Synthesis of Novel Selenides Bearing Benzenesulfonamide Moieties as Carbonic Anhydrase I, II, IV, VII, and IX Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.7b00387

A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for the inhibition of five human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IV, VII, and IX. These enzymes are involved in a variety of diseases, including glaucoma, retinitis pigmentosa, epilepsy, arthritis, and tumors. The investigated compounds showed potent inhibitory action against hCA II, VII, and IX, in the low nanomolar range, thus making them of interest for the development of isoform-selective inhibitors and as candidates for biomedical applications.

Full text of DOI:10.1021/acsmedchemlett.7b00387

Subscriber access provided by READING UNIV
Innovations
Synthesis of novel selenides bearing benzenesulfonamide
moieties as carbonic anhydrase I, II, IV, VII and IX inhibitors
Andrea Angeli, Damiano Tanini, Antonella Capperucci, and Claudiu T Supuran
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00387 • Publication Date (Web): 07 Nov 2017
Downloaded from http://pubs.acs.org on November 8, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Medicinal Chemistry Letters is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
9
Synthesis of novel selenides bearing benzenesulfonamide moieties as
carbonic anhydrase I, II, IV, VII and IX inhibitors
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Andrea Angeli,a Damiano Tanini,b Antonella Capperucci,b Claudiu T. Supuran a*
a Department of University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019
Sesto Fiorentino (Florence), Italy
b
Department of University of Florence, Department of Chemistry "Ugo Schiff", Via della Lastruccia 13, Iꢀ50019 Sesto
Fiorentino, Italy.
KEYWORDS carbonic anhydrase; inhibitor, metalloenzymes, selenium, selenides, organoselenium compounds
ABSTRACT: A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for the inhibition
of five human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IV, VII and IX. These enzymes are inꢀ
volved in a variety of diseases among which glaucoma, retinitis pigmentosa, epilepsy, arthritis and tumors. The investigated comꢀ
pounds showed potent inhibitory action against hCA II, VII and IX, in the low nanomolar range, thus making them of interest for
the development of isoformꢀselective inhibitors and as candidates for biomedical applications.
In the present study, we investigated different selenides incorꢀ
porating a benzenesulfonamide moiety as CAI. We began our
investigation with the synthesis of diselenide 3, as shown in
the Scheme 1. The diazonium salt of sulfanilamide was preꢀ
Selenium has a long history of association with human health
and disease.1,2 Interest in the potential biological, pharmacoꢀ
logical and therapeutic exploitation of synthetic organoseleniꢀ
um compounds started several decades ago. Organochalcogen
pared by reaction of 1 with sodium nitrite in the presence of
derivatives played a crucial role in identifying free radical
acid (Sandmeyer reaction) and used as key intermediate for
scavengers or antioxidants that can inhibit or retard oxidative
the synthesis of compound 2. Successively, the selenocyanate
derivative 2 was converted easily into the diselenide 3 by reacꢀ
tion with NaBH4 in ethanol, as outlined in Scheme 1.
damage.3,4 Oxidative stress, induced by the generation of reacꢀ
tive oxygen species (ROS), is considered a major causative
factor of many serious conditions, including diabetes, cardioꢀ
Scheme 1: Synthesis of selenocyanate and diselenide bearing
vascular diseases, cancer and several neurodegenerative disꢀ
eases.5,6 Furthermore, organoselenium derivatives showed inꢀ
hibitory effects on a variety of enzymes such as nitric oxide
synthase (NOS)7ꢀ10, lipoxygenases (LOX)11 and, carbonic anꢀ
hydrases12ꢀ14 (CAs, EC 4.2.1.1). CAs are metalloenzymes that
catalyse a very simple reaction: the hydration of carbon dioxꢀ
ide to bicarbonate and protons15. This reaction plays an imꢀ
portant role in many physiological and pathological processes
associated with pH control, ion transport, fluid secretion, bioꢀ
synthetic reactions, etc.16ꢀ17 For this reason, we continued to
investigate a new type of organoselenium derivatives as huꢀ
man (h) CA inhibitors (CAIs). Our long standing interest on
the reactivity of strained heterocycles with chalcogenꢀ
containing nucleophiles led us to disclose novel procedures for
the synthesis of a wide variety of functionalized seleniumꢀ and
telluriumꢀcontaining organic small molecules.18ꢀ21 Some of
these structures exhibited interesting catalytic antioxidant acꢀ
tivity.22ꢀ24 With the aim of synthesising a new series of hyꢀ
droxyꢀ and aminoꢀ functionalized selenium containing CAI,
we sought to exploit the reactivity of threeꢀmembered ring,
such as epoxides and aziridines, with a suitable selenolate,
bearing the benzenesulfonamide moiety (as CA inhibiting
chemotype),25 generated from the corresponding diselenide 3.
benzenesulfonamide moiety
SO2NH2
SO2NH2
i) HCl, NaNO2
ii) KSeCN
Se
NaBH4
2
EtOH r.t.
H2NO2S
NH2
SeCN
1
2
3
Having obtained the diselenide 3, we evaluated the possibility
to access βꢀhydroxy selenides by using the ring opening reacꢀ
tion of this compound with epoxides.26ꢀ28 Thus, 3 was reduced
with NaBH4 to the corresponding selenolate which was treated
in situ with benzyl glycidyl ether 4a, affording the βꢀ
hydroxyselenide 5a in good yield (Table 1, entry 1). The proꢀ
cess proved to be highly regioselective, as only the isomer
arising from the nucleophilic attack at the less hindered carbon
of the oxirane was observed. On the basis of these results, and
in order to study the generality of such a procedure, a series of
epoxides was reacted with 3 under the same conditions, as reꢀ
ported in Table 1. Thus, differently substituted hydroxyl
selenides 5b-g were obtained from the corresponding epoxides
4b-g through a regioselective ring opening route (Table 1, enꢀ
tries 2ꢀ4). Interestingly, epibromohydrin 4e was smoothly
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 2 of 5
converted into 5e in excellent yields; the nucleophilic attack Finally, the free selenoamine 8 was obtained from the NꢀBoc
1
2
3
4
5
6
7
occured exclusively on the epoxide, the halide being preserved
on the side chain (Table 1, entry 5). Disubstituted hydroxy
selenides 5f, g were obtained by reacting 3 with cyclohexene
oxide 4f and limonene oxide 4g (Table 1, entries 6,7).
derivative 7c by the acetyl chloride promoted cleavage of the
protecting group (Scheme 3).31
Scheme 3: Synthesis of βꢀamino selenide bearing benzenesulꢀ
fonamide moiety
Table 1: Synthesis of βꢀhydroxy selenides bearing benzeneꢀ
sulfonamide moiety
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As a further investigation, in order to propose an alternative
way to access the target compounds, we sought to achieve βꢀ
hydroxyꢀ and βꢀaminoꢀ selenides from the selenocyanate 2,
thus avoiding the synthesis of the diselenide 3. After having
optimized the reaction conditions, we were pleased to observe
that selenides 5a,b and 7a were obtained by ring opening of
epoxides 4a,b and aziridine 6a with the selenolate, in situ genꢀ
erated by reducing 2, as reported in the Scheme 4.
Scheme 4: Synthesis of selenides bearing benzenesulfonamide
moiety
We investigated the CA inhibitory proprieties of compounds
2, 3, 5a-g, 7a-c and 8 against the physiologically relevant hCA
isoforms I, II, IV, VII and IX by means of the stoppedꢀflow
carbon dioxide hydration assay32 after a period of 15 min of
incubation of the enzyme and inhibitor solutions.33–38 Their
activities were compared to the standard CAI acetazolamide
(AAZ) (Table 2).
Table 2. Inhibition data of human CA isoforms I, II, IV, VII
and IX with compounds 2, 3, 5a-g, 7a-c and 8 and AAZ by a
stopped flow CO2 hydrase assay.32
In order to access benzenesulfonamideꢀsubstituted selenides
bearing the amino group, the procedure was extended to difꢀ
ferently Nꢀprotected aziridines 6,29,30 synthesised from natural
aminoacids. As reported in the Scheme 2, enantioenriched Nꢀ
Tosyl and NꢀBoc selenides 7aꢀc were obtained in good yields
from 6aꢀc through a regioꢀ and stereoꢀselective reaction.
Scheme 2: Synthesis of Nꢀprotected βꢀamino selenides bearꢀ
ing benzenesulfonamide moiety
ACS Paragon Plus Environment

Page 3 of 5
ACS Medicinal Chemistry Letters
iii)
The last cytosolic human isoform studied, hCA VII,
1
2
3
4
5
6
7
8
was inhibited by all compounds in the subnanomolar – nanoꢀ
molar range (Kis of 0.35 – 74.2 nM, Table 2). Many of the
new seleniumꢀcontaining derivatives, such as 5b, 5d, 5f, 5g
and 7a were subnanomolar hCA VII inhibitors,m making them
of great interest for further studies, considering that this isoꢀ
form was shown to be involved in oxidative stress.39,40 The
presence of Nꢀprotecting groups for compounds 7a and 7c,
increased the efficacy 10 times for the Boc moiety and, 100
times for tosyl moiety. with respect to the compound without
such moieties (8).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
iv)
Almost all compounds investigated here possessed
low inhibitory activity for the membraneꢀbound hCA IV with
Kis spanning between the high nanomolar range to the miꢀ
cromolar range. Compound 2 showed the best activity against
this isoform with a Ki of 30.6 nM but, the efficacy decreased
for the diselenide derivative 4 (Ki 298.4 nM). Different subꢀ
stituents on the βꢀhydroxy selenides 5a-g did not influenced
significantly the inhibition activity. except for 5c which had a
decrease of the efficacy (Ki 8133 nM). Compound 7a, with a
tosyl moiety as protecting group, proved to have a better inhiꢀ
bition profile compared to the other βꢀamino selenides investiꢀ
gated here.
v)
The transmembrane, tumorꢀassociated hCA IX, was
effectively inhibited by all compounds investigated here, in
the low nanomolar range (Kis of 2.3 – 154.9 nM), all of them
being more effective inhibitors compared to the clibnically
used standard acetazolamide (AAZ) – Table 1. As for the othꢀ
er membrane isoform, hCA IV, the substituents on the βꢀ
hydroxy selenides 5a-g did not influenced significantly the
inhibitory efficacy in this small series of derivatives. Nꢀ
protection for compounds 7a and 7c did not change signifiꢀ
cantly the inhibition profile compared to the βꢀamino selenide
8. A special mention regading the important differences of inꢀ
hibitory activity of 5b and 5c against all isoforms except CA
IX. In fact, the two compounds only differ by the presence of
an allyl instead of an isoꢀpropyl moiety. Although these strucꢀ
tural differences are minor, in many similar cases when the Xꢀ
ray structures were reported in complex with various CA
isoforms,41,42 important differences in the orientation within
the active site were observed, which may explain the differꢀ
ence of inhibitory power of these quite similar derivatives.
* Mean from 3 different assays, by a stopped flow technique
(errors were in the range of ± 5ꢀ10 % of the reported values).
The following structure activity relationship (SAR) may be
noted regarding the inhibition data of Table 2:
i)
The ubiquitous cytosolic hCA I was inhibited by all
compounds with Ki spanning between low nanomolar (8.4
nM) to the high micromolar range (Ki 8084.3 nM). Selenocyaꢀ
nate derivative 2 inhibited hCA I in the medium nanomolar
range (Ki 95 nM) but the diselenide 3 showed a decreased poꢀ
tency of inhibition by almost 15ꢀfold. The βꢀhydroxy selenide
5g showed the best inhibition potency, with a Ki of 8.4 nM.
Moreover, a less bulky tail moiety such as in the cyclohexane
derivative (5f) decreased the activity 16 folds. Compound 8
inhibited this isoform in medium nanomolar range with a Ki of
93 nM. Compound with different Nꢀ protecting groups, such
as 7a and 7c led to a decrease of the inhibitory activity of
nearly 9 times (with the tosyl group in 7a) and 18 times (for
the Boc derivative 7c) compared to 8.
In conclusion, we have developed methods for the synthesis of
novel series of selenoethers as inhibitors on five αꢀcarbonic
anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance,
i.e., hCA I, II, IV, VII and IX. These isoform are drug targets
for antiglaucoma (hCA I, II and IV), antiepileptic (hCA VII)
or antitumor (hCA IX) agents. βꢀHydroxy 5a-g and Nꢀ
protected βꢀamino selenides prove to be potent inhibitor for
hCA VII. Indeed, βꢀamino selenide 8 showed a potent inhibiꢀ
tion against hCA II. In this contest, the investigated selenoꢀ
ether compounds showed potent inhibitory action, thus making
them interesting leads for the development of more potent and
more isoformꢀselective inhibitors.
ii)
The dominant cytosolic human isoform hCA II, was
inhibited in the lowꢀmedium nanomolar range by all comꢀ
pounds investigated here, except for derivative 5c which acted
in the high nanomolar range (Ki 920.8 nM). Selenocyanate
derivate 2 showed a 6 folds loss of activity compared to the
diselenide 3. βꢀHydroxy selenides 5a-g proved to be potent
inhibitors of this isoform, with Kis ranging between 0.18 and
8.8 nM, except for 5c mentioned earlier. In addition, the βꢀ
amino selenide 8 showed a very potent inhibition profile of
hCA II (Ki of 0.51 nM). The introduction of Nꢀprotecting
groups as in 7a and 7c led to a decrease of the inhibition poꢀ
tency of nearly 29 times compared to 8.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 4 of 5
anhydrase I, II, IV, VII and IX inhibitors, Bioorg Med Chem.
2017; 25, 2518.
Synthetic procedures, characterization of compounds and in vitro
kinetic procedure (PDF).
1
2
3
4
5
6
7
8
14. Angeli A., Peat T.S., Bartolucci G., Nocentini A.,
Supuran C.T., Carta F., Intramolecular oxidative deselenizaꢀ
tion of acylselenoureas: a facile synthesis of benzoxazole amꢀ
ides and carbonic anhydrase inhibitors, Org Biomol Chem.
2016; 14, 11353ꢀ11356.
15. Supuran, C.T. Carbonic anhydrases: novel therapeutic
applications for inhibitors and activators. Nature Rev Drug
Discov. 2008; 2, 168– 181.
16. Supuran, C.T. How many carbonic anhydrase inhibiꢀ
tion mechanisms exist? J Enzyme Inhib Med Chem. 2016; 31,
345–360.
17. Supuran C.T., Structure and function of carbonic anhyꢀ
drases. Biochem J. 2016; 473, 2023–2032.
AUTHOR INFORMATION
Corresponding Author
* (C.T.S.) Tel./fax:+39ꢀ055ꢀ4573729; eꢀmail: clauꢀ
diu.supuran@unifi.it
Author Contributions
9
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Notes
18. Tanini D., Grechi A., Dei S., Teodori E., Capperucci
A., An easy oneꢀstep procedure for the synthesis of novel βꢀ
functionalised tellurides, Tetrahedron, 2017; 73, 5646ꢀ5653.
19. Tanini D., Capperucci A., Degl'Innocenti A.,
Bis(trimethylsilyl)selenide in the Selective Synthesis of βꢀ
Hydroxy, βꢀMercapto, and βꢀAmino Diorganyl Diselenides
and Selenides Through Ring Opening of Strained Heterocyꢀ
cles, Eur. J. Org. Chem, 2015, 357ꢀ369.
20. Capperucci A., Tanini D., Borgogni C., Degl'Innocenti
A., Thiosilaneꢀ and OrganoselenosilaneꢀMediated Novel Acꢀ
cess to 3,7ꢀDisubstitutedꢀ1,2,5ꢀ trithiepanes and ꢀ1,2,5ꢀ
dithiaselenepanes, Heteroat. Chem., 2014, 25, 678ꢀ683.
21. Capperucci A., Tiberi C., Pollicino S., Degl'Innocenti
A., Fluoride Ion Induced Thiophilic Reactivity of Orgaꢀ
nosilanes with Sulfines:ꢁ Regiospecific Access to Allyl and
Benzyl Sulfoxides, Tetrahedron Lett., 2009, 50, 2808ꢀ2810.
22. Tanini D., D'Esopo V., Chen D., Barchielli G., Capꢀ
perucci A., Novel sulfur and seleniumꢀcontaining antioxiꢀ
dants: Synthesis and evaluation of their GPxꢀlike activity,
Phosphorus, Sulfur Silicon Relat. Elem., 2017, 192, 166ꢀ168.
23. Menichetti S., Capperucci A., Tanini D., Braga A. L.,
Botteselle G. V., Viglianisi C., A OneꢀPot Access to
Benzo[b][1,4]selenazines from 2ꢀAminoaryl Diselenides, Eur.
J. Org. Chem. 2016, 3097–3102.
24. Tanini D., Panzella L., Amorati R., Capperucci A.,
Pizzo E., Napolitano A., Menichetti S., D'Ischia M.,
Resveratrolꢀbased benzoselenophenes with an enhanced
antioxidant and chain breaking capacity, Org. Biol. Chem.
2015, 13, 5757ꢀ5764.
25. Capperucci A., Tanini D., Siliconꢀassisted synthesis
and functionalization of sulfurated and selenated compounds,
Phosphorus Sulfur Silicon Relat. Elem. 2015; 190, 1320ꢀ1338
26. Silva P. C., Borges E. L., Lima D. B., Jacob R. G., Leꢀ
nardão E. J., Perin G., Silva M. S., A simple and nonꢀ
conventional method for the synthesis of selected βꢀ
arylalkylchalcogeno substituted alcohols, amines and carboxꢀ
ylic acids Arkivoc, 2016, 5, 376ꢀ389.
The authors declare no competing financial interest.
ABBREVIATIONS
CAI(s), carbonic anhydrase inhibitor(s); AAZ, acetazolamide;
(h)CA, (human) carbonic anhydrase; KI, inhibition constant
REFERENCES
1. Olcott H.S., Brown W.D., Van Derveen J., Selenomethiꢀ
onine as an Antioxidant, Nature. 1961; 191, 1201.
2. Walter R., Schwartz I.L., Roy J., Can selenoamino acids
act as reversible biological antioxidants? Ann N Y Acad Sci.
1972; 192, 175ꢀ180.
3. Halliwel B., Gutteridge J.M.C. In Free Radicals in Biolꢀ
ogy and Medicine, 4th ed.; Oxford University Press: Oxford,
2007.
4. Halliwell B., Reactive species and antioxidants. Redox
biology is a fundamental theme of aerobic life. Plant Physiol.
2006; 141, 312.
5. Andersen J.K., Oxidative stress in neurodegeneration:
cause or consequence?, Nat. Rev. Neurosci. 2004; 5, S18ꢀ25.
6. Seet R.C.S., Lee C.ꢀY.J., Lima E.C.H., J.J.H. Tan,
A.M.L. Quek, W.ꢀL. Chong, W.ꢀF. Looi, S.ꢀH. Huang, H.
Wang, Y.ꢀH. Chand, B. Halliwell, Oxidative damage in Parꢀ
kinson disease: Measurement using accurate biomarkers. Free
Radical Biol. Med. 2010; 48, 560.
7. Wang J.ꢀF., Komarov P., Sies H., de Groot H., Inhibition
of superoxide and nitric oxide release and protection from reꢀ
oxygenation injury, Hepatology. 1992; 15, 1112.
8. Wang J.ꢀF., Komarov P., Sies H., de Groot H., Contribuꢀ
tion of nitric oxide synthase to luminolꢀdependent chemiluꢀ
minescence generated by phorbolꢀesterꢀactivated Kupffer
cells. Biochem. J. 1991; 279, 311.
9. Zembowicz A., Hatchett R.J., Radziszewski W.,
Gryglewski R.J., Inhibition of endothelial nitric oxide synꢀ
thase by ebselen. Prevention by thiols suggests the inactivaꢀ
tion by ebselen of a critical thiol essential for the catalytic acꢀ
tivity of nitric oxide synthase. J. Pharmacol. Exp. Therap.
1993; 267, 1112;
10. Southan G.J., Salzman A.L., Szabó C., Potent inhibiꢀ
tion of the inducible isoform of nitric oxide synthase by amiꢀ
noethylisoselenourea and related compounds. Life Sci. 1996;
58, 1139.
11. Schewe C., Schewe T., Wendel A., Strong inhibition of
mammalian lipoxygenases by the antiinflammatory selenoꢀ
organic compound ebselen in the absence of glutathione. Bio-
chem. Pharmacol. 1994; 48, 65.
27. Ganesh V., Chandrasekaran S., OneꢀPot Synthesis of βꢀ
Amino/βꢀHydroxy Selenides and Sulfides from Aziridines
and Epoxides. Synthesis, 2009, 19, 3267ꢀ3278.
28. Tiecco M., Testaferri L., Marini F., Sternativo S., Santi
C., Bagnoli L., Temperini A., intramolecular addition of carꢀ
bon radicals to aldehydes: synthesis of enantiopure tetrahyꢀ
drofuranꢀ3ꢀols, Tetrahedron, 2007, 63, 5482ꢀ5489.
29. Tanini D., Barchielli G., Benelli F., Degl’Innocenti A.,
Capperucci A., Aziridines Ring Opening by Silyl Chalcogenꢀ
ides: a Stereoselective Access to Polyfunctionalized Moleꢀ
cules as Precursor of Sulfurated and Selenated Heterocycles,
Phosphorus, Sulfur, Silicon Relat. Elem. 2015, 190, 1265ꢀ
1270
30 Braga A. L., Schneider P. H., Paixao M. W., Deobald
A. M., Peppe C., Bottega D. P., Chiral SelenoꢀAmines from
Indium Selenolates. A Straightforward Synthesis of Selenoꢀ
cysteine Derivatives, J. Org. Chem., 2006, 71, 4305ꢀ4307.
31. Charrat C., Biscotti A., Godeau G., Greiner J., Vierling
P., Guigonis J. M., Di Giorgio C., Formulation of highly funcꢀ
12. Angeli A., Carta F., Bartolucci G., Supuran C.T., Synꢀ
thesis of novel acyl selenoureido benzensulfonamides as carꢀ
bonic anhydrase I, II, VII and IX inhibitors, Bioorg Med
Chem. 2017; 25, 3567.
13. Angeli A., Tanini D., Viglianisi C., Panzella L., Capꢀ
perucci A., Menichetti S., Supuran C.T., Evaluation of seleꢀ
nide, diselenide and selenoheterocycle derivatives as carbonic
ACS Paragon Plus Environment

Page 5 of 5
ACS Medicinal Chemistry Letters
tionalizable DNA nanoparticles based on 1,2ꢀdithiolane deꢀ
rivatives, ChemBioChem, 2015; 16, 792ꢀ804.
32. Khalifah R. G., The carbon dioxide hydration activity
of carbonic anhydrase. I. Stop flow kinetic studies on the naꢀ
tive human isoenzymes B and C. J. Biol. Chem. 1971, 246,
2561.
38. AbdelꢀAziz A.A., Angeli A., ElꢀAzab A.S., Abu ElꢀEnin
M.A., Supuran C.T., Synthesis and biological evaluation of
cyclic imides incorporating benzenesulfonamide moieties as
carbonic anhydrase I, II, IV and IX inhibitors, Bioorg Med
Chem. 2017; 25, 1666ꢀ1671.
39. Monti, D.M.; De Simone, G.; Langella, E.; Supuran,
C.T.; Di Fiore, A.; Monti, S.M. Insights into the role of reacꢀ
tive sulfhydryl groups of Carbonic Anhydrase III and VII durꢀ
ing oxidative damage. J. Enzyme Inhib. Med. Chem. 2017, 32,
5ꢀ12.
1
2
3
4
5
6
7
8
33. Mollica A., Locatelli M., Macedonio G., Carradori S.,
Sobolev A.P., De Salvador R.F., Monti S.M, Buonanno M.,
Zengin G., Angeli A., Supuran C.T.. Microwaveꢀassisted exꢀ
traction, HPLC analysis, and inhibitory effects on carbonic
anhydrase I, II, VA, and VII isoforms of 14 blueberry Italian
cultivars, J. Enzyme Inhib. Med. Chem., 2016; 31(sup 4), 1ꢀ6.
34. De Vita D., Angeli A., Pandolfi F., Bortolami M., Costi
R., Di Santo R., Suffredini E., Ceruso M., Del Prete S., Caꢀ
passo C., Scipione L., Supuran C.T., Inhibition of the αꢀ
carbonic anhydrase from Vibrio cholerae with amides and
sulfonamide incorporating imidazole moieties, J. Enzyme In-
hib. Med. Chem., 2017; 32, 798.
35. Bruno E., Buemi M.R., Di Fiore A., De Luca L., Ferro
S., Angeli A., Cirilli R., Sadutto D., Alterio V., Monti S.M.,
Supuran C.T., De Simone G., Gitto R., Probing Molecular Inꢀ
teractions between Human Carbonic Anhydrases (hCAs) and
a Novel Class of Benzenesulfonamides, J Med Chem., 2017;
60, 4316.
40. Del Giudice, R.; Monti, D.M.; Truppo, E.; Arciello, A.;
Supuran, C.T.; De Simone, G.; Monti, S.M. Human carbonic
anhydrase VII protects cells from oxidative damage. Biol.
Chem. 2013, 394, 1343ꢀ8.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
41. De Simone, G.; Langella, E.; Esposito, D.; Supuran,
C.T.; Monti, S.M.; Winum, J.Y.; Alterio, V. Insights into the
binding mode of sulphamates and sulphamides to hCA II:
crystallographic studies and binding free energy calculations.
J. Enzyme Inhib. Med. Chem. 2017, 32, 1002ꢀ1011.
42. Kalinin, S.; Kopylov, S.; Tuccinardi, T.; Sapegin, A.;
Dar'in, D.; Angeli, A.; Supuran, C.T.; Krasavin, M. Lucky
Switcheroo: Dramatic Potency and Selectivity Improvement
of Imidazoline Inhibitors of Human Carbonic Anhydrase VII.
ACS Med. Chem. Lett. 2017, 8, 1105ꢀ1109.
36. Abdoli M., Angeli A., Bozdag M., Carta F., Kakanejaꢀ
difard A., Saeidian H., Supuran C.T., Synthesis and carbonic
anhydrase I, II, VII, and IX inhibition studies with a series of
benzo[d]thiazoleꢀ5ꢀ and 6ꢀsulfonamides, J Enzyme Inhib Med
Chem. 2017; 32, 1071ꢀ1078.
37. Mishra C.B., Kumari S., Angeli A., Monti S.M., Buoꢀ
nanno M., Tiwari M., Supuran C.T., Discovery of Benzeneꢀ
sulfonamides with Potent Human Carbonic Anhydrase Inhibiꢀ
tory and Effective Anticonvulsant Action: Design, Synthesis,
and Pharmacological Assessment, J Med Chem. 2017; 60,
2456ꢀ2469.
ACS Paragon Plus Environment