Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-yl)aryl)benzenesulfonamides as anti-cancer compounds against sensitive and resistant cells

Article abstract of DOI:10.1016/j.bmcl.2017.03.054

We recently described a new family of bioactive molecules with interesting anti-cancer activities: the N-(4-(3-aminophenyl)thiazol-2-yl)acetamides. The lead compound of the series (1) displays significant anti-proliferative and cytotoxic activities against a panel of cancer cell lines, either sensitive or resistant to standard treatments. This molecule also shows a good pharmacological profile and high in vivo potency towards mice xenografts, without signs of toxicity on the animals. In the present article, we disclose the structure-activity relationships of this lead compound, which have provided clear information about the replacement of the acetamide function and the substitution pattern of the benzenesulfonamide ring. An improved high-yielding synthetic procedure towards these compounds has also been developed. Our drug design resulted in potency enhancement of 1, our new optimized lead compound being 19. These findings are of great interest to further improve this scaffold for the development of future clinical candidates.

Full text of DOI:10.1016/j.bmcl.2017.03.054

Accepted Manuscript
Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-
yl)aryl)benzenesulfonamides as anti-cancer compounds against sensitive and
resistant cells
Cyril Ronco, Antoine Millet, Magali Plaisant, Patricia Abbe, Nedra Hamouda-
Tekaya, Stéphane Rocchi, Rachid Benhida
PII:
S0960-894X(17)30302-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.03.054
BMCL 24806
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 January 2017
20 March 2017
21 March 2017
Please cite this article as: Ronco, C., Millet, A., Plaisant, M., Abbe, P., Hamouda-Tekaya, N., Rocchi, S., Benhida,
R., Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-yl)aryl)benzenesulfonamides as anti-
cancer compounds against sensitive and resistant cells, Bioorganic & Medicinal Chemistry Letters (2017), doi:
http://dx.doi.org/10.1016/j.bmcl.2017.03.054
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Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-
yl)aryl)benzenesulfonamides as anti-cancer compounds against sensitive and
resistant cells
Cyril Roncoa#, Antoine Milleta#, Magali Plaisantb#, Patricia Abbeb, Nedra Hamouda-Tekayab, Stéphane
Rocchib* and Rachid Benhidaa*
a Université Côte d’Azur, CNRS, Institut de Chimie de Nice UMR7272 – 06108 Nice, France; b Université Côte d’Azur, INSERM, U1065, Centre Méditerranéen
de Médecine Moléculaire (C3M), Equipe Biologie et Pathologie des cellules mélanocytaires: de la pigmentation cutanée au mélanome, 151 Route de Saint-
Antoine, 06200 Nice, France
Abstract: We recently described a new family of bioactive molecules with interesting anti-cancer activities: the N-(4-(3-
aminophenyl)thiazol-2-yl)acetamides. The lead compound of the series (1) displays significant anti-proliferative and cytotoxic activities
against a panel of cancer cell lines, either sensitive or resistant to standard treatments. This molecule also shows a good
pharmacological profile and high in vivo potency towards mice xenografts, without signs of toxicity on the animals. In the present
article, we disclose the structure-activity relationships of this lead compound, which have provided clear information about the
replacement of the acetamide function and the substitution pattern of the benzenesulfonamide ring. An improved high-yielding
synthetic procedure towards these compounds has also been developed. Our drug design resulted in potency enhancement of 1, our new
optimized lead compound being 19. These findings are of great interest to further improve this scaffold for the development of future
clinical candidates.
Keywords: Thiazolyl-benzenesulfonamides, Structure activity relationship, Lead optimization, Drug resistance, Cancer, Autophagy
and Apoptosis.
Main Text:
Despite constant research progress, cancer remains the leading cause of death in developed countries.1 Classical radio- and
chemotherapies based on DNA-damaging methods usually suffer from low success rates and limited benefit for patients because of
severe adverse effects.2,3 The advent of targeted therapies has improved the clinical outcomes of certain patients with various types of
cancer.4,5 However, rapid emergence of resistance against these agents and particularly toward kinase inhibitors is frequently observed
contributing therefore to treatment failure.6-9 In this context, the development of new bioactive molecules featuring a new mode of
action is urgently needed to overcome drug resistance.10,11
We recently described a new class of compounds, belonging to the N-(4-(3-aminophenyl)thiazol-2-yl)acetamides family, that showed
significant cytotoxic activities on different cancers, including cells resistant to the standard treatments.12-15 Our previous results pointed
out the importance of a sulfonamide over an amide link to retain the biological activity, and suggested a preference for substituted

phenyl groups attached to the sulfonamide, over heteroaromatics. The most active compound of the series (1, Figure 1), which bears a
4-(oct-1-yn-1-yl) chain, displayed high potency towards a panel of sensitive and resistant cells, both in vitro and in vivo models.12,13,16
However, the exact contribution of the alkyne-side chain and the acetamide group (R1 and R2, Figure 1) to the overall activity was not
clearly established. To this end, we report herein the synthesis and the biological evaluation of a new set of analogues aimed at
improving the bioactivity and at deciphering the structure-activity relationships of this class of compounds, on a melanoma A375 cell
line model. Two types of analogues have been prepared depending on the modified moiety (Figure 1). The first one explores the
modification of the octyn-1-yl chain on the phenyl ring, with a focus on the importance of the presence of the alkyne function, the
substitution position, and the size of the hydrophobic chain. The second aimed at studying the effect of the acetamide group.
Figure 1. Structure of previous lead compound 1 and the envisioned modifications.
To this end, four new aryl bromide precursors 5a-c and 6 were synthesized using a four-steps sequence: α-bromination / Hantzsch
thiazole coupling / nitro reduction / sulfonylation (Scheme 1). These syntheses were performed from commercially available 3-
nitroacetophenone following previously described or adapted procedures.17-20 Briefly, after quantitative AlCl3-catalyzed α-bromination
of 3-nitroacetophenone, Hantzsch thiazole cyclocondensation with different suitable thioureas was performed with high yields to get the
corresponding thiazoles 3a-c (Scheme 3).16-18 The nitro groups were subsequently reduced with NaBH4-Pd/C to afford the
corresponding anilines 4a-c. Coupling with the suitable sulfonyl chlorides under standard conditions afforded bromosulfonamides 5a-c
and 6.
Scheme 1. Synthesis of intermediates 3a-c, 4a-c, 5a-c and 6.
Br
O
(i)
(ii)
(iii)
N
N
S
N
H2N
O2N
O2N
Br
92-100%
NH
R2
NH
R2
N
45-100%
NH
R2
O
37-88%
H
O
S
S
S
4a* R2 = COCH3
4b R2 = CH3
4c R2 = Ph
3a* R2 = COCH3
3b R2 = CH3
3c R2 = Ph
2
5a R1 = para-Br; R2 = COCH3
5b R1 = para-Br; R2 = CH3
5c R1 = para-Br; R2 = Ph
6
R1 = meta-Br; R2 = COCH3
Reagents and conditions: (i) Br2, AlCl3, Et2O, 0°C to r.t., 1 h; (ii) Corresponding thiourea, EtOH, 80°C, 2 h; (iii) NaBH4, 10% Pd/C;
MeOH, 0°C to r.t., 3 h; (iv) 3- or 4-bromobenzenesulfonyl chloride, Et3N, DMF, r.t., 1 h. * Already described compound12
The first set of analogues was prepared to assess the impact of the variation of the oct-1-yn-1-yl chain on the biological activity. Thus,
derivatives bearing various substituted alkynyl, alkenyl and alkyl chains of different sizes were synthetized (Scheme 2). The
substitution pattern in meta or para position was also evaluated through the synthesis of both isomers for several compounds.

Notably, the synthetic route towards these compounds was revisited and optimized, particularly for the Sonogashira coupling reaction
step. Whereas our previous coupling conditions using an aryl iodide and a Pd(II) source led to low and non-reliable yields, the
replacement by a Pd(0) catalyst with aryl bromide was significantly more efficient. From precursors 5a and 6, optimal Sonogashira
coupling conditions using Pd(PPh3)4 and CuI in a mixture of benzene and triethylamine allowed the preparation of derivatives 7-10 and
12-16 with significantly improved yields compared to our previous procedure using Pd(OAc)2 and a iodo aryl compound (71-88% vs
25-35%). Subsequently the trimethylsilyl derivatives 10 and 16 were deprotected using K2CO3 in methanol to afford true alkynes 11
and 17 (Scheme 2).
Scheme 2. Synthesis of derivatives 7-17.
R1
(i)
O
O
5a or
6
S
N
34-97%
N
H
NH
O
S
R1 =
para series
meta series
1
5
14
7*
5
3
HO
HO
15
8
9
16
17
Si
(ii)
10
11
Si
H
H
(ii)
12
13
7
Ph
Reagents and conditions: (i) corresponding alkyne, Pd(PPh3)4, CuI, Et3N/benzene, 1/1: v/v, 70°C, 2-4 h; (ii) K2CO3, MeOH/CH2Cl2,
1/1: v/v, 14 h.* Already described compound12
The alkene 18 and alkanes 19-20 were prepared by catalytic hydrogenation of the corresponding alkynes 1 or 7 (Scheme 3). 18 was
synthesized by partial hydrogenation of 1 catalyzed by Lindlar palladium with satisfying 74% yield. Alkanes 19 and 20 were prepared
by full reduction of the triple bond of respectively 1 and 7 in the presence of H2/Pd/C.
Scheme 3. Synthesis of derivatives 18-20.
O
S
N
(i)
N
H
NH
O
O
n
S
74%
18
O
S
N
N
H
NH
O
O
S
(ii)
1 n = 5
7 n = 3
O
60-87%
n
S
N
N
H
NH
O
S
19 n = 5
20 n = 3
O
Reagent and conditions: (i) Pd Lindlar, H2 (1 atm), MeOH, r.t., 2 h; (ii) 10% Pd/C, H2 (1 atm), MeOH, r.t, 10 to 20 min.

The second set of analogues was prepared to study modifications on the aminothiazole function. Thus, N-phenyl, N-methyl and free
aniline derivatives 21, 22 and 23 were synthesized from bromosulfonamide precursors 5a-c by using the above described optimized
Sonogashira coupling reaction procedure (Scheme 4). Free aniline analogue 23 was obtained from 1, after the acetyl group cleavage
using aqueous HCl in ethanol at 80°C.
Scheme 4. Synthesis of derivatives 21-23.
5
(i)
O
5a-c
S
N
N
23-65%
NH
R2
O
H
S
1 R2 = COCH3
21 R2 = CH3
22 R2 = Ph
(ii)
quant.
23 R2 = H
Reagents and conditions: (i) Oct-1-yne, Pd(PPh3)4, CuI, Et3N/benzene, 1/1: v/v, 70°C, 2-4 h; (ii) 2M aq.HCl/EtOH, 1/1: v/v, 80°C,
1h30.
Therefore, nineteen analogues of 1 were synthesized and fully characterized. They were divided into two groups depending on the
modified region. Derivatives of group A include compounds 5-20 and present modifications on the benzenesulfonamide moiety,
whereas derivatives 21-23 belong to group B and are modified on the aminothiazole.
The presented analogues have been designed to explore several structural modifications of the lead compound 1. The length of the oct-
1-yn-1-yl chain was evaluated through derivatives 1 vs 6-7-12 and 19-20, whereas its nature was evaluated with derivatives 8-11 and
13. The necessity of the presence of the triple bond – as it is or though possible oxidative metabolism thereof – was estimated through
analogues 1 vs 8, 11, 18, 19 and 20. The orientation of the chain was evaluated with different meta and para isomers bearing the same
chain: 1/14, 5a/6, 11/17, and 8/15. Finally, the aminothiazole substitution was probed with derivatives 1 vs 21, 22 and 23.
We first based our SAR study on viability assays on A375 melanoma cells. Indeed, melanoma, an aggressive form of skin cancer, was
used as a cancer model as (i) its resistance to recent B-Raf inhibitors is a major concern, and (ii) because it still displays one of the
highest mortality rates.9 Derivatives of groups A and B were incubated with melanoma cells for 48h at three different doses: 10 µM, 5
µM, and 1 µM and cell counting was performed following the trypan blue exclusion assay method.
The cell viabilities of group A and B are summarized in Table 1. We found that the bromo derivative 5a was significantly less active
than its already described bulkier iodo analogue12 (25.6% vs <1% at 10 µM). A similar activity was obtained for the meta-bromo isomer
6. The 3-hydroxyprop-1-yn-1-yl derivatives 8 and 15 showed a significant decrease of the activity with an EC50 ~ 10 µM. The terminal
alkynes 11 and 17 displayed viabilities values in the same range than the reference compound 1, slightly lower. Of note, the
trimethylsilylated precursors 10 and 16 were somewhat more active than the corresponding terminal alkynes 11 and 17. The meta-
branched oct-1-yn-1-yl analogue showed similar activities compared to the parent compound 1 (para-substituted).

Table 1. Evaluation of the activity of group A and group B derivatives.
% Cell viabilitiya
5 µM
Compound
2-thiazole substituent
position
10 µM
1 µM
1
NH-acetyl
-
para
para
meta
para
para
para
para
para
para
para
meta
meta
meta
meta
para
para
para
para
para
para
5.8 7.3
25.6 11.2
36.0 8.0
< 1.0b
12.8 2.0
19.7 5.3
67.4 7.3
9.3 2.0
99.3 17.2
1.2 2.0
4.2 0.6
38.3 4.9
8.9 3.8
4.2 3.0
1.2 2.0
66.2 7.0
< 1.0b
40.7 2.0
n.a.c
5a
6
-
n.a.c
7
-
73.2 12.6
81.3 10.1
52.3 24.6
94.3 10.5
59.2 4.9
39.6 14.9
11.5 3.5
56.9 2.0
85.4 7.4
61.6 10.6
74.3 14.5
48.8 4.9
34.8 9.9
49.9 7.3
36.6 7.4
87.1 9.9
97.6 9.9
8
-
48.8 4.9
1.2 2.0
< 1.0b
9
-
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
-
1.2 2.0
< 1.0b
-
-
< 1.0b
-
< 1.0b
-
-
45.3 4.9
5.8 2.0
18.6 5.3
2.3 2.0
< 1.0b
-
29.0 8.8
2.3 4.0
< 1.0b
< 1.0b
-
-
-
< 1.0b
NH-methyl
NH-phenyl
NH2
1.2 2.0
5.8 4.0
3.5 3.5
8.1 8.0
59.2 6.0
< 1.0b
a Cell viability on A375 melanoma cells after a 48 h treatment of the indicated compounds at the defined concentration relative to a
DMSO control SD from three independent experiments, as determined by trypan blue exclusion assay. b No viable cells. c Not active.
These first data with different meta- and para-substituted analogues pointed out three important results. First, a bulky apolar group
seems to be clearly preferred over a smaller group or a polar function. Second, from 6-carbons, the elongation of the apolar chain did
not bring much improvement of the activity. Third, meta and para-isomers showed similar behaviors, suggesting that high activity
could be provided through attachment of a bulky apolar substituent probably by the concomitant modification of the global activity of
the molecules. Therefore, all the other analogues were synthesized by introducing the substitution only at the para position. To examine
the effect of the triple bond and the chain length, derivatives 9, 18, 19 and 20 were evaluated. Compound 9 featuring a cyclohexyl-
ended alkyne displayed better activity than the parent compound 1. Similar results were obtained for the partially reduced Z-alkene. The
most active compounds are those containing the fully reduced side chain, compounds 19 and 20, with no cell survival at 5 µM. These
latter data suggest that the presence of a triple bond is not required since the activity is mainly provided by a bulky apolar group.
Group B derivatives were then evaluated to test the effect of the amino function on the thiazole ring. The phenylaniline in 22 appeared
slightly detrimental to the activity whereas the methyl analogue 21 and the free aniline 23 proved slightly more active. This data is of
particular interest, considering that the potential cleavage of the acetamide function by plasmatic or cellular hydrolases might still
deliver a very active compound. These preliminary results suggest a variation tolerance at this position, which could be taken into
account for further modifications towards chemical biology purposes (fluorescence and biotin-labeling).
From these data, ten compounds proved more active than the parent compound 1. The five most promising ones (9, 14, 18, 19, 20) were
then evaluated at several concentrations to evaluate their dose-response profile (see Supplementary Material).
These assays clearly confirmed a similar or slightly improved activity of derivatives 9, 14, 18, 19 and 20 compared to the reference
compound, particularly for derivative 19 with EC50 ~ 0.5 µM. Following these results, we evaluated three of the most promising

compounds 18, 19 and 20 against resistant melanoma cell lines as well as against one hematologic cancer (Chronic Myelogenous
Leukemia, CML) and one solid cancer (pancreatic cancer). The focus on these particular cancers was driven by the high occurrence of
resistance phenomena in these diseases. Moreover, CML is a largely studied and well characterized tumor cell model; and pancreatic
cancer possess no targeted therapy option, its treatment relying on the only use of the nucleoside analogue gemcitabine, which displays
low response rates, high toxicity, severe adverse effects and rapid resistance, leading to overall low benefit/risk rates for patients.21-24
The growth inhibition was tested by viability measurements on seven human cancer cell lines: A375, A375 RIV and A375 R5C3
(melanoma), K562 and K562R (CML) and BxPC3 and MiaPaCa-2 (pancreas). Of note, four of these seven cell lines are resistant to the
currently applied therapies. A375 R5C3 and A375 RIV are resistant to the B-Raf inhibitor vemurafenib (after excessive prolonged
exposure to the drug respectively in vitro and in vivo, respectively); K562R cell line is resistant to BCR-Abl inhibitor imatinib; and
MiaPaCa-2 cell line is resistant to gemcitabine. All these cell lines are particularly aggressive and the development of new agents
targeting them is urgently needed. Viability assays were then performed for selected compounds 18, 19 and 20 (Table 2).
Table 2. Evaluation of the activity of 18, 19 and 20 against selected sensitive and resistant cell lines.
18
19
20
Vemurafenib
(5 µM)12
Imatinib
(1 µM)12
Gemcitabine
(0.1 µM)12
Cell lines
Cancer
Status
% Cell viability (10 µM)a
A375
Sensitive
Resistant
Resistant
Sensitive
Resistant
Sensitive
Resistant
< 1.0b
< 1.0b
3.6 0.7
3.4 0.6
1.4 0.7
23.2 1.0
41.6 8.9
5.9 1.0
1.3 0.3
44 3.6
-
-
A375 RIV
A375 R5C3
K562
< 1.0b
2.6 0.3
1.4 0.7
3.8 0.3
10.1 4.9
4.9 0.3
11.4 1.2
101.4 1.9
-
-
< 1.0b
76.7 3.3
-
-
8.9 7.2
41.1 12.6
2.0 0.3
11.4 1.2
-
-
-
-
9.7 0.5
-
K562R
85.5 17.7
-
BxPC3
-
2.0 0.4
MiaPaCa-2
-
86.5 1.2
a Cell viability on the specified cells after a 48 h treatment of the indicated compounds at the defined concentration relative to a DMSO
control SD from three independent experiments, as determined by trypan blue exclusion assay. b No viable cells.
Overall, the treatment with 10 µM of 18, 19 and 20 strongly affected the cell viability of all tested cell lines. It appeared that the
melanoma and the pancreatic cell lines were the most sensitive to the activity of these derivatives (Figure 2). Notably, these activities
are much higher than those observed with vemurafenib, for which almost no response is observed in resistant cells A375 R5C3 and
A375 RIV. For K562 CML cells, the compounds were generally less active than on melanoma A375 cells, but they still showed
activities below 42% in all cases. Compound 19 was particularly interesting with a strong effect on both sensitive and resistant K562
cells compared to imatinib, which is completely inefficient. BxPC3 and MiaPaCa-2 pancreatic cancer cells were also strongly affected
by the treatment with these compounds showing viabilities less than 11.4% for all three tested compounds. Especially interesting is their

high activity on resistant MiaPaCa-2 cells that are fully resistant to the gold-standard drug gemcitabine. Overall, 19 appeared to be the
most potent compound and allowed a strong decrease in cell viability (<10%) in all tested cell lines. Strikingly, this compound retains a
strong cytotoxic activity in all four resistant cell lines.
Figure 2. Western blot analysis of ER stress key markers by western blot analysis.
A375 melanoma cells were with compound 19 at 2.5, 5 and 10 µM. CTRL-: negative control (DMSO), CTRL+: positive control
(HA15, 10 µM).13 The cells were lysed at 12h, 24h and 48h and analyzed by western blotting using the indicated antibodies.
To confirm whether compound 19 displays the same ER stress related mechanism as already observed for compound 1, we studied the
key players of ER stress by western blot analysis on the lysate of A375 cells treated for different times with different concentrations of
compound 19 (Figure 2). After 12 h of treatment with compound 19 at different concentrations, we observed a shift of PERK migration
suggesting a phosphorylation of protein and a strongly increase in CHOP expression. This increase in expression and phosphorylation
persisted after 48 h of treatment. These results suggest that compound 19 is able to induce an ER stress in A375 melanoma cells. We
also observed that 19 induced a cleavage of PARP protein and conversion of LC3 I to LC3 II, attesting therefore for cancer cell death
by a concomitant induction of apoptosis and autophagy induction.25,26
In summary, we reported the synthesis and biological evaluation of fifteen new N-(4-(3-aminophenyl)thiazol-2-yl)acetamides
derivatives as anti-cancer compounds against sensitive and resistant cells. This study aimed at complementing and refining the
structure-activity relationships of our previous lead compound 1. Interestingly, both the chemical synthesis and the biological activity
were significantly optimized. Our results showed that the activity of this class of compounds is mainly due to an increase in lipophilicity
rather than to the alkyne geometry. Moreover, the tolerance towards acetamide variations is also useful information to explore this new
chemical space in future analogues. Western blot analyses suggest that the activity relies on an ER stress related mechanism by a
concomitant induction of apoptosis and autophagy cell deaths. Overall, these findings together with the potent activity of this class of

compounds notably on resistant cell lines are of great importance for the design and synthsesis of new potent bioactive molecules and
anti-cancer agents,27-31 in the search of a potential pre-clinical candidate.
Acknowledgments
This research was supported by CNRS, INSERM, University of Nice Sophia-Antipolis (AM grant), INSERM Transfert (COPOC
grant), Canceropole PACA (Emerging projects) and ARC (contract n° SFI 20121205378). M. Plaisant is a recipient of "contrat
INSERM Transfert". INSERM U1065, team 1 is «équipe labelisée ligue 2010 ».
Author Contributions: # Co-first authors, equal contribution. * Co-corresponding and co-last authors
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Supplementary material
Procedures, biological and spectral data of all compounds are provided in Supplementary material.