Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides

Article abstract of DOI:10.1016/j.bmcl.2017.03.018

Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization.

Full text of DOI:10.1016/j.bmcl.2017.03.018

Accepted Manuscript
Synthesis and anti-cancer activities of new sulfonamides 4-substituted- triazolyl
nucleosides
Soukaina Alaoui, Maeva Dufies, Mohsine Driowya, Luc Demange, Khalid
Bougrin, Guillaume Robert, Patrick Auberger, Gilles Pages, Rachid Benhida
PII:
S0960-894X(17)30254-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.03.018
BMCL 24770
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 December 2016
7 March 2017
8 March 2017
Please cite this article as: Alaoui, S., Dufies, M., Driowya, M., Demange, L., Bougrin, K., Robert, G., Auberger, P.,
Pages, G., Benhida, R., Synthesis and anti-cancer activities of new sulfonamides 4-substituted- triazolyl nucleosides,
Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.03.018
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Synthesis and anti-cancer activities of new
sulfonamides 4-substituted- triazolyl nucleosides
Soukaina ALAOUIa,b,† Maeva DUFIES,c† Mohsine DRIOWYA,b† Luc DEMANGE,a,d
Khalid BOUGRIN,b* Guillaume ROBERT,e Patrick AUBERGER,e Gilles PAGESc and
Rachid BENHIDAa*
a
Université Côte d’Azur, CNRS, Institut de Chimie de Nice UMR 7272 - 06108 Nice,
France.
b
Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23,
Faculté des Sciences, Université Mohammed V, B.P. 1014 Rabat, Maroc.
c
Université Côte d’Azur, CNRS UMR 7284 and INSERM U 1081, Institute for Research on
Cancer and Aging (IRCAN), 28 Avenue de Valombrose, 06107 Nice, France.
d Département de Chimie, Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences
Pharmaceutiques, 4 avenue de l’Observatoire & UFR Biomédicale des Saints Pères, 45 rue
des Saints Pères, Paris Fr-75006, France.
e
Université Côte d’Azur, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire
(C3M), Bâtiment ARCHIMED, 151 Route de Saint-Antoine de Ginestière, BP 2 3194, 06204
Nice Cedex 3, France.
*Correspondence should be addressed to:
Rachid Benhida, e-mail: Rachid.benhida@unice.fr; phone: +33 4 92 07 61 43
† These authors contribute equally to this work.

ABSTRACT
Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer
chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest
such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in
different cell lines, AICAR is under clinical development for several pathologies, thanks to its original
mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism,
to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To
improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-
substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these
molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4
and MDA-MB 231. Among them, nucleoside analogue 5i belonging to the ribose series was found to
be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i
displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making
therefore this class of molecules highly promising for further hit-to-lead optimization.
KEYWORDS
Nucleoside analogues; Sequential reactions; Dipolar cycloaddition; Antitumor agents

Nucleoside analogues are an important class of bioactive molecules widely used in medicinal
chemistry and drug discovery because of their high potential applications as chemotherapeutic agents.
They represent, for a long time, the cornerstone of antiviral chemotherapy for the treatment of
different RNA and DNA viruses including HIV, HCV and HBV, for a millions of patients
worldwide.1-6 Recently, the increased interest in such analogues also rose from their high potential
application in the modulation of gene expression7,8 and also for several biophysical and biochemical
applications such as DNA and RNA labelling,9-13 supra molecular chemistry or as specific ligands for
oncogenic proteins and RNA.14-15 Moreover, several nucleosides are currently used in cancer
chemotherapy for the treatment of aggressive cancers, i.e. 5-azacytidine and decitabine, known as
epigenetic drugs.16-19 An other interesting example of bioactive ribonucleoside which has particularly
retain our attention is AICAR (5-aminoimidazole carboxamide ribosyl), a strong activator of AMP-
activated protein kinase (Figure 1).20,21 This drug has a broad spectrum of therapeutic applications
even if its real mechanism of action remains unclear. Interestingly, we recently reported that, while
this compound has a very low activity in several tumor cell lines (IC50 in mM range) its mode of action
is highly original. Indeed, AICAR inhibits cancer proliferation in naïve and resistant cells by inducing
a pure autophagy cell death, different from apoptosis.22 Therefore, the development of potent
analogues that retain this mode of action could be of utmost importance. To achieve this goal we focus
on 1,4-substituted triazolyl-nucleosides, which are highly accessible in few steps compared to
imidazole series, by using 1,3-dipolar cycloaddition.23,24 Based on our recent finding in triazolyl-
nucleoside series25-28 and on the known pharmacological properties of sulfonamide derivatives,
substituted sulfonamides were introduced at position 4 of triazole to increase the molecular diversity
(Figure 1).23-24 In line with this consideration, and in continuation of our investigations for the
development of original routes to bioactive nucleosides,29-33 we report herein a straightforward
synthesis of functionalized 4-substituted 1,2,3-triazolylsulfonamide-nucleosides and their biological
evaluation against two types of cancer cells, RCC4 and MDA-MB-231.
Figure 1. Structures of nucleoside analogues featuring anti-cancer activities, and general scaffold of the new
series of 4-sulfonamide substituted 1,2,3-triazolyl nucleosides.
The new 1,2,3-triazolyl-nucleosides have been synthesized through a convergent procedure outlined in
scheme 1. According to our previously reported route to azidoglycosides, intermediates 2 have been
obtained through a CuI/FeIII co-catalyzed sequential azidation.34 This one-pot synthesis combines
either iron, as Lewis acid catalyst (FeCl3, 20% mol), and SO2(N3)2, generated in situ by mixing NaN3

and SOCl2, which is used as soluble azide source. This reaction is achieved in 45 min under ultrasonic
activation and at room temperature. It is to note that the expected azidoglycosides are obtained as pure
-anomers in good yields, either with mono-saccharides and di-saccharides.
O
O
AcO
(AcO)n
AcO
(AcO)n
OAc
N3
(a)
50%-97%
N
N
R2
N
N
O
N
R2
N
AcO
(AcO)n
N
O
2
HO
(HO)n
N
O
(e)
(d)
O
S
S
quant.
R1
Cl
O
40%-97%
O
O
R2
R2
O
R1
R1
S
5n, 6i, 9c, 9d, 10b
5a-k: ribofuranose
(b)
(c)
34%-95%
O
O
O
O
N
N
6a-i: glucopyranose
H
S
S
R1
+
40%-90%
7:
8:
D-galactopyranose
D-mannopyranose
R1
R2
NH2
3
4
9a-d: lactose
10a-b: maltose
Scheme 1. Synthesis of the 1,2,3-triazolyl nucleosides. (a) NaN3, SOCl2, FeCl3, CH2Cl2, 45 min; (b)
Na2CO3/water, r.t., 1.5 h; (c) propargyl bromide, K2CO3, DMF, CH3CN, r.t., 3 h; (d) CuI, sodium ascorbate,
water/n-butanol (1/1, v/v), r.t., overnight.; (e) Na2CO3, CH3OH, r.t., 1 h.
On the other hand, sulfonamide derivatives have been synthesized by means of two successive
nucleophilic substitutions. In the first step, sulfonyl chlorides were reacted in aqueous media at room
temperature with primary amines and using Na2CO3 as base. The expected mono-substituted
sulfonamides 3 have been obtained under a short reaction time (1.5 h) in 40%-90% yields. Importantly,
these intermediates are isolated as crude material, and subsequently used in the next step without
purification. The subsequent additions of propargyl bromide to sulfonamides 3 at room temperature in
a mixture of DMF and CH3CN, and in presence of K2CO3, afforded the corresponding alkyne-
sulfonamides 4 in moderate to excellent yields (34%-95%).
Lastly, the Cu-catalyzed 1,3-dipolar cycloaddition of the azidoglycosides 2 to the alkyne-sulfonamides
4 has been carried out in aqueous media (water/n-butanol, 1/1, v/v), using CuI and sodium ascorbate.16
This dipolar cycloaddition has been performed overnight at room temperature and without activation.
All the corresponding acetylated triazolyl-nucleosides 5a-10b (Table 1, entries 1 to 31), have been
isolated with moderate to excellent yields (40% to 97%) after purification by flash chromatography.35
It is worth noting that despite the long reaction times of the dipolar cycloaddition, no racemization
occurred at the anomeric position of the carbohydrate, i.e. the stereochemistry of all products remained
unchanged during this reaction. Indeed, all the pure isolated compounds belonging to the ribofuranose
series (5a-l) exhibit a coupling constant JH1’-H2’ ranking between 3.3 Hz and 3.9 Hz, which evidences
unambiguously the -configuration of the anomeric position (SI). In the case of compound 5a, the 2D
NMR study revealed NOESY correlation between H1’ and H4’ (SI, Figure S1). Similarly, in the case
of the glycopyranose series, the 2D NMR study highlights NOESY correlations between H1’ and H3’
and also between H1’ and H5’, as illustrated for compound 6g (SI, Figure S1), confirming therefore
the -conformation of the saccharide.

All these newly synthesized nucleosides, including a short selection of deprotected ones, have been
submitted to XTT assays in order to evaluate their anti-cancer activity against RCC4 and MDA-MB-
231 cell lines at 5, 10, 25 and 50 µM, or at higher doses for those exhibiting lower activity.36 These
specific cell types have been chosen because they are representative of very aggressive cancers
(RCC4: metastatic kidney cancer; MDA-MB 231: metastatic triple negative breast cancer), that are
currently incurable.37,38 Hence, new therapeutic options are urgently needed. The structures and the
biological activities of all compounds are depicted in Table 1.
R3
N
N
N
O
RO
(RO)n
R1= sugar
O
N
S
O
R2
Entry
Cpd.
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
R1
R2
CH3
R3
RCC4
MDA-MB 231
IC50 (M)
1
2
3
4
5
6
7
8
9
C6H5
180 ± 6
190 ± 5
235 ± 4
125 ± 1
50 ± 2
250 ± 8
140 ± 3
29 ± 3
250 ± 2
160 ± 2
100 ± 3
250 ± 5
240 ± 7
225 ± 2
225 ± 2
31 ± 1
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C6H5
C6H5
C6H5
CH3
m-MeOC6H5
p-CN C6H5
CH2CO2CH3
C(CH3)2CO2CH3
C4H9
tri-O-acetyl-
ribofuranose
C6H13
C14H29
C16H33
13 ± 3
15 ± 3
10
11
12
13
14
p-Cl C6H5
C6H5
p-Me C6H5
p-ClC6H5
p-CN C6H5
250 ± 3
150 ± 6
230 ± 4
250 ± 9
250 ± 2
250 ± 2
100 ± 4
205 ± 7
250 ± 9
>250
5m
5n
Ribofuranose
15
16
17
18
19
20
21
22
23
24
CH3
CH3
CH3
CH3
C2H5
C2H5
C6H5
C6H5
CH3
CH3
m-MeOC6H5
p-CN C6H5
CH2CO2CH3
C(CH3)2CO2CH3
C6H5
p-ClC6H5
p-MeC6H5
p-ClC6H5
200 ± 7
120 ± 3
>250
240 ± 4
175 ± 4
>250
130 ± 2
115 ± 4
200 ± 3
170 ± 7
220 ± 5
215 ± 4
>250
225 ± 5
155 ± 6
>250
180 ± 7
135 ± 3
185 ± 4
100 ± 5
6a
6b
6c
6d
6e
6f
6g
6h
6i
tetra-O-acetyl-
glucopyranose
Glucopyranose
tetra-O-acetyl-
galactopyranose
tetra-O-acetyl-
mannopyranose
hepta-O-acetyl-
Lactose
p-CN C6H5
p-CN C6H5
7
25
CH3
p-CN C6H5
240 ± 8
230 ± 6
8
26
27
28
29
30
9a
9b
9c
9d
10a
CH3
C2H5
CH3
C2H5
CH3
p-CN C6H5
p-ClC6H5
p-CN C6H5
p-ClC6H5
50 ± 2
70 ± 3
160 ± 9
120 ± 7
200 ± 4
230 ± 3
150 ± 18
250 ± 9
215 ± 8
230 ± 4
Lactose
hepta-O-acetyl-
maltose
p-CN C6H5
31
32
33
Maltose
AICAR (Acadesine)
Sunitinib
CH3
p-CN C6H5
250 ± 6
250 ± 9
4 ± 2
250 ± 5
1000± 10
6 ± 3
10b
Ref-1
Ref-2

Table 1. IC50 of synthtetic compounds on RCC4 and MDA-MB-231 cancer cell lines after a 48 h treatment of
the indicated compounds relative to a DMSO control ± SD from independent experiments, as determined by
XTT assays.
Briefly, this screening highlights that three molecules exert a significant activity against RCC4 and/or
MDA-MB-231 cells, namely: 5h, 5i and 9a (entries 8, 9 and 26, respectively). Interestingly, all these
compounds share a methyl group in the sulfonamide moiety (R2= CH3). The most promising
nucleoside belongs to the ribofuranose series (compound 5i, entry 9), and exhibits an IC50 in the 13
µM range against the two cancer cell lines. Interestingly, these results showed that 5i is 19- to 66-fold
more active than AICAR (entries 9 and 32: 13 vs 250 µM on RCC4 and 15 vs 250 µM on MDA-MB-
231) and only 3-fold less active than sunitinib (entry 9 vs entry 33), the gold standard of care in the
treatment of renal cell carcinoma (RCC). Moreover, at the concentration of 50 µM this molecule
totally eradicates RCC4 and MDA-MB-231 cells (Figure 2). It is worth noting that the nature and the
size of the R3 substituent had a significant effect. Indeed, while several compounds with aromatic or
alkyl-ester substituents on the N-sulfonamide exhibited low activities, compounds with alkyl chain
allowed a clear structure-activity relationship. We found that the bioactivity increased with increasing
chain length as shown for compounds 5f, 5g, 5h and 5i (Table 1, entries 6-9, respectively) since the
activity increased from 250 M for 5f (C4) to 13-15 M for 5i (C16).39
Figure 2. Dose-response curves of compounds 5h (C14 alkyl chain) and 5i (C16 alkyl chain).
Among the other hits, two molecules belonging to the ribofuranose (5e, entry 5) and the lactose (9a,
entry 26) series exhibit an IC50 against the RCC4 and/or the MDA-MB-231 cells in the 50-70 µM
range. Furthermore, comparison of the cytotoxicity exerted by 5b vs 5n, 6b vs 6i and 10a vs 10b
suggests that the deprotection of sugar has only a minimal effect on the biological activity, except in
the lactose series where the protected compound 9a exhibited better activity than its free analogue 9c
(IC50 = 50 vs 120 M on CCR4 and 70 vs 150 M on MDA-MB-231, entries 26 and 28, respectively).
Furthermore, to get insight into the mode of action of this new class of compounds we set up a
preliminary experiment aimed at investigating the mechanism of cell death in comparison with
AICAR, known to induce pure autophagy cell death. RCC4 cells were treated with 5i or AICAR for

48h. Then, PARP cleavage (poly ADP-ribose polymerase, marker of apoptosis) and LC3 conversion
(autophagy marker) were analyzed by immunoblotting (SI, Figure S2). Importantly, we observed that
while AICAR induced a pure autophagy cell death in CCR4 as previously reported, 5i induced both
apoptosis (PARP cleavage) and autophagy cell death by increasing LC3 lipidation and cleavage, a
hallmark of autophagy induction. This mechanism of action that combines both apoptosis and
autophagy cell deaths in cancer cells is of great interest to overcome drug resistance and is currently
under investigation in our group.28
In summary, we reported the synthesis, the chemical characterization and the anti-cancer activity of a
new series of functionalized 4-sulfonamide-1,2,3-triazolyl-nucleosides. These molecules have been
easily obtained through a convergent procedure involving azidation, propargyl-sulfonamide formation
and Cu-catalyzed 1,3-dipolar cycloaddition. NMR studies revealed that no epimerization occurred at
the anomeric position during the cycloaddition step. Among this series of nucleoside analogues,
several derivatives exerted promising cytotoxic activities against RCC4 and MDA-MB-231 cells, with
IC50 ranging from 13 µM to 50 µM. Interestingly, the most potent compound (5i) displayed an IC50 of
13-15 µM, and fully eradicates RCC4 and MDA-MB-231 cancer cells when used at a dose of 50 µM.
Moreover, Western blot analyses on RCC4 cells showed that 5i exhibited an interesting mode of
action involving a dual apoptosis and autophagy cell death. Taken together, these results clearly
showed the potential of this class of molecules for exploring apoptosis and autophagy signalling and
for further hit-to-lead optimization toward the development of new therapeutic agents against different
forms of cancer.
Acknowledgments
This work is supported by PHC Toubkal MA/14/304 (30330ZF), CNRS, CNRST, the Ligue Nationale
Contre le Cancer (LNCC Equipe Labellisée 2011), the Association pour la Recherche sur le Cancer
(ARC), the Institut National du Cancer INCa-PL2011-0249, the Fondation de France (MD financial
supports) and Cancéropôle PACA. European COST Action CA15135 supports this article.
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A. Supplementary material
Supplementary data associated with this article can be found in the online version.