New potent STS inhibitors based on fluorinated 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates

Article abstract of DOI:10.1080/10286020.2019.1680642

A series of fluorinated analogs based on the frameworks of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates have been synthesized as steroid sulfatase (STS) inhibitors. The design of chemical structures of new potential STS inhibitors was supported by molecular docking techniques to identify potential interactions between inhibitors and amino acid residues located in the STS active site. The STS inhibitory potency was evaluated on STS isolated from human placenta. We found that compounds substituted with fluorine atom at the meta position demonstrated the highest inhibitory effects in enzymatic STS assay. The most active analog 12e–inhibited STS enzyme with the IC₅₀ value of 36 nM.

Full text of DOI:10.1080/10286020.2019.1680642

Journal of Asian Natural Products Research
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New potent STS inhibitors based on fluorinated 4-
(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates
Mateusz Daśko, Sebastian Demkowicz, Janusz Rachon, Karol Biernacki,
Justyna Aszyk, Witold Kozak, Maciej Masłyk & Konrad Kubiński
To cite this article: Mateusz Daśko, Sebastian Demkowicz, Janusz Rachon, Karol Biernacki,
Justyna Aszyk, Witold Kozak, Maciej Masłyk & Konrad Kubiński (2019): New potent STS inhibitors
based on fluorinated 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates, Journal of Asian Natural
Products Research, DOI: 10.1080/10286020.2019.1680642
To link to this article: https://doi.org/10.1080/10286020.2019.1680642
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JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
https://doi.org/10.1080/10286020.2019.1680642
New potent STS inhibitors based on fluorinated
4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates
a
b
b
b
ꢀ
Mateusz Dasko , Sebastian Demkowicz , Janusz Rachon , Karol Biernacki ,
c
d
e
e
ꢀ
Justyna Aszyk , Witold Kozak , Maciej Masłyk and Konrad Kubinski
aDepartment of Inorganic Chemistry, Faculty of Chemistry, Gdansk University of Technology,
b
Narutowicza 11/12, Gdansk 80-233, Poland; Department of Organic Chemistry, Faculty of Chemistry,
c
Gdansk University of Technology, Narutowicza 11/12, Gdansk 80-233, Poland; Department of
Analytical Chemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza 11/12,
d
Gdansk 80-233, Poland; Department of Physical Chemistry, Faculty of Chemistry, University of
e
Gdansk, Wita Stwosza 63, Gdansk 80-308, Poland; Department of Molecular Biology, Faculty of
Biotechnology and Environment Sciences, the John Paul II Catholic University of Lublin,
ꢀ
Konstantynow 1i, Lublin 20-708, Poland
ABSTRACT
ARTICLE HISTORY
Received 6 March 2019
Accepted 8 October 2019
A series of fluorinated analogs based on the frameworks of 4-(1-
phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates have been synthe-
sized as steroid sulfatase (STS) inhibitors. The design of chemical
structures of new potential STS inhibitors was supported by
molecular docking techniques to identify potential interactions
between inhibitors and amino acid residues located in the STS
active site. The STS inhibitory potency was evaluated on STS iso-
lated from human placenta. We found that compounds substi-
tuted with fluorine atom at the meta position demonstrated the
highest inhibitory effects in enzymatic STS assay. The most active
analog 12e – inhibited STS enzyme with the IC50 value of 36 nM.
KEYWORDS
Triazoles; steroid sulfatase;
breast cancer; STS
inhibitors; sulfamates
ꢀ
CONTACT Mateusz Dasko
mateusz.dasko@pg.edu.pl
Department of Inorganic Chemistry, Faculty of
Chemistry, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland; Sebastian Demkowicz
sebdemko@pg.edu.pl Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of
Technology, Narutowicza 11/12, 80-233 Gdansk, Poland
Supplementary data for this article is available online at https://doi.org/10.1080/10286020.2019.1680642.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

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M. DASKO ET AL.
2
1. Introduction
Hormone-dependent breast cancer (HDBC) is a major cause of mortality, and there
is pressing need to develop novel treatment methods. According to International
Agency of Research on Cancer (IARC), 2.1 million cases of breast cancer will be diag-
nosed in 2018. Furthermore, the breast cancer will be a cause of death in 620,000
cases. Over the past decades, numerous reports have suggested the importance of bio-
logically active hormone precursors in regulating the supply of estrogens to HDBC.
One approach for treatment of HDBC involves inhibitors of enzymes responsible for
the biosynthesis of estrogens in peripheral tissues [1].
There are different enzyme pathways responsible for the formation of active estrogens
in the breast tissue, e.g. the aromatase enzyme complex (implicated in the conversion of
androgens into estrogens during steroidogenesis) [2], the 17b-hydroxysteroid
dehydrogenase (17b-HSD) (implicated in the interconversion of E1 and E2), the 3b-
hydroxysteroid dehydrogenase/isomerase (3b-HSD) isoenzymes (implicated in the forma-
tion of all cases of active steroid hormones) [3] and steroid sulfatase enzyme (STS).
Within these pathways, STS plays a major role in the formation of biologically active
estrogens or androgens and acts by hydrolyzing aryl and alkyl steroid sulfates (including
E1S and DHEAS) [1]. It is worth noting that STS expression is detected in 90% of breast
tumors, with much higher activity than the aromatase complex [4]. Wide distribution of
the STS enzyme throughout the body is an indication of its involvement in numerous
physiological and pathological conditions [5].
In recent years, there has been intensive research toward finding novel effective
inhibitors of STS. Approaches to design efficacious STS inhibitors include three dif-
ferent categories of compounds: alternative substrates (including competitive revers-
ible inhibitors), reversible inhibitors, and irreversible inhibitors [6]. One of the
strategies for designing of the STS inhibitors was a replacement of sulfate moiety, pre-
sent in natural substrate, into the sulfamate group. One of the most promising syn-
thesized compounds was EMATE 1 (Figure 1), which exhibited very high activity in
MCF-7 cells, with an IC50 value of 65 pM [7]. The unique activity of this compound
has since spawned a large library of such sulfamate-based STS inhibitors based
around the aryl sulfamate pharmacophore [8,9]. A series of nonsteroidal analogues
with different functional groups have been synthesized, including sulfamates, phos-
phates, phosphonates, and thiophosphonates – as potent STS inhibitors [10–16]. The
sulfamated coumarin derivatives (e.g. coumarin-7-O-sulfamate 2) were proved to be
an important class of compounds exhibiting a high inhibitory potency against STS. In
contrast to EMATE, they demonstrated fewer adverse effects and much weaker estro-
genic properties. The first potent inhibitor based on the coumarin scaffold was 4-
methylcoumarin-7-O-sulfamate 3 (COUMATE), which exhibited good activity with
an IC50 value of 380 nM, when evaluated against placental microsomes [17]. Further
modifications of its structure led to a wide range of tricyclic coumarin derivatives
that mimicked the ABC rings of steroids. These compounds displayed a significantly
more potent inhibitory activity than COUMATE (e.g. 667-COUMATE 4 demon-
strated potent activity toward STS with IC50 value of 8 nM) [18].
Recently, the strategy based on the introduction of fluorine atoms to the chemical
structure of coumarin derivatives has been used in designing of novel STS inhibitors.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Figure 1. Chemical structures of STS inhibitors 1–9.
The introduction of fluorine atoms into the structure of biologically active com-
pounds alters nearly all physical properties of the compounds and modifies their
absorption, distribution, metabolism and excretion. As potent STS inhibitors, the flu-
orinated 3-phenylcoumarin-7-O-sulfamate derivatives have been synthesized [19].
Two fluorinated compounds, 5 and 6, demonstrated the highest inhibitory activity in
the enzymatic assay, with IC50 values of 270 nM in both cases. Furthermore, the
introduction of additional fluorinated aromatic ring via amide moiety led to obtain a
series of N-acylated derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate [20].
Compounds 7 and 8 inhibited the STS enzyme with IC50 values of 180 nM in both
cases. The fluorination strategy has been used also in case of STS inhibitors based on
N-acylated tyramine sulfamates [21]. The 4-(2-perfluoroundecanoylaminoethyl)-
phenyl sulfamate 9 exhibited the greatest inhibitory effect, with an IC50 value
of 2.18 mM.
In the present work, we described a convenient method for the synthesis of com-
pounds, based on nonsteroidal core of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl
sulfamate, as potent STS inhibitors. We found that the aforementioned nonsteroidal
scaffold perfectly imitates the steroid core of the natural substrate and may undergo
numerous electrostatic interactions affecting the stabilization of the inhibitor-enzyme
complexes within the active site of STS. Furthermore, in the design and synthesis of
the novel STS inhibitors, the fluorination strategy has been involved.

ꢀ
M. DASKO ET AL.
4
2. Results and discussion
2.1. Chemistry
In the course of our research, we synthesized newly designed STS inhibitors, based
on fluorinated 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamates, according to
click chemistry approach [22]. The detailed synthesis pathway is shown in Scheme 1.
In the first step, 4-(trimethylsilyl)ethynyl)phenol 10 was obtained by the Sonogashira
coupling between the 4-iodophenol and trimethylsilyl acetylene. Next, the commer-
cially available aniline derivatives were transformed into azides [by the reaction with
tert-butyl nitrite (t-BuONO) and azidotrimethylsilane (TMSN3)] and then directly
coupled to 10 in the presence of CuSO4 (0.1 equiv.), ascorbic acid (0.2 equiv.), and
tetrabutylammonium fluoride (TBAF) to bring about the deprotection of 10 in the
reaction mixture. Finally, the OH groups of obtained 4-(1-phenyl-1H-[1,2,3]triazol-4-
yl)- phenol derivatives 11a-n were sulfamoylated. In these cases, the solutions of stable
fluorinated derivatives of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenol 11a-n in N,N-
dimethylacetamide (DMA) were treated with H2NSO2Cl, previously generated in the
reaction of chlorosulfonyl isocyanate and formic acid in the presence of a catalytic
amount of DMA. After the standard isolation procedure, we obtained desired com-
pounds 12a-n.
Scheme 1. Synthesis of 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamate derivatives 12a-n (R1,
R2, R3, R4, R5 ¼ H, F, CF3, OCF3).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
2.2. Molecular modeling
To determine the binding modes of proposed structures of fluorinated 4-(1-phenyl-
1H-[1,2,3]triazol-4-yl)-phenyl sulfamate to the STS active site, the molecular docking
approach was applied. The computational studies allowed us to identify potential inter-
actions between specified functional groups, atoms of inhibitors and amino acid resi-
dues forming the binding site of STS. The docking procedures of the properly
optimized ligands to the prepared structure of the STS enzyme (retrieved from Protein
Data Bank – 1P49 accession code) were performed using Autodock Vina 1.1.2 software
(Molecular Graphics Laboratory, The Scripps Research Institute, La Jolla, CA, USA).
The calculated free binding energies (Table 1), for the newly designed candidates
12a-n, were in the range from –5.3 to –7.1 kcal molꢀ1 and in almost every cases were
significantly lower than the free binding energy values for the reference inhibitors:
coumarin-7-O-sulfamate (–2.9 kcal molꢀ1), COUMATE (–4.1 kcal molꢀ1),
667-COUMATE (–5.4 kcal molꢀ1). The best docking results were determined for
compounds 12d (–6.7 kcal molꢀ1), 12e (–6.7 kcal molꢀ1), 12f (–6.7 kcal molꢀ1), and
12 h (–7.1 kcal molꢀ1). It is worth noting that in the structures of compounds 12d,
12e, 12f, and 12 h the terminal aromatic ring is substituted with fluorine atom or tri-
fluoromethyl group at the meta position. Our docking analysis, for the newly
designed STS inhibitor candidates 12a-n, showed that these compounds could be well
associated with the active site of STS.
Table 1. Activities of the synthesized compounds 12a-n, and reference inhibitors in the STS
enzyme assays.
No.
R1
R2
R3
R4
R5
Free binding energy (kcal molꢀ1
)
IC50 [mM]a
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
2
H
H
H
H
H
F
H
H
CF3
H
F
CF3
H
OCF3
–
–
–
H
H
F
F
F
F
H
CF3
H
CF3
H
H
H
H
–
H
F
H
F
H
F
CF3
H
H
H
CF3
F
OCF3
H
–
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
–
ꢀ6.1
ꢀ6.5
ꢀ6.3
ꢀ6.7
ꢀ6.7
ꢀ6.7
ꢀ5.9
ꢀ7.1
ꢀ6.2
ꢀ6.6
ꢀ5.9
ꢀ6.4
ꢀ6.2
ꢀ5.3
ꢀ2.9
ꢀ4.1
ꢀ5.4
0.35 0.05
0.30 0.04
0.072 0.01
0.063 0.01
0.036 0.004
0.058 0.007
0.14 0.05
0.18 0.06
0.18 0.07
0.82 0.05
0.35 0.05
0.45 0.06
0.24 0.03
1.5 0.2
H
H
H
F
H
H
H
H
CF3
H
H
H
H
–
1.04 0.32
0.3 0.07
0.025 0.008
3
4
–
–
–
–
–
–
–
–
aAll measurements were performed in triplicate.

ꢀ
M. DASKO ET AL.
6
Figure 2. Docked binding modes and distances to Arg98 and Thr484 of compounds 12d (red), 12e
(blue), 12f (CPK coloured), and 667 COUMATE (green).
The binding modes of compounds 12a-n were similar to the mode of the reported
STS inhibitor 667-COUMATE. The Figure 2 shows structures of compounds 12d,
12e, 12f, and the reference inhibitor 667-COUMATE docked to the active site of the
STS enzyme. We found that the sulfamate functional groups are located very close to
the catalytic amino acid residue FGly75 (ꢁ3.0 Å) coordinated to the Ca2þ ion.
Furthermore, they are surrounded by the catalytically essential residues (Asp35,
Asp36, Arg79, Lys134, His136, and Lys368). The tricyclic cores of the designed candi-
dates 12a-n are well accommodated in the binding cavity formed by the lipophilic
amino acids (Arg98, Leu103, Phe104, Leu167, Val 177, Phe178, Phe182, Leu185,
Phe230, Phe233, Phe237, Thr484, Val486, Phe488, Trp550, and Phe553). In the course
of our docking studies, we noticed that the central triazole rings are located close to
Thr484 residue indicating the possibility to create a putative electrostatic interaction.
Furthermore, we detected that fluorine atoms of a terminal aromatic ring of designed
candidates 12a-n are able to electrostatically interact with Arg98 residue. Taking the
example of compound 12f (Figure 2, right side), we noticed that the shortest distance
between the fluorine atom and the Arg98 residue occurs, when the fluorine atom is
at the meta position. This observation may explain the lowest free binding energy val-
ues calculated for analogues with fluorinated substituent at the meta position (12d,
12e, 12f, and 12h). Additionally, this may allow us to suppose that the more favor-
able stabilization of the inhibitor-enzyme complexes and more effective inhibition of
the enzyme is possible in cases of analogues with fluorinated substituent at the
meta position.
2.3. STS enzyme assays
To evaluate the STS inhibitory activities of synthesized compounds 12a-n, we per-
formed an enzymatic assay according to the previously reported methods [23,24] with
STS enzyme isolated from human placenta. As a direct source of the STS enzyme we
used the fraction after purification by a 3-step chromatographic procedure. The sum-
marized results of the enzymatic assay, for newly synthesized fluorinated 4-(1-phenyl-
1H-[1,2,3]triazol-4-yl)-phenyl sulfamate derivatives 12a-n and reference compounds
(coumarin-7-O-sulfamate 2, COUMATE 3, and 667-COUMATE 4), are presented in
Table 1.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
In the course of our investigations, we found that newly synthesized compounds
12a-n are very potent STS inhibitors. 4-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]-
phenyl sulfamate 12d, 4-[1-(3,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]-phenyl sulfa-
mate 12e and 4-[1-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-4-yl]-phenyl sulfamate 12f
exhibited the highest inhibitory activities (the IC50 values of 0.063 mM, 0.036 mM, and
0.058 mM, respectively). This results are in agreement with the data obtained from
molecular docking studies that showed the most favorable free binding energy values
for compounds with fluorine atom at the meta position of terminal aromatic ring.
Furthermore, the inhibitory potency of the most active derivative 4-[1-(3,5-difluoro-
phenyl)-1H-1,2,3-triazol-4-yl]-phenyl sulfamate 12e (the IC50 value of 0.036 mM) was
comparable with 667 COUMATE (the IC50 value of 0.025 mM), which is known as
potent STS inhibitor.
In the present work, we described the synthesis and biological evaluation of a
series of new STS inhibitors 12a-n based on fluorinated 4-(1-phenyl-1H-[1,2,3]triazol-
4-yl)-phenyl sulfamate core. Additionally, the computational analyses were carried
out as a support in designing the chemical structures of potential inhibitors. In the
course of our docking studies, we found that the fluorinated derivatives of 4-(1-
phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamate 12a-n are well accommodated in the
binding cavity of STS. According to the computational research, we noticed that the
most favorable free binding energy values were calculated for derivatives with a fluor-
ine atom at the meta position of terminal aromatic ring (12d, 12e, 12f, and 12h).
This result may be explained by the shortest distances between fluorine atoms at the
meta position and the Arg98 residue located in the active site of STS. The molecular
modeling results were confirmed by the biological research. In the course of our
biological evaluation studies, we found that the newly synthesized compounds based
on fluorinated 4-(1-phenyl-1H-[1,2,3]triazol-4-yl)-phenyl sulfamate core 12a-n
exhibited very high inhibitory potency. The highest inhibitory activities were demon-
strated by compounds contained the fluorine atom at the meta position of terminal
aromatic ring: 4-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]-phenyl sulfamate 12d,
4-[1-(3,5-difluoro-phenyl)-1H-1,2,3-triazol-4-yl]-phenyl sulfamate 12e and 4-[1-(2,3,4-
trifluorophenyl)-1H-1,2,3-triazol-4-yl]-phenyl sulfamate 12f (the IC50 values of
0.063 mM, 0.036 mM and 0.058 mM, respectively). Furthermore, the inhibitory potency
of the most active derivative 4-[1-(3,5-difluoro-phenyl)-1H-1,2,3-triazol-4-yl]-phenyl
sulfamate 12e (the IC50 value of 0.036 mM) was comparable with 667 COUMATE
(the IC50 value of 0.025 mM).
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
We gratefully acknowledge the National Science Centre (Poland) for financial support
(PRELUDIUM grant no. 2015/19/N/NZ7/00938 and ETIUDA fellowship no. 2017/24/T/NZ7/
00271). Furthermore, we gratefully acknowledge the Foundation for Polish Science (FNP) for
financial support in the form of the fellowship START for one of the coauthors.

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M. DASKO ET AL.
8
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