New potent steroid sulphatase inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives

Article abstract of DOI:10.1080/14756366.2020.1858820

In the present work, we report a new class of potent steroid sulphatase (STS) inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives. Within the set of new STS inhibitors, 6-(1-(1,2,3-trifluorophenyl)-1H-1,2,3-triazol

Full text of DOI:10.1080/14756366.2020.1858820

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ienz20
New potent steroid sulphatase inhibitors based
on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
sulphamate derivatives
Olga Ciupak , Mateusz Daśko , Karol Biernacki , Janusz Rachon , Maciej
Masłyk , Konrad Kubiński , Aleksandra Martyna & Sebastian Demkowicz
To cite this article: Olga Ciupak , Mateusz Daśko , Karol Biernacki , Janusz Rachon , Maciej
Masłyk , Konrad Kubiński , Aleksandra Martyna & Sebastian Demkowicz (2021) New potent steroid
sulphatase inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate
derivatives, Journal of Enzyme Inhibition and Medicinal Chemistry, 36:1, 238-247, DOI:
10.1080/14756366.2020.1858820
To link to this article: https://doi.org/10.1080/14756366.2020.1858820
© 2020 The Author(s). Published by Informa
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Group.
Published online: 15 Dec 2020.
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
2021, VOL. 36, NO. 1, 238–247
https://doi.org/10.1080/14756366.2020.1858820
RESEARCH PAPER
New potent steroid sulphatase inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-
yl)naphthalen-2-yl sulphamate derivatives
a
b
c
c
, Karol Biernackia , Janusz Rachona , Maciej Masłyk , Konrad Kubinski
,
ꢀ
ꢀ
Olga Ciupak , Mateusz Dasko
Aleksandra Martynac
and Sebastian Demkowicza
a
b
ꢀ
ꢀ
Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of Technology, Gdansk, Poland; Department of Inorganic
c
ꢀ
ꢀ
Chemistry, Faculty of Chemistry, Gdansk University of Technology, Gdansk, Poland; Department of Molecular Biology, The John Paul II Catholic
University of Lublin, Lublin, Poland
ABSTRACT
ARTICLE HISTORY
Received 8 October 2020
Revised 28 November 2020
Accepted 30 November 2020
In the present work, we report a new class of potent steroid sulphatase (STS) inhibitors based on 6-(1-phe-
nyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives. Within the set of new STS inhibitors, 6-(1-
(1,2,3-trifluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate 3L demonstrated the highest activity
in the enzymatic assay inhibiting the STS activity to 7.98% at 0.5 mM concentration. Furthermore, to verify
whether the obtained STS inhibitors are able to pass through the cellular membrane effectively, cell line
experiments have been carried out. We found that the lowest STS activities were measured in the pres-
ence of compound 3L (remaining STS activity of 5.22%, 27.48% and 99.0% at 100, 10 and 1 nM concentra-
tions, respectively). The measured STS activities for Irosustat (used as a reference) were 5.72%, 12.93% and
16.83% in the same concentration range. Moreover, a determined IC50 value of 15.97 nM for 3L showed
that this compound is a very promising candidate for further preclinical investigations.
KEYWORDS
Steroid sulphatase;
hormone-dependent cancer;
breast cancer; STS
inhibitors; triazoles
Introduction
expression is significantly lower than STS11. Furthermore, there are
studies demonstrating a significant increment of STS and 17b-
HSD1 following aromatase inhibitor therapy of ER positive post-
menopausal breast carcinoma patients due to the compensatory
response of breast carcinoma tissues to oestrogen depletion12.
Nowadays, STS has been considered as an attractive molecular
target for the development of hormone-dependent cancer thera-
pies, and therefore, the synthesis of new, efficient, selective STS
inhibitors is of particular importance for modern medicinal chem-
istry. Recently, there has been intensive research towards finding
novel STS inhibitors. Scientists have developed, both, steroidal
and non-steroidal compounds containing various functional
groups (e.g. sulphamate and phosphorus moieties)13. For example,
one of the most promising drug candidate based on a sulphamoy-
lated coumarin core is Irosustat (also known as 667-COUMATE or
STX64). Irosustat is in clinical trials (phase II clinical studies) and
exhibits quite good results towards treating hormone-dependent
breast cancer (without having in vivo and in vitro oestrogenic
properties)14–20. Although Irosustat showed very promising clinical
effects in the treatment of hormone-dependent tumours, in rela-
tion to endometrium (where occurs high STS activity) Irosustat did
not demonstrate activity sufficient for future commercial develop-
ment21. For this reason, the search for more effective STS inhibi-
tors is still ongoing.
Cancer is the second leading cause of death worldwide. As
reported by International Agency for Research on Cancer, there
were more than 18 million new cases diagnosed and 9.5 million
tumour-related deaths in 2018 worldwide1. The most common
types of cancer are lung, breast, colorectal, prostate, and stomach,
which constitute almost 50% of all tumour cases. Moreover, lung,
colorectal, stomach, liver, and breast cancers are responsible for
nearly 50% of all deaths. National Cancer Institute estimates that
more than 270 000 (15.3%) new cases of breast cancer will be
diagnosed and more than 42 000 (7.0%) deaths will be reported of
this disease in the United States of America in 20202.
Approximately 95% of breast cancer cases in the primary stage
are hormone-sensitive, and therefore, biological active hormones
(including oestrogens and androgens) play a crucial role in the
proliferation of tumours cells3. The biosynthesis of active steroids
in cancer tissues mainly depends on the following three enzymatic
pathways: aromatase (responsible for the transformation of andro-
gens into oestrogens), 17b-hydroxysteroid dehydrogenase (impli-
cated in the reduction of oestrone to oestradiol) and steroid
sulphatase (STS). STS acts by hydrolysing steroid sulphates (includ-
ing oestrone sulphate and dehydroepiandrosterone sulphate) and
therefore plays a pivotal role in human steroidogenesis process4–7
.
Current breast cancer therapies are based on chemotherapeutics
that act as selective oestrogen receptor modulators (SERMs) (e.g.
Tamoxifen) or inhibitors of the aromatase enzyme complex (e.g.
Letrozole or Anastrozole)8–10. Unfortunately, both methods of treat-
ment are unsatisfactory. The main reason for the failure of the
In the present work, we described our recent research on the
design, synthesis, and biological evaluation of compounds based
on non-steroidal core containing triazole and naphthalene rings in
their structure as new and potent STS inhibitors. The presence of
the triazole ring in the structure of obtained compounds is justi-
therapy based on aromatase inhibitors is the fact that aromatase fied by the fact that triazoles are a class of compounds showing
CONTACT Sebastian Demkowicz
sebastian.demkowicz@pg.edu.pl
Narutowicza 11/12, 80-233 Gdansk, Poland
ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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
239
very attractive properties and are successfully used in the design General method for the synthesis of 6–(1-phenyl-1H-1,2,3-triazol-
of new pharmaceuticals22. One of the most important triazoles
4-yl)naphthalen-2-ol derivatives 2 A-L
feature is that they do not undergo hydrolysis under acidic, basic,
and redox conditions and they are stable to metabolic degrad-
ation. Moreover, these compounds are weakly acidic and weakly
basic. Some properties like hydrogen bond formation, p-p stacking
interaction, strong dipole moments, and bioisosteric effects make
triazole derivatives an attractive type of compounds in the field of
medicinal chemistry. Despite the fact that 1,2,3-triazoles do not
exist in the nature23 such compounds exhibit many biological
activities (e.g. anticancer24,25, antimicrobial26,27, anti-infective28).
To an ice-cooled solution of corresponding amine (2.63 mmol) in
ACN (6.1 ml), t-BuONO (325 mg, 3.16 mmol) was added dropwise,
followed by TMSN3 (333 mg, 2.89 mmol). Solution was stirred at
room temperature for 4 h and in the next step, 1 (632 mg,
2.63 mmol) and 1 M solution of TBAF in THF (2.89 ml) were added.
The reaction mixture was stirred at 0 ꢀC for 30 min. Subsequently,
CuSO4 ꢂ 5H2O (65.7 mg, 0.263 mmol) and a freshly prepared aque-
ous solution (0.526 ml) of sodium ascorbate (104 mg, 0.526 mmol)
were added, and the obtained solution was stirred for 24 h under
an argon atmosphere at room temperature. Afterwards, the reac-
tion mixture was concentrated under vacuum and the crude prod-
uct was dissolved in AcOEt (30 ml). Obtained solution was washed
with 0.1 M hydrochloric acid. After separation organic phase was
dried using MgSO4, solvent was evaporated and the resulting resi-
due was crystallised from ACN to give the desired products 2 A-L.
6-(1-Phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-ol 2A Yield
64%; mp (with decomposition) 228-230 ꢀC; ꢀmax (KBr)/cmꢁ1 3293,
3137, 1598, 1504, 1228, 1036, 871, 683; 1H NMR dH (400 MHz,
DMSO-d6) 9.87 (1H, s, OH), 9.35 (1H, s, CH), 8.39 (1H, s, Ar-H), 8.02-
7.96 (3H, m, Ar-H), 7.86 (1H, d, J ¼ 8.8 Hz, Ar-H), 7.82 (1H, d,
J ¼ 8.7 Hz, Ar-H), 7.65 (2H, t, J ¼ 7.9 Hz, Ar-H), 7.53 (1H, t, J ¼ 7.4 Hz,
Ar-H), 7.18 (1H, d, J ¼ 2.3 Hz, Ar-H), 7.15 (1H, dd, J ¼ 8.7, 2.4 Hz, Ar-
H); 13C NMR dC (101 MHz, DMSO-d6) 156.2, 148.2, 137.2, 134.9,
130.4, 130.2, 129.1, 128.2, 127.3, 125.0, 124.4, 124.3, 120.4, 119.8,
119.7, 109.3; Anal. calcd for: C18H13N3O, C, 75.25; H, 4.56; N, 14.63;
O, 5.57. Found: C, 75.31; H, 4.49; N, 14.71; O, 5.49%. HRMS (m/z)
[M þ H]þ calcd 288.1132, found 288.3504.
Materials and methods
General methods and materials
6-Bromo-2-naphthol, trimethylsilylacetylene, palladium(II) chloride,
triphenylphosphine, copper(I) iodide, triethylamine, the appropri-
ate aniline derivatives, tert-butyl nitrite (t-BuONO), azidotrimethyl-
silane (TMSN3), 1 M solution of tetrabutylammonium fluoride
(TBAF) in tetrahydrofuran (THF), sodium ascorbate, copper(II) sul-
phate pentahydrate, chlorosulphonyl isocyanate, N,N-dimethylace-
tamide (N,N-DMA), and formic acid were commercially available
from Sigma-Aldrich. Radiolabelled [3H] oestrone sulphate for
enzyme and cellular assays was purchased from PerkinElmer.
Acetonitrile (ACN) and dichloromethane (DCM) were dried and dis-
tilled using standard procedures. Melting points (uncorrected)
were determined with a Stuart Scientific SMP30 apparatus. Infra-
red spectra were measured on a Nicolet 8700 spectrometer. 1H
and 13C NMR spectra were recorded on a Bruker Avance III HD
400 MHz spectrometer. Chemical shifts d are reported in parts per
million relative to the residual solvent peak (CDCl3 ¼ 7.26 ppm for
6-(1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-ol 2B
Yield 43%; mp (with decomposition) 219-220 ꢀC; ꢀmax (KBr)/cmꢁ1
3251, 3125, 2352, 1600, 1498, 1231, 1033, 870, 677; 1H NMR dH
(400 MHz, DMSO-d6) 9.88 (1H, s, OH), 9.40 (1H, s, CH), 8.37 (1H, s,
Ar-H), 7.95 (1H, dd, J ¼ 8.5, 1.7 Hz, Ar-H), 7.93-7.80 (4H, m, Ar-H),
7.70 (1H, td, J ¼ 8.3, 6.5 Hz, Ar-H), 7.38 (1H, tdd, J ¼ 8.5, 2.5, 0.7 Hz,
Ar-H), 7.18 (1H, d, J ¼ 2.1 Hz, Ar-H), 7.15 (1H, dd, J ¼ 8.7, 2.4 Hz, Ar-
1
1H, 77.0 ppm for 13C, DMSO-d6 2.49 ppm for H, and 39.5 ppm for
13C). Coupling constants are given in Hertz. Mass spectra were
recorded on an Agilent 6540 Accurate Mass Q-TOF LC/MS System.
Elemental analysis was performed using CHNS-Carlo Erba EA-1108.
Preparative thin-layer chromatography (TLC) was carried out with
Polygram SIL G/UV254, silica gel (Macherey-Nagel GmbH & Co. KG,
1
H); 13C NMR dC (101 MHz, DMSO-d6) 162.9 (d, JC-F ¼ 245.1 Hz),
3
3
156.3, 148.3, 138.4 (d, JC-F ¼ 10.5 Hz), 134.9, 132.4 (d, JC-F
¼
€
Duren, Germany). Column chromatography was performed using
9.2 Hz), 130.2, 128.1, 127.3, 124.8, 124.3, 119.9, 119.8, 116.3 (d,
4JC-F ¼ 3.0 Hz), 115.8 (d, JC-F ¼ 21.0 Hz), 109.3, 107.9 (d, JC-F
¼
2
2
silica gel 60 (230-400 mesh, Merck).
26.5 Hz); Anal. calcd for: C18H12FN3O, C, 70.81; H, 3.96; F, 6.22; N,
13.76; O, 5.24. Found: C, 70.79; H, 3.99; F, 6.24; N, 13.69; O, 5.29%.
HRMS (m/z) [M þ H]þ calcd 306.1038, found 306.3540.
General method for the synthesis of 6-((trimethylsilyl)ethynyl)-
naphthalen-2-ol 1
6-(1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-ol 2C
Yield 45%; mp (with decomposition) 229-231 ꢀC; ꢀmax (KBr)/cmꢁ1
3254, 3129, 2345, 1598, 1221, 1035, 869, 679; 1H NMR dH
(400 MHz, DMSO-d6) 9.88 (1H, s, OH), 9.43 (1H, s, CH), 8.37 (1H, s,
Ar-H), 8.12 (1H, t, J ¼ 2.0 Hz, Ar-H), 8.01 (1H, ddd, J ¼ 8.1, 2.0,
0.9 Hz, Ar-H), 7.95 (1H, dd, J ¼ 8.5, 1.7 Hz, Ar-H), 7.86 (1H, d,
J ¼ 8.8 Hz, Ar-H), 7.82 (1H, d, J ¼ 8.6 Hz, Ar-H) 7.68 (1H, t, J ¼ 8.1 Hz,
Ar-H), 7.59 (1H, ddd, J ¼ 8.1, 1.9, 0.9 Hz, Ar-H), 7.19-7.17 (1H, m, Ar-
H), 7.15 (1H, dd, J ¼ 8.7, 2.4 Hz, Ar-H); 13C NMR dC (101 MHz,
DMSO-d6) 156.3, 148.3, 138.2, 134.9, 134.7, 132.2, 130.2, 128.9,
128.1, 127.3, 124.8, 124.3, 120.2, 119.9, 119.8, 118.9, 109.3; Anal.
calcd for: C18H12ClN3O, C, 67.19; H, 3.76; Cl, 11.02; N, 13.06; O,
4.97. Found: C, 67.09; H, 3.84; Cl, 11.09; N, 12.99; O, 4.99%. HRMS
(m/z) [M þ H]þ calcd 321.0669, found 322.3397.
A solution of 6-bromo-2-naphthol (892 mg, 4 mmol), trimethylsily-
lacetylene (0.831 ml, 6 mmol), palladium(II) chloride (35.5 mg,
0.20 mmol), triphenylphosphine (105 mg, 0.40 mmol), copper(I) iod-
ide (19 mg, 0.10 mmol) and triethylamine (3.94 ml, 28.2 mmol) in
dry ACN (20 ml) was refluxed under an argon atmosphere. After
3 h of heating, the reaction mixture was cooled down and filtered.
The filtrate was concentrated under reduced pressure and crude
product was purified with column chromatography using AcOEt/
hexane (1:4) as eluent to afford the desired compound 1.
6-((Trimethylsilyl)ethynyl)naphthalen-2-ol 1 Yield 68%; mp
92-94 ꢀC; ꢀmax (KBr)/cmꢁ1 3245, 2166, 1602, 1506, 1248, 941, 836,
1
703; H NMR dH (400 MHz, CDCl3) 7.96 (1H, s, Ar-H), 7.73-7.70 (1H,
m, Ar-H), 7.61 (1H, d, J ¼ 8.5 Hz, Ar-H), 7.49 (1H, dd, J ¼ 8.5, 1.6 Hz,
Ar-H), 7.14-7.11 (2H, m, Ar-H), 5.55-4.53 (1H, brs, OH) 0.31 (9H, s,
CH3); 13C NMR dC (101 MHz, CDCl3) 154.1, 134.2, 132.0, 129.9,
129.3, 128.3, 126.3, 118.4, 118.1, 109.6, 105.7, 93.8, 0.1; Anal. calcd
for: C15H16OSi, C, 74.95; H, 6.71; O, 6.66; Si, 11.68. Found: C, 74.90;
6-(1-(3-Bromophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-ol
2D Yield 42%; mp (with decomposition) 226-228 ꢀC; ꢀmax (KBr)/
cmꢁ1 3271, 3130, 2922, 2350, 1583, 1489, 1034, 782; 1H NMR dH
(400 MHz, DMSO-d6) 9.88 (1H, s, OH), 9.43 (1H, s, CH), 8.37 (1H, s,
H, 6.75; O, 6.70; Si, 11.68%. HRMS (m/z) [M—H]– calcd 239.1155, Ar-H), 8.24 (1H, s, Ar-H), 8.04 (1H, d, J ¼ 8.1 Hz, Ar-H), 7.95 (1H, d,
found 239.0897.
J ¼ 8.2 Hz, Ar-H), 7.86 (1H, d, J ¼ 8.8 Hz, Ar-H), 7.82 (1H, d,

240
O. CIUPAK ET AL.
J ¼ 8.6 Hz, Ar-H), 7.72 (1H, d, J ¼ 7.8 Hz, Ar-H), 7.61 (1H, t, (1H, s, OH), 9.08 (1H, s, CH), 8.39 (1H, s, Ar-H), 7.96 (1H, dd, J ¼ 8.5,
J ¼ 8.0 Hz, Ar-H), 7.18 (1H, s, Ar-H), 7.15 (1H, d, J ¼ 8.9 Hz, Ar-H); 1.6 Hz, Ar-H), 7.90-7.75 (4H, m, Ar-H), 7.73–7.59 (2H, m, Ar-H), 7.21-
13C NMR dC (101 MHz, DMSO-d6) 156.3, 148.3, 138.3, 134.9, 132.4, 7.11 (2H, m, Ar-H); 13C NMR dC (101 MHz, DMSO-d6) 156.3, 147.4,
131.8, 130.2, 128.1, 127.3, 124.8, 124.3, 123.0, 122.9, 119.9, 119.8, 135.1, 134.9, 132.2, 131.1, 130.2, 129.0, 128.9, 128.8, 128.2, 127.3,
119.3, 109.3; Anal. calcd for: C18H12BrN3O, C, 59.03; H, 3.30; Br, 124.9, 124.4, 124.3, 123.7, 119.8, 109.3; Anal. calcd for:
21.82; N, 11.47; O, 4.37. Found: C, 59.11; H, 3.28; Br, 21.87; N, C18H12ClN3O, C, 67.19; H, 3.76; Cl, 11.02; N, 13.06; O, 4.97. Found:
11.50; O, 4.24%. HRMS (m/z) [M þ H]þ calcd 366.0237, C, 67.22; H, 3.70; Cl, 11.08; N, 13.11; O, 4.89%. HRMS (m/z)
found 366.3458.
[M þ H]þ calcd 322.0742, found 322.3377.
6-(1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-ol 2E
6-(1-(2-Bromophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-ol
Yield 74%; mp (with decomposition) 237-239 ꢀC; ꢀmax (KBr)/cmꢁ1 2J Yield 68%; mp 105-107 ꢀC; ꢀmax (KBr)/cmꢁ1 3135, 1611, 1493,
3651, 3199, 3124, 2920, 2347, 1614, 1507, 1039, 802; 1H NMR dH 1283, 1048, 909; 1H NMR dH (400 MHz, DMSO-d6) 9.86 (1H, s, OH),
(400 MHz, DMSO-d6) 9.86 (1H, s, OH), 9.33 (1H, s, CH), 8.37 (1H, s, 9.05 (1H, s, CH), 8.39 (1H, s, Ar-H), 7.97-7.95 (2H, m, Ar-H), 7.83
Ar-H), 8.06-8.00 (2H, m, Ar-H), 7.96 (1H, dd, J ¼ 8.5, 1.5 Hz, Ar-H),
(2H, dd, J ¼ 18.6, 8.7 Hz, Ar-H), 7.77 (1H, dd, J ¼ 7.8, 1.6 Hz), 7.67
7.86 (1H, d, J ¼ 8.8 Hz, Ar-H), 7.82 (1H, d, J ¼ 8.6 Hz, Ar-H), 7.52 (2H,
(1H, td, J ¼ 7.7, 1.4 Hz, Ar-H), 7.60 (1H, td, J ¼ 7.7, 1.4 Hz, Ar-H),
t, J ¼ 8.8 Hz, Ar-H), 7.17 (1H, s, Ar-H), 7.15 (1H, dd, J ¼ 8.8, 2.3 Hz, 7.21-7.18 (1H, m, Ar-H), 7.14 (1H, dd, J ¼ 8.8, 2.4 Hz, Ar-H); 13C NMR
1
Ar-H); 13C NMR dC (101 MHz, DMSO-d6) 162.1 (d, JC-F ¼ 245.8 Hz),
dC (101 MHz, DMSO-d6) 156.2, 147.3, 136.8, 134.9, 134.2, 132.5,
4
156.2, 148.2, 134.9, 133.8 (d, JC-F ¼ 2.8 Hz), 130.1, 128.2, 127.3,
130.2, 129.5, 129.2, 128.2, 127.3, 125.0, 124.4, 124.3, 123.7, 119.8,
119.4, 109.3; Anal. calcd for: C18H12BrN3O, C, 59.03; H, 3.30; Br,
3
125.0, 124.4, 124.2, 122.8 (d, JC-F ¼ 8.8 Hz), 120.0, 119.8, 117.3 (d,
2JC-F ¼ 23.3 Hz), 109.2; Anal. calcd for: C18H12FN3O, C, 70.81; H,
21.82; N, 11.47; O, 4.37. Found: C, 59.10; H, 3.26; Br, 21.86; N,
11.36; O, 4,42%. HRMS (m/z) [M þ H]þ calcd 366.0237,
3.96; F, 6.22; N, 13.76; O, 5.24. Found: C, 70.75; H, 3.99; F, 6.27; N,
13.81; O, 5.18%. HRMS (m/z) [M þ H]þ calcd 306.1038,
found 366.3130.
found 306.3524.
6-(1-(3,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-
ol 2K Yield 39%; mp (with decomposition) 210-212 ꢀC; ꢀmax (KBr)/
cmꢁ1 3128, 1607, 1482, 1303, 1050, 911; 1H NMR dH (400 MHz,
DMSO-d6) 9.88 (1H, s, OH), 9.43 (1H, s, CH), 8.35 (1H, s, Ar-H), 7.95-
7.80 (4H, m, Ar-H), 7.46 (1H, tt, J ¼ 9.2, 2.2 Hz, Ar-H), 7.20-7.17 (2H,
m, Ar-H), 7.15 (1H, dd, J ¼ 8.7, 2.4 Hz, Ar-H); 13C NMR dC (101 MHz,
6-(1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-ol
2F Yield 74%; mp (with decomposition) 256-257 ꢀC; ꢀmax (KBr)/
cmꢁ1 3286, 3119, 2294, 1611, 1550, 1032, 831; 1H NMR dH
(400 MHz, DMSO-d6) 9.86 (1H, s, OH), 9.38 (1H, s, CH), 8.37 (1H, s,
Ar-H) 8.03 (2H, d, J ¼ 8.9 Hz, Ar-H), 7.95 (1H, dd, J ¼ 8.5, 1.6 Hz, Ar-
H), 7.86 (1H, d, J ¼ 8.8 Hz, Ar-H), 7.82 (1H, d, J ¼ 8.6 Hz, Ar-H), 7.73
(2H, d, J ¼ 8.9 Hz, Ar-H), 7.17 (1H, s, Ar-H), 7.15 (1H, dd, J ¼ 8.7,
2.3 Hz, Ar-H); 13C NMR dC (101 MHz, DMSO-d6) 156.3, 148.3, 136.0,
134.9, 133.4, 130.4, 130.2, 128.2, 127.3, 124.9, 124.4, 124.3, 122.1,
119.8, 109.3; Anal. calcd for: C18H12ClN3O, C, 67.19; H, 3.76; Cl,
11.02; N, 13.06; O, 4.97. Found: C, 67.24; H, 3.69; Cl, 11.09; N,
13.04; O, 4.49%. HRMS (m/z) [M þ H]þ calcd 322.0742,
found 322.3345.
1
3
DMSO-d6) 163.2 (dd, JC-F ¼ 246.9, JC-F ¼ 14.6 Hz), 156.4, 148.4,
3
138.9 (t, JC-F ¼ 13.3 Hz), 135.0, 130.2, 128.1, 127.4, 124.6, 124.4,
124.2, 120.0, 119.9, 109.3, 104.4, 104; Anal. calcd for: C18H11F2N3O,
C, 66.87; H, 3.43; F, 11.75; N, 13.00; O, 4.95. Found: C, 66.90; H,
3.39; F, 11.83; N, 12.96; O, 4.92%. HRMS (m/z) [M þ H]þ calcd
324.0943, found. 324.3554.
6-(1-(2,3,4-Trifluorophenyl)-1H-1,2,3-triazol-4-yl)naphtha-
len-2-ol 2L Yield 13%; mp (with decomposition) 212-214 ꢀC; ꢀmax
(KBr)/cmꢁ1 3175, 1630, 1509, 1305, 1043, 912; 1H NMR dH
(400 MHz, DMSO-d6) 9.88 (1H, s, OH), 9.14 (1H, d, J ¼ 1.7 Hz, CH),
8.40 (1H, s, Ar-H), 7.97 (1H, dd, J ¼ 8.5, 1.6 Hz, Ar-H), 7.89-7.77 (3H,
m, Ar-H), 7.65 (1H, qd, J ¼ 8.5, 1.6 Hz, Ar-H), 7.18-7.16 (1H, m, Ar-
H), 7.14 (1H, dd, J ¼ 8.7, 2.3 Hz, Ar-H); 13C NMR dC (101 MHz,
DMSO-d6) 156.3, 152.4-152.0 (m), 149.8-149.5 (m), 147.9, 145.8-
145.4 (m), 143.2-142.9 (m), 141.6-141.2 (m), 139.2-138.7 (m), 135.0,
6-(1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-ol
2G Yield 62%; mp (with decomposition) 254-256 ꢀC; ꢀmax (KBr)/
cmꢁ1 3470, 3119, 1612, 1495, 1200, 1030, 867, 810; 1H NMR dH
(400 MHz, DMSO-d6) 9.86 (1H, s, OH), 9.38 (1H, s, CH), 8.37 (1H, s,
Ar-H), 7.99-7.93 (3H, m, Ar-H), 7.88-7.80 (4H, m, Ar-H), 7.17 (1H, s,
Ar-H), 7.15 (1H, dd, J ¼ 8.7, 2.4 Hz, Ar-H); 13C NMR dC (101 MHz,
DMSO-d6) 156.3, 148.3, 136.4, 134.9, 133.3, 130.2, 128.1, 127.3,
124.9, 124.4, 124.3, 122.3, 121.7, 119.8, 119.7, 109.3; Anal. calcd
for: C18H12BrN3O, C, 59.03; H, 3.30; Br, 21.82; N, 11.47; O, 4.37.
Found: C, 59.07; H, 3.32; Br, 21.78; N, 11.54; O, 4.29%. HRMS (m/z)
[M þ H]þ calcd 366.0237, found 366.3154.
3
4
130.2, 128.1, 127.3, 124.5, 124.5, 124.4, 123.1 (dd, JC-F ¼ 8.3, JC-F
4
3
4
¼ 3.7 Hz), 122.9 (d, JC-F ¼ 3.3 Hz), 121.0 (dd, JC-F ¼ 8.5, JC-F
¼
2
3
3.9 Hz), 119.8, 113.8 (dd, JC-F ¼ 18.6, JC-F ¼ 3.8 Hz), 109.; Anal.
calcd for: C18H10F3N3O, C, 63.35; H, 2.95; F, 16.70; N, 12.31; O, 4.69.
Found: C, 63.41; H, 2.89; F, 16.78; N, 12.39; O, 4.53%. HRMS (m/z)
[M þ H]þ calcd 342.0849, found. 342.3574.
6-(1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-ol
2H Yield 47%; mp (with decomposition) 207-208 ꢀC; ꢀmax (KBr)/
cmꢁ1 3177, 1614, 1511, 1048, 864, 819; 1H NMR dH (400 MHz,
DMSO-d6) 9.86 (1H, s, OH), 9.12 (1H, d, J ¼ 1.9 Hz, CH), 8.41 (1H, s,
Ar-H), 8.02-7.91 (2H, m, Ar-H), 7.83 (2H, dd, J ¼ 20.5, 8.7 Hz, Ar-H),
General method for the synthesis of 6-(1-phenyl-1H-1,2,3-triazol-4-
yl)naphthalen-2-yl sulphamate derivatives 3A-L
7.68-7.58 (2H, m, Ar-H), 7.54-7.45 (1H, m, Ar-H), 7.19-7.09 (2H, m,
1
Ar-H); 13C NMR dC (101 MHz, DMSO-d6) 156.3, 154.3 (d, JC-F
250.8 Hz), 147.8, 134.8, 131.8 (d,
¼
A solution of chlorosulphonyl isocyanate (212.0 mg, 1.50 mmol) in
anhydrous DCM (0.5 ml) was prepared. In the next step, a solution
of formic acid (70.9 mg, 1.54 mmol) and N,N-DMA (1.4 mg,
0.016 mmol) was added, and the reaction mixture was stirred at
40 ꢀC for 3.5 h. Then, a solution of the corresponding derivative
2A-L (1.00 mmol) in N,N-DMA (3.4 ml) was added, and the
obtained solution was stirred at room temperature overnight.
Subsequently, reaction mixture was poured into water (50 ml). The
resulting precipitate was filtered and washed with water. The
3
2JC-F ¼ 7.8 Hz), 130.2, 128.2, 127.3, 126.5, 126.1 (d, JC-F
¼
¼
2
3
3.7 Hz), 125.3 (d, JC-F ¼ 11.0 Hz), 124.8, 124.4, 122.9 (d, JC-F
4.1 Hz), 119.8, 117.8, 117.6, 108.9; Anal. calcd for: C18H12FN3O, C,
70.81; H, 3.96; F, 6.22; N, 13.76; O, 5.24. Found: C, 70.78; H, 3.99; F,
6.28; N, 13.70; O, 5.25%. HRMS (m/z) [M þ H]þ calcd 306.1038,
found 306.3529.
6-(1-(2-Chlorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-ol
2I Yield 62%; mp 104-106 ꢀC; ꢀmax (KBr)/cmꢁ1 3133, 1616, 1493, crude product was recrystallized from ACN to give the desired
1493, 1196, 1050, 862, 804; 1H NMR dH (400 MHz, DMSO-d6) 9.86 products 3A-L.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
241
6-(1-Phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulpha- 8.34. Found: C, 56.27; H, 3.37; F, 4.93; N, 14.62; O, 12.53; S, 8.28%.
HRMS (m/z) [M þ H]þ calcd 385.0766, found 385.3823.
mate 3A Yield 70%; mp (with decomposition) 210-211 ꢀC; ꢀmax
(KBr)/cmꢁ1 3119, 2915, 2358, 1595, 1352, 1168, 759, 672; 1H NMR
dH (400 MHz, DMSO-d6) 9.47 (1H, s, CH), 8.59 (1H, s, Ar-H), 8.16
(1H, dd, J ¼ 8.6, 1.5 Hz, Ar-H), 8.15-8.10 (4H, m, Ar-H, NH2), 8.00
(2H, d, J ¼ 7.6 Hz, Ar-H), 7.88 (1H, d, J ¼ 2.2 Hz, Ar-H), 7.67 (2H, t,
J ¼ 7.9 Hz, Ar-H), 7.54 (1H, t, J ¼ 7.4 Hz, Ar-H), 7.51 (1H, dd, J ¼ 8.9,
2.4 Hz, Ar-H); 13C NMR dC (101 MHz, DMSO-d6) 148.5, 147.6, 137.1,
133.4, 131.9, 130.5, 130.4, 129.3, 129.1, 128.4, 125.0, 124.0, 122.9,
120.6, 120.5, 119.8; Anal. calcd for: C18H14N4O3S, C, 59.01; H, 3.85;
N, 15.29; O, 13.10; S, 8.75. Found: C, 58.98; H, 3.88; N, 15.34; O,
13.12; S, 8.68%. HRMS (m/z) [M þ H]þ calcd 367.0860,
found 367.3750.
6-(1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
sulphamate 3F Yield 40%; mp (with decomposition) 226-229 ꢀC;
ꢀmax (KBr)/cmꢁ1 3372, 3269, 1502, 1352, 1173, 813; 1H NMR dH
(400 MHz, DMSO-d6) 9.49 (1H, s, CH), 8.58 (1H, s, Ar-H), 8.15-8.09
(5H, m, Ar-H, NH2), 8.04 (2H, d, J ¼ 8.9 Hz, Ar-H), 7.88 (1H, d,
J ¼ 2.2 Hz, Ar-H), 7.75 (2H, d, J ¼ 8.8 Hz, Ar-H), 7.50 (1H, dd, J ¼ 8.9,
2.4 Hz, Ar-H); 13C NMR dC (101 MHz, DMSO-d6) 148.5, 147.7, 135.9,
133.52, 133.48, 131.9, 130.5, 130.4, 129.2, 128.3, 125.0, 124.1,
122.9, 122.2, 120.7, 119.7; Anal. calcd for: C18H13ClN4O3S, C, 53.94;
H, 3.27; Cl, 8.84; N, 13.98; O, 11.97; S, 8.00. Found: C, 53.90; H,
3.31; Cl, 8.91; N, 14.01; O, 11.94; S, 7.93%. HRMS (m/z) [M þ H]þ
calcd 401.0470, found 401.3596.
6-(1-(3-Fluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
sulphamate 3B Yield 43%; mp (with decomposition) 210-212 ꢀC;
ꢀmax (KBr)/cmꢁ1 3120, 2560, 1600, 1358, 1173, 782, 673; 1H NMR
dH (400 MHz, DMSO-d6) 9.52 (1H, s, CH), 8.58 (1H, s, Ar-H), 8.18-
8.06 (5H, m, Ar-H, NH2), 7.96-7.86 (3H, m, Ar-H), 7.72 (1H, q,
J ¼ 7.4 Hz, Ar-H), 7.50 (1H, dd, J ¼ 8.9, 2.2 Hz, Ar-H), 7.41 (1H, td,
6-(1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
sulphamate 3G Yield 45%; mp (with decomposition) 234-235 ꢀC;
ꢀmax (KBr)/cmꢁ1 3378, 3273, 3143, 1498, 1144, 710; 1H NMR dH
(400 MHz, DMSO-d6) 9.50 (1H, s, CH), 8.58 (1H, s, Ar-H), 8.16-8.10
(5H, m, Ar-H, NH2), 7.97 (2H, d, J ¼ 8.9 Hz, Ar-H), 7.89-7.86 (3H, m,
Ar-H), 7.50 (1H, dd, J ¼ 8.9, 2.3 Hz, Ar-H); 13C NMR dC (101 MHz,
DMSO-d6) 148.5, 147.7, 136.3, 133.5, 133.4, 131.9, 130.5, 129.2,
128.2, 125.0, 124.1, 122.9, 122.4, 121.9, 120.7, 119.7; Anal. calcd
for: C18H13BrN4O3S, C, 48.55; H, 2.94; Br, 17.94; N, 12.58; O, 10.78;
S, 7.20. Found: C, 48.59; H, 2.90; Br, 17.97; N, 12.61; O, 10.81; S,
7.12%. HRMS (m/z) [M þ H]þ calcd 445.3490, found 446.9945.
6-(1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
sulphamate 3H Yield 34%; mp (with decomposition) 206-207 ꢀC;
ꢀmax (KBr)/cmꢁ1 3398, 3277, 3148, 1502, 1111, 728; 1H NMR dH
(400 MHz, DMSO-d6) 9.50 (1H, d, J ¼ 1.8 Hz, CH), 8.61 (1H, s, Ar-H),
8.21-8.06 (5H, m, Ar-H, NH2), 7.95 (1H, td, J ¼ 7.9, 1.1 Hz, Ar-H),
1
J ¼ 8.7, 2.3 Hz, Ar-H); 13C NMR dC (101 MHz, DMSO-d6) 162.9 (d, JC-
3
¼ 245.2 Hz), 148.6, 147.7, 138.3, (d, JC-F ¼ 10.5 Hz), 133.5, 132.4
F
3
(d, JC-F ¼ 9.1 Hz), 131.9, 130.5, 129.2, 128.2, 125.0, 124.1, 122.9,
4
2
120.8, 119.8, 116.4 (d, JC-F ¼ 3.0 Hz), 116.0 (d, JC-F ¼ 21.0 Hz),
2
108.0 (d, JC-F ¼ 26.5 Hz); Anal. calcd for: C18H13FN4O3S, C, 56.24;
H, 3.41; F, 4.94; N, 14.58; O, 12.49; S, 8.34. Found: C, 56.30; H, 3.45;
F, 4.90; N, 14.60; O, 12.41; S, 8,43%. HRMS (m/z) [M þ H]þ calcd
385.0766, found 385.3810.
6-(1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
sulphamate 3C Yield 67%; mp (with decomposition) 214-216 ꢀC;
ꢀmax (KBr)/cmꢁ1 3132, 2915, 2376, 1591, 1381, 1177, 784, 676; 1H
NMR dH (400 MHz, DMSO-d6) 9.53 (1H, s, CH), 8.57 (1H, s, Ar-H),
8.16-8.07 (6H, m, Ar-H, NH2), 8.01 (1H, dd, J ¼ 7.9, 1.2 Hz, Ar-H),
7.88 (1H, d, J ¼ 2.1 Hz, Ar-H), 7.69 (1H, t, J ¼ 8.1 Hz, Ar-H), 7.61 (1H,
dd, J ¼ 8.0, 0.8 Hz, Ar-H), 7.51 (1H, dd, J ¼ 8.9, 2.3 Hz, Ar-H); 13C
NMR dC (101 MHz, DMSO-d6) 148.5, 147.7, 138.1, 134.7, 133.5,
132.2, 131.9, 130.5, 129.2, 129.0, 128.2, 124.9, 124.1, 122.9, 120.8,
120.3, 119.8, 119.0; Anal. calcd for: C18H13ClN4O3S, C, 53.94; H,
3.27; Cl, 8.84; N, 13.98; O, 11.97; S, 8.00. Found: C, 53.98; H, 3.29;
Cl, 8.80; N, 13.94; O, 11.92; S, 8.07%. HRMS (m/z) [M þ H]þ calcd
401.0470, found 401.3646.
7.88 (1H, d, J ¼ 2.0 Hz, Ar-H), 7.70-7.60 (2H, m, Ar-H), 7.55-7.45 (2H,
m, Ar-H); 13C NMR dC (101 MHz, DMSO-d6) 154.5 (d, JC-F
¼
1
250.9 Hz), 148.5, 147.2, 133.5, 131.9, 130.5, 129.1, 128.2, 126.5,
3
2
126.1 (d, JC-F ¼ 3.8 Hz), 125.3 (d, JC-F ¼ 10.5 Hz), 125.1, 124.1,
3
123.8 (d, JC-F ¼ 4.1 Hz), 122.9, 119.7, 117.8, 117.6; Anal. calcd for:
C18H13FN4O3S, C, 56.24; H, 3.41; F, 4.94; N, 14.58; O, 12.49; S, 8.34.
Found: C, 56.31; H, 3.39; F, 4.90; N,14.56; O, 12.53; S, 8.31%. HRMS
(m/z) [M þ H]þ calcd 385.0766, found 385.3785.
6-(1-(2-Bromophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
sulphamate 3J Yield 52%; mp (with decomposition) 188-189 ꢀC;
6-(1-(3-Bromophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
ꢀmax (KBr)/cmꢁ1 3307, 3146, 3052, 1605, 1491, 1370, 929; H NMR
1
sulphamate 3D Yield 34%; mp (with decomposition) 219-221 ꢀC;
1
ꢀmax (KBr)/cmꢁ1 3298, 3171, 2363, 1484, 1368, 1182, 800; H NMR
dH (400 MHz, DMSO-d6) 9.19 (1H, s, CH), 8.60 (1H, s, Ar-H), 8.20-
8.06 (5H, m, Ar-H, NH2), 7.98 (1H, dd, J ¼ 8.0, 1.3 Hz, Ar-H), 7.88
(1H, d, J ¼ 2.2 Hz, Ar-H), 7.79 (1H, dd, J ¼ 7.8, 1.6 Hz, Ar-H), 7.68
(1H, td, J ¼ 7.6, 1.4 Hz, Ar-H), 7.61 (1H, td, J ¼ 7.7, 1.7 Hz, Ar-H), 7.50
(1H, dd, J ¼ 8.9, 2.4 Hz, Ar-H); 13C NMR dC (101 MHz, DMSO-d6)
153.7, 150.4, 137.9, 133.1, 132.2, 132.1, 131.4, 129.0, 128.9, 128.5,
126.2, 125.8, 124.7, 122.1, 120.7, 118.7, 115.5, 114.9; Anal. calcd
for: C18H13BrN4O3S, C, 48.55; H, 2.94; Br, 17.94; N, 12.58; O, 10.78;
S, 7.20. Found: C, 48.59, H, 2.96; Br, 17.93; N, 12.57; O, 10.72; S,
7.23%. HRMS (m/z) [M þ H]þ calcd 444.9965, found. 445.3399
6-(1-(3,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-
yl sulphamate 3K Yield 37%; mp (with decomposition) 214-
215 ꢀC; ꢀmax (KBr)/cmꢁ1 3296, 3153, 3052, 1627, 1473, 1357, 916;
1H NMR dH (400 MHz, DMSO-d6) 9.55 (1H, s, CH), 8.56 (1H, s, Ar-H),
8.19-8.05 (5H, m, Ar-H, NH2), 7.88 (1H, d, J ¼ 2.1 Hz, Ar-H), 7.85 (2H,
dd, J ¼ 7.8, 2.0 Hz, Ar-H), 7.51 (1H, dd, J ¼ 8.8, 2.3 Hz, Ar-H), 7.46
(1H, dt, J ¼ 9.2, 2.2 Hz, Ar-H); 13C NMR dC (101 MHz, DMSO-d6)
dH (400 MHz, DMSO-d6) 9.55 (1H, s, CH), 8.58 (1H, s, Ar-H), 8.26
(1H, t, J ¼ 1.8 Hz, Ar-H), 8.16-8.09 (5H, m, Ar-H, NH2), 8.06 (1H, dd,
J ¼ 8.1, 1.2 Hz, Ar-H), 7.88 (1H, d, J ¼ 2.1 Hz, Ar-H), 7.75 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.63 (1H, t, J ¼ 8.1 Hz, Ar-H), 7.50 (1H, dd, J ¼ 8.9,
2.3 Hz, Ar-H); 13C NMR dC (101 MHz, DMSO-d6) 148.6, 147.7, 138.2,
133.5, 132.4, 132.0, 131.9, 130.5, 129.2, 128.2, 124.9, 124.1, 123.0,
122.99, 122.90, 120.9, 119.8, 119.4; Anal. calcd for: C18H13BrN4O3S,
C, 48.55; H, 2.94; Br, 17.94; N, 12.58; O, 10.78; S, 7.20. Found: C,
48.59; H, 2.96; Br, 17.90; N, 12.55; O, 10.74; S, 7.26%. HRMS (m/z)
[M þ H]þ calcd 444.9965, found 445.3408.
6-(1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
sulphamate 3E Yield 36%; mp (with decomposition) 226-227 ꢀC;
ꢀmax (KBr)/cmꢁ1 3314, 3159, 1515, 1357, 1180, 838; 1H NMR dH
(400 MHz, DMSO-d6) 9.44 (1H, s, CH), 8.57 (1H, s, Ar-H), 8.17-8.09
(5H, m, Ar-H, NH2), 8.07-8.01 (2H, m, Ar-H), 7.88 (1H, dd, J ¼ 2.0 Hz,
Ar-H), 7.58-7.46 (3H, m, Ar-H); 13C NMR dC (101 MHz, DMSO-d6)
1
3
1
4
163.3 (dd, JC-F ¼ 247.0 Hz, JC-F ¼ 14.6 Hz), 148.6, 147.7, 138.8 (t,
3JC-F ¼ 13.2 Hz), 133.6, 131.9, 130.5, 129.3, 128.0, 124.9, 124.2,
122.9, 121.0, 119.8, 104.8, 104.5, 104.; Anal. calcd for:
162.2 (d, JC-F ¼ 245.9 Hz), 148.5, 147.6, 133.7 (d, JC-F ¼ 2.8 Hz),
3
133.4, 131.9, 130.5, 129.1, 128.4, 125.0, 124.0, 122.9 (d, JC-F
¼
2
5.0 Hz), 122.8, 120.9, 119.8, 117.3 (d, JC-F ¼ 23.3 Hz); Anal. calcd
for: C18H13FN4O3S, C, 56.24; H, 3.41; F, 4.94; N, 14.58; O, 12.49; S, C18H12F2N4O3S, C, 53.73; H, 3.01; F, 9.44; N, 13.92; O, 11.93; S, 7.97.

242
O. CIUPAK ET AL.
Found: C, 53.76; H, 3.06; F, 9.39; N, 13.87; O, 11.96; S, 7.96%. HRMS reaction mixtures (90 mL) were collected from each well, and the
product formed by STS-mediated hydrolysis of [3H]E1 was
(m/z) [M þ H]þ calcd 403.0671, found. 403.3818.
6-(1-(2,3,4-Trifluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen- extracted with toluene (0.5 ml). Next 0.3 ml of toluene was com-
2-yl sulphamate 3L Yield 26%; mp (with decomposition) 198- bined with 0.3 ml of scintillation liquid. STS activity was measured
200 ꢀC; ꢀmax (KBr)/cmꢁ1 3262, 3175, 3021, 1618, 1509, 1384, 915; using the radioluminometer MicroBeta (Perkin Elmer). Assays were
1H NMR dH (400 MHz, DMSO-d6) 9.27 (1H, d, J ¼ 1.6 Hz, CH), 8.61 performed in triplicate.
(1H, s, Ar-H), 8.20-8.07 (5H, m, Ar-H, NH2), 7.91-7.83 (2H, m, Ar-H),
7.67 (1H, qd, J ¼ 9.8, 2.2 Hz, Ar-H), 7.50 (1H, dd, J ¼ 8.9, 2.3 Hz, Ar-
H); 13C NMR dC (101 MHz, DMSO-d6) 152.4–152.1 (m), 149.9-149.6
In vitro cellular assay using MCF-7 breast cancer cell line
Inhibition of STS activity in the MCF-7 breast cancer cell line was
(m), 148.6, 147.3, 145.9-145.6 (m), 143.3-143.0 (m), 141.7-141.2 (m),
139.2–138.7 (m), 133.5, 131.9, 130.5, 129.2, 127.9, 125.0, 124.3,
37
measured according to the method described by Purohit et al.
.
4
3
4
MCF-7 cells were maintained in Dulbecco’s Modified Eagle Medium
supplemented with 10% of foetal bovine serum and cultured until
80% of confluence was received. Cells were seeded in 24-well
microplates (Nest Biotechnology) at a density of 1ꢂ105 cells/well. In
order to assure an equal amount of cells in each reaction sample
123.8 (d, JC-F ¼ 3.3 Hz), 123.0 (dd, JC-F ¼ 8.3, JC-F ¼ 3.7 Hz),
3
4
2
122.9, 121.1 (dd, JC-F ¼ 8.5, JC-F ¼ 4.0 Hz), 119.7, 113.8 (dd, JC-F
3
¼ 18.6, JC-F ¼ 3.8 Hz); Anal. calcd for: C18H11F3N4O3S, C, 51.43; H,
2.64; F, 13.56; N, 13.33; O, 11.42; S, 7.63. Found: C, 51.39; H, 2.71;
F, 13.51; N, 13.29; O, 11.48; S, 7.62%. HRMS (m/z) [M þ H]þ calcd
421.0577, found. 421.3945.
€
the number of cells was determined using a Burker Counting
Chamber. The STS activity was evaluated in living MCF-7 cells.
Incubation of cells was conducted for 20 h at 37ꢀC in a 5% CO2
humidified incubator in a serum-free medium (0.5ml) with radiola-
belled oestrone sulphate [3H]E1S (4ꢂ105 cpm, 3 nM) with or without
an inhibitor. After incubation, a medium containing STS-mediated
reaction product was collected (0.45 ml) from each well and the
product was isolated from the mixture by extraction with toluene
(4ml). The STS activity expressed as the level of product radioactiv-
ity was measured using the Radioluminometer MicroBeta (Perkin
Elmer). Cellular assay was carried out in triplicate. IC50 values were
calculated using GraphPad Prism software.
Molecular docking
Ligands and molecular target preparation
The 3 D structures of the potential steroid sulphatase inhibitors
(ligands) were prepared using Portable HyperChem 8.0.7 Release
(Hypercube, Inc., Gainesville, FL, USA)29. Before docking calcula-
tions, the structures of all ligands were optimised with an
MM þ force field30 and the Polak-Ribiere conjugate gradient algo-
ꢁ
rithm (terminating at a gradient of 0.05 kcalꢂmolꢁ1 Åꢁ1). The X-ray
structure of human STS was obtained from Protein Data Bank
(accession code 1P49) and was prepared using standard proced-
3–
ure. Initially, the NAG, BOG, PO4 and water molecules from crys-
tallisation were removed from the structure, and the catalytic
amino acid fGly75 was converted to gem-diol form using the
Results and discussion
Molecular docking
€
Maestro Protein Preparation Wizard module (Schrodinger, LLC,
Initially, to verify that the 6–(1-phenyl-1H-1,2,3-triazol-4-yl)naphtha-
len-2-yl sulphamate derivatives are able to effectively bind to the
STS active site, molecular docking studies were performed. The X-
ray structure of STS was retrieved from the Protein Data Bank
(Protein Data Bank accession code 1P49) and properly prepared for
docking calculations. The docking procedure of the optimised
ligands was performed using AutoDock Vina 1.1.2 software
(Molecular Graphics Laboratory, The Scripps Research Institute,
LaJolla, CA). The calculated results for the proposed structures of
the inhibitors 3A-L were at a satisfactory, comparable level in the
range of ꢁ6.0 to ꢁ8.3 kcalꢂmolꢁ1 (the measurement error for the
AutoDock Vina software is 2.85 kcalꢂmolꢁ1) (Table 1) and lower than
the free energy of binding value of the reference inhibitor Irosustat
(–5.4 kcalꢂmolꢁ1). The most favourable binding energy was deter-
mined for compound 3L (–8.3 kcalꢂmolꢁ1) suggesting that this com-
pound could theoretically create the most stable inhibitor-enzyme
complex in the STS active site, leading to effective inhibition.
New York, NY, USA)31. Then, hydrogen atoms were introduced
into the structure, and prepared model of the enzyme was opti-
mised using the OPLS-AA force field32.
Molecular docking
Docking calculations of the optimised ligands to the prepared
structure of human STS were carried out with AutoDock Vina 1.1.2
software (The Molecular Graphic Laboratory, The Scripps Research
Institute, La Jolla, CA, USA)33. For all of docking studies, a grid box
was centred on the Cb atom of amino acid 75 of the prepared
STS structure, and the size of the grid box was 24 Å ꢃ 24 Å ꢃ
24 Å. Then, the best binding modes for a particular ligand were
inspected visually. Illustrations of the 3D models were prepared
using VMD 1.9 (University of Illinois at Urbana-Champaign,
Urbana, IL, USA)34. Identification of the ligand-protein interactions
was performed using Discovery Studio Visualiser v20. 1. 0. 19295
In order to analyse the ligand-protein interactions that could
be responsible for the stabilisation of the inhibitor-enzyme com-
35
ꢀ
(BIOVIA, Dassault Systemes, San Diego, CA, USA) .
ꢀ
plexes, studies using BIOVIA, Dassault Systemes, Discovery Studio
Visualiser software have been carried out. Our research has shown
that the newly designed potential STS inhibitors based on 6–(1-
phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives
Biological assays
In vitro STS assay
The STS enzyme was extracted from the human placenta, and were able to create the complexes with the STS protein stabilised
purified using the 3-step chromatographic procedure according to by a number of interactions including p-alkyl, alkyl, p-sulphur, con-
the described method36. The reaction mixtures, at a final volume ventional hydrogen bond, carbon hydrogen bond, p-cation, or
of 100 mL, containing 20 mM Tris-HCl pH ¼ 7.4, 3 nM radiolabelled p-sigma (listed in Table 2). The largest number of interactions was
[3H] oestrone sulphate, various concentrations of inhibitor and 5 U detected for compounds 3E, 3F, 3G. However, apart from the
of purified enzyme (1 U is the amount of enzyme that hydrolyses above-mentioned numerous interactions, an extremely important
100 nM radiolabelled [3H] oestrone sulphate in 1 h at 37 ꢀC). The aspect (influencing the inhibitory properties of STS inhibitors
reactions were performed at 37 ꢀC for 30 min. Afterwards, the based on aryl-sulphamate derivatives) is their ability to undergo

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
243
Table 1. Free energies of binding calculated for compounds 3 A-L and Irosustat.
Chemistry
The newly designed compounds 3A-L based on 6–(1-phenyl-1H-
1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives were syn-
thesised according to the route shown in (Scheme 1). In the first
step, we synthesised 6-((trimethylsilyl)ethynyl)naphthalen-2-ol 1 by
the Sonogashira coupling reaction between 6-bromo-2-naphthol
and trimethylsilylacetylene. Next step included the preparation of
6–(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-ol derivatives 2 A-L
by a 1,3-dipolar cycloaddition reaction. In this case the corre-
sponding azide derivatives (obtained from commercially available
anilines by the reaction with t-BuONO and TMSN3) were treated
with 1 in the presence of CuSO4 ꢂ 5H2O (0.1 equiv.), sodium ascor-
bate (0.2 equiv.), and TBAF. Finally, 6–(1-phenyl-1H-1,2,3-triazol-4-
yl)naphthalen-2-ol derivatives 2 A-L were sulphamoylated using
sulphamoyl chloride previously generated in the reaction of chlor-
osulphonyl isocyanate and formic acid in the presence of a cata-
lytic amount of N,N-DMA. After standard isolation, the desired
derivatives 3A-L were obtained.
Free energies of
No.
R1
R2
R3
R4
R5
binding [kcalꢂmol-1]
3A
3B
3C
3D
3E
3F
3G
3H
3I
3J
3K
H
H
H
H
H
H
H
F
Cl
Br
H
F
H
F
H
H
H
H
F
Cl
Br
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
–
–7.4
–7.7
–6.4
–6.3
–7.6
–7.6
–6.0
–8.0
–7.9
–8.0
–7.9
–8.3
–5.4
Cl
Br
H
H
H
H
H
H
F
Biological evaluation
Enzymatic assay using the STS enzyme isolated from the
human placenta
3L
Irosustat
F
–
H
–
In the next step of our investigation, the synthesised new STS
inhibitors based on 6–(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-
yl sulphamate derivatives 3A-L were tested in the enzymatic assay
(at 0.5 mM of inhibitor concentration) in order to verify their theor-
etical potential to inhibit of the STS activity. Screening tests were
performed using the STS enzyme isolated from the human pla-
centa and purified by a 3-step chromatography procedure. After
purification, the obtained fraction was used directly as the enzyme
source. In this activity assay, a radiolabelled [3H] oestrone sulphate
has been used as a substrate to provide higher selectivity and
more reliable results. The summarised results of the enzymatic
assay for newly synthesised 6–(1-phenyl-1H-1,2,3-triazol-4-yl)naph-
thalen-2-yl sulphamate derivatives 3A-L are presented in Table 3.
The received data showed that all compounds effectively inhibited
the activity of the steroid sulphatase to a level from 7.98 to
27.17%. In the course of the research, we found that the highest
inhibitory activity was exhibited by the compound 3L containing
three fluorine atoms in its structure (remaining STS activity of
7.98%). This result was in agreement with the data from the
molecular modelling studies. It was observed that the substitution
of the terminal aromatic ring with a less halogen atoms resulted
in a decrease in the activity of the tested compounds towards
STS. This observation may confirm our assumptions that the
higher number of electronegative heteroatoms may reduce the
pKa value of the inhibitor cores, making them more susceptible to
nucleophilic substitution reaction on the sulphur atom. The
obtained results may also suggest that the position of the halo-
gen substitution in the above-mentioned aryl ring may be crucial
for the potency of evaluated compounds. As it turns out, the pres-
ence of halogen atoms at the R1 and R2 positions may have the
greatest influence on the increase of inhibitory potency. On the
other hand, the type of substituent is slightly less significant.
–
–
the nucleophilic substitution reactions on the sulphur atom.
Although the mechanism of action is not confirmed and remains
a topic of discussion, a sulphamate functional group (sulphate
mimic) might be transferred to fGly75 residue leading to irrevers-
ible inhibition of the STS enzyme21. The visualisation of the puta-
tive binding mode for compounds 3L using VMD 1.9 (University
of Illinois at Urbana-Champaign, Urbana, IL, USA) is shown in
Figure 1. The sulphamate functional group, which is directly
responsible for the inactivation of the enzyme, is located in the
catalytic region of STS close to the fGly75 residue coordinated to
Ca2þ and stabilised by p-sulphur interaction with His290 (the dis-
tance between the sulphur atom of 3L and OH group of fGly75 is
2.90 Å). For this reason, we suppose that the compound 3L (des-
pite a smaller number of electrostatic interactions indicated by
the docking program) may prove to be the most effective due to
the very close distance of the sulphamate group to fGly75 residue.
Furthermore, the tetracyclic core of compound 3L is well accom-
modated in the STS active site and is surrounded by some hydro-
phobic amino acid residues (e.g. Leu103, Leu167, Phe178, Phe182,
Phe237, Val486, Phe488, and Phe553). Interestingly, the fluorine
atoms of compound 3L are within a short distance to the nitrogen
atoms of the Arg98 residue (4.12 and 4.29 Å), indicating the possi-
bility of electrostatic interactions (undetected by the Discovery
Studio Visualiser). On the other hand, the presence of the fluorine
atoms may be crucial for its potentially increased ability to
undergo the enzymatic reaction. Highly electronegative fluorine
atoms may reduce the pKa value of the molecule, making it a
good leaving group in the nucleophilic substitution reaction on
the sulphur atom. In addition, the molecular modelling studies
indicated (Figure 1) that the triazole ring of compound 3L is
located close to the Thr484 residue, suggesting an additional
interaction including hydrogen bond between OH group of
Thr484 and ring-nitrogen atom (5.81 Å). These detected interaction
Evaluation of STS inhibition in the MCF-7 cell line
The next step of the biological evaluation was to verify whether
points may be responsible for an enhancement of inhibitory the obtained new STS inhibitors based on 6–(1-phenyl-1H-1,2,3-tri-
potency by stabilisation of the potential STS inhibitor in the azol-4-yl)naphthalen-2-yl sulphamates 3A-L are able to inhibit STS
enzyme’s active site.
activity in the MCF-7 cancer cell line. In the course of our study,

244
O. CIUPAK ET AL.
ꢀ
Table 2. The ligand-protein interactions (and distances [Å]) identified using BIOVIA, Dassault Systemes, Discovery Studio Visualiser.
Conventional
Hydrogen Bond
Carbon
Hydrogen Bond
No.
p–Alkyl
Alkyl
p–Sulphur
p–Cation
p–Sigma
3A
LEU103 (6.16, 6.50); VAL486 (5.86);
VAL101 (4.93, 6.33); VAL177 (6.12)
LEU103 (6.13, 6.47); VAL486 (5.50,
6.07), VAL101 (5.31), VAL177
(5.50, 5.57)
LEU103 (5.91); VAL486 (6.16); VAL101 ARG98 (2.99),
(5.43); VAL177 (5.43, 5.63) TRP550 (6.97)
LEU103 (5.51); VAL101 (4.85); VAL177 ARG98 (3.08);
(4.85, 5.55)
ARG98 (4.57, 6.35);
VAL177 (6.26); VAL486 (5.36),
VAL101 (6.07)
ARG98 (4.74); VAL177
(6.49); VAL101 (5.81),
VAL486 (5.37)
ARG98 (4.95); VAL177 (5.24, 5.96),
VAL486 (5.30), VAL101 (6.42)
–
HIS290 (5.76);
HIS136 (6.93)
HIS290 (6.00)
THR165 (4.11)
–
–
–
3B
–
FGLY75 (4.18),
LYS368 (5.02)
HIS136
–
–
–
(5.74, 7.12)
3C
3D
3E
HIS290 (5.75);
HIS136 (7.13)
HIS290 (5.79);
HIS136 (7.11)
HIS290 (5.43);
HIS136 (6.78)
–
–
HIS136 (6.04)
–
ARG98 (4.40)
ARG98 (4.83)
–
TRP550 (6.86)
–
LYS134 (6.65); ASP36
(4.96);
GLN343 (5.61)
LYS134 (5.37),
THR165 (4.20)
THR165 (5.41)
VAL101 (4.93)
VAL101 (4.78)
VAL101 (5.29)
3F
–
HIS290 (5.29);
HIS136 (6.73)
–
–
–
3G
LEU185 (5.88)
HIS290 (4.87,
5.32); HIS136
(6.72)
LYS368 (5.58), LYS134
(6.45), GLN343
(5.45), ASP36 (4.95),
ASP35 (4.95)
HIS136 (5.58)
3H
3I
LEU103 (6.23, 6.49); VAL486 (6.21);
VAL101 (5.38); VAL177 (5.49, 5.69)
–
–
–
HIS290 (5.96);
HIS136 (7.09)
FGLY75 (4.25, 5.14);
LYS368
(3.69)
HIS136 (5.74)
HIS136 (5.73)
–
–
–
–
PHE178 (4.53); LEU103 (6.27, 6.56);
VAL177 (5.46, 5.79); VAL486 (5.96),
VAL101 (5.42)
PHE178 (4.48); LEU103
(6.15, 6.43), VAL177 (5.50, 5.67);
VAL486 (6.08);
HIS290 (6.01);
HIS136 (7.08)
LYS368 (5.15)
–
3J
HIS290 (5.92);
HIS136 (7.05)
LYS368 (5.18); FGLY75 HIS136 (5.69)
(3.04,
4.27)
ARG98 (4.90)
VAL101 (5.34)
3K
3L
LEU103 (6.18, 6.60);
–
HIS290 (5.91);
HIS136 (7.05)
ARG98 (5.14)
HIS136 (5.67)
–
–
VAL486 (5.95); VAL101
(5.40); VAL177 (5.26, 5.68)
VAL177 (4.32); VAL486 (5.09, 5.61);
LEU74 (6.53)
–
–
HIS290 (5.57)
–
–
–
–
VAL101 (5.12)
VAL486 (4.67)
Irosustat VAL177 (6.51); VAL486
HIS290 (5.73);
HIS136 (6.84)
LYS368 (5.49);
FGLY75 (3.04)
HIS136 (6.03)
(4.87, 5.08) VAL101 (5.09)
we determined the level of STS inhibition in the MCF-7 cells after reference compound – Irosustat (remaining STS activity of 5.72%).
incubation in the presence of inhibitors at 100, 10, and 1 nM con- In the next step, six of the most promising derivatives 3G-L were
centrations. The summarised results are presented in Table 4. selected and tested at an inhibitor concentration of 10 nM.
In the course of our research, we found that in the presence of Among these compounds, the highest STS inhibitory activities
inhibitor at 100 nM concentration, the lowest STS activities were were observed for the derivatives 3I, 3K, and 3L (remaining STS
measured for derivatives 3K (5.43% of STS activity) and 3L (5.29% activity of 42.09%, 42.01% and 27.48%, respectively). As the
of STS activity) substituted at R1, R2 or R3 position with fluorine research showed, the tested compounds showed slightly weaker
atoms. These results were comparable with those obtained for the activity in comparison with Irosustat (remaining STS activity of

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
245
Figure 1. Docked binding modes and distance to fGly75, Arg98 and Thr484 for compound 3 L (CPK coloured) and Irosustat (pink).
Scheme 1. Synthesis of 6-((trimethylsilyl)ethynyl)naphthalen-2-ol 1 and 6–(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives (R1, R2, R3, R4, R5 ¼ H,
F, Cl, or Br) 3 A-L.

246
O. CIUPAK ET AL.
Table 3. The STS inhibitory effect of the newly synthesised compounds 3 A-L at
0.5 mM inhibitor concentration.
potent STS inhibitors characterised by low IC50 values of 30.14,
17.02, 15.97 nM, respectively (IC50 parameter determined for
Irosustat was 1.14 nM). The obtained results indicated that 6–(1-
phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamates may be
very promising in further in vivo studies. Overall, among all the
newly prepared compounds, the highest activity was shown by
those with fluorine atoms in their structures. We assume that their
effectiveness may be influenced by the possibility of electrostatic
interactions between fluorine atoms and the Arg98 residue in the
STS active site (as suggested in molecular modelling studies) as
well as a higher susceptibility of these structures to nucleophilic
substitution reaction on the sulphur atom. Moreover, the presence
of C-F bonds in the structure of biologically active compounds
often affects a number of favourable properties, including meta-
bolic stability, leading to higher therapeutic effectiveness.
No.
R1
R2
R3
R4
R5
Remaining STS activity [%]
3A
3B
3C
3D
3E
3F
3G
3H
3I
H
H
H
H
H
H
H
F
Cl
Br
H
F
H
F
H
H
H
H
F
Cl
Br
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
24.50 1.36
17.40 0.87
9.66 0.48
9.62 0.48
23.75 1.22
18.71 0.94
23.07 1.15
27.17 1.36
16.93 0.83
15.93 0.80
14.03 0.70
7.98 0.40
Cl
Br
H
H
H
H
H
H
F
Conclusions
In the present work, we described our research on molecular
modelling, synthesis, and biological evaluation of 6–(1-phenyl-1H-
1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives 3A-L as
new very potent STS inhibitors. Screening enzymatic assay, per-
formed using the STS enzyme isolated from the human placenta
indicated that all of the newly synthesised inhibitors 3A-L were
able to effectively inhibit the action of STS. Among them, the
highest inhibitory activity was exhibited by compound 3L contain-
ing three fluorine atoms in its structure (remaining STS activity of
7.98%). In the course of the cell line experiment, we observed the
highest inhibition of STS in the presence of 6–(1-phenyl-1H-1,2,3-
triazol-4-yl)naphthalen-2-yl sulphamates 3I, 3K, and 3L character-
ised by low IC50 values of 30.14, 17.02, 15.97 nM, respectively (IC50
value determined for Irosustat was 1.14 nM). The presented results
3J
3K
3L
F
H
Table 4. Remaining STS activity in MCF-7 cells after incubation with compounds
3 A-L and Irosustat at 100, 10 and 1 nM inhibitor concentrations.
showed
that
6–(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl
sulphamate derivatives may be very promising anticancer agents
and their therapeutic potential should be confirmed in further
in vivo studies. Furthermore, the data of enzymatic and cell line
experiments suggested that the possibility of creating electrostatic
interactions between the fluorine atoms of compounds and the
Arg98 residue in the active site of STS as well as a higher suscepti-
bility to nucleophilic substitution reaction on the sulphur atom
could be critical for their inhibitory effects.
Remaining STS activity [%]
No.
R1 R2 R3 R4 R5 100 [nM]
10 [nM]
1 [nM]
IC50 [nM]
3A
3B
3C
3D
3E
3F
3G
3H
3I
3J
3K
H
H
H
H
H
H
H
F
Cl
Br
H
F
H
F
H
H
H
H
F
Cl
Br
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
–
15.52 0.78
12.22 0.61
22.05 1.10
20.59 1.03
11.32 0.57
13.25 0.66
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Disclosure statement
Cl
Br
H
H
H
H
H
H
F
The authors report no conflict of interest.
8.68 0.43 59.86 2.99
8.80 0.44 55.84 2.79
7.44 0.37 42.09 2.10 84.32 4.22 30.14 1.51
Funding
Financial support for this study was provided by the National
Centre for Research and Development (Poland) for: TANGO pro-
gram - grant agreement no. TANGO-IV-A/0004/2019-00.
7.30 0.37 59.45 2.97
–
–
5.43 0.27 42.01 2.10 79.30 3.96 17.02 0.85
5.29 0.26 27.48 1.37 99.00 4.95 15.97 0.80
5.72 0.29 12.93 0.65 16.83 0.84 1.14 0.06
3L
Irosustat
F
–
H
–
–
–
ORCID
12.93% at an inhibitor concentration of 10 nM). In order to further
verify the potential of the new selected compounds, the STS activ-
ity was measured in the presence of 3I, 3K, and 3L at the inhibi-
tor concentration of 1 nM. For these compounds, an IC50
parameter was determined as well. The studies showed that the
tested compounds based on 6–(1-phenyl-1H-1,2,3-triazol-4-
ꢀ
Mateusz Dasko
Karol Biernacki
Janusz Rachon
Konrad Kubinski
Aleksandra Martyna
http://orcid.org/0000-0002-3367-6491
http://orcid.org/0000-0003-3036-8693
http://orcid.org/0000-0001-5377-8228
http://orcid.org/0000-0001-6870-845X
http://orcid.org/0000-0002-7602-002X
ꢀ
yl)naphthalen-2-yl sulphamates 3I, 3K, and 3L found to be very Sebastian Demkowicz
http://orcid.org/0000-0002-4252-4297

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
247
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(IRIS) – trial results. J Clin Oncol 2016;34:549.
20. Palmieri C, Szydlo R, Miller M, et al. IPET study: an FLT-PET
window study to assess the activity of the steroid sulfatase
inhibitor irosustat in early breast cancer. Breast Cancer Res
Treat 2017;166:527–39.
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