Carbonic Anhydrases inhibitory effects of new benzenesulfonamides synthesized by using superacid chemistry

Article abstract of DOI:10.3109/14756366.2011.638921

A series of benzofused sultams and fluorinated benzenesulfonamides were synthesized in superacid HF/SbF5 from simple N-allylic derivatives. Almost all of these original compounds showed micromolar inhibitory activities against carbonic anhydrases I and II

Full text of DOI:10.3109/14756366.2011.638921

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(6): 886–891
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.638921
RESEARCH ARTICLE
Carbonic Anhydrases inhibitory effects of new
benzenesulfonamides synthesized by using
superacid chemistry
Fei Liu1, Agnès Martin-Mingot1, F. Lecornué1, Marie-Paule Jouannetaud1,
Alfonso Maresca2, Sebastien ibaudeau1, and Claudiu T. Supuran2
1Laboratoire “Synthèse et Réactivité des Substances Naturelles”, Poitiers Cedex, France and
2Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino, Firenze, Italy
Abstract
A series of benzofused sultams and fluorinated benzenesulfonamides were synthesized in superacid HF/SbF from
simple N-allylic derivatives. Almost all of these original compounds showed micromolar inhibitory activities a5gainst
carbonic anhydrases I and II. The fluorinated derivatives inhibit better the tumor-associated isoforms IX and XII, and
one of the tested compounds showed inhibition in the nanomolar range.
Keywords: Hypoxic tumors, superelectrophiles, fluorine chemistry, sultams
Introduction
hCA II adducts (Figure 1), shows several active site water
molecules, interactions which may be responsible for this
difference of activity. In addition, the variety of aromatic/
heterocyclic sulfonamides showing affinity for hCA IX
isoform suggesting value in carrying on a drug design
campaign of inhibitors in this family. Herein, we report
a series of new benzofused sultams, β-fluorinated ben-
zenesulfonamides and 4-aminobenzenesulfonamides,
synthesized in superacid HF/SbF514, which show hCAs
inhibition properties.
Sixteen different α-carbonic anhydrase isoforms have
been isolated and characterized in mammals and many
of them are well established therapeutic targets to treat
a wide range of disorders1–4. Although inhibition of
α-carbonic anhydrases (α-CAs) by aromatic and hetero-
cyclic sulfonamides has been largely studied for 50 years
with applications in the treatment of various diseases5–7
,
this class of compounds remains an attractive chemical
family in the design of new inhibitors, as shown by the
ongoing research in this field8–12. As already reported,
small modifications on benzenesulfonamides can induce
significant differences in the bioactive profile of this type
of compounds. For example, a modification on the aro-
matic ring can induce very different behavior against
Material and methods
Chemistry
e authors draw the reader’s attention to the dangerous
features of superacidic chemistry. Handling of hydro-
gen fluoride and antimony pentafluoride must be done
by experienced chemists with all the necessary safety
arrangements in place.
Reactions performed in superacid were carried out in
a sealed Teflon® flask with a magnetic stirrer. No further
human carbonic anhydrases (Figure 1, Table 1)11,13
.
While chlorthalidone 1 and furosemide 3 are efficient
inhibitors against CA II, indapamide 2 is a much weaker
one. However, this latter one shows good inhibition
activity against isozyme IX and XII whereas furosemide
3 is significantly weaker. X-ray crystal structures of their
Address for Correspondence: Dr. Sebastien ibaudeau, Laboratoire “Synthese et Reactivite des Substances Naturelles”, UMR 6514, 40,
avenue du Recteur Pineau, F-86022, Poitiers Cedex, France. Tel: +33 549454588. Fax: +33 549453501. E-mail: sebastien.thibaudeau@univ-
poitiers.fr; Claudiu T. Supuran, Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino, Firenze, Italy.
E-mail: claudiu.supuran@unifi.it
(Received 19 October 2011; revised 02 November 2011; accepted 03 November 2011)
886

CAs inhibitory effects of new benzenesulfonamides 887
Figure 1. Comparison of interactions in which the thiazide/high-celling diuretics chlorthalidone 1 (A), indapamide 2 (B) and furosemide
3 (C) participate when bound to the hCA II active site, as observed in the corresponding X-ray crystal structures (PDB files 3F4X, 3BL1 and
1Z9Y).
1
1H-1H and H-13C experiments were used to confirm the
Table 1. Inhibition data of chlorthalidone 1, indapamide 2 and
NMR peaks assignments.
Melting points were determined in a capillary tube
and are uncorrected.
Mass spectra were performed with coupled gas chro-
matography (electronic impact).
All separations were done under flash-chromatogra-
phy conditions on silica gel (15–40 µm).
furosemide 3 against isoforms hCA I, II, IX and XII.
Kia (µm)
Compound
hCA Ib
348
hCA IIb
hCA IXc
hCA XIIc
4.5
1
2
3
138
23
51,900
2 520
65
36
10
62
420
261
aErrors in the range of 5% of the reported data from three
different assay.
bRecombinant isoforms16,17
.
Optimized procedure to synthesize benzofused
sultams of type A
cCatalytic domain, recombinant enzymes16,17
.
To a mixture of HF/SbF5 (6 mL, 4/2 molar ratio) main-
tained at −20°C, was added nitrogen derivative (1
mmol). e mixture was magnetically stirred at the
same temperature for reaction time. e reaction
mixture was then neutralized with water-ice-Na2CO3,
extracted with dichloromethane (×3). e combined
organic phases were dried (MgSO4) and concentrated
precautions have to be taken to prevent mixture from
moisture (test reaction worked out in anhydrous condi-
tions leads to the same results as expected).
Yields refer to isolated pure products.
1H, 13C and 19F NMR were recorded on a 300 MHz and
400 MHz spectrometers using CDCl3 as solvent. COSY
© 2012 Informa UK, Ltd.

888 F. Liu et al.
in vacuo. Products were isolated by column chroma-
tography over silica gel.
For example: Compound A1: 4,6-dimethyl-3,4-di-
hydro-2H-benzo[e][1,2]thiazine 1,1-dioxide
and 20 mM Na2SO4 (for maintaining constant the ionic
strength), following the initial rates of the CA-catalyzed
CO2 hydration reaction for a period of 10–100 s. e CO2
concentrations ranged from 1.7 to 17 mM for the deter-
mination of the kinetic parameters and inhibition con-
stants. For each inhibitor, at least six traces of the initial
5–10% of the reaction have been used for determining the
initial velocity. e uncatalyzed rates were determined in
the same manner and subtracted from the total observed
rates. Stock solutions of inhibitor (0.1 mM) were pre-
pared 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 temperature prior to assay, in
order to allow for the formation of the E-I complex. e
inhibition constants were obtained by non-linear least-
squares methods using PRISM 3, as reported earlier, and
represent the mean from at least three different determi-
nations16. CA isofoms were recombinant ones obtained
Optimized procedure (10 min reaction time) was fol-
lowed, starting from 211 mg of N-tosyl-N-allylamine (1
mmol). Purification by flash column chromatography
(98/2: dichloromethane/methanol) afforded 270 mg of
the title compound as a colourless oil (64%).
1H NMR (300 MHz, CDCl3, ppm): 1.34 (d, J= 7.2 Hz,
3H, CH3), 2.37 (s, 3H, CH3), 2.98 (m, 1H, H-4), 3.41 (m, 1H,
H-3), 3.82 (m, 1H, H-3), 4.89 (t, J= 7.7 Hz, 1H, NH), 7.09
(s, 1H, H-5), 7.14 (d, J= 8.1 Hz, 1H, H-7), 7.62 (d, J= 8.1 Hz,
1H, H-8). 13C NMR (75 MHz, CDCl3, ppm): 19.5 (CH3),
21.6 (CH3), 31.5 (CH, C-4), 48.2 (CH2, C-3), 124.0 (CH,
C-7), 128.2 (CH, C-8), 129.0 (C-5), 134.2 (C-8a), 140.2
(C-6), 142.7 (C-4a). MS (GCT, CI+): m/z (relative inten-
sity %) 211 [M]+ (40). HRMS (ESI): Calc for C10H13NO2S:
211.06670, found 211.0664.
in house as reported earlier16,17
.
Optimized procedure to synthesize β-fluorinated
benzenesulfonamides of type B
Results and discussion
To a mixture of HF/SbF5 (3 mL, 7/1 molar ratio) main-
tained at −20°C, was added nitrogen derivative (1
mmol). e mixture was magnetically stirred at the
same temperature for reaction time. e reaction
mixture was then neutralized with water-ice-Na2CO3,
extracted with dichloromethane (×3). e combined
organic phases were dried (MgSO4) and concentrated
in vacuo. Products were isolated by column chroma-
tography over silica gel.
Chemistry
In due course of a part of our work focused on the
development of new reactions in superacid to access to
fluorinated nitrogen containing compounds, going from
high valued building blocks18–20 to bioactive elaborated
molecules21,22, we recently applied this original chemistry
toward the synthesis of novel compounds in the benze-
nesulfonamide family23. Starting from simple N-allylic
benzenesulfonamides, after superelectrophilic activa-
tion24, either benzofused sultams of type A are obtained
after intramolecular Friedel-Crafts reaction (condition
A) or β-fluorinated benzenesulfonamides of type B can
be formed after hydrofluorination reaction (condition
B). is method allowed the synthesis of a large variety
of new benzofused sultams (A1–A10) and β-fluorinated
benzene sulfonamides (B1–B18) (Scheme 1).
For example: Compound B4: 4-fluoro-N-(2-fluoro-
propyl)-benzenesulfonamide
Optimized procedure (10 min reaction time) was
followed; starting from 215 mg of the corresponding
allylic starting material (1 mmol), 207 mg of the title
compound (88%) was obtained without purification as
a solid.
1H NMR (300 MHz, CDCl3, ppm): 1.20 (dd, JHF = 23.9
3
Hz, J = 6.2 Hz, 3H, H-3′), 3.03 (m, 2H, H-1′), 4.62 (dm,
2JHF = 48.8 Hz, 1H, H-2′), 5.47 (bs, 1H, NH), 7.11 (t, 3JHF = 8.6
Hz, 2H, H-3), 7.80 (m, 2H, H-2). 13C NMR (75 MHz,
In addition, by following synthetic sequences involv-
ing superacid chemistry at various stages, 4-aminoben-
zenesulfonamides 4–6 and 9 were formed (Scheme 2)25.
2
CDCl3, ppm): 18.4 (d, JC-F = 22 Hz, CH3, C-3′), 48.5 (d,
1
2JC-F = 21 Hz, CH2, C-1′), 89.5 (d, JC-F = 167 Hz, CH, C-2′),
Carbonic anhydrase inhibition
2
3
116.8 (d, JC-F = 22 Hz, 2CH, C-3), 130.1 (d, JC-F = 9 Hz,
Compounds A1–A10 were screened for the inhibition of
cytosolic isoforms hCA I and II (Table 2)15–17. e benzo-
fused sultams A1–A10 showed inhibition constants in
the range of 3–51 µM against the slow cytosolic isoform
hCA I.
e inhibition constants against the physiologically
dominant isoform hCA II were in the range of 4.4–85 µM.
Among the tested benzofused sultams, the 4-halogenated
substrates A5–A7 showed the best inhibition, and were
around one order of magnitude more effective compared
to the other substrates. is effect of the halogen on the
inhibitor activity against hCA, difficult to be explained at
this stage, can be compared to similar reported effects of
halogen on sulfanilamide derivatives16,17. However, the
4
1
2CH, C-2), 136.3 (d, JC-F = 3 Hz, C-1), 165.5 (d, JC-F = 253
Hz, C-4). 19F {1H} NMR (282 MHz, CDCl3, ppm): -105.5
(CF) and -180.1 (CHF). MS (GCT, CI+): m/z (relative
intensity %) 188 [M-CH3CHF]+ (80). HRMS (ESI): Calc
for: (C9H11NO2F2S) 235.04786, found 235.0458. Melting
Point (°C): 91.7.
CA inhibition assay
An Applied Photophysics stopped-flow instrument has
been used for assaying the CA catalysed CO2 hydration
activity15. Phenol red (at a concentration of 0.2 mM) has
been used as indicator, working at the absorbance maxi-
mum of 557 nm, with 20 mM Hepes (pH 7.5) as buffer,
Journal of Enzyme Inhibition and Medicinal Chemistry

CAs inhibitory effects of new benzenesulfonamides 889
Scheme 1. Synthesis of benzofuzed sultams A and β-fluorinated benzenesulfonamides B in superacid HF/SbF5. Condition A: 10min,
−20°C, substrate concentration c=0.16 mol·L−1, % mol SbF5 =13.6; Condition B: 10min, −20°C, substrate concentration c=0.33 mol·L−1,
%mol SbF5 =3.8.
Scheme 2. Synthesis of 4-aminobenzofuzed sultams 4, 5, 6 and 9. (a) HF/SbF5 (% mol SbF5 =3.8), −20°C, 10min, 42%. (b) CH3I, K2CO3, DMF, rt,
12h, >95% (c) CuI, L-proline, octylamine, K3PO4, DMSO, 90°C, 24h, 62%. (d) HF/SbF5 (% mol SbF5 =13.6), −20°C, 10min, 62%.(e) CuI, L-proline,
2-aminobutanol, Cs2CO3, DMSO, 90°C, 24h, 70%. (f) CuI, L-proline, aq. NH3, K3PO4, DMSO, 90°C, 24h, 81%. (g) allylbromide, K2CO3, DMF, rt,
12h, 83%. (h) CuI, L-proline, morpholine, K3PO4, DMSO, 90°C, 24h, 70%. (i) HF/SbF5 (% mol SbF5 =3.8), −20°C, 10min, 69%.
4-fluorinated benzofused sultam A4 did not show a simi-
lar activity. In addition, a steric hindrance effect seems
to be in favor of hCA II inhibition compared to hCA I, as
shown by the obtained results from substrates A8–A10.
e research focused on the involvement of isozymes
CA IX and XII in cancer has progressed significantly in
recent years. ese isozymes are overexpressed in tumor
cells in response to the hypoxia inducible factor (HIF)
pathway26. Since the report on the X-ray crystal structure
of CA IX27, many classes of compounds have been tested
as CA IX inhibitors26. Among them, fluorine containing
sulfonamides showed good affinity for this isoform28.
In addition, by testing α-fluoro and α,α-difluoro-
benzenemethanesulfonamides, it has been reported that
© 2012 Informa UK, Ltd.

890 F. Liu et al.
Table 2. hCA I and II inhibition data with sulfonamides A1–A10,
by the CO2 hydrase method15.
Table 3. CA inhibition data with β-fluorinated derivatives
B1–B18 and 4-aminobenzenesulfonamides 4–6, 9 and SA
as standard inhibitor, against isozymes I, II, IX and XII, by a
stopped-flow CO2 hydrase assay.
Kia (µm)
Compound
hCA Ib
20
hCA IIb
21
Kia (µm)
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
Compound
B1
hCA Ib
4.4
hCA IIb
4.2
hCA IXc
hCA XIIc
3.6
23
85
3.9
18
21
B2
4.6
2.2
4.2
4.1
34
38
B3
3.3
3.9
4.8
3.4
3.2
9
4.4
8.6
9.8
24
B4
4.2
4.4
4.3
3.2
B5
4.4
3.3
3.4
2.5
3.4
51
B6
3.1
4.5
3.3
3.0
B7
4.6
4.5
3.9
3.1
30
8.5
9.5
B8
4.8
4.6
4.4
1.1
39
B9
4.5
2.4
2.2
4.2
aErrors in the range of 5% of the reported data from three
different assay.
B10
B11
B12
B13
B14
B15
B16
B17
B18
4
4.8
4.1
4.6
1.4
bRecombinant isoforms16,17
.
4.7
4.3
4.9
1.1
4.5
4.4
3.8
4.1
4.8
2.7
5.7
4.3
after α-fluorination of sulfonamide, through the electron
withdrawing effect of fluorine atom(s)29, a correlation
between sulfonamide acidity enhancement and car-
bonic anhydrase inhibition exists30. Taking into account
these data a series of β-fluorinated benzenesulfonamides
B1–B18 were tested as inhibitors against hCA I and II,
and against tumor-associated isozymes hCA IX and XII
4.5
4.3
3.0
4.6
4.2
3.0
2.1
4.0
4.6
2.1
2.9
4.6
4.6
2.3
2.7
3.8
4.8
2.0
2.5
4.5
>500d
>500d
0.637
>500d
25
>500d
>500d
0.431
>500d
0.24
ND
ND
0.136
ND
0.294
ND
ND
0.298
ND
0.037
5
(Table 3)15–17
.
6
All the β-fluorinated benzene sulfonamides are potent
hCA inhibitors with very close inhibition constants of
3.1–4.8 µM against the cytosolic form hCA I and of 2.0–
4.5 µM against hCA II. Although the previously described
benzofused sultams showed low micromolar inhibition
constants, the linear β-fluorinated benzene sulfonamides
are better inhibitors for hCA I and II. ese observations
seem to underline a potent fluorine influence on isozyme
inhibition, which could be attributed to a modification of
the sulfonamide function pKa. However, no significant
effect of the aromatic substitution, either on the inhibition
or on the selectivity, can be taken out from these results.
e tumor-associated transmembrane isoforms hCA IX
and XII were also inhibited by all the tested β-fluorinated
benzene sulfonamides with inhibition constants in the
range of 2.1–5.7 µM against hCA IX and of 1.1–4.6 µM
against hCA XII. Again no real SAR emerged from differ-
ent substitution patterns.
9
SA
aErrors in the range of 5% of the reported data from three
different assay.
bRecombinant isoforms16,17
cCatalytic domain
dNot active.
.
tumor-associated isoforms hCA IX and XII over the
physiologically dominant isoform hCA II is of crucial
importance in the search of new lead compounds that
selectively inhibit hCA IX and XII. Interestingly, even
if the inhibitor potency of compound 6 is medium, it
can be considered as a selective inhibitor of tumor-
associated isoforms over cytosolic ones (selectivity
ratio I/IX = 4.7; I/XII = 2.1; II/IX = 3.2; II/XII = 1.4) and a
new lead compound for further investigations.
Taking into account the known hCA inhibitor prop-
erties of 4-aminobenzene sulfonamides such as sulfa-
nilamide SA31, four 4-aminobenzenesulfonamides 4–6
and 9 were also tested and compared to SA (Table 3).
Unfortunately, N-substituted 4-aminobenzenesulfon-
amides 4, 5 and 9 were found to be inactive toward
hCAs. By considering a potent negative effect of the
substitution on the nitrogen atom, corresponding pri-
mary amine 6 was tested. is compound was found
to be the best carbonic anhydrase inhibitor tested in
this project. Compound 6 showed nanomolar inhibi-
tion potency against the four tested isoforms and was
more active than SA against the tumor-associated iso-
form IX. e selectivity ratio for the inhibition of the
Conclusion
In conclusion, we report here a series of new benzo-
fused sultams, β-fluorinated benzenesulfonamides
and 4-aminobenzofused sultams prepared by using
superacid chemistry. ese compounds have been
investigated as inhibitors of cytosolic human car-
bonic anhydrases I and II and transmembrane tumor-
associated carbonic anhydrases isoforms IX and XII.
For almost all the tested compounds, inhibition at very
low micromolar range has been observed against the
tested hCAs. One compound showing inhibition at
the nanomolar level has been identified. ese results
emphasize the potential of using superacid chemistry
Journal of Enzyme Inhibition and Medicinal Chemistry

CAs inhibitory effects of new benzenesulfonamides 891
14. Olah GA, Prakash GKS, Molnar A, Sommer J. Superacids, 2nd
Edition. New York: Wiley; 2009.
15. Khalifah RG. e carbon dioxide hydration activity of carbonic
anhydrase. I. Stop-flow kinetic studies on the native human
isoenzymes B and C. J Biol Chem 1971;246:2561–2573.
as a new synthetic tool in the discovery of new carbonic
anhydrase inhibitors with potential use as antitumor
agents31,32
.
16. Ilies MA, Vullo D, Pastorek J, Scozzafava A, Ilies M, Caproiu
MT et al. Carbonic anhydrase inhibitors. Inhibition of
tumor-associated isozyme IX by halogenosulfanilamide and
Acknowledgement
We thank the region Poitou-Charentes (grant to F.Liu.),
the CNRS and the University of Poitiers for financial sup-
port and an EU FP7 grant (Metoxia, to CTS).
halogenophenylaminobenzolamide derivatives.
2003;46:2187–2196.
J Med Chem
17. Biswas S, Aggarwal M, Güzel Ö, Scozzafava A, McKenna R, Supuran
CT. Conformational variability of different sulfonamide inhibitors
with thienyl-acetamido moieties attributes to differential binding
in the active site of cytosolic human carbonic anhydrase isoforms.
Bioorg Med Chem 2011;19:3732–3738.
Declaration of interest
Financial support and EU FP7 grant (Metoxia, to CTS)
were provided by the region Poitou-Charentes (grant to
F.Liu.), the CNRS and the University of Poitierregion. e
authors report no declarations of interest.
18. Jacquesy J-C. Organic Synthesis in Superacid. In: Olah GA, (ed).
Carbocation Chemistry. New York: Wiley; 2009. pp 359–376.
19. ibaudeau S, Martin-Mingot A, Jouannetaud M-P, Karam
O, Zunino F.
A novel, facile route to β-fluoroamines by
hydrofluorination reaction in superacid HF-SbF5. Chem Commun
2007;3198–3200.
20. Vardelle E, Gamba-Sanchez D, Martin-Mingot A, Jouannetaud
M-P, ibaudeau S, Marrot J. Cyclisation/fluoriantion of nitrogen
containing dienes in superacid HF-SbF5 : A new route to 3- and
4-fluoropiperidines. Chem Commun 2008;1473–1475.
21. Fahy J, Duflos A, Ribert J-P, Jacquesy J-C, Berrier C, Jouannetaud
M-P, Zunino F. Vinca alkaloids in superacidic media: A method
for creating a new family of antitumor derivatives. J Am Chem Soc
1997;119:8576–8577.
References
1. Supuran CT. Carbonic anhydrases: Novel therapeutic applications
for inhibitors and activators. Nat Rev Drug Discov 2008;7:168–181.
2. Supuran CT. Carbonic Anhydrases as Drug Targets—General
Presentation. In: Supuran CT, Winum JY, (eds). Drug Design of Zinc-
Enzyme Inhibitors: Functional, Structural, and Disease Applications.
Hoboken, NJ: Wiley; 2009. pp 15–38.
22. Debarge S, ibaudeau S, Violeau B, Martin-Minfot A,
Jouannetaud M-P, Jacquesy J-C, Cousson A. Rearrangement or
gem-difluorination of quinine and 9-epiquinine and their acetates
in superacid. Tetrahedron 2005;61:2065–2073.
23. Liu F, Martin-Mingot A, Jouannetaud MP, Zunino F, ibaudeau
S. Superelectrophilic activation in superacid HF/SbF(5) and
synthesis of benzofused sultams. Org Lett 2010;12:868–871.
24. Olah GA, Klumpp D. Superelectrophiles and their chemistry. New
York: Wiley; 2008.
25. Liu F, Musadji NY, Lecornué F, Jouannetaud M-P, ibaudeau S.
Superacid mediated reactions applied to 4-aminobenzofused
sultams and fluorinated 4-aminobenzene sulfonamides synthesis.
Tetrahedron 2010;66:7112–7118.
3. Winum JY, Rami M, Scozzafava A, Montero JL, Supuran C. Carbonic
anhydrase IX: A new druggable target for the design of antitumor
agents. Med Res Rev 2008;28:445–463.
4. SupuranCT, ScozzafavaA, CasiniA. Carbonicanhydraseinhibitors.
Med Res Rev 2003;23:146–189.
5. iry A, Dogné JM, Masereel B, Supuran CT. Targeting tumor-
associated carbonic anhydrase IX in cancer therapy. Trends
Pharmacol Sci 2006;27:566–573.
6. Supuran CT, Scozzafava A. Carbonic anhydrases as targets for
medicinal chemistry. Bioorg Med Chem 2007;15:4336–4350.
7. Supuran CT. Carbonic anhydrase inhibition/activation: Trip of a
scientist around the world in the search of novel chemotypes and
drug targets. Curr Pharm Des 2010;16:3233–3245.
26. iry A, Supuran CT, Masereel B, Dogné JM. Recent developments
of carbonic anhydrase inhibitors as potential anticancer drugs.
J Med Chem 2008;51:3051–3056.
27. Alterio V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S
et al. Crystal structure of the catalytic domain of the tumor-
associated human carbonic anhydrase IX. Proc Natl Acad Sci USA
2009;106:16233–16238.
8. Rami M, Maresca A, Smaine FZ, Montero JL, Scozzafava A, Winum
JY et al. Sulfonamides incorporating boroxazolidone moieties
are potent inhibitors of the transmembrane, tumor-associated
carbonic anhydrase isoforms IX and XII. Bioorg Med Chem Lett
2011;21:2975–2979.
9. Capkauskaite E, Baranauskiene L, Golovenko D, Manakova
E, Gražulis S, Tumkevicius
S
et al. Indapamide-like
28. Vullo D, Scozzafava A, Pastorekova S, Pastorek J, Supuran CT.
Carbonic anhydrase inhibitors: Inhibition of the tumor-associated
isozyme IX with fluorine-containing sulfonamides. e first
subnanomolar CA IX inhibitor discovered. Bioorg Med Chem Lett
2004;14:2351–2356.
29. O’Hagan D. Understanding organofluorine chemistry. An
introduction to the C-F bond. Chem Soc Rev 2008;37:308–319.
30. Blackburn GM, Türkmen H. Synthesis of alpha-fluoro- and alpha,
alpha-difluoro-benzenemethanesulfonamides: New inhibitors of
carbonic anhydrase. Org Biomol Chem 2005;3:225–226.
31. Alterio V, Di Fiore A, D’Ambrosio K, Supuran CT, De Simone G.
X-ray crystallography of ca inhibitors and its importance in drug
design. In: Supuran CT, Winum JYed, . Drug Design of Zinc-Enzyme
Inhibitors: Functional, Structural, and Disease Applications.
Hoboken, NJ: Wiley; 2009. pp 73–138.
benzenesulfonamides as inhibitors of carbonic anhydrases I, II,
VII, and XIII. Bioorg Med Chem 2010;18:7357–7364.
10. Mader P, Brynda J, Gitto R, Agnello S, Pachl P, Supuran CT et al.
Structural basis for the interaction between carbonic anhydrase
and 1,2,3,4-tetrahydroisoquinolin-2-ylsulfonamides. J Med Chem
2011;54:2522–2526.
11. Mincione F, Benedini F, Biondi S, Cecchi A, Temperini C,
Formicola G et al. Synthesis and crystallographic analysis of new
sulfonamides incorporating NO-donating moieties with potent
antiglaucoma action. Bioorg Med Chem Lett 2011;21:3216–3221.
12. Bertucci A, Innocenti A, Scozzafava A, Tambutté S, Zoccola D,
Supuran CT. Carbonic anhydrase inhibitors. Inhibition studies
with anions and sulfonamides of a new cytosolic enzyme from the
scleractinian coral Stylophora pistillata. Bioorg Med Chem Lett
2011;21:710–714.
32. Neri D, Supuran CT. Interfering with pH regulation in tumours as a
therapeutic strategy. Nat Rev Drug Discov 2011;10:767–777.
13. Supuran CT. Carbonic anhydrase inhibitors. Bioorg Med Chem
Lett 2010;20:3467–3474.
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