Pyrazolo[4,3-e][1,2,4]triazine sulfonamides as carbonic anhydrase inhibitors with antitumor activity

Article abstract of DOI:10.1016/j.bmc.2014.03.029

A series of sildenafil analogues and aniline substituted pyrazolo[4,3-e][1,2,4]triazine sulfonamides were prepared and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors and for their anticancer activity against two human breast cancer cell lines (MCF-7, MDA-MB-231). The new compounds were ineffective as CA I inhibitors, poorly inhibited CA II, but were more effective against the tumor-associated isoforms CA IX and XII, with some compounds acting as low nanomolar inhibitors. Evaluation of the cytotoxicity by using an MTT assay, the inhibition of [³H]thymidine incorporation into DNA as well as collagen synthesis inhibition, demonstrated that these sulfonamides exhibit cytotoxic effects on breast cancer cell lines ex vivo.

Full text of DOI:10.1016/j.bmc.2014.03.029

Bioorganic & Medicinal Chemistry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Pyrazolo[4,3-e][1,2,4]triazine sulfonamides as carbonic anhydrase
inhibitors with antitumor activity
b
b
c
c,d,
Mariusz Mojzych a, , Anna Bielawska , Krzysztof Bielawski , Mariangela Ceruso , Claudiu T. Supuran
⇑
⇑
a Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3-go Maja 54, 08-110 Siedlce, Poland
b Department of Medicinal Chemistry and Drug Technology, Medical University of Bialystok, Bialystok, Poland
c Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy
d Università degli Studi di Firenze, NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of sildenafil analogues and aniline substituted pyrazolo[4,3-e][1,2,4]triazine sulfonamides were
prepared and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors and for their anticancer activity
against two human breast cancer cell lines (MCF-7, MDA-MB-231). The new compounds were ineffective
as CA I inhibitors, poorly inhibited CA II, but were more effective against the tumor-associated isoforms
CA IX and XII, with some compounds acting as low nanomolar inhibitors. Evaluation of the cytotoxicity by
using an MTT assay, the inhibition of [3H]thymidine incorporation into DNA as well as collagen synthesis
inhibition, demonstrated that these sulfonamides exhibit cytotoxic effects on breast cancer cell lines
ex vivo.
Received 21 January 2014
Revised 14 March 2014
Accepted 17 March 2014
Available online xxxx
Keywords:
Sulfonamides
MDA-MB-231
MCF-7
Ó 2014 Elsevier Ltd. All rights reserved.
Cytotoxicity
Carbonic anhydrase inhibitors
Pyrazolo[4,3-e][1,2,4]triazine
1. Introduction
Considering our interest in the development of new anticancer
agents belonging to the carbonic anhydrase (CA, EC 4.2.1.1) inhib-
The pyrazolo-1,2,4-triazines have received considerable
attention due to their pharmacological activities as antiviral,1
antitumour,2 antifungal,3 analgesic,4 anti-inflammatory,4 and anti-
pyretic agents.5 However, despite of the wide range of biological
activity the pyrazolo[4,3-e][1,2,4]triazines are a less known class
in the group of condensed pyrazolotriazines. In the past decades,
the isolation and structural characterization of naturally occurring
pyrazolo[4,3-e][1,2,4]triazines, pseudoiodinine, nostocine A and
fluviols A–E, was reported.5–7 In addition, these compounds were
reported to have cytotoxic activity on human cancer cell, such as
A549 (lung adenocarcinoma).8
itor class, in this work we report the synthesis of new series of
pyrazolo[4,3-e][1,2,4]triazines derivatives belonging two groups,
that is, analogues of sildenafil and aniline substituted pyrazol-
o[4,3-e][1,2,4]triazine sulfonamides. The new compounds were
evaluated as CA inhibitors and for their cytotoxic effects on several
breast cancer cell lines.
2. Results and discussion
2.1. Chemistry
The sulfonamides represent an important class of pharmaceuti-
cal compounds with a wide spectrum of biological activities9 such
as anticancer,10 carbonic anhydrase (CA) inhibitory,11 antibacte-
rial,12 antimalarial,13 antitumor,14 antihypertensive,15 anti-inflam-
matory,16 and antiprotozoal activities among others.17
2.1.1. Synthesis of 4a–j
The synthesis of the aza-sildenafil analogues 4a–j was achieved
starting from 1,3-dimethyl-5-methylsulfanyl-1H-pyrazolo[4,3-e]-
[1,2,4]triazine (1)18 which was reacted19 with 2-ethoxyphenylbo-
ronic acid in the presence of copper(I) 3-methylsalicylate, leading
to derivative 2 in an excellent yield. Chlorosulfonylation of 2 with
chlorosulfonic acid at 0 °C proceeded smoothly and selectively at
the 50-position of the phenyl ring to give compound 3 in excellent
yield. The chlorosulfonyl derivative 3 was then coupled with the
⇑
Corresponding authors. Tel.: +48 025 643 1105; fax: +48 025 6442045 (M.M.);
tel.: +39 055 457 3005; fax: +39 055 457 3385 (C.T.S.).
E-mail addresses: mmojzych@yahoo.com (M. Mojzych), claudiu.supuran@unifi.it
(C.T. Supuran).
http://dx.doi.org/10.1016/j.bmc.2014.03.029
0968-0896/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mojzych, M.; et al. Bioorg. Med. Chem. (2014), http://dx.doi.org/10.1016/j.bmc.2014.03.029

2
M. Mojzych et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
Scheme 1. Reagents and conditions: (a) ethoxyphenylboronic acid, Pd(PPh3)4, CuMeSal, THF, Ar, reflux, overnight; (b) ClSO3H, 0 °C to rt, 2 h; (c) NH3/H2O or amine, MeCN, rt;
(d) KMnO4, Bu4NBr, CH3COOH, benzene-H2O, rt, 1 h and (e) aniline, seal tube, 9 days, 150 °C.
appropriate amine in acetonitrile at room temperature to give sul-
fonamides 4a–j as new aza-analogues of sildenafil (Scheme 1).
(Table 1). In terms of reduction in cell viability, the compounds rank
in both MCF-7 and MDA-MB-231 cells in the order chlorambucil >
4d > 4a > 4e > 4f > 4h > 4b > 4c > 4g > 4i.
2.1.2. Synthesis of 8a–j
We studied the effect of compounds 4a–4i and chlorambucil on
DNA synthesis in both MDA-MB-231 and MCF-7 breast cancer cells
(Table 1). All of the tested compounds showed concentration
dependent activity, yet with different potency. The concentrations
of 4g, 4i needed to inhibit [3H]thymidine incorporation into DNA
Derivative 1 was treated with potassium manganate(VII) under
phase transfer catalytic conditions at room temperature for 1 h to
give sulfone 5 in nearly quantitative yield.20 Compound 5 was then
reacted with anhydrous aniline in a sealed tube at 150 °C for
9 days. Chlorosulfonylation of the aniline substituted pyrazolotri-
azine 5 with chlorosulfonic acid at 0 °C proceeded selectively at
the 40-position of the phenyl ring, and gave compound 6 in an
excellent yield. The chlorosulfonyl derivative 6 was then coupled
with amines to produce the target sulfonamides 8a–j as shown
in Scheme 1.
by 50% (IC50
200 M suggesting low cytotoxic potency compared to chlorambu-
cil (IC50 = 49 M and 56 M, respectively). The concentra-
) in MDA-MB-231 and MCF-7 cells was above
l
2
l
2 l
tions of 4d, 4f, 4e, 4a, 4h, 4c, 4b needed to 50% reduction in
[3H]thymidine incorporation into DNA in breast cancer MCF-7
(IC50) obtained in the range 112 1 to 150
2 lM.
Structures and purity of the newly synthesized compounds
were characterized using the 1H and 13C NMR, as well as MS meth-
ods together with elemental analysis. The spectral data was pub-
lished earlier21,22 and they fully confirmed the structures of all
obtained sulfonamides.
2.2.2. Cytotoxic activity of 8a–8i
The cytotoxicity was determined as described above for com-
pounds 4a–i (Table 2).23 In terms of reduction in cell viability,
the compounds ranked in both MCF-7 and MDA-MB-231 cells
in the order: chlorambucil > 8a > 8g > 8f > 8h > 8b > 8d,8c,8i,8e.
Among these derivatives, compound 8a in both MDA-MB-231
and MCF-7 proved to be only slightly less potent than chlorambu-
2.2. Pharmacology
2.2.1. Cytotoxic activity of 4a–4i
cil, with IC50 values of 99 2 and 102
2 lM, respectively, com-
The viability of MCF-7 and MDA-MB-231 breast cancer cells was
measured by the method of Carmichael using 3-(4,5-dimethylthia-
zol-2-yl)-2,5-diphenyltetrazolium (Table 1).23 Although growth
inhibition was concentration-dependent in either cell line, it was
more pronounced at shorter times, in MCF-7 than MDA-MB-231
pared to 93 2 and 97 M for chlorambucil.
2 l
We studied the effect of compounds 8a–8i and chlorambucil on
DNA synthesis in both MDA-MB-231 and MCF-7 breast cancer cells
(Table 2). All of the tested compounds showed concentration
dependent activity, yet with different potency. The concentrations
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M. Mojzych et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
3
Table 1
Cytotoxic and cytostatic activities of new sulfonamides derivatives of pyrazolo[4,3-e][1,2,4]triazines 4a–4i after 24 h incubation
a
a
Compd
MTT assay, IC50
(lM)
[3H]thymidine incorporation, IC50
(lM)
MCF-7
MDA-MB-231
MCF-7
MDA-MB-231
4a
4b
4c
4d
4e
4f
4g
4h
110
172
181
105
112
123
190
132
>200
2
115
182
189
98
120
130
>200
136
>200
2
2
2
2
2
1
140
150
148
112
130
129
>200
145
>200
1
152
164
160
126
159
115
200
156
>200
2
2
1
2
1
1
1
2
2
2
3
2
2
1
2
2
1
1
2
2
2
1
4i
Chlorambucil
97
2
93
2
56
2
49
2
a
Data represent the mean S.D. of each compound from four independent experiments.
Table 2
Cytotoxic and cytostatic activities of new sulfonamides derivatives of pyrazolo[4,3-e][1,2,4]triazines 8a–8i after 24 h incubation
[3H]thymidine incorporation, IC50
(l
M)
a
a
Compd
MTT assay, IC50
(lM)
MCF-7
MDA-MB-231
MCF-7
MDA-MB-231
8a
102
2
99
2
87
2
80
2
8b
8c
8d
8e
8f
8g
8h
8i
150
>200
200
>200
140
126
146
>200
2
130
>200
140
>200
155
120
125
>200
93
2
170
>200
150
>200
123
85
99
2
2
1
103
>200
135
>200
150
90
120
>200
49
2
1
2
2
2
1
3
1
1
2
1
2
1
1
1
>200
56
Chlorambucil
97
2
2
2
2
a
Data represent the mean S.D. of each compound from four independent experiments.
of 8c, 8e, 8i needed to inhibit [3H]thymidine incorporation into
(in MDA-MB231: 47
lM and 52
lM, in MCF-7: 58
lM and 72
lM,
DNA by 50% (IC50) in MDA-MB-231 and MCF-7 cells was above
respectively) showed specific inhibitory effect of compound 8a on
collagen biosynthesis.
200
cil (IC50 = 49
l
M suggesting low cytotoxic potency compared to chlorambu-
M and 56 M, respectively). The concentra-
2
l
2
l
Our experimental studies have demonstrated that sildenafil
analogue 4a–i and aniline substituted pyrazolo[4,3-e][1,2,4]tri-
azine sulfonamides 8a–i treatment prevented the exponential
growth and decreased the number of viable cells in both estrogen
receptor-positive and estrogen receptor-negative breast cancer
cells. The structure–activity correlation of the obtained results
revealed that the presence of the NH spacer between the pyrazol-
otriazine moiety and phenyl ring is ‘essential’ for biological
activity. The compound 8a, which possess a N-metylpiperazine
function, is the most cytotoxic compound among a series of
aniline substituted pyrazolo[4,3-e][1,2,4]triazine sulfonamides
we have synthesized to date. Further investigations on the
mechanisms of the cytotoxicity, and preparation of new pyrazol-
o[4,3-e][1,2,4]triazine derivatives are now in progress.
tions of 8b, 8d, 8f, 8g, 8h, needed to 50% reduction in
[3H]thymidine incorporation into DNA in breast cancer MCF-7
(IC50) obtained in the range 85 1 to 170
2 lM. Among the deriv-
atives, compound 8a in both MDA-MB-231 and MCF-7 proved to
be slightly less potent than chlorambucil, with IC50 values of
80 2 and 87
2 lM, respectively.
Collagen biosynthesis was measured in MCF-7 and MDA-
MB231 breast cancer cells treated with various concentrations of
compounds 8a–8i (Table 3) and chlorambucil for 24 h. In both cell
lines compound 8a was found to be more effective inhibitor of col-
lagen biosynthesis than chlorambucil. IC50 for 8a and chlorambucil
Table 3
Collagen synthesis, measured by 5-[3H]-proline incorporation into proteins suscep-
tible to the action of bacterial collagenase, in MCF-7 and MDA-MB-231 breast cancer
cells in the presence of compounds 8a–8i and chlorambucil
2.2.3. CA activity of 8a–8j
As sulfonamides are the preferred pharmacophore for the inhi-
bition of carbonic anhyrases (CAs, EC 4.2.1.1)25 we investigated
whether the new compounds reported here may show such an
activity. We investigated inhibition of the cytosolic ubiquitous
isoform hCA I and II (h = human isoform) as well as the transmem-
brane, tumor-associated ones hCA IX and XII with compounds 5–8
reported in the paper (Table 4).
It may be observed that hCA I was not inhibited by all deriva-
tives except 8j (the primary sulfonamide) which acted as a weak
inhibitor, comparable to the clinically used acetazolamide.
The physiologically dominant isoform hCA II was potently inhib-
ited (KIs of 6.3–8.0 nM) only by 8e and 8j, incorporating the five-
membered heterocyclic ring and the SO2NH2 group, respectively,
whereas the remaining derivatives showed quite weak activity
against this isoform, with inhibition constants ranging between
a
Compd
IC50
(l
M)
MCF-7
MDA-MB-231
8a
47
1
58
2
8b
8c
8d
8e
8f
8g
8h
8i
175
>200
163
>200
133
112
1
180
>200
145
>200
135
95
2
1
2
2
2
1
1
1
1
140
>200
137
>200
Chlorambucil
52
1
72
2
a
Mean values from three independent experiments done in duplicates stan-
dard deviation (S.D.) are presented.
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4
M. Mojzych et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
Table 4
washed three times with PBS and then incubated for4 h in 1 ml
of MTT solution (0.5 mg/ml of PBS) at 37 °C in 5% CO2 in an incuba-
tor. The medium was removed and 1 ml of 0.1 mol/l HCI in abso-
lute isopropanol was added to attached cells. Absorbance of
converted dye in living cells was measured at a wavelength of
570 nm. Cell viability of breast cancer cells cultured in the pres-
ence of studied compounds was calculated as a per cent of control
cells. The experiments were performed in triplicates. After treat-
ment of the cells with drug, the ratio of survived to dead cells in
tested and control (untreated) cells was calculated for each drug
concentration. Cell number was plotted versus drug concentration,
and IC50 values were calculated from dose-response curves as the
concentration of drugs that reduce the number of viable cells to
50% of control using an Origin 7.5 software.
CA I, II, IX and XII inhibition data for compounds 5, 6 and sulphonamides 8a–8i24
Compd
KI* (nM)
hCA IX
hCA I
hCA II
hCA XII
5
6
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
>50,000
>50,000
>50,000
>50,000
nt
774
826
667
703
nt
89
82
>50,000
>50,000
nt
6.6
9.0
5.3
5.7
nt
>50,000
>50,000
>50,000
>50,000
>50,000
>50,000
270
492
6.3
>50,000
652
>50,000
23.7
824
26.5
6.2
8.1
5.9
7.1
6.2
7.5
7.9
5.8
918
62.1
719
772
8.0
43.8
25
Acetazolamide
250
12
3.1.4. Collagen synthesis assay
Acetazolamide (5-acetamido-1,3,4-thiadiazole-2-sulfonamide) was used as stan-
Incorporation of a radioactive precursor into proteins was
dard drug in the assay.
nt = not tested.
measured after labeling the cells with 5-[3H]proline (5
lCi/mL,
*
28 Ci/mmol) for 24 h in growth medium with varying concentra-
tions of PAMAM-CH conjugate or chlorambucil.27 Incorporation
of a tracer into collagen was determined by digesting proteins with
purified Clostridium histolyticum collagenase, according to the
method of Peterkofsky.28 Results were shown as combined values
for cell plus medium fractions.
Mean from 3 different assay, by a CO2 hydration stopped-flow assay method.
62.1–918 nM. It is difficult to explain the striking difference of
activity between 8e (an effective CAI) and the structurally congen-
ers related 8d and 8f, differing by few atoms compared to 8e, and
acting as ineffective hCA II inhibitors (Table 4).
3.1.5. CA activity and inhibition measurements
The tumor-associated isoforms hCA IX and XII,26 were on the
other hand better inhibited by some of the derivatives investigated
here. Thus, hCA IX was not at all inhibited by four of the new deriv-
atives (8a, 8b, 8d and 8f), was weakly inhibited by two of them (8e
and 8h), whereas 5, 6, 8g, 8i and 8j were more effective as hCA IX
inhibitors, with KIs in the range of 23.7–89 nM.
An applied photophysics stopped-flow instrument has been used
for assaying the CA catalysed CO2 hydration activity. Phenol red (at a
concentration of 0.2 mM) has been used as indicator, working at the
absorbance maximum of 557 nm, with 10–20 mM Hepes (pH 7.5) as
buffer, and 20 mM Na2SO4 for maintaining constant the ionic
strength, following the initial rates of the CA-catalyzed CO2 hydra-
tion reaction for a period of 10–100 s.24 The CO2 concentrations ran-
ged from 1.7 to 17 mM for the determination of the kinetic
parameters and inhibition constants. For each inhibitor, at least
six traces of the initial 5–10% of the reaction have been used for
determining the initial velocity. The uncatalyzed rates were deter-
mined in the same manner and subtracted from the total observed
rates. Stock solutions of inhibitors (0.01 mM) were prepared in
distilled-deionized water and dilutions up to 0.01 nM were done
thereafter with distilled-deionized water. Inhibitor and enzyme
solutions were preincubated together for 15 min at room tempera-
ture prior to assay, in order to allow for the formation of the E–I
complex. The inhibition constants were obtained by non-linear
least-squares methods using PRISM 3 and the Cheng–Prusoff equa-
tion, whereas the kinetic parameters for the uninhibited enzymes
from Lineweaver–Burk plots, as reported earlier,29 and represent
the mean from at least three different determinations.
On the contrary, hCA XII was potently inhibited (KIs <10 nM) by
all the reported compounds from the ms (Table 4).
3. Experimental
3.1. Pharmacology
3.1.1. Cell culture
Human breast cancer MDA-MB-231 and MCF-7 cells were
maintained in DMEM supplemented with 10% fetal bovine serum
(FBS), 50 U/ml penicillin, 50 lg/ml streptomycin at 37 °C. Cells
were cultured in Costar flasks and subconfluent cells were
detached with 0.05% trypsin and 0.02%EDTA in calcium-free phos-
phate buffered saline, counted in hemocytometers and plated at
5 ꢀ 105 cells per well of 6-well plates (Nunc) in 2 ml of growth
medium (DMEM without phenol red with 10% CPSR1). Cells
reached about 80% of confluency at day 3 and in most cases such
cells were used for the assays.
4. Conclusion
3.1.2. DNA synthesis assay
In conclusion, we report a practical, high yielding, and scalable
method for the preparation of two groups of new 1H-pyrazolo[4,3-
e][1,2,4]triazine sulfonamides from simple, available starting
materials. The preliminary antitumor studies revealed that these
derivatives exhibited moderate antitumor activity in breast cancer
cells ex vivo. These compounds were ineffectively as hCA I and II
inhibitors, but inhibited appreciably the tumor-associated iso-
forms hCA IX and XII.
MCF-7 and MDA-MB-231 cells were seeded in 6-well plates and
were incubated with varying concentrations of 6a–6l or chloram-
bucil and 0.5 l
Ci of [3H]-thymidine for 24 h at 37 °C. The cells were
then harvested by trypsinization, washed with cold phosphate-
buffered saline and centrifuged for 10 min at 1500 g several times
(4–5) until the dpm in the washes were similar to the reagent con-
trol. Radioactivity was determined by liquid scintillation counting.
[3H]-thymidine uptake was expressed as dpm/well.
3.1.3. Cell viability assay
Acknowledgement
The assay was performed according to the method of Carmi-
chael using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium
bromide (MTT).23 Confluent cells, cultured for 24 h with various
concentrations of studied compounds in 6-well plates were
This research was funded by the National Science Centre,
Poland (Grant NN405 092340) and by an FP7 EU project (Metoxia),
to CTS.
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M. Mojzych et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
5
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Please cite this article in press as: Mojzych, M.; et al. Bioorg. Med. Chem. (2014), http://dx.doi.org/10.1016/j.bmc.2014.03.029