Synthesis and promising in Vitro antiproliferative activity of sulfones of a 5-nitrothiazole series

Article abstract of DOI:10.3390/molecules18010097

The synthesis in water of new sulfone derivatives under microwave irradiation is described. This eco-friendly process leads to the expected products in good yields by reaction of various substituted sulfinates (commercially available or obtained by reduction of the corresponding sulfonyl chlorides) with 4-chloromethyl-2-methyl-5-nitro-1,3- thiazole. In order to evaluate the antiproliferative effect of these compounds, several sulfone derivatives are also dichlorinated on the Ca next to the sulfonyl group. An evaluation on different cancer cell lines reveals promising selective in vitro antiproliferative activity toward HepG2 human cell lines by dihydrogenated sulfones, suggesting further research should be to explore their anticancer potential in the treatment of liver cancer.

Full text of DOI:10.3390/molecules18010097

Molecules 2013, 18, 97-113; doi:10.3390/molecules18010097
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Promising in Vitro Antiproliferative Activity of
Sulfones of a 5-Nitrothiazole Series
Anita Cohen 1,2, Maxime D. Crozet 1, Pascal Rathelot 1, Nadine Azas 2,* and Patrice Vanelle 1,*
1
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie,
Institut de Chimie Radicalaire ICR UMR 7273, Aix-Marseille Univ, CNRS,
27 Boulevard Jean Moulin - CS30064 - 13385 Marseille cedex 05, France
2
Infections Parasitaires, Transmission, Pharmacologie et Thérapeutique IP-TPT UMR MD3, Faculté
de Pharmacie, Aix-Marseille Univ, 27 Boulevard Jean Moulin - CS30064 - 13385 Marseille cedex 05,
France
* Authors to whom correspondence should be addressed; E-Mails: patrice.vanelle@univ-amu.fr
(P.V., for chemistry); nadine.azas@univ-amu.fr (N.A., for biology); Tel.: +33-4-9183-5573 (P.V.);
Fax: +33-4-8613-6822 (P.V.); Tel.: +33-4-9183-5564 (N.A.); Fax: +33-4-9183-5537 (N.A.).
Received: 6 November 2012; in revised form: 14 November 2012 / Accepted: 12 December 2012 /
Published: 21 December 2012
Abstract: The synthesis in water of new sulfone derivatives under microwave irradiation is
described. This eco-friendly process leads to the expected products in good yields by
reaction of various substituted sulfinates (commercially available or obtained by reduction
of the corresponding sulfonyl chlorides) with 4-chloromethyl-2-methyl-5-nitro-1,3-
thiazole. In order to evaluate the antiproliferative effect of these compounds, several sulfone
derivatives are also dichlorinated on the Cα next to the sulfonyl group. An evaluation on
different cancer cell lines reveals promising selective in vitro antiproliferative activity
toward HepG2 human cell lines by dihydrogenated sulfones, suggesting further research
should be to explore their anticancer potential in the treatment of liver cancer.
Keywords: 5-nitrothiazole; sulfones; microwave irradiation; in vitro antiproliferative;
HepG2 cell line; activity cellular specificity

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1. Introduction
Recent years have seen major advances in research and development concerning new small
molecules whose antiproliferative activity appears promising for the treatment of cancer [1,2]. Among
chemical compounds already developed as potential anticancer agents, some sulfones [3,4] such as
celecoxib [5], and heterocyclic molecules such as thiazole derivatives [6,7], have recently been
reported to display promising antiproliferative activity.
Thiazoles are one of the most prevalent heterocyclic nuclei, among compounds displaying
biological activities [8], such as β-lactams [9–11], urate-lowering drugs (febuxostat) [12], or
antiparasitic agents [13–15]. Furthermore, sulfonylmethyl groups are well-known to be useful in
synthetic methodologies and they can be used further for the preparation of various functionalized
products. For example, the expected acidity of the C-Hα next to sulfonyl groups offers the opportunity
to carry out various reactions at this position [16–18].
In continuation of our research program centered on the design and synthesis of novel molecules,
we focused our work on the synthesis and the evaluation of some new heterocyclic compounds
displaying diverse biological activities [19–24]. In this context, we decided to explore the
antiproliferative potential of new sulfonyl derivatives in the 5-nitro-1,3-thiazole series. We report
herein the synthesis of such molecules from the reaction in water of 4-chloromethyl-2-methyl-5-nitro-
1,3-thiazole (1) with various sulfinate anions under microwave irradiation. This is in continuation of
our research program directed towards the study of electron transfer reactions in heterocyclic series [25,26]
and microwave-assisted [27,28] eco-friendly processes [29,30]. The antiproliferative activity both of
sulfones and of some α-dichlorinated sulfonyl derivatives was comparatively evaluated on the CHO
and HepG2 cell lines, and results confirmed the promising antiproliferative effect of dihydrogenated
sulfones towards the HepG2 cell line.
2. Results and Discussion
2.1. Chemistry
The required starting material, 4-chloromethyl-2-methyl-5-nitro-1,3-thiazole (1), was prepared in
62% overall yield by sequential condensation between 1,3-dichloroacetone with thioacetamide [31],
cyclization using ZnCl2 in refluxing methanol, and nitration of 2-methyl-4-chloromethyl-1,3-thiazole
hydrochloride [32] (Scheme 1).
Scheme 1. Preparation of 4-chloromethyl-2-methyl-5-nitro-1,3-thiazole (1) [32].
CH3
Acetone
H3C
+
NH2
Cl
Cl
Cl
S
NH, HCl
5 h, rt
O
O
S
90%
1) H2SO4 concentrated
HNO3 fuming
24h, 100 °C
1) ZnCl2 (0.5 eq)
MeOH reflux 4 h
Cl
Cl
O2N
CH3
S NH, HCl
, HCl
N
S
N
Cl
CH3
CH3
2) Na2CO3
2) NaHCO3 / ice
S
O
1
3) CH3COCl, EtOH
89%
78%

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The synthesis of 2-methyl-5-nitro-4-phenylsulfonylmethyl-1,3-thiazole (2a) by reaction of 1 with
sodium phenylsulfinate in anhydrous methanol, under SRN1 conditions [33,34] (inert atmosphere (Ar)
and 60 W lamp irradiation), at room temperature (rt) for 24 h [32] has already been described. Based on
a number of reports suggesting that chemical reactions using water as a solvent in conjunction with
microwave heating [35–37] were more eco-friendly, we adapted this alternative method to the
synthesis of 2a. Water is an attractive alternative to traditional organic solvents due to its practical
advantages: it is inexpensive, non-flammable, non-toxic, and environmentally sustainable as it
removes the problem of pollution by organic solvents. Water has also proven to be an excellent solvent
for microwave-promoted synthesis [38–40]. Furthermore, as well as being energy efficient,
microwaves can also enhance reaction rates, and in many cases, improve yields [41–44].
Based on previous results for reduction reaction using microwave promotion, an initial irradiation
of 500 W at a temperature of 100 °C was applied [45]. We subsequently tried reducing the irradiation
power, finally establishing that the optimal experimental conditions to carry out the reactions under
microwave irradiation were 200 W and a temperature held at 100 °C until the completion of the
reaction (Scheme 2). In order to evaluate the efficiency of these latter experimental conditions versus
classical heating as previously described, we compared the synthesis of 2-methyl-5-nitro-4-
phenylsulfonylmethyl-1,3-thiazole (2a) by the two methods (classical heating in methanol [32] versus
microwave irradiation in water). As expected, it proved more convenient to carry out the reaction in
water and using microwave technology (Table 1 entry 1). Indeed, it took only 30 min to complete the
reaction with an excellent yield (96%) under these conditions, while the classical heating conditions
required a reaction time of 24 h to synthesize 2a in a lower yield (84%). The reaction rate was thus,
accelerated up to 48 times, and led to higher yields.
Scheme 2. Preparation of sulfones 2a, 2b, 2c by reaction of the corresponding
commercialized sulfinate salts with 4-chloromethyl-2-methyl-5-nitro-1,3-thiazole (1).
O
Cl
S
O
O2N
Ar
O
S-
N
H2O, 100 °C
MW, 0.5 h
N
Na+
+
O2N
CH3
Ar
O
CH3
S
S
2a Ar- = C6H5- (96%)
2b Ar- = p-CH3-C6H4- (86%)
2c Ar- = p-Cl-C6H4- (76%)
Following these excellent first results, we extended the study to p-tosyl and p-chlorophenyl
sulfinate anions, with a view to exploring the chemical and biological influence of the electron-
donating or -withdrawing character of the substrates. These reagents led to 2-methyl-5-nitro-4-
(tosylmethyl)-1,3-thiazole (2b) and 4-[(4-chlorophenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole
(2c), respectively (Table 1 entries 2 and 3). Similar good results were observed, which confirmed that
the microwave-assisted method led to a more rapid and efficient synthesis of original sulfones.

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Table 1. Classical heating method versus microwave-assisted synthesis of sulfones 2a to 2c.
Classical heating
conditions a
Microwave irradiation
conditions b
Entr
Ar-
y
Product
number
Product
Time (h)
Yield (%)
Time (h)
Yield (%)
O
S
C6H
1
84
2a
24
0.5
96
N
O
-
[32]
5
O2N
CH3
S
O
p-
S
O
0
H3C
CH3-
N
S
2
2
4
5
7
8
2
.
C6H4
O2N
C
b
6
5
-
O
S
p-
Cl
Cl-
N
O
3
2c
24
69
0.5
76
C6H4
O2N
CH
S
-
a This method was performed using 1 equivalent (equiv.) of 4-chloromethyl-2-methyl-5-nitro-1,3-thiazole (1)
and 2 equiv. of sodium arylsulfinate derivative in anhydrous methanol (10 mL), under inert atmosphere (Ar)
and 60 W lamp irradiation, at rt. b This method was performed using 1 equiv. of 4-chloromethyl-2-methyl-5-
nitro-1,3-thiazole (1) and 2 equiv. of sodium arylsulfinate derivative in water (20 mL). An initial microwave
irradiation of 200 W was used, the temperature being ramped up from r.t. to 100 °C and then held at 100 °C
until the end of the reaction.
Next, to further diversify the chemical substituents on the sulfonyl group and to evaluate their
influence on the antiproliferative activity of the corresponding products, these microwave-assisted
operating conditions were used to synthesize new sulfonyl derivatives of 1 by reactions with various
substituted sulfinate substrates. As such sulfinate salts are not commercially available, we performed
the sodium-mediated reduction of sulfonyl chloride derivatives into the corresponding sulfinate anions,
in aqueous conditions [46,47] and under microwave irradiation. Then, we investigated the above
method using a mixture of sodium sulfite, sodium bicarbonate and sulfonyl chloride derivatives [48]
and adapted it to the microwave methodology. Thus, the reduction of sulfonyl chloride derivatives was
conducted with 3.4 equiv. of Na2SO3, 3.4 equiv. of NaHCO3, and 1 equiv. of the sulfonyl chloride
derivative, in water at 100 °C, under microwave irradiation for 0.42 h. The compound 1 was directly
added to the crude mixture, which was stirred for 0.5 h under the above conditions (MW 200 W, 100 °C)
to give the corresponding sulfones 2d to 2l (Scheme 3) in moderate to good yields in a one-pot
protocol (Table 2).

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Scheme 3. Preparation of sulfones 2d to 2l.
Cl
O2N
N
CH3
S
O
S
1
R
O
S-
O
N
H2O, 100 °C
MW, 0.5 h
H2O, 100 °C
MW, 0.42 h
O
O2N
Na2SO3
NaHCO3
Na+
+
+ R S Cl
O
R
O
CH3
S
2d - 2l
Table 2. Microwave mediated preparation of several sulfones derivatives of
4-chloromethyl-2-methyl-5-nitro-1,3-thiazole (1).
R-
Product
Product number
Yield (%)
O
S
Br
p-Br-C6H4-
2d
68
N
O
O2N
CH3
N
S
O
S
F
p-F-C6H4-
2e
2f
82
65
O
O2N
CH3
S
F
O
S
m-F-C6H4-
N
O
O2N
CH3
S
F3C
O
S
m-CF3-C6H4-
2g
71
N
O
O2N
CH3
S
O
S
H3C
H3C
O
p-CH3O-C6H4-
p-C2H5-C6H4-
CH3-
2h
2i
60
31
52
N
N
O
O2N
CH3
S
S
O
S
O
O2N
CH3
O
S
O
H3C
2j
N
CH3
O2N
S

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Table 2. Cont.
R-
Product
O
Product number
2k
Yield (%)
S
2-bromothiophenyl-
58
N
S
O
Br
O2N
CH3
S
O
S
2-naphthyl-
2l
90
N
O
O2N
CH3
S
All the reactions were performed using 2 equiv. of sulfonyl chloride, 3.4 equiv. of sodium sulfite, 3.4 equiv.
of sodium carbonate in water (30 mL). An initial microwave irradiation of 200 W was used, the temperature
being ramped up from r.t. to 100 °C, where it was held for 0.42 h. 1 equiv. of 4-chloromethyl-2-methyl-5-
nitro-1,3-thiazole (1) was then added to the crude mixture, which was subsequently heated for 0.5 h.
To assess the importance of the methyl group next to sulfonyl for the biological activity, we then
evaluated a group of α-dichlorinated sulfonyl derivatives 3a to 3e. These compounds were prepared by
reaction of sulfonyl derivatives with hypochlorite-based bleach (2.6% active chlorine) under lower
microwave irradiation conditions (75 W, 40 °C) [49] (Scheme 4). Dichlorinated analogs were obtained
in good yields (Table 3).
Scheme 4. Preparation of dichlorinated sulfones 3a to 3e.
O
S
O
S
Cl
Cl
R
R
40 °C
N
N
+
NaOCl
O
O
O2N
O2N
CH3
CH3
MW, 1 h to 3.75 h
S
S
3a-3e
Table 3. Microwave-mediated preparation of dichlorinated sulfone derivatives.
R-
Product
Product number
Yield (%)
O
Cl
Cl
S
C6H5-
3a
81
N
O
O2N
CH3
S
O
S
Cl
Cl
H3C
p-CH3-C6H4-
3b
3c
61
68
N
O
O2N
CH3
S
O
S
Cl
Cl
Cl
-Cl-C6H4-
N
O
O2N
CH3
S

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Table 3. Cont.
R-
Product
Product number
3d
Yield (%)
O
Cl
Cl
N
Br
F
S
p-Br-C6H4-
79
O
O2N
CH3
S
O
S
Cl
Cl
p-F-C6H4-
3e
88
N
O
O2N
CH3
S
All the reactions were performed using 1 equiv. of sulfonyl derivative (2a to 2f) in 10 mL of sodium
hypochlorite. A microwave irradiation of 75 W was used, the temperature being ramped up from r.t. to 40 °C,
where the mixture was then held for 1 to 3.75 h.
The structure of compound 3c was unambiguously confirmed by X-ray structure analysis (Figure 1)
(CCDC 908240). The other structures were assigned by analogy and spectral comparison.
Figure 1. X-Ray structure of compound 3c.
2.2. In Vitro Biological Evaluation
The antiproliferative activity of the synthesized compounds was evaluated against two different
cancer cell lines, CHO and HepG2, employing the MTT method [50] and doxorubicin as a reference
drug. The cytotoxic activity in vitro was expressed as CC50 (µM), the concentration of compound that
inhibits proliferation of cells by 50% as compared to untreated cells. The results of substance screening
are summarized in Table 4.
All dihydrogenated sulfonyl derivatives displayed substantial antiproliferative activity towards
HepG2 cells (7.7 µM ≤ HepG2 CC50 ≤ 25.6 µM) compared with doxorubicin used as reference drug
(HepG2 CC50 = 0.2 µM), except compounds 2i and 2j for which no activity was observed on either of
the cell lines. These data show that neither an elongation of the carbon chain at the p-position of the phenyl
substituent nor an alkyl substituent on the sulfonyl group appears to favour the antiproliferative effects.

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Table 4. Antiproliferative activity of compounds 2a to 3e.
Cancer cell toxicity a (µM)
Product Number
CHO CC50
322.9 (± 4.66)
237.3 (± 5.55)
>62.5 c
HepG2 CC50
24.6 (± 0.78)
7.7 (± 1.42)
13.4 (± 1.47)
11.7 (± 2.09)
19.3 (± 1.21)
23.6 (± 0.58)
25.6 (± 2.13)
20.6 (± 0.74)
238.9 (± 2.27)
>250 c
2a
2b
2c
2d
>500 c
2e
229.3 (± 4.02)
321.1 (± 3.23)
138.6 (± 2.64)
136.8 (± 4.26)
>500 c
2f
2g
2h
2i
2j
>250 c
2k
47.3 (± 2.28)
106.2 (± 4.90)
2.5 (± 0.23)
1.2 (± 0.11)
1.4 (± 0.06)
1.3 (± 0.04)
1.3 (± 0.04)
0.6
13.8 (± 1.07)
8.5 (± 1.52)
1.2 (± 0.09)
1.0 (± 0.24)
1.1 (± 0.17)
1.2 (± 0.22)
1.2 (± 0.34)
0.2
2l
3a
3b
3c
3d
3e
Doxorubicin b
a CC50 (µM) indicates the compound concentration that inhibits the proliferation of cells by 50% as compared
b
to control untreated cells. The values are means ± SD of three independent experiments. Doxorubicin was
used as reference drug compound for cell toxicity. c No toxicity at the highest tested concentration.
Furthermore, this series was generally inactive on CHO cells, with CC50 values of between 47.3 and
≥500 µM, compared with doxorubicin (CHO CC50 = 0.6 µM). HepG2 is a commonly used human-derived
hepatocarcinoma cell line expressing many of the hepatocyte-specific metabolic enzymes. The aim of
this assay using HepG2 in addition to CHO cells was to evaluate the impact of metabolic activation of
the tested compounds on cell viability [51]. Our results indicate that dihydrogenated sulfonyl
derivatives, apart from 2i and 2j, need to be modified by a metabolic pathway to offer promising
antiproliferative activity. Compounds 2b and 2d in particular displayed an antiproliferative effect 31
and 43 times higher respectively toward the HepG2 than toward the CHO cell line, which confirmed
their high specificity for human liver tumor cells.
Dichlorinated sulfones 3a to 3e were much more cytotoxic toward both the cell lines
(1.0 µM ≤ CC50 ≤ 2.5 µM) than their dihydrogenated analogs, compared with doxorubicin used as
reference of cellular toxicity. This result highlights the lack of cellular specificity of dichlorinated
derivatives, confirming that the methyl group next to sulfonyl plays a key role in the antiproliferative
activity of this series on human liver tumor cells.

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3. Experimental
3.1. General
Melting points were determined on a Büchi B-540 and are uncorrected. Elemental analyses were
carried out on an Interscience Flash EA 1112 series (Thermo Finnigan, San Jose, CA, USA) elemental
analyzer at the Spectropole, Faculté des Sciences et Techniques de Saint-Jérome. Both 1H- and 13C-NMR
1
spectra were determined on a Bruker Avance 200 spectrometer (operating at 200 MHz for H and
13
1
13
50 MHz for C). H and C-NMR shifts (δ) were reported in parts per million (ppm) with respect
1
13
1
13
to CDCl3 7.26 ppm for H and 77.0 ppm for C and DMSO-d6 2.50 for H and 39.7 ppm for C.
Multiplicities were represented by s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet).
Coupling constants (J) are in Hertz (Hz). The following adsorbent was used for column
chromatography: silica gel 60 (Merck, Darmstadt, Germany, 230–400 mesh). Thin-layer
chromatography was performed with Merck 60F-254 silica gel (0.25 mm layer thickness) in an
appropriate solvent. All the reactions involving microwave instrumentation used the ETHOS Synth
Lab station multimode reactor (Ethos Start, Milestone Inc., Rockford, IL, USA). The multimode
microwave had a 25 twin magnetron (2 × 800 W, 2.45 GHz) with a maximum delivered power of 1,000 W
in 10 W increments (pulsed irradiation). The multimode microwave featured a built-in magnetic stirrer
(Teflon-coated stirring bar), direct temperature control of the reaction mixture with the aid of IR30
sensor on the reactor wall and software that enabled on line temperature control by regulation of
microwave power output.
3.2. General Procedure for the Reaction of Compound 1 and Sodium Arylsulfinates to Synthesize
Products 2a to 2c and Using Classical Heating Conditions
The corresponding sodium arylsulfinate (2 equiv.) was added to a solution of 1 (1 g, 5.2 mmol) in
anhydrous methanol (10 mL). The reaction mixture was stirred at r.t., for 24 h, under an inert
atmosphere (Ar) and 60 W lamp irradiation. After removal of the reaction mixture under reduced
pressure, purification by chromatography on silica gel, elution with ethyl acetate and recrystallization from
isopropanol (i-PrOH), the corresponding 4-arylsulfonylmethyl-2-methyl-5-nitro-1,3-thiazole was obtained.
3.3. General Procedure for the Reaction of Compound 1 and Sodium Arylsulfinates to Synthesize
Products 2a to 2c and Using Microwave Irradiation
The corresponding sodium arylsulfinate (2 equiv.) was added to a solution of 1 (1 g, 5.2 mmol) in
water (20 mL). The reaction mixture was irradiated in a microwave oven (200 W, 100 °C, 0.5 h).
A precipitate appeared and was filtered after cooling, washed with water (3 × 20 mL) and dried in a
vacuum drying oven. Recrystallization from i-PrOH gave the corresponding sulfonyl derivative.
1
2-Methyl-5-nitro-4-(tosylmethyl)-1,3-thiazole (2b): Yellow solid; m.p. 179 °C (i-PrOH); H-NMR
(CDCl3) δ: 2.43 (s, 3H, CH3), 2.70 (s, 3H, CH3), 5.02 (s, 2H, CH2), 7.31 (d, J = 7.9 Hz, 2H, 2 × CH),
7.68 (d, J = 7.9 Hz, 2H, 2 × CH); 13C-NMR (CDCl3) δ: 20.4 (CH3), 21.7 (CH3), 56.7 (CH2), 128.3 (2 × CH),
129.9 (2 × CH), 135.8 (C), 143.3 (C), 145.4 (C), 169.3 (C), C-NO2 not visible under these conditions;
Anal. Calcd for C12H12N2O4S2: C, 46.14; H, 3.87; N, 8.97. Found: C, 46.41; H, 3.89; N, 9.07.

Molecules 2013, 18
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4-[(4-Chlorophenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (2c): Yellow solid; m.p. 180 °C
(i-PrOH); 1H-NMR (CDCl3) δ: 2.70 (s, 3H, CH3), 5.04 (s, 2H, CH2), 7.51 (d, J = 8.8 Hz, 2H, 2 × CH),
7.76 (d, J = 8.8 Hz, 2H, 2 × CH); 13C-NMR (CDCl3) δ: 20.4 (CH3), 56.7 (CH2), 129.6 (2 × CH), 129.9
(2 × CH), 137.3 (C), 141.2 (C), 142.8 (C), 169.5 (C), C-NO2 not visible under these conditions; Anal.
Calcd for C11H9ClN2O4S2: C, 39.70; H, 2.73; N, 8.42. Found: C, 39.95; H, 2.69; N, 8.55.
3.4. General Procedure for the Reaction of Compound 1 and Variously Substituted Sulfinate Salts to
Synthesize Products 2d to 2l and Using Microwave Irradiation
Sodium sulfite (3.4 equiv.) and sodium bicarbonate (3.4 equiv.) were added to a solution of sulfonyl
chloride (600 mg, 1 equiv.) in water (30 mL). The reaction mixture was irradiated in a microwave
oven and reaction was carried out under irradiation at 100 °C at 200 W for 0.42 h. Then, compound 1
(300 mg, 1.56 mmol) was added in situ. The reaction mixture was irradiated for 0.5 h under the same
conditions. After cooling down, the mixture was then extracted with chloroform (5 × 15 mL). The
organic layers were dried over anhydrous sodium sulfate and removed under vacuum. Purification by
column chromatography on silica gel, eluting with the appropriate solvent (2d and 2e: CHCl3/EtOAc,
80/20; 2f, 2g, 2h, 2l: CHCl3/Et2O, 80/20; 2j: EtOAc; 2k: CHCl3/petroleum ether/EtOAc, 50/25/25) and
recrystallization from i-PrOH gave the corresponding target product.
4-[(4-Bromophenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (2d): Yellow solid; m.p. 184 °C
(i-PrOH); 1H-NMR (DMSO-d6) δ: 2.65 (s, 3H, CH3), 5.23 (s, 2H, CH2), 7.68 (d, J = 8.7 Hz, 2H, 2 × CH),
13
7.87 (d, J = 8.7 Hz, 2H, 2 × CH); C-NMR (DMSO-d6) δ: 20.1 (CH3), 56.2 (CH2), 128.8 (C), 130.3
(2 × CH), 132.6 (2 × CH), 138.0 (C), 143.3 (C), 170.4 (C), C-NO2 not visible under these conditions;
Anal. Calcd for C11H9BrN2O4S2: C, 35.02; H, 2.40; N, 7.43. Found: C, 35.05; H, 2.34; N, 7.40.
4-[(4-Fluorophenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (2e): Yellow solid; m.p. 183 °C
1
(i-PrOH); H-NMR (DMSO-d6) δ: 2.65 (s, 3H, CH3), 5.22 (s, 2H, CH2), 7.48 (m, 2H, 2 × CH), 7.83
13
(m, 2H, 2 × CH); C-NMR (DMSO-d6) δ: 20.1 (CH3), 56.3 (CH2), 116.8 (d, J = 23.5 Hz, 2 × CH),
131.6 (d, J = 7.0 Hz, 2 × CH), 135.1 (d, J = 4.7 Hz, C), 143.5 (C), 165.5 (d, J = 253.8 Hz, C-F), 170.4
(C), C-NO2 not visible under these conditions; Anal. Calcd for C11H9FN2O4S2: C, 41.77; H, 2.87; N,
8.86. Found: C, 41.75; H, 2.83; N, 8.85.
4-[(3-Fluorophenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (2f): Yellow solid; m.p. 154 °C
1
(i-PrOH); H-NMR (DMSO-d6) δ: 2.64 (s, 3H, CH3), 5.27 (s, 2H, CH2), 7.57–7.69 (m, 4H, 4 × CH);
13C-NMR (DMSO-d6) δ: 20.1 (CH3), 56.0 (CH2), 115.3 (d, J = 24.3 Hz, CH), 121.7 (d, J = 20.3 Hz,
CH), 124.6 (d, J = 3.4 Hz, CH), 132.0 (d, J = 8.0 Hz, CH), 140.8 (d, J = 7.0 Hz, C), 143.2 (C), 161.8
(d, J = 248.8 Hz, C-F), 170.4 (C), C-NO2 not visible under these conditions; Anal. Calcd for
C11H9FN2O4S2: C, 41.77; H, 2.87; N, 8.86. Found: C, 41.36; H, 2.73; N, 8.67.
2-Methyl-5-nitro-4-{[3-(trifluoromethyl)phenylsulfonyl]methyl}-1,3-thiazole (2g): White solid; m.p.
1
121 °C (i-PrOH); H-NMR (DMSO-d6) δ: 2.61 (s, 3H, CH3), 5.33 (s, 2H, CH2), 7.86–8.32 (m, 4H,
13
4 × CH); C-NMR (DMSO-d6) δ: 20.0 (CH3), 56.0 (CH2), 123.4 (q, J = 273.0 Hz, CF3), 125.1 (q,
J = 3.9 Hz, CH), 130.0 (q, J = 33.1 Hz, C-CF3), 131.2 (CH), 131.3 (q, J = 3.5 Hz, CH), 132.5 (CH),

Molecules 2013, 18
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139.9 (C), 143.2 (C), 146.6 (C), 170.5 (C); Anal. Calcd for C12H9F3N2O4S2: C, 39.34; H, 2.48; N, 7.65.
Found: C, 39.40; H, 2.45; N, 7.54.
4-[(4-Methoxyphenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (2h): Brown solid; m.p. 154 °C
1
(i-PrOH); H-NMR (DMSO-d6) δ: 2.66 (s, 3H, CH3), 3.85 (s, 3H, CH3), 5.12 (s, 2H, CH2), 7.12 (d,
J = 7.2 Hz, 2H, 2 × CH), 7.64 (d, J = 7.2 Hz, 2H, 2 × CH); 13C-NMR (DMSO-d6) δ: 20.1 (CH3), 56.0
(CH3), 56.6 (CH2), 114.7 (2 × CH), 130.2 (C), 130.5 (2 × CH), 143.7 (C), 143.9 (C), 163.8 (C), 170.2
(C); m/z (EI): [M+H]+, found 329.0258. C12H12N2O5S2 requires 329.0260.
4-[(4-Ethylphenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (2i): White solid; m.p. 162 °C
(i-PrOH); 1H-NMR (DMSO-d6) δ: 1.19 (t, J = 7.5 Hz, 3H, CH3), 2.65 (s, 3H, CH3), 2.70 (q, J = 7.5 Hz,
2H, CH2), 5.15 (s, 2H, CH2), 7.46 (d, J = 8.3 Hz, 2H, 2 × CH), 7.64 (d, J = 8.3 Hz, 2H, 2 × CH);
13C-NMR (DMSO-d6) δ: 15.3 (CH3), 20.1 (CH3), 28.3 (CH2), 56.4 (CH2), 128.3 (2 × CH), 128.9 (2 × CH),
136.1 (C), 143.7 (C), 151.2 (C), 170.2 (C), C-NO2 not visible under these conditions; m/z (EI):
[M+H]+, found 327.0468. C13H14N2O4S2 requires 327.0468.
2-Methyl-4-(methylsulfonylmethyl)-5-nitro-1,3-thiazole (2j): Brown solid; m.p. 127 °C (i-PrOH);
1H-NMR (DMSO-d6) δ: 2.75 (s, 3H, CH3), 3.13 (s, 3H, CH3), 5.07 (s, 2H, CH2); 13C-NMR (DMSO-d6)
δ: 20.2 (CH3), 41.7 (CH3), 54.6 (CH2), 144.4 (C), 170.7 (C), C-NO2 not visible under these conditions;
m/z (EI): [M+Na]+, found 258.9815. C6H8N2O4S2 requires 258.9818.
4-[(5-Bromothiophen-2-ylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (2k): Yellow solid; m.p. 167 °C
(i-PrOH); 1H-NMR (DMSO-d6) δ: 2.68 (s, 3H, CH3), 5.31 (s, 2H, CH2), 7.45 (d, J = 3.9 Hz, 1H, CH),
7.56 (d, J = 3.9 Hz, 1H, CH); 13C-NMR (DMSO-d6) δ: 20.1 (CH3), 57.3 (CH2), 122.6 (C), 132.4 (CH),
136.5 (CH), 140.0 (C), 143.1 (C), 146.6 (C), 170.5 (C); Anal. Calcd for C9H7BrN2O4S2: C, 28.20; H,
1.84; N, 7.31. Found: C, 27.82; H, 1.76; N, 7.08.
2-Methyl-4-[(naphtalen-2-ylsulfonyl)methyl]-5-nitro-1,3-thiazole (2l): Yellow solid; m.p. 163 °C
1
(i-PrOH); H-NMR (DMSO-d6) δ: 2.55 (s, 3H, CH3), 5.28 (s, 2H, CH2), 7.67–7.74 (m, 3H, 3 × CH),
13
8.09–8.17 (m, 2H, 2 × CH), 8.37 (d, J = 7.7 Hz, 1H, CH), 8.46 (d, J = 7.7 Hz, 1H, CH); C-NMR
(DMSO-d6) δ: 20.0 (CH3), 56.5 (CH2), 123.4 (CH), 124.9 (CH), 127.2 (CH), 128.6 (CH), 128.8 (CH),
129.4 (CH), 131.1 (CH), 133.8 (CH), 136.1 (C), 143.3 (C), 146.5 (C), 170.2 (C), C-NO2 not visible
under these conditions; Anal. Calcd for C15H12N2O4S2: C, 51.71; H, 3.47; N, 8.04. Found: C, 51.64; H,
3.48; N, 7.94.
3.5. General Procedure for the Dichlorination of Compounds 2a to 2e to Synthesize Products 3a to 3e
Using Microwave Irradiation
The corresponding sulfone (1 equiv.) was added to a solution of hypochlorite-based bleach (2.6%
active chlorine, 10 mL). The reaction mixture was irradiated in a microwave oven and reaction was
carried out at 40 °C at 75 W from 1h to 3.75 h. After being cooled down, the mixture was then
extracted with chloroform (3 × 20 mL). The organic layers were dried over anhydrous sodium sulfate
and removed under vacuum. Purification by column chromatography eluting with CHCl3 and
recrystallization from i-PrOH gave the corresponding required product.

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4-[Dichloro(phenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (3a): Yellow solid; m.p. 169 °C
(i-PrOH); 1H-NMR (CDCl3) δ: 2.76 (s, 3H, CH3), 7.57–7.80 (m, 3H, 3 × CH), 8.14–8.18 (m, 2H, 2 × CH);
13C-NMR (CDCl3) δ: 20.0 (CH3), 29.6 (C), 91.4 (C), 128.6 (2 × CH), 133.0 (2 × CH), 133.1 (C), 135.3
(CH), 143.2 (C), 165.5 (C); Anal. Calcd for C11H8Cl2N2O4S2: C, 35.98; H, 2.20; N, 7.63. Found: C,
36.04; H, 2.11; N, 7.39.
4-[Dichloro(tosyl)methyl]-2-methyl-5-nitro-1,3-thiazole (3b): Yellow solid; m.p. 165 °C (i-PrOH);
1H-NMR (CDCl3) δ: 2.49 (s, 3H, CH3), 2.75 (s, 3H, CH3), 7.39 (d, J = 8.2 Hz, 2H, 2 × CH), 8.03 (d,
13
J = 8.2 Hz, 2H, 2 × CH); C-NMR (CDCl3) δ: 20.0 (CH3), 21.8 (CH3), 129.3 (2 × CH), 129.9 (C),
133.1 (2 × CH), 143.4 (C), 146.9 (C), 156.4 (C), 165.3 (C); C-NO2 not visible under these conditions;
m/z (EI): [M+H]+, found 380.9532. C12H10Cl2N2O4S2 requires 380.9532.
4-[Dichloro(4-chlorophenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (3c): Yellow solid; m.p.
1
165 °C (i-PrOH); H-NMR (CDCl3) δ: 2.75 (s, 3H, CH3), 7.57 (d, J = 8.7 Hz, 2H, 2 × CH), 8.10 (d,
J = 8.7 Hz, 2H, 2 × CH); 13C-NMR (CDCl3) δ: 20.0 (CH3), 91.4 (C), 129.0 (2 × CH), 131.7 (C), 134.4
(2 × CH), 142.6 (C), 143.3 (C), 165.7 (C); C-NO2 not visible under these conditions; Anal. Calcd for
C11H7Cl3N2O4S2: C, 32.89; H, 1.76; N, 6.97. Found: C, 33.12; H, 1.70; N, 7.20.
C11H7N2O4S2, colorless prisms (0.25 × 0.15 × 0.1 mm3), MW = 401.66, orthorhombic, space group
P21/c (T = 293 K), a = 15.6219 (1) Å, b = 9.6399 (3) Å, c = 20.5410 (5) Å, α = 90°, β = 90°, γ = 90°;
V = 3093.34 (12) Å3, Z = 8, µ = 0.879 mm−1, F(000) = 1616, index ranges 0 ≤ h ≤ 22, 0 ≤ k ≤ 13,
−29 ≤ l ≤ 0; θ range = 1.98–31.00°, 199 variables and 0 restraints, were defined for 4807 independent
reflections with I ≥ 2σ(I) to R1 = 0.0600, wR2 = 0.1256, GooF = 1.052. CCDC 908240 contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/data_request/cif of from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; Fax: + 44 (1223) 336033; E-Mail: deposit@ccdc.cam.ac.uk.
4-[(4-Bromophenylsulfonyl)dichloromethyl]-2-methyl-5-nitro-1,3-thiazole (3d): Yellow solid; m.p.
1
165 °C (i-PrOH); H-NMR (CDCl3) δ: 2.76 (s, 3H, CH3), 7.75 (d, J = 8.6 Hz, 2H, 2 × CH), 8.03 (d,
J = 8.6 Hz, 2H, 2 × CH); 13C-NMR (CDCl3) δ: 20.1 (CH3), 91.3 (C), 131.3 (C), 132.0 (2 × CH), 132.2
(C), 134.4 (2 × CH), 143.3 (C), 165.7 (C); C-NO2 not visible under these conditions; Anal. Calcd for
C11H7BrCl2N2O4S2: C, 29.61; H, 1.58; N, 6.28. Found: C, 29.27; H, 1.51; N, 5.97.
4-[Dichloro(4-fluorophenylsulfonyl)methyl]-2-methyl-5-nitro-1,3-thiazole (3e): Yellow solid; m.p. 145 °C
(i-PrOH); 1H-NMR (CDCl3) δ: 2.76 (s, 3H, CH3), 7.26–7.32 (m, 2H, 2 × CH), 8.17–8.23 (m, 2H, 2 × CH);
13C-NMR (CDCl3) δ: 20.1 (CH3), 91.4 (C), 116.1 (d, J = 23.4 Hz, 2 × CH), 129.0 (d, J = 3.2 Hz, C-F),
136.1 (d, J = 10.3 Hz, 2 × CH), 143.3 (C), 164.5 (C), 165.6 (C), 169.6 (C); m/z (EI): [M+H]+, found
384.9280. C11H7FCl2N2O4S2 requires 384.9281.

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3.6. In Vitro Biological Evaluation
In Vitro Cytotoxicity Evaluation on CHO and HepG2 Cell Lines
CHO and HepG2 cell lines were maintained at 37 °C, 6% CO2, 14% O2, 80% N2, with 90%
humidity in RPMI supplemented with 10% fœtal bovine serum, 1% L-glutamine (200 mM) and
penicillin (100 U/mL) / streptomycin (100 µg/mL) (complete RPMI medium).
In vitro cytotoxicity evaluation on CHO and HepG2 cell lines was performed according to the
method described by Mosmann [50] with slight modifications. Briefly, 5 × 103 cells in 100 µL of
culture medium (RPMI + 10% CO2) were inoculated into each well of 96-well plates and incubated at
37 °C in a humidified 6% CO2, 14% O2, 80% N2 atmosphere. After 24 h incubation, 100 µL of
medium with various product concentrations was added and the plates were incubated from 24 h
(CHO) to 72 h (HepG2). Duplicate assays were performed for each sample. At the end of the treatment
and incubation, the medium was aspirated from the wells and 10 µL yellow MTT (3-(4,5-dimethyl-2-
thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) solution (5 mg MTT/mL in PBS) was added to each
well with 100 µL of medium without fœtal bovine serum. Cells were incubated for 2 h at 37 °C to
allow MTT oxidation by mitochondrial dehydrogenase in the viable cells. After 2 h, the MTT solution
was aspirated and DMSO (100 µL) was added to each well to dissolve the resulting blue formazan
crystals. Plates were then shaken vigorously (300 rpm) for a few minutes. The absorbance was
measured at 570 nm with 630 nm as reference wavelength, using a microplate spectrophotometer.
DMSO was used as blank and doxorubicin as positive control.
Cell viability was calculated as percentage of control (cells incubated without compound). The 50%
cytotoxic concentrations (CHO CC50 and HepG2 CC50) were determined by non-linear regression
analysis processed on dose-response curves, using the Table Curve software 2D v.5.0. CC50 values
represent the mean value calculated from three independent experiments.
4. Conclusions
We have developed an efficient, rapid and eco-friendly microwave-based method for synthesizing
4-alkyl- and 4-arylsulfonylmethyl-2-methyl-5-nitro-1,3-thiazoles by the reaction of 4-chloromethyl-2-
methyl-5-nitro-1,3-thiazole (1) with various substituted sodium sulfinates, either commercially
available or obtained from sulfonyl chlorides previously reduced by a sodium-mediated reaction in
aqueous medium.
Biological evaluation of these synthesized compounds revealed the promising antiproliferative
activity toward HepG2 cell line of most of the dihydrogenated sulfonyl derivatives after metabolic
activation. Their dichlorinated analogs were synthesized using hypochlorite-based bleach (2.6% active
chlorine) under microwave irradiation. Biological results showed that these compounds were much
more cytotoxic toward both cell lines, showing their lack of cellular specificity and confirming that the
methyl group next to sulfonyle played a key role in the antiproliferative activity of this series on
human liver tumor cells.
These promising results suggest that further research should be done on 4-arylsulfonylmethyl-2-
methyl-5-nitro-1,3-thiazoles as potential anticancer agents in the treatment of liver cancer.

Molecules 2013, 18
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Acknowledgements
This work was supported by the CNRS and the University of Aix-Marseille. The authors thank V.
Remusat for recording the 1H-NMR and 13C-NMR spectra.
Conflict of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2a to 3e are available from the authors.
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