, IFR 114, Université de Lille 2, 3 rue du Professeur Laguesse, BP 83, 59006 Lille, France
f Unité de Catalyse et Chimie du Solide, CNRS UMR 8181, Ecole Nationale Supérieure de Chimie de Lille, BP 90108, 59652 Villeneuve d’Ascq, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The design and synthesis of 2,6-diphenylthiazolo[3,2-b][1,2,4]triazoles characterized by a large aromatic
building block bearing cationic side chains are reported. These molecules are evaluated as telomeric G-
quadruplex stabilizers and for their selectivity towards duplex DNA by competition experiments. Two
compounds (14a, 19) were found active with high selectivity for telomeric G-quadruplex over duplex
DNA.
Received 10 April 2009
Revised 7 May 2009
Accepted 8 May 2009
Available online 12 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
G-quadruplex
Telomere
Cancer
2,6-Diphenylthiazolo[3,2-b][1,2,4]triazole
Telomeres are guanine-rich DNA sequences located at the end
of eukaryotic chromosomes, which protect them from fusion and
degradation.1 Human somatic cells undergo erosion of telomeres
after each cell division,2 leading to replicative senescence and
apoptosis.3 In contrast, most cancer cells are able to maintain telo-
mere length either by the activity of telomerase or by recombina-
tion between telomeres (alternative lengthening of telomeres).4
Almost two decades ago, it was shown that the telomeric G-over-
hang is able to fold into G-quadruplex structures, leading to inhibi-
tion of telomerase activity.5 The telomeric G-quadruplex building
blocks (called G-quartets) are based on stacked associations of
hoogsteen bonded guanines, forming square aromatic surfaces
whose dimensions are larger than the duplex DNA. This difference
constitutes the basis for designing selective telomeric G-quadru-
plex ligands that are capable of stabilizing them so as to inhibit tel-
omerase activity and reverse tumor cell immortalization.6,7 Indeed,
prolonged treatment of various tumor cell lines with telomeric G-
quadruplex ligands has been shown to provoke a telomerase-like
inhibition phenotype (including telomere shortening, delayed
growth inhibition and senescence induction), but also telomere
uncapping (including apoptosis, telomere fusion, anaphase bridges,
G-overhang degradation and DNA damage to telomeres).8,9
So far, several telomeric G-quadruplex interacting ligands have
been described (Scheme 1), such as acridine 1,10 anthraquinone 2,6
perylene 3,11 and dibenzophenanthroline 4,12 (for a recent review
see Ref. 13). Most of them include a large aromatic core suitable
for
p-p stacking interaction with terminal G-tetrads and possess
cationic side chains able to engage electrostatic bonds with DNA
phosphates.
Previous studies from our laboratory focused on the synthesis
and intercalative properties of
a
2-phenyl-6-thiazolyl[3,2-
b][1,2,4]triazole (PETT).14 Because Hoechst 33258 was shown to
present G-quadruplex binding properties15 and displayed some
scaffold similarities with PETT, we planned to develop new mole-
cules based on this bicyclic condensed system (Scheme 2), present-
ing these features. It confers a crescent shape to the extended
aromatic structure and above all, cationic chains substituting two
lateral phenyl rings.
We present here the synthesis of a series of 2,6-diphenylthiaz-
olo[3,2-b][1,2,4]triazoles 12a,b, 13a,b, 14a,b, 15–19 and the ability
of some of them to stabilize telomeric G-quadruplex.
The synthesis of substituted 2,6-diphenylthiazolo[3,2-b]
[1,2,4]triazoles was performed from ethyl 4-hydroxybenzoate.
The thiazolo[3,2-b][1,2,4]triazole scaffold was prepared as
* Corresponding author. Tel.: +33 14079 3698; fax: +33 14079 3705.
E-mail address: riou@mnhn.fr (J.-F. Riou).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.025

J. El Bakali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3434–3438
3435
+
N
H
O
H
NH
N
N+
O
N+
OH
O
O
O
N
H
N
H
N
H
N
N
N
O
+
+
H
H
OH
1
2
+
NH
+
HN
HN
O
O
HN
N
N
O
N
+
+
HN
NH
N
O
4
3
Scheme 1. Structure of some telomeric G-quadruplex ligands.
O
O
N
N
S
N
N
S
PETT
R2
+
NH
R1
+
HN
N
HN
N
N
H
N
N
S
14a, 16, 19
R1, R2 : cationic side chain
N
4
HO
N
N
N
N
HN
HN
Hoechst 33258
Scheme 2. Drug design of 2,6-diphenylthiazolo[3,2-b][1,2,4]triazoles.
R
O
R
R
R
OH
O
O
O
O
a
b
c
d
H
NH2
N
NH2
O
O
O
O
N
H
O
N
H
N
N
S
HN
SH
5 a,b
6 a,b
7 a,b
8 a,b
a : R = CH2CH2NC5H10
b : R = CH2C6H5
Scheme 3. Reagents and conditions: (a) 1-(2-Chloroethyl)piperidine or benzyl bromide (1.2 equiv), K2CO3 (3.2 equiv), DMF, 80 °C, 12 h, 95%; (b) NH2NH2,H2O (2.5 equiv),
EtOH, reflux, 72 h, 82–88%; (c) NH4SCN (2.5 equiv), 1 N HCl (2.5 equiv), EtOH, reflux, 60 h, 86%; (d) (i) 1% NaOH (2 equiv), 90 °C, 12 h, (ii) 1 N HCl (pH 6), 71–91%.
previously described,16,17 using appropriate 3-mercapto-5-aryl-
[1,2,4]-triazoles and -bromoketones. The O-alkylated 3-mer-
capto-5-aryl-[1,2,4]-triazoles 8a,b were obtained (Scheme 3) by
of hydrazine monohydrate on ester (hydrazides 6a,b); subsequent
addition of ammonium thiocyanate in acidic conditions gave thi-
osemicarbazides 7a,b. Cyclization in alkaline medium led to 3-
mercapto-5-aryl-[1,2,4]-triazoles 8a,b at very high yields.
a
O-alkylation of ethyl 4-hydroxybenzoate followed by the reaction

3436
J. El Bakali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3434–3438
O
O
O
O
O
O
Br
Br
a
b
a
OH
O
O
O
O
O
9
10
11
Scheme 4. Reagents and conditions: (a) Br2 (1.2 equiv), AcOH, rt, 12 h, 79–83%; (b) benzyl bromide (1.2 equiv), K2CO3 (3.2 equiv), DMF, 80 °C, 12 h, 98%.
a
-Bromoketones 9 and 11 were synthesized (Scheme 4) using a
thiazolo[3,2-b][1,2,4]triazoles 12a,b and 17 at high yields
(Scheme 5). After saponification of the esters 12a,b (lithium
hydroxide), the carboxylic acids 13a,b were engaged in an amida-
tion reaction with aminoethylpiperidine under peptidic conditions
(compounds 14a,b). Further O-debenzylation of 14b (and 17) lead-
ing to hydroxyphenylthiazolotriazole 15 (and 18) was found to be
modified version of the described procedure,18 by bromination of
the corresponding commercial methylketones (with previous ben-
zylation of 4-hydroxyacetophenone).
Condensation and cyclization of mercaptotriazoles 8a,b with
appropriate
a-bromoketones 9 and 11 led directly to 2,6-diphenyl-
R
O
N
N
HN
a
f
SH
8 a,b
O
O
O
R
O
O
N
N
N
S
N
N
N
S
12 a,b
17
g
b
OH
OH
O
R
HO
O
N
N
N
N
N
N
S
18
S
13 a,b
h
+
c
NH
+
NH
O
R
+
O
NH
O
NH
N
N
N
N
N
O
N
S
S
14 a,b
19
+
d
NH
OH
NH
+
O
+
NH
N
H
O
NH
N
N
N
N
N
e
N
O
S
S
15
16
+
a : R = CH2CH2NHC5H10
b : R = CH2C6H5
Scheme 5. Reagents and conditions: (a) 9 (1 equiv), EtOH, reflux, 72 h, 86–77%; (b) (i) 0.1 N LiOH (4 equiv), THF, rt, 12 h, (ii) 1 N HCl (pH 5), 94%; (c) (i) 1-(2-
aminoethyl)piperidine (1.5 equiv), HOBt (0.5 equiv), HBTU (1.5 equiv), DIPEA (2 equiv), DMF, rt, 12 h, (ii) HCl/i-PrOH, 75%; (d) (when 14b in its free base form) (i) BBr3 (1 M in
CH2Cl2, 3 equiv), CH2Cl2, ꢀ78 °C, 1 h, (ii) rt, 12 h, (iii) HCl/i-PrOH, 86%; (e) (i) 1-(2-chloroethyl)pyrrolidine (1.2 equiv), K2CO3 (3.2 equiv), DMF, 80 °C, (ii) HCl/i-PrOH, 21%; (f)
(when 8b) 11 (1 equiv), EtOH, reflux, 72 h, 79%; (g) (i) BBr3 (1 M in CH2Cl2, 6 equiv), CH2Cl2, ꢀ78 °C, 1 h, (ii) rt, 12 h, 81%; (h) (i) 1-(2-chloroethyl)piperidine (2.4 equiv), K2CO3
(6 equiv), DMF, 80 °C, (ii) HCl/i-PrOH, 64%.

J. El Bakali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3434–3438
3437
Table 1
Experimental conditions used for debenzylation of benzyl ether 14b
15
Entry
Experimental conditions
Yield (%)
12
9
1
2
3
4
5
6
H2/Pd, MeOH, rt, 12 h
H2/Pd, MeOH, 50 °C, 12 h
H2/Pd, MeOH, 50 °C, 50 bars, 12 h
H2/PtO2, 50 °C, 50 bars, 12 h
BBr3, CH2Cl2, rt, 16 h
0
0
0
0
18
86
0
3
BBr3, CH2Cl2, -78 °C, 1 h, then rt, 12 h
10
30
6
effective with boron tribromide (low temperature), whereas classi-
cal catalytic conditions failed (Table 1). Finally, O-alkylation was
completed with the appropriate chloroethylamine to give the tar-
get compounds 16, 19.
The planarity of the diphenylthiazolo[3,2-b][1,2,4]triazole sys-
tem was proved thanks to the X-ray structure of ester 12a
(Fig. 1) and was essential in enabling this aromatic system to
establish aromatic–aromatic stacking with G-tetrads.
Compounds 12b, 14a,b, 15–19 were evaluated for their ability
to bind and stabilize a telomeric G-quadruplex structure by a fluo-
rescence resonance energy transfer (FRET) assay using the 21-mer
d[(GGGTTA)3GGG] oligonucleotide end-labeled with a fluorescent
donor–acceptor pair (F21T).20,21 The change in F21T emission in
3
0
14a
16
19
Figure 2. Stabilization (
compounds 14a, 16 and 19 (3
30 M).
D
Tm for the F21T telomeric G-quadruplex at 0.2
lM) for
l
M) in the presence of ds26 competitor (0, 3, 10 and
l
prove activity. Replacement of this benzyl group by
a
piperidinoethyl group (compound 14a) or by a pyrrolidinoethyl
group (compound 16) significantly improved the biochemical
properties. Finally, the presence of an oxygen (compound 19) in-
stead of the amide group (compound 14a) did not significantly re-
duce activity. In contrast, the replacements of the two piperidinic
chains of compound 19 by two benzyl groups (compound 17) com-
pletely eliminated G-quadruplex stabilization and highlight the
importance of two cationic side chains.
To determine the selectivity of the interaction for the telomeric
G-quadruplex relative to duplex DNA, the melting temperature of
F21T (0.2
(3 M) was monitored (Fig. 2) with a 26-oligonucleotide duplex
(ds26) competitor (at 3, 10 and 30 M). In the presence of 30
the presence of the tested compounds (3
a function of temperature whether it be in Na+ (NaCl 100 mM) or
K+ (KCl 10 mM; LiCl 90 mM) conditions.22 The resulting
Tm values
lM) was monitored as
D
provide an indication of the stability of a ligand–quadruplex com-
plex and are summarized for Na+ and K+ (Table 2).
These results indicate that compounds 14a, 16 and 19 induce a
significant stabilization of the telomeric G-quadruplex (DTm >1 °C)
in both Na+ and K+ conditions. In agreement with previous studies,
these compounds were found more active in K+ than in Na+22,23 and
presented two cationic side chains able to interact with the groove
and/or the negatively charged phosphate backbone of a G-quadru-
plex.13 Compounds 12b, 14b, 17 and 18 did not present significant
G-quadruplex stabilizing properties. The presence of a piperidino-
ethylaminocarbonyl chain (compound 15) in place of one hydroxyl
group of the inactive derivative 18 produced moderate stabilizing
properties in K+ conditions. Replacement of the remaining hydro-
xyl of molecule 15 by a benzyl ether (compound 14b) did not im-
lM) in the presence of compounds 14a, 16 and 19
l
l
lM
ds26 oligonucleotide (i.e., a 150-fold molar excess), the stabiliza-
tion induced by compounds 14a and 19 was not significantly low-
ered, demonstrating that these two compounds display excellent
selectivity for G-quadruplex relative to duplex DNA. In contrast,
the stabilization induced by compound 16 decreased by about
3 °C in the presence of 30 lM ds26, indicating that this compound
displays lower selectivity for G-quadruplex. This concords well
with the work24 which showed that the replacement of the tertiary
amine piperidine by pyrrolidine provoked a slight increase of G-
quadruplex stabilization but also a decrease of selectivity. The
importance of the steric factor as well as the nature of the amine
substituent at the termini of the side chain and the ligand core con-
formation have already been found critical in terms of selectivity
and affinity for G-quadruplex.25–27
The putative binding modes of compounds 14a and 16 to the
telomeric G-quadruplex structure were then investigated by a
docking study carried out with Gold 4.0.1.28 Both compounds be-
haved similarly, yielding a single conformation forming a large
stacking with the bases of the terminal G-quartet (Fig. 3).
Figure 1. Perspective view of 12a.19
Table 2
F21T FRET-based
D lM) at the
Tm valuesa (°C) for compounds 12b, 14a,b, 15–19 (3
Comparison of the G-quadruplex stabilization by 14a and 19
with previously published derivatives such as telomestatin29 or
pyridine dicarboxamide 360A30,31 indicated that the ligands tested
here are, respectively, 5- and 30-fold less potent (based on the con-
centration of ligand necessary to obtain the same stabilization).32
The data presented here indicated that the melting profile of
14a and 19 was almost unaffected by the presence of 150 molar
equivalent of unlabeled ds-DNA competitor and represented one
of the highest levels of selectivity that we are aware of for the telo-
indicated ionic conditions
Compounds
Na+
K+
12b
14a
14b
15
16
17
<1
5.0 ( 1.0)
<1
<1
5.9 ( 1.8)
<1
<1
11.2 ( 1.2)
2.7 ( 0.5)
1.8 ( 2.3)
14.6 ( 0.6)
<1
18
19
<1
2.1 ( 0.2)
<1
8.7 ( 0.3)
meric G-quadruplex over duplex DNA,13,22 although
DTm values
a
are not the highest reported for G-quadruplex interacting ligands.
Therefore, these compounds represent interesting molecular
Values are means of three experiments, standard deviation is given in paren-
theses (<1 = inactive compound).

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J. El Bakali et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3434–3438
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19. Crystallographic data (excluding structure factors) for the structure of 12a
have been deposited at the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 727384. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44 (0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
20. Kaiser, M.; De Cian, A.; Sainlos, M.; Renner, C.; Mergny, J. L.; Teulade-Fichou, M.
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Figure 3. Docking of compounds 14a (yellow) and 16 (magenta) on the G-quartet
structure (green).
21. Quantitative FRET experiments were obtained on a Stratagene MX3000P (La
Jolla, CA) quantitative PCR apparatus using 0.2
l
M
F21T (50-FAM-
GGGTTAGGGTTAGGGTTAGGG-tetramethylrhodamine-30). Melting profiles
were recorded in a 10 mM Li cacodylate (pH 7.2) buffer with 100 mM NaCl
or 10 mM KCl + 90 mM LiCl. Excitation wavelength was 496 nm and emission
was recorded at 516 nm. For competition experiments, various concentrations
of the double-stranded ds26 competitor (50-CAATCGGATCGAATT-
CGATCCGATTG) were added prior to the melting experiment.
probes or tools to analyze the biological processes affected by G-
quadruplex stabilization. This work has revealed the interest of
substituted diphenylthiazolo[3,2-b][1,2,4]triazole as a promising
scaffold for the design of telomeric G-quadruplex stabilizers. Fur-
ther studies -with isomeric diphenylthiazolo[2,3-c][1,2,4]triazoles
conferring an orientation to various charged side chains close to
the one recently described26,27—are ongoing and will be presented
in due course.
22. De Cian, A.; Guittat, L.; Kaiser, M.; Saccà, B.; Amrane, S.; Bourdoncle, A.; Alberti,
P.; Teulade-Fichou, M. P.; Lacroix, L.; Mergny, J. L. Methods 2007, 42, 183.
23. Brassart, B.; Gomez, D.; De Cian, A.; Paterski, R.; Montagnac, A.; Qui, K. H.;
Temime-Smaali, N.; Trentesaux, C.; Mergny, J. L.; Gueritte, F.; Riou, J. F. Mol.
Pharmacol. 2007, 72, 631.
24. Moorhouse, A. D.; Haider, S.; Gunaratnam, M.; Munnur, D.; Neidle, S.; Moses, J.
E. Mol. BioSyst. 2008, 4, 629.
Acknowledgments
25. Moorhouse, A. D.; Santos, A. M.; Gunaratnam, M.; Moore, M.; Neidle, S.; Moses,
J. E. J. Am. Chem. Soc. 2006, 128, 15972.
26. Drewe, W. C.; Neidle, S. Chem. Commun. 2008, 5295.
This work was supported by the ‘Ligue Nationale contre le Can-
cer, Equipe Labellisée 2006’ (to J.F.R.) and EU FP6 ‘MolCancerMed’
LSHC-CT-2004-502943 (to J.L.M.) grants.
27. Drewe, W. C.; Nanjunda, R.; Gunaratnam, M.; Beltran, M.; Parkinson, G. N.;
Reszka, A. P.; Wilson, W. D.; Neidle, S. J. Med. Chem. 2008, 51, 7751.
28. The G-quadruplex structure was retrieved from the PDB (entry 143d was used,
as its sequence is closer to the G-quadruplex structure employed in the tests).
The consistency of the 30 resulting docking conformations was assessed
visually and the most representative conformations were taken as the final
docking results.
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32. The concentrations of ligands necessary to induce
10 and 15 °C were found equal to 0.1 and 0.3 M for pyridine dicarboxamide
360A, and to 0.6 and 0.8
M for telomestatin, as determined in K+ conditions.
DTm variations equivalent to
l
l