Інгібування глутатіон-S-трансфераз калікс[4]аренфосфіновими кислотами
Calix[4]arene-, thiacalix[4]arene- and sulfonylcalix[4]arene-based derivatives with upper rim phosphinic acid groups were studied as inhibitors of glutathione S-transferases. It was found that the macrocyclic compounds can exhibit good to potent activity against GST from equine liver and human recom...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
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| author | Kobzar, Oleksandr L. Shulha, Yuriy V. Buldenko, Vladyslav M. Drapailo, Andriy B. Kalchenko, Vitaly I. Vovk, Andriy I. |
| author_facet | Kobzar, Oleksandr L. Shulha, Yuriy V. Buldenko, Vladyslav M. Drapailo, Andriy B. Kalchenko, Vitaly I. Vovk, Andriy I. |
| author_institution_txt_mv | [
{
"author": "Oleksandr L. Kobzar",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Yuriy V. Shulha",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Vladyslav M. Buldenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Andriy B. Drapailo",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Vitaly I. Kalchenko",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Andriy I. Vovk",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
}
] |
| author_sort | Kobzar, Oleksandr L. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:53Z |
| description | Calix[4]arene-, thiacalix[4]arene- and sulfonylcalix[4]arene-based derivatives with upper rim phosphinic acid groups were studied as inhibitors of glutathione S-transferases. It was found that the macrocyclic compounds can exhibit good to potent activity against GST from equine liver and human recombinant GSTA1-1, while being selective over the enzyme from human placenta and GSTP1-1. The thiacalix[4]arene phosphinic acid was the most active inhibitor of equine liver GST and GSTA1-1 with IC50 values of 85 nM and 50 nM, respectively. Kinetic studies revealed that the inhibition was of non-competitive type concerning both enzyme substrates, glutathione, and 1-chloro-2,4-dinitrobenzene. Molecular docking was carried out to predict possible binding sites for thiacalix[4]arene-based phosphinic acid on the surface of homodimeric GSTA1-1. |
| doi_str_mv | 10.15407/bioorganica2022.01.086 |
| first_indexed | 2025-07-17T12:19:26Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
UDC 547.639+ 577.152.2
DOI: https://doi.org/10.15407/bioorganica2022.01.086
86
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
Inhibition of glutathione S-transferases by calix[4]arene-based
phosphinic acids
Oleksandr L. Kobzar1, Yuriy V. Shulha1, Vladyslav M. Buldenko1, Andriy B. Drapailo2,
Vitaly I. Kalchenko2, Andriy I. Vovk1*
1 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
2 Institute of Organic Chemistry of the NAS of Ukraine, 5 Murmanska St., Kyiv, 02094, Ukraine
Abstract: Calix[4]arene-, thiacalix[4]arene- and sulfonylcalix[4]arene-based derivatives with upper rim phosphinic acid groups were
studied as inhibitors of glutathione S-transferases. It was found that the macrocyclic compounds can exhibit good to potent activity against
GST from equine liver and human recombinant GSTA1-1, while being selective over the enzyme from human placenta and GSTP1-1. The
thiacalix[4]arene phosphinic acid was the most active inhibitor of equine liver GST and GSTA1-1 with IC50 values of 85 nM and 50 nM,
respectively. Kinetic studies revealed that the inhibition was of non-competitive type concerning both enzyme substrates, glutathione, and
1-chloro-2,4-dinitrobenzene. Molecular docking was carried out to predict possible binding sites for thiacalix[4]arene-based phosphinic
acid on the surface of homodimeric GSTA1-1.
Keywords: phosphinic acid; calix[4]arene; thiacalix[4]arene; sulfonylcalix[4]arene; glutathione S-transferase; inhibition, molecular
docking.
Introduction
Glutathione S-transferases (GSTs; EC 2.5.1.18) as phase
II detoxification enzymes catalyze nucleophilic attachment
of reduced glutathione to exogenous and endogenous
electrophilic compounds in bacterial, plant, and mammalian
cells. The formed S-glutathione conjugates characterized by
better water solubility and lower cytotoxicity can be
eliminated from the cells through mercapturic acid pathway
[1, 2]. In addition, GSTs are known to be involved in the
synthesis of prostaglandins and leukotrienes, display thiol
transferase activity, catalyse isomerization of
maleylacetoacetate, contribute to intracellular transport of
hydrophobic non-substrate ligands, and regulate activities
of some signaling proteins [3]. Overexpression of GSTs is
often associated with carcinogenesis and cellular resistance
Received:
Revised:
Accepted:
Published online:
06.04.2022
20.04.2022
27.04.2022
30.06.2022
Corresponding author. Tel.: +380-44-558-5388;
e-mail: vovk@bpci.kiev.ua (A. I. Vovk)
ORCID: 0000-0001-6167-076X
to anticancer drugs [1, 4, 5]. In this connection, numerous
inhibitors of GSTs were discovered including derivatives of
glutathione, benzoquinone, benzophenone, benzoxadiazole,
and curcumin [1, 6]. Ethacrynic acid, clinically used as a
diuretic drug, demonstrates inhibitory activity against
GSTP1-1. Clinical trials for the treatment of ovarian, breast,
and colorectal cancers are conducted for glutathione analogs
ezatiostat (TLK199) and canfosfamide (TLK286) targeting
GSTP1-1 [7, 8].
Calix[4]arenes represent a unique class of three-
dimensional macrocyclic compounds that can be
functionalized with many different substituents both at the
lower and upper rim of the macrocycle. Specific and
selective complexation of the calix[4]arene derivatives with
metal ions, natural compounds, peptides, or any other
biomolecules is widely studied in bioorganic and medicinal
chemistry [9-11]. Calix[4]arenes can possess antiviral,
antibacterial, antifungal, antithrombotic, and anticancer
activities [12-14] showing inhibitory potential against
therapeutically important enzymes [15, 16]. Among them,
calix[4]arene-based phosphonic acids were found to inhibit
alkaline phosphatases [17-19] and protein tyrosine
phosphatases [20-23]. We previously demonstrated that
© Kobzar O. L. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
mailto:vovk@bpci.kiev.ua
https://orcid.org/0000-0001-6167-076X
O. L. Kobzar, Y. V. Shulha, V. M. Buldenko et al.
87
calix[4]arenes functionalized by α-hydroxyphosphonic acid
group exhibited inhibitory effects towards GSTs from the
equine liver and human placenta [24, 25].
Compounds bearing phosphinic acid fragments display
anti-inflammatory, anti-Alzheimer`s, antiparasitic, anti-
HIV, anti-influenza, antiproliferative, and antimalarial
effects [26, 27]. Phosphinic peptide analogues turned out to
be inhibitors of hydrolases, transferases, ligases, or other
enzymes [28-30]. At the same time, phosphinic acids of a
non-peptidic nature were found to possess inhibitory
activity against tyrosinase [31], matrix metalloproteinases
[32], aminopeptidases [33], acetylcholinesterase, carbonic
anhydrases [34], and urease [35]. Recently, calix[4]arene-
based phosphinic acids were identified as inhibitors of
protein tyrosine phosphatases [36]. The present study aimed
to evaluate the phosphinic acids derivatives of
calix[4]arene, thiacalix[4]arene, and sulfonilcalix[4]arene
1a-b (Figure 1) as inhibitors of glutathione S-transferases.
Figure 1. Calix[4]arene phosphinic acids assessed as inhibitors of
GSTs.
Results and discussion
In vitro studies were carried out using glutathione
S-transferases from the equine liver (GST-EL) and human
placenta (GST-HP) as well as cytosolic recombinant human
GSTA1-1 and GSTP1-1. Among these enzymes, GST-EL
and GSTA1-1 reportedly have a high degree of shared
amino acid identity [37], whereas the structure of GST-HP
is comparable to that of GSTP1-1. The macrocyclic
compounds 1a-c were found to exhibit good to potent
activity against GST from equine liver and human
recombinant GSTA1-1, while being selective over the
enzyme from human placenta and GSTP1-1. In particular,
the calix[4]arene-, thiacalix[4]arene- and sulfonylcalix-
[4]arene-based phosphinic acids at a concentration of
25 µM exhibited low or no inhibitory effect on the activity
of GST-HP and GSTP1-1, whereas GST-EL and GSTA1-1
were inhibited by these compounds in the low micromolar
and nanomolar concentration range (Table 1). The
inhibition potential of compounds 1a-c against GSTs is
illustrated in Figure 2. In the case of thiacalix[4]arene-based
phosphinic acid 1b, the calculated Hill coefficients were
0.78 and 0.63, respectively, which may suggest about one
binding site on the enzyme surface.
The IC50 values (Table 1) calculated from linear plots of
the enzyme residual activity versus inhibitor concentration
indicate that the effects of calix[4]arene-, thiacalix[4]arent-
and sulfonylcalix[4]arene-based phosphinic acids on the
activity of GST-EL and GSTA1-1 depend on the nature of
the macrocyclic scaffold. Among the compounds,
sulfonylcalix[4]arene derivative 1c was the weakest
inhibitor of the GSTs. Calix[4]arene phosphinic acid 1a
showed IC50 value of 1.73 μM for GST-EL and 1.32 μM for
GSTA1-1. Thiacalix[4]arene inhibitor 1b demonstrated
high affinity to GST-EL and GSTA1-1 with IC50 values of
85 nM and 50 nM, respectively.
Kinetic study was performed to elucidate the mechanism
of GSTs inhibition by thiacalix[4]arene-based phosphinic
acid 1b. Lineweaver-Burk plots demonstrating the influence
of the compound 1b on the activity of GST-EL are given in
Figure 3 at different concentrations of each of the two
substrates, 1-chloro-2,4-dinitrobenzene (CDNB) or
glutathione (GSH). The data obtained agreed with a non-
competitive inhibition type when the inhibitor binds to the
enzyme without competing with both substrates for the
active site. The values of inhibition constants (Ki) calculated
from the Lineweaver-Burk reciprocal plots were 69±10 nM
and 61±10 nM for CDNB and GSH, respectively.
Kinetic data suggest that thiacalix[4]arene-based
phosphinic acid 1b, acting via a non-competitive inhibition,
may bind to a potential site of GST that is remote from the
location of both substrates. The GSTs are known to be
catalytically active as homodimers and heterodimers, with
each subunit having a highly specific G-site for binding
glutathione and H-site for binding diverse electrophilic
substrates [1, 38]. The two distinct active sites of dimers of
GSTP1-1 [1], which work synergistically, are well-
Table 1. Inhibition potential of calix[4]arene-, thiacalix[4]arene- and sylfonylcalix[4]arene-based phosphinic acids towards
GSTsa.
Compound
IC50, µM Inhibitory potential (%)b
GST EL GSTA1-1 GST HP GSTP1-1
1a 1.73±0.61 1.32±0.36 8 20
1b 0.085±0.02 0.05±0.015 20 13
1c 1.91±0.59 9.23±1.91 n. a. n. a.
a IC50 values are the means of 2-3 assays ± standard deviations; bInhibitor concentration was 25 µM; n. a. – not active.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
88
Figure 2. Dose-dependent curves for inhibition of GST-EL (left) and recombinant human GSTA1-1 (right) by compound 1a (□), 1b (∆),
and 1c (○).
Figure 3. Lineweaver-Burke plots of GST-EL inhibition by compound 1b. Concentrations of inhibitor were 0 (○), 40 nM (□), 80 nM (∆)
and 120 nM (◊).
separated and located in a solvent-accessible V-shaped cleft
at the intersubunit interface [39]. The blind docking of the
four possible conformers of thiacalix[4]arene phosphinic
acid 1b [40, 41] was performed by AutoDock Vina to the
whole surface of homodimeric human GSTA1-1 (PDB code
6ATO) containing two molecules of GSH. The predicted
binding modes of the compound suggest that all conformers
preferably bind at the bottom of V-shaped cleft. This region
of GST was described as a non-substrate ligand-binding site
(L-site) for several compounds [39, 42-44]. The calculated
affinity of cone (C4v symmetry), partial cone, 1,2-alternate,
and 1,3-alternate conformers were -10.8 kcal/mol, -10.5
kcal/mol, -10.4 kcal/mol, and -11.1 kcal/mol, respectively.
Although in our case 1,3-altrenate of thiacalix[4]arene
phosphinic acid 1b was estimated to be slightly better for
binding at L-site of human GSTA1-1, the cone conformer
of calix[4]arene derivatives with C4v symmetry was
presented in all PDB crystal complexes with cytochrome C
and some other proteins [45-47].
Results of the computer modeling suggest that the cone
conformer with C4v symmetry of thiacalix[4]arene
phosphinic acid 1b may fit well into the V-shaped cleft of
human GSTA1-1. In the process of binding, the lower rim
of the compound may interact with subunit A, while its
upper rim is directed to subunit B of the homodimer (Figure
4). The hydroxyl groups of thiacalix[4]arene platform tend
to form intramolecular hydrogen bonds stabilizing the cone
conformation of the inhibitor. Hydrogen bond was observed
between the sulfur atom of the thiacalix[4]arene scaffold
and amino acid residue Lys120 of subunit A. At the same
time, the opposite bridge atom of the macrocyclic platform
interacted with Gln54 of the subunit B. Aromatic ring of the
thiacalix[4]arene platform which is positioned at the bottom
of V-shaped cleft of the enzyme can facilitate hydrogen
bond formation with a backbone carbonyl group of
A:Asp101. One of the phosphinic acid substituents of the
macrocycle was observed to participate in hydrogen
bonding with the γ-glutamic acid residue of the glutathione
molecule as well as to form π-cationic interaction with
B:Arg69. The second phosphinic acid fragment was located
between residues Glu104 of subunit A and Glu104 of
subunit B. The third phosphinic substituent located near
B:Leu108 and B:Val111 participated in intramolecular
electrostatic interaction with the aromatic ring of the
macrocyclic scaffold. The fourth phosphinic fragment
interacted through hydrogen bond formation with
the glycine part of the glutathione molecule and
showed hydrophobic and electrostatic interactions with
Ala216, Phe220, and Phe222 of subunit B of homodimeric
GSTA1-1.
The ligand-accessible V-shaped cleft and polarity of the
H-site can determine the substrate specificity and functions
of different classes of GSTs [1]. The structures of GSTs of
O. L. Kobzar, Y. V. Shulha, V. M. Buldenko et al.
89
Figure 4. Possible binding mode of thiacalix[4]arene phosphinic acid 1b in V-shaped cleft between subunit A (colored as grey) and B
(colored as red) of GSTA1-1.
alpha and pi class are most similar, and their differences are
mainly due to variations of the C terminus, which is longer
in GSTA1-1 by some eight residues. These residues form an
α-helix that is a part of a wall of the hydrophobic
electrophile binding site and functions as a lid over the
active site when the H-site is occupied [48, 49]. The binding
affinity of non-substrate ligands is enhanced when the helix
is immobilized and stabilized after ligand binding at the
G-site which is in agreement with non-competitive inhibi-
tion of GSTA1-1 by thiacalix[4]arene phosphinic acid 1b.
In addition, the Phe222 of α-helix and Val111 from domain
II which form a hydrophobic wall for the binding site and
can contribute structurally to the formation of a higher
affinity non-substrate site in the V-shaped cleft [50],
showed interaction with two phosphinic acid fragments.
Conclusions
In summary, the inhibitory potential of calix[4]arene,
thiacalix[4]arene, and sulfonilcalix[4]arene derivatives
modified with phosphinic acid groups against alpha and pi
class of GSTs were evaluated. The inhibition efficiency of
the phosphinic acids was found to depend on the nature of
the macrocyclic scaffold. The thiacalix[4]arene-based
phosphinic acid 1b exhibited the highest activity as a
nanomolar non-competitive inhibitor of GST from the
equine liver and human GSTA1-1. The molecular docking
results suggested that thiacalix[4]arene inhibitors can bind
to L-site located at the intersubunit interface of GSTA1-1.
The obtained data provide a basis for further development
of thiacalix[4]arene derivatives as inhibitors of GSTs.
Experimental section
3.1. Synthesis of calix[4]arene derivatives 1a-b
The calix[4]arene phosphinic acid 1a and its
thiacalix[4]arene analogues 1b and 1c were synthesized as
described previously [36], starting from tetrachloro-
methylcalix[4]arene or tetrachloromethylthiacalix[4]arene
followed by Arbuzov reaction, dealkylation of the isopropyl
esters with trimethylbromosilane and metanalysis of the
silyl ester intermediates. Sulfonylcalix[4]arene isopropyl
ester derivative was obtained by oxidation of sulfur atoms
in the corresponding thiacalix[4]arene intermediate.
3.2. In vitro studies of GSTs inhibition by calix[4]arene-,
thiacalix[4]arene- and sulfonylcalix[4]arene-based phos-
phinic acids
The GST-EL and GST-HP as well as recombinant
GSTA1-1 and GSTP1-1 were purchased from Sigma-
Aldrich. Before use in the experiment, GSTs from the
equine liver and GST from the human placenta were diluted
in water (0.25 mg/ml) whereas GSTA1-1 and GSTP1-1
were diluted in 50 mM Tris-HCl buffer (pH 7.5), 50 mM
NaCl, 1 mM DTT, 5 mM EDTA and 50 % glycerol (25 µL
of purchased enzyme solution in 1 ml of storage buffer).
The calix[4]arene derivatives were dissolved in pure
DMSO. An in vitro model system for testing compounds
1a-b consisted of 0.1 M sodium phosphate buffer (pH 6.5),
0.1 mM EDTA, 2.5 vol. % DMSO, water, 20 μl of enzyme
solution, and inhibitor. This mixture was incubated for 5
min at 25 °C and then the reaction was started by the
addition of 1 mM L-glutathione and 1 mM 1-chloro-2,4-
dinitrobenzene. The enzyme activity was monitored
spectrophotometrically by an accumulation of glutathione
conjugate, which has an absorption maximum at 340 nm.
The spectral data were recalculated using a molar extinction
coefficient of dinitrophenyl S-glutathione of 9600 M-1cm-1
[51].
3.3. Molecular docking modeling
The file of PDB crystal of human GSTA1-1 (PDB code:
6ATO) was downloaded from the server RCSB Protein
Data Bank (RCSB PDB, https://www.rcsb.org) [52]. The
molecules of (4S)-2-methyl-2,4-pentanediol and water were
removed from the file before blind docking calculations
ISSN 1814-9758. Ukr. Bioorg. Acta, 2022, Vol. 17, N 1
90
which were carried out by the program AutoDock Vina
[53]. The pdbqt file of the enzyme was prepared by the
program AutoDockTools (version 1.5.6) [54]. The
configuration file for AutoDock Vina program included
parameters that involved the whole surface of the
homodimeric structure in docking calculations.
The four conformers of thiacalix[4]aren phosphinic acid
1b, which are cone, partial cone, 1,2-alternate, and
1,3-alternate, which were prepared and optimized in
MMFF94s force field by the Avogadro program [55].
Further conformers optimization process was conducted
using AM1 semi-empirical quantum mechanical method in
program MOPAC2016 [56]. The resulting files were saved
in pdbqt format with the following re-saving using
AutoDockTools software [54] and only then used for
calculations. Discovery Studio 3.5 visualizer (Accelrys
Software Inc., San Diego, CA, USA) was used for binding
mode analysis.
Notes
Acknowledgments. This work was supported by the
National Research Foundation of Ukraine (grant
2020.02/0031).
The authors declare no conflict of interest.
Author contributions. O. L. K.: conceptualization,
supervision, molecular docking simulation, writing-original
draft. Y. V. S.: investigation of bioactivity. V. M. B.:
investigation of bioactivity. A. B. D.: synthesis of
compounds, investigation, analysis. V. I. K.: supervision,
writing-review, and editing. A. I. V.: conceptualization,
supervision, writing-review, and editing.
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Інгібування глутатіон-S-трансфераз калікс[4]аренфосфіновими кислотами
О. Л. Кобзар1, Ю. В. Шульга1, В. М. Булденко1, А. Б. Драпайло2, В. І. Кальченко2, А. І. Вовк1*
1 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094, Україна
2 Інститут органічної хімії НАН України, вул. Мурманська, 5, Київ, 02094, Україна
Резюме: Похідні калікс[4]арену, тіакалікс[4]арену і сульфонілкалікс[4]арену, що містять залишки фосфінової кислоти на верхньому вінці
макроциклічної платформи, були оцінені як інгібітори глутатіон-S-трансфераз. Встановлено, що сполуки 1a-c є мікромолярними і
субмікромолярними інгібіторами GST з печінки коня і рекомбінантної людської GSTA1-1 із селективністю cтосовно ензиму з плаценти людини
та GSTP1-1. Найкращим інгібітором GST з печінки коня і GSTA1-1 зі значеннями IC50 85 нМ та 50 нМ, відповідно, виявилась
тіакалікс[4]аренфосфінова кислота 1b. Кінетичні дослідження продемонстрували неконкурентний тип інгібування GST з печінки коня стосовно
обох субстратів, глутатіону і 1-хлор-2,4-динітробензолу. На основі результатів розрахунків методом молекулярного докінгу запропоновано
можливий сайт зв’язування інгібітора на поверхні гомодимерної GSTA1-1.
Ключові слова: фосфінові кислоти; калікс[4]арен; тіакалікс[4]арен; сульфонілкалікс[4]арен; глутатіон-S-трансфераза; інгібування; молекулярний
докінг.
Notes
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| id | oai:ojs2.bioorganica.com.ua:article-16 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:28Z |
| publishDate | 2022 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/08/748eefbd74232f31a6a182e6ffdfe308.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-162026-07-19T14:56:53Z Inhibition of glutathione S-transferases by calix[4]arene-based phosphinic acids Інгібування глутатіон-S-трансфераз калікс[4]аренфосфіновими кислотами Kobzar, Oleksandr L. Shulha, Yuriy V. Buldenko, Vladyslav M. Drapailo, Andriy B. Kalchenko, Vitaly I. Vovk, Andriy I. phosphinic acid calix[4]arene thiacalix[4]arene sulfonylcalix[4]arene glutathione S-transferase inhibition molecular docking фосфінові кислоти калікс[4]арен тіакалікс[4]арен сульфонілкалікс[4]арен глутатіон-S-трансфераза інгібування молекулярний докінг Calix[4]arene-, thiacalix[4]arene- and sulfonylcalix[4]arene-based derivatives with upper rim phosphinic acid groups were studied as inhibitors of glutathione S-transferases. It was found that the macrocyclic compounds can exhibit good to potent activity against GST from equine liver and human recombinant GSTA1-1, while being selective over the enzyme from human placenta and GSTP1-1. The thiacalix[4]arene phosphinic acid was the most active inhibitor of equine liver GST and GSTA1-1 with IC50 values of 85 nM and 50 nM, respectively. Kinetic studies revealed that the inhibition was of non-competitive type concerning both enzyme substrates, glutathione, and 1-chloro-2,4-dinitrobenzene. Molecular docking was carried out to predict possible binding sites for thiacalix[4]arene-based phosphinic acid on the surface of homodimeric GSTA1-1. Похідні калікс[4]арену, тіакалікс[4]арену і сульфонілкалікс[4]арену, що містять залишки фосфінової кислоти на верхньому вінці макроциклічної платформи, були оцінені як інгібітори глутатіон-S-трансфераз. Встановлено, що сполуки 1a-c є мікромолярними і субмікромолярними інгібіторами GST з печінки коня і рекомбінантної людської GSTA1-1 із селективністю cтосовно ензиму з плаценти людини та GSTP1-1. Найкращим інгібітором GST з печінки коня і GSTA1-1 зі значеннями IC50 85 нМ та 50 нМ, відповідно, виявилась тіакалікс[4]аренфосфінова кислота 1b. Кінетичні дослідження продемонстрували неконкурентний тип інгібування GST з печінки коня стосовно обох субстратів, глутатіону і 1-хлор-2,4-динітробензолу. На основі результатів розрахунків методом молекулярного докінгу запропоновано можливий сайт зв’язування інгібітора на поверхні гомодимерної GSTA1-1. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2022-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/16 10.15407/bioorganica2022.01.086 Ukrainica Bioorganica Acta; Vol. 17 No. 1 (2022): Ukrainica Bioorganica Acta; 86-91 Ukrainica Bioorganica Acta; Том 17 № 1 (2022): Ukrainica Bioorganica Acta; 86-91 1814-9766 1814-9758 10.15407/bioorganica2022.01 en https://bioorganica.com.ua/index.php/journal/article/view/16/20 Copyright (c) 2022 Oleksandr L. Kobzar, Yuriy V. Shulha, Vladyslav M. Buldenko, Andriy B. Drapailo, Vitaly I. Kalchenko, Andriy I. Vovk https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | фосфінові кислоти калікс[4]арен тіакалікс[4]арен сульфонілкалікс[4]арен глутатіон-S-трансфераза інгібування молекулярний докінг Kobzar, Oleksandr L. Shulha, Yuriy V. Buldenko, Vladyslav M. Drapailo, Andriy B. Kalchenko, Vitaly I. Vovk, Andriy I. Інгібування глутатіон-S-трансфераз калікс[4]аренфосфіновими кислотами |
| title | Інгібування глутатіон-S-трансфераз калікс[4]аренфосфіновими кислотами |
| title_alt | Inhibition of glutathione S-transferases by calix[4]arene-based phosphinic acids |
| title_full | Інгібування глутатіон-S-трансфераз калікс[4]аренфосфіновими кислотами |
| title_fullStr | Інгібування глутатіон-S-трансфераз калікс[4]аренфосфіновими кислотами |
| title_full_unstemmed | Інгібування глутатіон-S-трансфераз калікс[4]аренфосфіновими кислотами |
| title_short | Інгібування глутатіон-S-трансфераз калікс[4]аренфосфіновими кислотами |
| title_sort | інгібування глутатіон-s-трансфераз калікс[4]аренфосфіновими кислотами |
| topic | фосфінові кислоти калікс[4]арен тіакалікс[4]арен сульфонілкалікс[4]арен глутатіон-S-трансфераза інгібування молекулярний докінг |
| topic_facet | phosphinic acid calix[4]arene thiacalix[4]arene sulfonylcalix[4]arene glutathione S-transferase inhibition molecular docking фосфінові кислоти калікс[4]арен тіакалікс[4]арен сульфонілкалікс[4]арен глутатіон-S-трансфераза інгібування молекулярний докінг |
| url | https://bioorganica.com.ua/index.php/journal/article/view/16 |
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