Sulfocoumarins as dual inhibitors of human carbonic anhydrase isoforms IX/XII and of human thioredoxin reductase

Article abstract of DOI:10.1080/14756366.2020.1712596

The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and–hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents.

Full text of DOI:10.1080/14756366.2020.1712596

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: https://www.tandfonline.com/loi/ienz20
Sulfocoumarins as dual inhibitors of human
carbonic anhydrase isoforms IX/XII and of human
thioredoxin reductase
Mikhail Krasavin, Raivis Žalubovskis, Aiga Grandāne, Ilona Domračeva, Petr
Zhmurov & Claudiu T. Supuran
To cite this article: Mikhail Krasavin, Raivis Žalubovskis, Aiga Grandāne, Ilona Domračeva,
Petr Zhmurov & Claudiu T. Supuran (2020) Sulfocoumarins as dual inhibitors of human carbonic
anhydrase isoforms IX/XII and of human thioredoxin reductase, Journal of Enzyme Inhibition and
Medicinal Chemistry, 35:1, 506-510, DOI: 10.1080/14756366.2020.1712596
To link to this article: https://doi.org/10.1080/14756366.2020.1712596
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
2020, VOL. 35, NO. 1, 506–510
https://doi.org/10.1080/14756366.2020.1712596
SHORT COMMUNICATION
Sulfocoumarins as dual inhibitors of human carbonic anhydrase isoforms IX/XII
and of human thioredoxin reductase
a
b,c
b
b
a
ꢀ
ꢁ
ꢀ
Mikhail Krasavin , Raivis Zalubovskis , Aiga Grandane , Ilona Domraceva , Petr Zhmurov and
Claudiu T. Supurand
b
aDepartment of Chemistry, Saint Petersburg State University, Saint Petersburg, Russian Federation; Latvian Institute of Organic Synthesis, Riga,
c
Latvia; Faculty of Materials Science and Applied Chemistry, Institute of Technology of Organic Chemistry, Riga Technical University, Riga,
d
Latvia; Neurofarba Department, Universita degli Studi di Firenze, Florence, Italy
ABSTRACT
ARTICLE HISTORY
Received 9 December 2019
Accepted 1 January 2020
The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) can-
cer-associated isoforms hCA IX and – hCA XII is being able to also inhibit thioredoxin reductase was veri-
fied and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative
stress, may both contribute to the observed antiproliferative profile of these compounds against many
cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for design-
ing innovative therapeutic agents.
KEYWORDS
Anticancer agents; carbonic
anhydrase inhibition;
thioredoxin reductase
inhibition; hypoxia;
oxidative stress
1. Introduction
to lead to retardation of tumour growth and, ultimately, reduction
of tumour size10.
Earlier, we reported 6-substituted sulfocoumarins 11 (designed as
isosteres of the structurally related coumarins2–6) as potent and
remarkably isoform-selective inhibitors of the metallo-enzyme car-
bonic anhydrase (CA, EC 4.2.1.1)7,8. The ability of sulfocoumarins
to selectively inhibit membrane-bound hCA IX and XII isoforms
were attributed to the unique mechanism of action of these com-
pounds whereby they act as prodrugs activated by CA-mediated
hydrolysis1–6. This makes these inhibitors fundamentally different
from the classical carbonic anhydrase inhibitors (CAIs) – e.g. those
of sulphonamide type which act by binding to the CA prosthetic
zinc ion present in all isoforms, which makes designing isoform-
selective sulphonamide CAIs particularly difficult. On the contrary,
CA-mediated hydrolysis of sulfocoumarins 1 (as well as their pro-
genitors coumarins) leads to the in situ formation of the Z-config-
ured stiryl sulphonic acid (Z)-2 which is likely to isomerise to (E)-2,
the active inhibitor form whose binding to CA was confirmed by
X-ray crystallography1. This inhibitor activation and binding appar-
ently occurs only in the protein environment of the two mem-
brane-bound isoforms (hCA IX and XII) which makes these
mechanistically distinct inhibitors ideal tools for targeting hypoxia
survival mechanism in tumour cells providing which overexpres-
sion of precisely these two isoforms is considered responsible for9.
Another principal mechanism of tumour survival which we
have been recently tackling11,12 as
a target for anticancer
agent design, is that providing tumour cell defence against oxida-
tive stress (reactive oxygen species or ROS). In particular, tumour
cells have been shown to overexpress thioredoxin reductase
(TrxR, EC 1.8.1.9) which contributes to their resistant phenotype
characterised by higher levels of ROS13. Thus, targeting TrxR1 (the
most widespread cytosolic isoform of human TrxR) has
been investigated as an emerging approach to selective killing of
cancer cells14. This selenocysteine (Sec) enzyme, along with
NADPH and thioredoxin (Trx) is part of the Trx system and respon-
sible for maintaining Trx in its reduced bis-sulfhydryl state.
Among several classes of inhibitors of varying degree of electro-
philicity towards the catalytic Sec residue (recently reviewed by
Bellelli15 and Fang16), we found covalent Michael acceptor inhibi-
tors (such as Ugi-type adducts 3 which we dubbed “Ugi Michael
Acceptors” or UMAs) to be particularly efficacious12. The mechan-
ism of inhibitory action of UMAs towards TrxR1 likely involves the
irreversible covalent trapping of the selenide group of the cata-
lytic Sec residue (which exists in the ionised form at physiological
pH17) by the electrophilic b-benzoylacrylamide moiety present
Indeed, selective targeting of hCA IX and XII has been confirmed in 3.
CONTACT Mikhail Krasavin
u.supuran@unifi.it Neurofarba Dept, Universita degli Studi di Firenze, Florence, Italy
ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
m.krasavin@spbu.ru
Saint Petersburg State University, Saint Petersburg 199034, Russian Federation; Claudiu T. Supuran
claudi
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
507
Figure 1. Sulfocoumarins 1 and their CA inhibition mechanism, the previously reported Ugi Michael acceptor TrxR inhibitors (fragments originating from the four com-
ponents of the Ugi reaction are colour-coded) and the hypothesis for dual CA/TrxR targeting verified in this work.
Considering the presence of a potential Michael acceptor moi- 2.2.1. 4-(4-Chlorophenyl)-1-(2,2-dioxido-1,2-benzoxathiin-6-yl)-1H-
ety in sulfocoumarins 1, we hypothesised that in addition to their
inhibitory activity towards hCAs, these compounds could poten-
tially act as Michael acceptor-type TrxR inhibitors (Figure 1), thus
acting as dual inhibitors which target two cancer cell defence
mechanisms at a time. Herein, we present our preliminary results
obtained in the course of verifying this hypothesis.
1,2,3-triazole (1a)
Prepared from
4
(0.15 g, 0.67 mmol), 4-chlorophenylacetylene
(0.18 g, 1.34 mmol), CuI (0.26 g, 1.34 mmol), and DIPEA (5.85 mL,
33.6 mmol) according to GP1. Crystallisation from ethanol afforded
1a as yellow crystalline solid (0.19 g, 77%). Mp 236–237 ꢀC. IR (KBr,
cmꢁ1) ꢀmax: 1369 (S–O), 1179 (S–O), and 1169 (S–O). 1H NMR
(400 MHz, DMSO-d6) d: 7.55–7.60 (m, 2H), 7.70 (d, J¼ 10.4 Hz, 1H),
7.75 (d, J¼ 8.9 Hz, 1H), 7.84 (d, J¼ 10.4 Hz, 1H), 7.92–7.97 (m, 2H),
8.12 (dd, J¼ 8.9, 2.7 Hz, 1H), 8.39 (d, J¼ 2.7 Hz, 1H), and 9.38 (s,
1H). 13C NMR (100 MHz, DMSO-d6) d: 119.9, 120.2, 120.3, 121.4,
123.7, 124.0, 127.0, 128.9, 129.2, 132.9, 134.2, 135.8, 146.4, and
150.1. Anal. Calcd. for C16H10N3O3SCl (359.79): C, 53.41; H, 2.80; N,
11.68. Found: C, 53.22; H, 2.79; N, 11.32.
2. Materials and methods
2.1. Chemical syntheses – general
Reagents and starting materials were obtained from commercial
sources (Sigma-Aldrich, St. Louis, MO) and used as received. The
solvents were purified and dried by standard procedures prior to
use; petroleum ether of boiling range 40–60ꢀ C was used. Flash
chromatography was carried out using Merck silica gel
(230–400 mesh). Thin-layer chromatography was performed on sil-
ica gel, spots were visualised with UV light (254 and 365 nM).
Melting points were determined on an OptiMelt automated melt-
ing point system. IR spectra were measured on a Shimadzu FTIR
IR Prestige-21 spectrometer. NMR spectra were recorded on Varian
Mercury (400 MHz) spectrometer with chemical shifts values (d) in
ppm relative to TMS using the residual DMSO-d6 signal as an
internal standard. Elemental analyses were performed on a Carlo
Erba CHNSeO EA-1108 apparatus. Starting material sulfocoumarins
(418 and 519) were prepared as described previously. Alkynes
employed in the synthesis of 1a–b are commercially available.
Tetrazoles employed in the synthesis of 1c–d were prepared
according to the literature protocols20,21. All reagents for bio-
logical assays were purchased from Sigma (St. Louis, MO).
2.2.2. 1-(2,2-Dioxido-1,2-benzoxathiin-6-yl)-4-(4-fluorophenyl)-1H-
1,2,3-triazole (1b)
Prepared from
4 (0.15 g, 0.67 mmol), 4-fluorophenylacetylene
(0.16 g, 1.34 mmol), CuI (0.26 g, 1.34 mmol), and DIPEA (5.85 mL,
33.6 mmol) according to GP1. Yellow crystalline solid (0.19 g, 80%).
Mp 224–225 ꢀC. IR (KBr, cmꢁ1) ꢀmax: 1359 (S–O) and 1179 (S–O).
1H NMR (400 MHz, DMSO-d6) d: 7.32–7.39 (m, 2H), 7.71 (d,
J¼ 10.4 Hz, 1H), 7.75 (d, J¼ 8.9 Hz, 1H), 7.84 (d, J¼ 10.4 Hz, 1H),
7.94–8.00 (m, 2H), 8.12 (dd, J¼ 8.9, 2.6 Hz, 1H), 8.39 (d, J¼ 2.6 Hz,
1H), and 9.33 (s, 1H). 13C NMR (100 MHz, DMSO-d6) d: 116.1 (d,
J¼ 21.9 Hz), 119.8, 119.9, 120.2, 121.4, 123.7, 124.0, 126.6 (d,
J¼ 3.2 Hz), 127.4 (d, J¼ 8.3 Hz), 134.2, 135.9, 146.6, 150.1, and
162.4 (d, J¼ 245.3 Hz). Anal. Calcd. for C16H10N3O3SF (343.33): C,
55.97; H, 2.94; N, 12.24. Found: C, 55.78; H, 2.94; N, 12.24.
2.2.3. 5-(2,2-Dioxido-1,2-benzoxathiin-6-yl)-1-phenyl-1H-tetrazole (1c)
Compound 5 (0.200 g, 0.649 mmol), 1-phenyl-1,2,3,4-tetrazole20
(0.190 g, 1.30 mmol), Cs2CO3 (0.233 g, 0.714 mmol), CuI (0.124 g,
0.649 mmol), Pd(OAc)2 (0.0146 g, 0.0649 mmol), and tris(2-furyl)
phosphine (0.030 g, 0.130 mmol) were suspended in dry toluene
(3 mL). The mixture was stirred at 40 ꢀC under argon for 20 h, then
EtOAc (20 mL) was added and the mixture was filtered through
celite. Celite was washed with EtOAc (50 mL). The filtrate and
washings were combined and concentrated under reduced pres-
sure. The residue was purified by silica gel chromatography (pet-
roleum ether/EtOAc 2:1) and additionally crystallised from EtOH to
give 1c as yellow crystalline solid (0.076 g, 36%). Mp 189–190 ꢀC.
2.2. General procedure 1: preparation of sulfocoumarins
1a–b (GP1)
To a solution of 4 (1.0 equiv.) in dry THF (1 mL per mmol of 4)
N,N-diisopropylethylamine (DIPEA) (50 equiv.), the appropriate
alkyne (1.1, 2.0, or 5.0 equiv.), and CuI (2 equiv.) were added. The
resulting mixture was stirred at room temperature under an argon
atmosphere for 20 h. Saturated NH4Cl was added and extracted
with EtOAc, washed with brine and dried over Na2SO4,
and evaporated.
1
IR (KBr, cmꢁ1) ꢀmax: 1370 (S–O) and 1178 (S–O). H NMR (400 MHz,
DMSO-d6) d: 7.49–7.56 (m, 2H), 7.58–7.68 (m, 6H), 7.78 (d, 1H,
J¼ 10.4 Hz), and 8.09–8.12 (m, 1H). 13C NMR (100 MHz, DMSO-d6)

508
M. KRASAVIN ET AL.
d: 119.2, 119.3, 121.6, 123.6, 126.0, 130.0, 130.8, 131.0, 132.5, activity was calculated as a percentage of enzyme activity of that
133.8, 135.9, 152.2, and 152.4. Anal. Calcd. for C15H10N4O3S of DMSO vehicle treated sample.
(326.33): C,55.21; H, 3.09; N, 17.17. Found: C, 55.25; H, 3.09;
N, 17.08.
2.5. Cytotoxicity assay
Thus, monolayer tumour cell lines HT-1080 (human fibrosarcoma),
SHSY5Y (human neuroblastoma), and MCF-7 (breast adenocarcin-
2.2.4. 1-(2,2-Dioxido-1,2-benzoxathiin-6-yl)-5-(4-fluorophenyl)-1H-
1,2,3-triazole (1d)
oma) were cultured in standard medium DMEM (Dulbecco’s modi-
To a solution of 5 (0.25 g, 1.12 mmol) and 4-fluorophenylacetylene
fied Eagle’s medium) supplemented with 10% foetal bovine
ꢂ
(0.27 g, 2.24 mmol) in dry DMF (0.7 mL), Cp Ru(PPh3)2Cl
serum. About 2000–4000 cells per well (depending on line nature)
(0.01 mmol) was added and the resulting mixture was stirred at
were placed in 96-well plates and after 24 h compounds were
100 ꢀC under an argon atmosphere for 20 h. The solvent was
added to the wells. Untreated cells were used as a control. The
removed under reduced pressure. The residue was purified by sil-
ica gel chromatography (petroleum ether/EtOAc 2:1) to give 1d as
yellow crystalline solid (0.11 g, 28%). Mp 157–158 ꢀC. IR (neat,
plates were incubated for 48 h, 37 ꢀC, and 5% CO2. The number of
surviving cells was determined using 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolinium bromide (MTT). MTT-test: after incubat-
ing culture medium was removed and 200 mL fresh medium with
20 mL MTT (2 mg/mL in HBSS) was added in each well of the plate.
After incubation (3 h, 37 ꢀC, 5% CO2), the medium with MTT was
removed and 200 mL DMSO were added at once to each sample.
The samples were tested at 540 nm on Thermo Scientific
Multiskan EX microplate photometer. The half-maximal inhibitory
concentration (IC50) of each compound was calculated using
1
cmꢁ1) ꢀmax: 1373 (S–O) and 1176 (S–O). H NMR (400 MHz, DMSO-
d6) d: 7.25–7.33 (m, 2H), 7.37–7.43 (m, 2H), 7.56 (dd, J¼ 8.8, 2.5 Hz,
1H), 7.61 (d, J¼ 8.8 Hz, 1H), 7.67 (d, J¼ 10.4 Hz, 1H), 7.75 (d,
J¼ 10.4 Hz, 1H), 7.97 (d, J¼ 2.5 Hz, 1H), and 8.17 (s, 1H). 13C NMR
(100 MHz, DMSO-d6) d: 116.1 (d, J¼ 22.1 Hz), 119.6, 119.8, 122.4 (d,
J¼ 3.2 Hz), 123.7, 127.1, 129.3, 131.1 (d, J¼ 8.8 Hz), 133.4, 133.6,
135.7, 137.0, 150.8, and 162.6 (d, J¼ 247.7 Hz). Anal. Calcd. for
C16H10N3O3SF (343.33): C, 55.97; H, 2.94; N, 12.24. Found: C, 56.17;
H, 2.93; N, 11.93.
R
Graph Pad PrismV 3.0 (GraphPad Software, La Jolla, CA).
3. Results and discussion
2.3. Carbonic anhydrase inhibition assay
3.1. Chemistry
An Applied Photophysics stopped-flow instrument has been used
for assaying the CA catalysed CO2 hydration activity22. Phenol red
(at a concentration of 0.2 mM) has been used as indicator, working
at the absorbance maximum of 557 nm, with 20 mM Tris (pH 8.3)
as buffer, and 20 mM Na2SO4 (for maintaining constant the ionic
strength), following the initial rates of the CA-catalysed CO2 hydra-
tion reaction for a period of 10–100 s. The CO2 concentrations
ranged 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 uncatalysed rates were deter-
mined in the same manner and subtracted from the total
observed rates. Stock solutions of inhibitor (0.1 mM) were pre-
pared in distilled-deionised water and dilutions up to 0.005 nM
were done thereafter with the assay buffer. Inhibitor and enzyme
solutions were pre-incubated together for 15 min at room tem-
perature 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, as reported earlier, and represent the mean from at least
three different determinations. All CA isoforms were recombinant
Compounds 1a and 1b were synthesised from azide 4 as
described previously18. CuI-catalysed Huisgen azide-alkyne cyclo-
addition gave 1,4-disubstituted 1,2,3-triazole 1a while employing
RuII-catalysed protocol gave 1,5-disusbstituted 1,2,3-triazole 1b.
For the synthesis of 1,5-disubstituted tetrazoles 1c–d, the previ-
ously described19 Pd-catalysed arylation of 1-aryl tetrazoles with
aryl iodide 5 was employed (Scheme 1).
3.2. Biological evaluation
To our utmost delight, when the previously established18,19 potent
and selective inhibitory profile of compounds 1a–d towards can-
cer-related hCA IX and hCA XII isoforms was confirmed in refer-
ence to known CAI acetazolamide (AAZ), we have also found
these compounds to display dose-dependent inhibition of TrxR
activity in SHSY5Y cell lysate with IC50 values confidently residing
in the 10ꢁ5 … 10ꢁ4 M range. Adding to the satisfaction over hav-
ing our initial hypothesis regarding the dual CA/TrxR inhibitory
effects of compounds 1, rather potent antiproliferative activity
was established as evaluated against cultures of cancer cells such
as HT-1080 (human fibrosarcoma), SHSY5Y (human neuroblast-
oma), and MCF-7 (breast adenocarcinoma). These findings are
summarised in Table 1.
ones obtained in-house23–26
.
2.4. TrxR activity by DTNB reduction assay
Determination of TrxR activity in SHSY5Y cell lysate. TrxR activity
in cell lysate was measured in 96-well plates using previously
described methods27,28. For TrxR activity measurement, com-
4. Conclusions
The previously described sulfocoumarins that were shown to
pounds of different concentrations were incubated with 50 mg of potently and selectively inhibit cancer-related hCA IX and hCAXII
cell lysate and 200 mM NADPH in a volume of 100 mL of 50 mM isoforms (whose overexpression is a well-established mechanism
Tris–HCl and 1 mM EDTA, pH 7.5 (TE buffer), for different time of tumour cell defence against hypoxia) also display noticeable,
points in 96-well plates at room temperature. Then, 100 mL of TE dose-dependent inhibition of TrxR activity in cancer cell lysates.
buffer containing DTNB and NADPH was added (final concentra- As overexpression of TrxR in cancer cells is a defence mechanism
tion: 2.5 mM and 200 mM, respectively), and the linear increase in against oxidative stress, the established dual inhibition pattern
absorbance at 412 nm during the initial 2 min was measured with constitutes a significant starting point for the design and discov-
a Tecan Infinite M1000 multifunctional microplate reader. TrxR ery of new anticancer agents based on the dual targeting of the

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
509
Scheme 1. Synthesis of compounds 1a–d.
Table 1. Inhibitory profile towards four hCA isoforms, TrxR activity in SHSY5Y cell lysate and cytotoxicity towards cancer cell lines determined for compounds 1a–d
(nd: not determined).
IC50, lM
Ki, nM
Compound
HT-1080
SHSY5Y
MCF-7
TrxR IC50, lM
hCA I
hCA II
hCA IX
hCA XII
1a
1b
1c
1d
AAZ
11.0
8.7
12.3
7.9
nd
22.0
29.0
18.4
18.5
nd
1.8
79.0
101
50.0
nd
154
40
156
125
nd
>10,000
>10,000
>10,000
>10,000
250
>10,000
>10,000
>10,000
>10,000
12
7.8
8.3
8.5
6.9
25
17.7
7.8
7.1
5.4
5.7
two defence mechanisms crucial for cancer cell survival. This com-
munication opens a new line of research in our laboratories aimed
at investigating the practical aspects of the new dual inhibitor
design and establishing a well-understood link between inhibition
of these two enzyme groups and the dual inhibitors’ antitumor
activity. The results of this research will be reported in due course.
inhibitors of tumor-associated carbonic anhydrases. J Med
Chem 2013;56:293–300.
2. Maresca A, Temperini C, Vu H, et al. Non-zinc mediated
inhibition of carbonic anhydrases: coumarins are a new class
of suicide inhibitors. J Am Chem Soc 2009;131:3057–62.
3. Touisni N, Maresca A, McDonald PC, et al. Glycosyl coumarin
carbonic anhydrase IX and XII inhibitors strongly attenuate
the growth of primary breast tumors. J Med Chem 2011;54:
8271–7.
Disclosure statement
4. Carta F, Maresca A, Scozzafava A, Supuran CT. 5- and
6-Membered (thio)lactones are prodrug type carbonic
anhydrase inhibitors. Bioorg Med Chem Lett 2012;22:
267–70.
No potential conflict of interest was reported by the authors.
Funding
5. Maresca A, Temperini C, Pochet L, et al. Deciphering the
mechanism of carbonic anhydrase inhibition with coumarins
and thiocoumarins. J Med Chem 2010;53:335–44.
6. Davis RA, Vullo D, Maresca A, et al. Natural product coumar-
ins that inhibit human carbonic anhydrases. Bioorg Med
Chem 2013;21:539–43.
7. Alterio V, Di Fiore A, D’Ambrosio K, et al. Multiple binding
modes of inhibitors to carbonic anhydrases: how to design
specific drugs targeting 15 different isoforms? Chem Rev
2012;112:4421–68.
This work was supported by the Russian Foundation for Basic
Research (project grant 18-515-76001) as well as by ERA.Net RUS
plus Joint Programme grant RUS_ST2017-309 and State Education
Development Agency of Republic of Latvia (“THIOREDIN”). AG is
grateful to European Regional Development Fund (ERDF, project
no. 1.1.1.2/VIAA/1/16/235). PZ is indebted to Saint Petersburg
State University for providing his postdoctoral fellowship.
8. Supuran CT. Carbonic anhydrases: novel therapeutic applica-
tions for inhibitors and activators. Nat Rev Drug Discov
2008;7:168–81.
ORCID
Claudiu T. Supuran
http://orcid.org/0000-0003-4262-0323
9. Schwartz L, Supuran CT, Alfarouk KO. The Warburg effect
and the hallmarks of cancer. Anti-Cancer Agents Med Chem
2017;17:164–70.
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