Синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів протеїнтирозинфосфатаз та глутатіон-S-трансфераз
Thiazole-containing derivatives of rhodanine-3-alkanoic acids with propanoic or undecanoic acid groups were synthesized and evaluated as inhibitors of some protein tyrosine phosphatases and glutathione S-transferases. The rhodanines bearing longer carboxylated N-alkyl chain were found to inhibit PTP...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2020
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Ukrainica Bioorganica Acta| _version_ | 1871193575676444672 |
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| author | Kobzar, Oleksandr L. Sinenko, Vitaliy O. Shulha, Yuriy V. Buldenko, Vladyslav M. Hodyna, Diana M. Pilyo, Stepan G. Brovarets, Volodymyr S. Vovk, Andriy I. |
| author_facet | Kobzar, Oleksandr L. Sinenko, Vitaliy O. Shulha, Yuriy V. Buldenko, Vladyslav M. Hodyna, Diana M. Pilyo, Stepan G. Brovarets, Volodymyr S. 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": "Vitaliy O. Sinenko",
"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": "Diana M. Hodyna",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Stepan G. Pilyo",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Volodymyr S. Brovarets",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 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 | Thiazole-containing derivatives of rhodanine-3-alkanoic acids with propanoic or undecanoic acid groups were synthesized and evaluated as inhibitors of some protein tyrosine phosphatases and glutathione S-transferases. The rhodanines bearing longer carboxylated N-alkyl chain were found to inhibit PTP1B, MEG1, MEG2, and VE-PTP as well as GST from equine liver and GSTA1-1 with IC50 values in the low micromolar range. The inhibitory effect on protein tyrosine phosphatase activity depends on substituent at position 2 of the thiazole ring. The best compound showed a competitive type of VE-PTP inhibition. In case of GST from equine liver, the inhibition was of mixed or non-competitive type with respect to glutathione or CDNB substrate, respectively. Possible binding modes of the inhibitors were discussed based on molecular docking calculations |
| doi_str_mv | 10.15407/bioorganica2020.02.033 |
| first_indexed | 2025-07-17T12:19:40Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
UDC 547.789+577.152.2/.3
DOI: https://doi.org/10.15407/bioorganica2020.02.033
33
RESEARCH ARTICLE
Synthesis and evaluation of new thiazole-containing
rhodanine-3-alkanoic acids as inhibitors of protein tyrosine
phosphatases and glutathione S-transferases
Oleksandr L. Kobzar, Vitaliy O. Sinenko, Yuriy V. Shulha, Vladyslav M. Buldenko,
Diana M. Hodyna, Stepan G. Pilyo, Volodymyr S. Brovarets and Andriy I. Vovk*
V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
Abstract: Thiazole-containing derivatives of rhodanine-3-alkanoic acids with propanoic or undecanoic acid groups were synthesized and
evaluated as inhibitors of some protein tyrosine phosphatases and glutathione S-transferases. The rhodanines bearing longer carboxylated
N-alkyl chain were found to inhibit PTP1B, MEG1, MEG2, and VE-PTP as well as GST from equine liver and GSTA1-1 with IC50 values
in the low micromolar range. The inhibitory effect on protein tyrosine phosphatase activity depends on substituent at position 2 of the
thiazole ring. The best compound showed a competitive type of VE-PTP inhibition. In case of GST from equine liver, the inhibition was of
mixed or non-competitive type with respect to glutathione or CDNB substrate, respectively. Possible binding modes of the inhibitors were
discussed based on molecular docking calculations.
Keywords: rhodanine; thiazole; protein tyrosine phosphatase, glutathione S-transferase; enzyme inhibition; molecular docking.
Introduction
Thiazole derivatives represent a number of natural and
synthetic biologically active compounds with anticancer
[1], antibacterial [2], and antiviral activities [3]. Many of
rhodanine-based compounds turned out to have low
toxicity, exhibit antidiabetic, anti-inflammatory, anti-
Alzheimer's, anticancer, antibacterial, antifungal, and
antiviral activities [4]. The best known anti-hyperglycemic,
hypoglycemic and hypolipidemic effects of rhodanine
derivatives are based on their agonist activity against
PPARs and FFAR1 receptors, as well as inhibition of
ALR2, PTP1B, and α-glucosidase [5]. Anticancer activity
of the compounds can be attributed to the inhibition
capacity against pan-PIM kinases [6-7], protooncogene
transcription factor c-Myc [8-9], protein disulfide isomerase
(PDI) [10], histone acetyltransferases [11], topoisomera-
Received:
Revised:
Accepted:
Published online:
22.10.2020
29.10.2020
05.11.2020
30.12.2020
Corresponding author. Tel.: +380-44-558-5388;
e-mail: vovk@bpci.kiev.ua (A. I. Vovk)
ORCID: 0000-0001-6167-076X
se II [11], as well as Bcl-XL and Mcl-1 families of the
proteins [13]. Antibacterial effects of rhodanine derivatives
can be realized via inhibition of bacterial penicillin-binding
proteins [14] and β-lactamases [15-16].
The protein tyrosine dephosphorylation is a fundamental
regulatory mechanism of many signal transduction
pathways in processes of growth, proliferation,
differentiation, or survival of eukaryotic cells. It was shown
that elevated activity of classical non-receptor and receptor-
like protein tyrosine phosphatases (PTPs) coincides with a
number of pathologies [17-18]. PTP1B, being a negative
regulator of insulin and leptin signaling is considered as a
promising therapeutic target for treatment of type 2 diabetes
and obesity [19]. Overexpression of this phosphatase was
also found to contribute to tumorigenesis of cells [20-21].
Megakaryocyte protein tyrosine phosphatase MEG-2 which
involved in regulating of hematopoietic signaling and blood
glucose homeostasis is of interest as a therapeutic target for
treatment of type 2 diabetes and myeloproliferative
disorders [23-25]. PTPβ, also called as vascular endothelial-
protein tyrosine phosphatase (VE-PTP), downregulates Tie2
signaling and often associated with development of variety
endothelial dysfunctions. In this connection, a number of
chemical compounds were developed as inhibitors of the
protein tyrosine phosphatases.
© 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.
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
mailto:vovk@bpci.kiev.ua
https://orcid.org/0000-0001-6167-076X
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
34
Among them, aryl and hetaryl compounds [26],
including derivatives of rhodanine [27-29] and its closely
related analog, thiazolidinedione [30-31], were studied as
PTPs inhibitors. Compounds bearing carboxylic [32],
phosphonic [33-34], sulfonic groups [35] were designed as
pTyr mimetics for inhibition of PTP1B. As a drug for
treatment of diabetic macular edema, diabetic retinopathy,
and ocular hypertension, the inhibitor of VE-PTP
AKB-9778/Razuprotafib was developed [36-38].
It was reported previously that thiazolyl-2,4-
thiazolidinedione/rhodanine compounds possess anticancer
activities against hepatocellular carcinoma cell lines having
resistance to chemotherapeutic agents [39]. The drug
resistance caused by drug-metabolizing enzymes is
considered a serious problem in treatment of cancer
diseases [40]. Glutathione S-transferases (GSTs) comprise a
superfamily of multifunctional phase II detoxification
enzymes catalyzing the conjugation of glutathione (GSH)
with a variety of exogenous and endogenous xenobiotics.
The glutathione conjugates having less cytotoxicity and
greater hydrophilicity excreted from the cells via the
mercapturic acid pathway [41]. Overexpression of GSTs
was noticed in a number of tumor cases [42-44].
Chemotherapeutic alkylating agents such as busulfan,
melphalan, chlorambucil, brostallicin, and
immunosuppressant azathioprine described as the substrates
of these enzymes. Therefore, many compounds including
analogs of glutathione and its conjugates as well as
derivatives of benzoquinone, benzophenone,
nitrobenzoxadiazole, and curcumin were designed as
inhibitors of GSTs [41-44].
Previously, a series of rhodanine-3-alkanoic acid
derivatives were described as potential inhibitors of protein
tyrosine phosphatase [45]. In the current study, we report
synthesis of thiazole-containing rhodanine-3-alkanoic acids
and their in vitro evaluation as inhibitors of PTPs and
GSTs.
Results and discussion
Synthesis of 5-(thiazol-5-ylmethylene)-2-thioxothiazo-
lidin-4-one derivative
The synthesis of thiazole-containing rhodanine-3-
carboxyalkyl acids 3a-f is outlined in Scheme 1. The
compounds were obtained by Knoevenagel condensation of
corresponding rhodanines with aldehydes. Ethanol solution
containing a proper 1,3-thiazolecarbaldehyde (compounds
1a-c), N-alkyl carboxylated rhodanine (compounds 2a, b),
and 2-aminoethanol was heated for 3h. The obtained
precipitate was filtered off and recrystallized from ethanol
[46]. The compounds were obtained in moderate to good
yield and were characterized by 1H NMR, 13C NMR and
mass spectra. The data of NMR spectra showed that the
newly synthesized compounds are represented by one of
two Z/E isomeric forms. It should be noted that similar
thiazole-contained rhodanine derivatives were described as
Z-isomers [39].
Biological evaluation of thiazole-containing rhodani-
ne-3-alkanoic acids as inhibitors of protein tyrosine phos-
phatases and glutathione S-transferases
Human recombinant protein tyrosine phosphatases
PTP1B, VE-PTP, MEG1, and MEG2 were used for in vitro
assays of the synthesized thiazole-containing rhodanine-3-
carboxyalkyl acids 3a-f. Values of the half maximal
inhibitory concentrations (IC50) for the compounds are
presented in Table 1.
As can be seen from Table 1, rhodanine derivatives 3a-c
containing shorter alkyl carboxylated group were less
effective inhibitors of PTPs than derivatives 3d-f bearing
longer N-alkyl chain. Compound 3a, which possesses
butyric acid fragment in N-3 position of rhodanine scaffold
and phenyl substituent at C-2 position of 1,3-thiazol-5-
ylmethylene moiety, was found to be a weak inhibitor of
Scheme 1. Synthesis of thiazole-containing rhodanine-3-alkanoic acids.
O. L. Kobzar, V. O.Sinenko, Y. V. Shulga et al.
35
Table 1. IC50 values of thiazole-containing rhodanine derivatives 3a-f as inhibitors of protein tyrosine phosphatases*
Compd
IC50, µM
PTP1B MEG1 MEG2 VE-PTP
3a > 25 > 25 > 25 > 25
3b 17.0 ± 4.4 >25 18.7±3.2 > 25
3c > 25 > 25 > 25 > 25
3d 4.1 ± 1.2 23.1 ± 3.9 2.4 ± 0.4 2.4 ± 0.7
3e 0.82 ± 0.17 12.4 ± 3.5 0.54 ± 0.12 0.43 ± 0.07
3f 2.5 ± 0.6 11.0 ± 1.4 2.4 ± 0.5 3.1 ± 0.6
*IC50 values represent the mean of 2–3 assays ± standard deviation.
PTPs. The introduction of a chlorine substituent into the
para-position of phenyl group of this rhodanine derivative
slightly increases inhibitory effects of compound 3b against
PTP1B and MEG2. However, the replacement of
4-chlorophenyl residue by dimethylamino one, as well as
introduction of phenyl group at C-4 position of 1,3-thiazol-
5-ylmethylene moiety (compound 3c) caused a decrease in
inhibitory effects. The rhodanine derivative 3d bearing
undecanoic acid fragment at position N-3 showed
significant increase in inhibition of PTP1B, VE-PTP, and
MEG2 as compared to structure of compound 3a with
butyric acid fragment. Similarly to the effects obtained for
rhodanine derivative 3b, the introduction of chlorine atom
in the para-position of phenyl group of 1,3-thiazol-5-
ylmethylene moiety of compound 3d led to increased
inhibitory potential of rhodanine derivative 3e. IC50 values
of this compound were 0.82 µM, 0.54, and 0.43 µM µM for
PTP1B, MEG2, and VE-PTP, respectively.
Kinetic studies were carried out to elucidate the possible
mechanism of protein tyrosine phosphatases inhibition by
the thiazole-containing rhodanine derivatives. According to
Lineweaver-Burk plots (Figure 1), compound 3e is a
competitive-type inhibitor of protein tyrosine phosphatase
VE-PTP with the calculated value of inhibition constant Ki
of 0.20 µM.
Figure 1. Lineweaver-Burk plots for inhibition of VE-PTP by
compound 3e. The inhibitor concentrations were 0 (○) and
0.5 µM (□).
Figure 2. Possible binding modes of rhodanine derivative 3e to human recombinant VE-PTP with open (A) and closed (B) conformations.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
36
Molecular docking was performed to predict possible
binding mode of carboxylated rhodanine derivative with
PTPs. Synthetic studies described 5-ene-rhodanines mainly
as Z-isomeres [4, 39]. In this connection, Z-isomer of
compound 3e was chosen to be docked into the active site
region of the open and closed conformations of human
VE-PTP. The estimated affinity of carboxylated rhodanine
derivative 3e to the active site of VE-PTP in open
conformation was found to be -5.9 kcal/mol. The rhodanine
scaffold of the inhibitor formed hydrogen bonds with amino
acids residues of Lys1811 and Arg1910. The carboxylic
group of the alkyl chain occupies active site near catalytic
Cys1904 forming hydrogen bonds with amino acid residues
Ala1906, Gly1906, Val1908, and Gly1909, while thiazole
ring provided π-stacking interaction with Tyr1733 (Figure
2A).
In case of closed enzyme conformation, the estimated
binding energy was -6.4 kcal/mol. The obtained model
indicates that compound may be oriented into the active site
of VE-PTP by carboxylic group of alkyl chain. This
fragment form hydrogen bonds with amino acid residues
Ser1905, Ala1906, and Arg1910. The thiazole ring of
compound 3e is involved in hydrogen bond formation with
Gln1948 and π-cation interaction with His1945. The
2-chlorophenyl group forms π-cation interactions with
Lys1711 and Arg1940 as well as halogen bond of chlorine
atom with Arg1940 (Figure 2B).
The thiazole-containing rhodanine-3-carboxyalkyl acids
were studied as inhibitors of GST from equine liver and
human recombinant GSTA1-1. The obtained results
(Table 2) demonstrated that compounds 3d-f were more
potent inhibitors in comparison with derivatives 3a-c
bearing butyric acid fragment at N-3 position of rhodanine
scaffold. Better inhibition effects against GST from equine
liver were observed in the case of compounds 3d-f modified
at N-3 position of rhodanine ring with undecanoic acid
group. Further studies showed that these compounds can
also inhibit the recombinant form of human GSTA1-1 with
IC50 values in the low micromolar range.
Table 2. Inhibition activity of 5-(thiazol-5-ylmethylene)-2-
thioxothiazolidin-4-one derivatives 3a-f against GST from
equine liver and human recombinant GSTA1-1*.
Compd
IC50, µM
GST from equine liver GSTA1-1
3a > 25 -
3b 24.1 ± 2.7 -
3c > 25 -
3d 5.2 ± 1.4 1.1 ± 0.2
3e 4.5 ± 0.5 0.83 ± 0.22
3f 6.2 ± 0.9 2.7 ± 0.7
*IC50 values are the means of 2-3 assays ± standard deviation.
Lineweaver-Burk plots (Figure 3) showed mixed-type or
non-competitive inhibition of GST from equine liver by
compound 3d toward glutathione or CDNB substrate.
According to the mixed-type inhibition, the calculated
values of inhibition constants Ki and Ki' were 12.9±3.7 µM
and 20.2±5.8 µM, respectively, while the non-competitive
inhibition constant Ki was 6.8±1.8 µM.
The results of computer modeling suggest that Z-isomer
of rhodanine derivative 3d may occupy interdomain cavity
near active site of human GSTA1-1 (Figure 4A) with the
calculated docking energy of -9.3 kcal/mol. Deregulation of
the interdomain contacts in structure of GSTA1-1 was
shown to lead to disruption of the enzyme catalytic
functions [47] which may explain the inhibition of the
enzyme. The compound position (Figure 4B) is
characterized by interaction of the inhibitor with
hydrophobic amino acid residues Thr68, Leu72, Ile96,
Ile99, Ala100, Ile106, Leu107, and Leu163. Thiazole ring
at C-5 position of rhodanine scaffold formed π-stacking
interaction with Tyr166, while phenyl fragment at C-2
position of the thiazole ring provided π-cation interaction
with Arg13. Hydrogen bond was observed between oxygen
atom of rhodanine scaffold and Ser18. Carboxylate group of
the inhibitor is adjacent to the active G-site and provides
Figure 3. Lineweaver-Burk plots for inhibition of GST from equine liver by compound 3d. The inhibitor concentrations were 0 (○),
5 µM (∆) and 7.5 µM (□).
O. L. Kobzar, V. O.Sinenko, Y. V. Shulga et al.
37
Figure 4. Possible binding mode of rhodanine derivative 3d to homodimer structure of human GSTA1-1.
hydrogen bonds with amino acid residues Arg69 and Arg15
which is involved in interaction with GSH.
Conclusions
The study reported synthesis of new rhodanine-3-
alkanoic acids with propanoic or undecanoic acid groups.
The data obtained showed that compounds 3d-f bearing
undecanoic acid group at N-3 position of rhodanine scaffold
possess good inhibitory effects against PTP1B, MEG1,
MEG2, and VE-PTP as well as GSTA1-1. According to
kinetic data, thiazole-containing rhodanines can be
competitive-type inhibitors of VE-PTP. In case of GST
from equine liver, the compounds can be considered as
mixed-type inhibitors toward GSH and non-competitive
toward CDNB substrate. Molecular docking results indicate
that the inhibitors may occupy VE-PTP active site, while
inhibition of GSTA1-1 might be explained by the location
of rhodanine derivative between C- and N-terminal subunits
of the enzyme.
Experimental section
Chemistry
1H (500 MHz) and 13C (125 MHz) NMR spectra were
recorded on Bruker Avance DRX 500 spectrometer in
DMSO-d6 solution. IR spectra were recorded on a Vertex
70 spectrometer from KBr pellets. Melting points were
measured with a Büchi melting point apparatus and are
uncorrected. LC-MS spectra were obtained using HPLC
apparatus, Agilent 1100 Series, equipped with diode-matrix
and mass-selective detector Agilent LC/MSD SL.
General procedure for synthesis of compounds 3a-f
A solution of 0.002 mol of rhodanine derivative 2a or 2b
in 5 mL of ethanol and 0.02 mL of 2-aminoethanol were
added to a solution of 0.002 mol of corresponding aldehyde
(1a-c) in 5 mL of ethanol. The mixture was refluxed for 3 h
and cooled. The precipitate was filtered off and
recrystallized from EtOH.
4-{4-Oxo-5-[(2-phenyl-1,3-thiazol-5-yl)methylidene]-2-
sulfanylidene-1,3-thiazolidin-3-yl}butanoic acid (3a).
Yield: 0.531 g (68%); yelow crystals; mp 190-191 °C.
1H NMR (500 MHz, DMSO-d6) δ 12.11 (br s, 1H, COOH),
8.48 (s, 1H, CH), 8.12 (s, 1H, C4-Hthiazol), 8.03 (d, J 7.7 Hz,
2H, Ph), 7.49-7.59 (m, 3H, Ph), 4.06 (t, J 6.8 Hz, 2H, CH2),
2.30 (t, J 7.2 Hz, 2H, CH2), 1.84-1.95 (m, 2H, CH2).
13C NMR (125 MHz, DMSO-d6) δ 192.5, 174.1, 172.8,
166.8, 151.2, 133.7, 132.6, 132.0, 129.9, 127.1, 123.7,
123.2, 44.4, 31.4, 22.4. LC/MS (CI) m/z 391 (M)+. Anal.
Calcd. for C17H14N2O3S3: C, 52.29; H, 3.61; N, 7.17; S,
24.63. Found: C, 52.35; H, 3.60; N, 7.10; S, 24.64.
4-(5-{[2-(4-Chlorophenyl)-1,3-thiazol-5-yl]methylide-
ne}-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl)butanoic
acid (3b).
Yield: 0.484 g (57%); yelow crystals; mp 201-202 °C.
1H NMR (500 MHz, DMSO-d6) δ 12.12 (br s, 1H, COOH),
8.47 (s, 1H, CH), 8.10 (s, 1H, C4-Hthiazol), 8.02 (d, J 8.5 Hz,
2H, C6H4-p-Cl), 7.56 (d, J 8.5 Hz, 2H, C6H4-p-Cl), 4.05 (t,
J 6.8 Hz, 2H, CH2), 2.31 (t, J 7.1 Hz, 2H, CH2), 1.83-1.93
(m, 2H, CH2). 13C NMR (125 MHz, DMSO-d6) δ 190.2,
171.9, 169.0, 164.6, 148.9, 134.4, 131.8, 129.2, 127.7,
126.5, 121.7, 120.8, 42.2, 29.2, 20.1. LC/MS (CI) m/z 426
(M)+. Anal. Calcd. for C17H13ClN2O3S3: C, 48.05; H, 3.08;
N, 6.59; S, 22.64. Found: C, 48.14; H, 3.04; N, 6.53;
S, 22.54.
4-(5-{[2-(Dimethylamino)-4-phenyl-1,3-thiazol-5-yl]
methylidene}-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-
yl)butanoic acid (3c).
Yield: 0.702 g (81%); yelow crystals; mp 179-180 °C.
1H NMR (500 MHz, DMSO-d6) δ 7.63 (s, 1H, CH), 7.50-
7.62 (m, 5H, Ph), 3.98 (t, J 6.5 Hz, 2H, CH2), 3.20 (s, 6H,
N(CH3)2), 2.16 (t, J 7.2 Hz, 2H, CH2), 1.74-1.87 (m, 2H,
CH2). 13C NMR (125 MHz, DMSO-d6) δ 191.2, 174.2,
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
38
172.2, 166.4, 161.8, 133.6, 129.7, 129.4, 128.7, 125.4,
116.9, 113.8, 44.0, 41.7, 32.0, 22.5. LC/MS (CI) m/z 434
(M)+. Anal. Calcd. for C19H19N3O3S3: C, 52.64; H, 4.42;
N, 9.69; S, 22.19. Found: C, 52.68; H, 4.39; N, 9.68; S,
22.12.
11-{4-Oxo-5-[(2-phenyl-1,3-thiazol-5-yl)methylidene]-2-
sulfanylidene-1,3-thiazolidin-3-yl}undecanoic acid (3d).
Yield: 0.733 g (75%); yelow crystals; mp 141-142 °C.
1H NMR (500 MHz, DMSO-d6) δ 8.43 (s, 1H, CH), 8.07 (s,
1H, C4-Hthiazol), 7.99 (d, J 8.1 Hz, 2H, Ph), 7.46-7.56 (m,
3H, Ph), 3.94 (t, J 7.3 Hz, 2H, CH2), 2.16 (t, J 7.4 Hz,
2H, CH2), 1.54-1.64 (m, 2H, CH2), 1.41-1.51 (m, 2H,
CH2), 1.16-1.29 (m, 12H, (CH2)6). 13C NMR (125 MHz,
DMSO-d6) δ 192.1, 174.9, 172.8, 166.6, 151.3, 133.6,
132.6, 132.0, 129.8, 127.1, 123.5, 123.4, 44.9, 34.1, 29.3,
29.3, 29.2, 29.0, 29.0, 26.7, 26.6, 25.0. LC/MS (CI) m/z 489
(M)+. Anal. Calcd. for C24H28N2O3S3: C, 58.99; H, 5.78;
N, 5.73; S, 19.68. Found: C, 59.10; H, 5.73; N, 5.70;
S, 19.69.
11-(5-{[2-(4-Chlorophenyl)-1, 3-thiazol-5-yl]methylide-
ne}-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl)undecanoic
acid (3e).
Yield: 0.764 g (73%); yelow crystals; mp 173-174 °C.
1H NMR (500 MHz, DMSO-d6) δ 11.76 (br s, 1H, COOH),
8.41 (s, 1H, CH), 8.06 (s, 1H, C4-Hthiazol), 7.99 (d, J 7.7 Hz,
2H, C6H4-p-Cl), 7.54 (d, J 7.7 Hz, 2H, C6H4-p-Cl), 3.94-
4.00 (m, 2H, CH2), 2.16 (t, J 7.4 Hz, 2H, CH2), 1.58-1.65
(m, 2H, CH2), 1.44-1.51 (m, 2H, CH2), 1.19-1.30 (m, 12H,
(CH2)6). 13C NMR (125 MHz, DMSO-d6) δ 189.8, 172.4,
169.1, 164.4, 148.9, 134.4, 131.8, 129.3, 127.7, 126.5,
121.7, 120.9, 42.7, 31.9, 27.0, 26.9, 26.9, 26.7, 26.7, 24.4,
24.3, 22.7. LC/MS (CI) m/z 524 (M)+. Anal. Calcd. for
C24H27ClN2O3S3: C, 55.10; H, 5.20; N, 5.35; S, 18.39.
Found: C, 55.14; H, 5.15; N, 5.32; S, 18.37.
11-(5-{[2-(Dimethylamino)-4-phenyl-1,3-thiazol-5-yl]-
methylidene}-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-
yl)undecanoic acid (3f).
Yield: 0.744 g (70%); yelow crystals; mp 114-115 °C.
1H NMR (500 MHz, DMSO-d6) δ 7.67 (s, 1H, CH), 7.47-
7.63 (m, 5H, Ph), 3.89-3.99 (m, 2H, CH2), 3.21 (s, 6H,
N(CH3)2), 2.15 (t, J 6.6 Hz, 2H, CH2), 1.54-1.62 (m, 2H,
CH2), 1.42-1.50 (m, 2H, CH2), 1.16-1.29 (m, 12H, (CH2)6).
13C NMR (125 MHz, DMSO-d6) δ 189.3, 172.5, 170.5,
164.5, 160.0, 131.9, 127.6, 126.9, 123.7, 123.6, 115.1,
112.0, 42.5, 32.0, 26.9, 26.9, 26.8, 26.8, 26.7, 26.6, 24.5,
24.3, 22.8. LC/MS (CI) m/z 532 (M)+. Anal. Calcd. for
C26H33N3O3S3: C, 58.73; H, 6.26; N, 7.90; S, 18.09. Found:
C, 58.79; H, 6.26; N, 7.84; S, 18.03.
Biological tests
In vitro study of thiazole-containing rhodanine-3-
alkanoic acid derivatives as inhibitors of protein tyrosine
phosphatases and glutathione S-transferases
Protein tyrosine phosphatases were purchased in Sigma-
Aldrich. Prior to experiments, the defined volume of
PTP1B, VE-PTP, MEG1 and MEG2 were diluted in a
solution of 50 mM Bis-Tris buffer (pH 7.2) containing 30%
glycerol, 3 mM EDTA, 2 mM DTT, 75 mM NaCl, and
0.05% Tween-20. The system for inhibition study consisted
of 50 mM Bis-Tris buffer (pH 7.2), 100 mM NaCl, 3 mM
EDTA, 1 mM DTT, 1 vol. % DMSO, inhibitor and enzyme.
The mixture was thermostated at 30 ºC during 5 min and
reaction was started by adding the substrate (pNPP) at
concentration near Km value for each of the enzymes. The
activity of enzymes was measured spectrophotometrically at
410 nm. The molar extinction coefficient of 18300 M-1cm-1
was used for calculation of p-nitrophenol concentration.
GST from equine liver and human recombinant
GSTA1-1 was purchased from Sigma-Aldrich. Before use
in the experiments, 0.25 mg of GST from equine liver was
diluted in 1 ml of distillated water, and 25 µL of GSTA1-1
was diluted in 1 ml of solution consisted of 50 mM
Tris-HCl buffer (ph 7.5), 50 mM NaCl, 1 mM DTT, 5 mM
EDTA and 50 vol. % glycerol. The rhodanine derivatives
were dissolved in DMSO. In vitro studies were carried out
in system consisting 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. After incubation of this
mixture at 25 ºC during 5 min, the reaction was started by
addition 200 µL of 10 mM reduced L-glutathione (GSH)
and 20 µL of 100 mM 1-chloro-2,4-dinitrobenzene
(CDNB). The enzyme activity was monitored
spectrophotometrically at 340 nm. The molar extinction
coefficient of 9600 M-1cm-1 was used for calculation of
dinitrophenyl-S-glutathione concentration [48].
Molecular docking calculation
Crystal structures of open and closed conformation of
VE-PTP (PDB code 2AHS and 2H02, respectively) and
GSTA1-1 (PDB code 6ATO) were downloaded from PDB
server (https://www.rcsb.org) [49]. Before docking
calculation, the ligands, water molecules and amino acids
conformers were removed from obtained PDB files. The
structure of thiazole-containing rhodanine derivatives were
drawn using MarvinSketch [50] and optimized with
MMFF94s force field in Avogadro software [51]. Docking
files were prepared using AutoDockTools (version 1.5.6)
[52]. The docking calculations were carried out by
Autodock Vina software [53]. The models visualizations
and analysis was performed using Discovery Studio 3.5
Visualizer (Accelrys Inc., San Diego, CA, USA).
Notes
Acknowledgements. This research was supported by the
National Academy of Sciences of Ukraine (grant for
research project of young scientists by National Academy
of Sciences of Ukraine № 76-09/04-2020).
The authors declare no conflict of interest.
Author contributions. O. L. K.: conceptualization,
supervision, molecular docking simulation, writing-original
draft. V. O. S.: synthesis of compounds, investigation,
formal analysis. Y. V. S.: investigation of bioactivity.
V. M. B.: investigation of bioactivity. D. M. H.:
O. L. Kobzar, V. O.Sinenko, Y. V. Shulga et al.
39
investigation. S. G. P.: synthesis of compounds, analysis.
V. S. B.: supervision, writing-review and editing. A. I. V.
conceptualization, supervision, writing-review and editing.
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Синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів
протеїнтирозинфосфатаз та глутатіон-S-трансфераз
О. Л. Кобзар, В. О. Синенко, Ю. В. Шульга, В. М. Булденко, Д. М. Година, С. Г. Пільо, В. С. Броварець, А. І. Вовк
Інститут біоорганічної хімії та нафтохімії ім. В. П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094,Україна.
Резюме: Тіазоловмісні похідні роданін-3-алканової кислоти, модифіковані залишками пропанової чи ундеканової кислот, синтезовано та оцінено
як інгібітори деяких протеїнтирозинфосфатаз та глутатіон-S-трансфераз. Сполуки отримано за реакцією Кновевенагеля взаємодією відповідних
роданінів з альдегідами. Встановлено, що роданіни з довшим карбоксильованим N-алкільним ланцюгом інгібують активність PTP1B, MEG1,
MEG2 та VE-PTP, а також GST з печінки коня та людську рекомбінантну GSTA1-1 зі значеннями IC50 у низькому мікромолярному діапазоні.
Інгібувальний ефект на активність протеїнтирозинфосфатаз залежав від замісника в 2 положенні тіазолового кільця, тоді як природа замісників у
положенні 2 та 4 мала незначний вплив на інгібувальну активність сполук щодо глутатіон-S-трансфераз. Найкраща сполука, 11-(5-{[2-(4-
хлорфеніл)-1,3-тіазол-5-іл]метиліден}}-4-оксо-2-сульфаніліден-1,3-тіазолідин-3-іл)ундеканова кислота, продемонструвала конкурентний тип
інгібування VE-PTP. У випадку GST з печінки коня сполука виявилась змішаним інгібітором при використанні GSH як субстрату та
неконкурентним інгібітором у разі CDNB. Результати молекулярного докінгу вказують на те, що інгібітор може займати активний центр
протеїнтирозинфосфатази VE-PTP, тоді як інгібування людської рекомбінантної GSTA1-1 може бути пояснено розташуванням похідної роданіну
між С- та N-кінцевими доменами однієї з субодиниць ферменту.
Ключові слова: роданін; тіазол; протеїнтирозинфосфатаза; глутатіон-S-трансфераза; інгібування ферменту; молекулярний докінг.
Notes
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| spelling | oai:ojs2.bioorganica.com.ua:article-392026-07-19T14:56:53Z Synthesis and evaluation of new thiazole-containing rhodanine-3-alkanoic acids as inhibitors of protein tyrosine phosphatases and glutathione S-transferases Синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів протеїнтирозинфосфатаз та глутатіон-S-трансфераз Kobzar, Oleksandr L. Sinenko, Vitaliy O. Shulha, Yuriy V. Buldenko, Vladyslav M. Hodyna, Diana M. Pilyo, Stepan G. Brovarets, Volodymyr S. Vovk, Andriy I. rhodanine thiazole protein tyrosine phosphatase glutathione S-transferase enzyme inhibition molecular docking роданін тіазол протеїнтирозинфосфатаза глутатіон-S-трансфераза інгібування ферменту молекулярний докінг Thiazole-containing derivatives of rhodanine-3-alkanoic acids with propanoic or undecanoic acid groups were synthesized and evaluated as inhibitors of some protein tyrosine phosphatases and glutathione S-transferases. The rhodanines bearing longer carboxylated N-alkyl chain were found to inhibit PTP1B, MEG1, MEG2, and VE-PTP as well as GST from equine liver and GSTA1-1 with IC50 values in the low micromolar range. The inhibitory effect on protein tyrosine phosphatase activity depends on substituent at position 2 of the thiazole ring. The best compound showed a competitive type of VE-PTP inhibition. In case of GST from equine liver, the inhibition was of mixed or non-competitive type with respect to glutathione or CDNB substrate, respectively. Possible binding modes of the inhibitors were discussed based on molecular docking calculations Тіазоловмісні похідні роданін-3-алканової кислоти, модифіковані залишками пропанової чи ундеканової кислот, синтезовано та оцінено як інгібітори деяких протеїнтирозинфосфатаз та глутатіон-S-трансфераз. Сполуки отримано за реакцією Кновевенагеля взаємодією відповідних роданінів з альдегідами. Встановлено, що роданіни з довшим карбоксильованим N-алкільним ланцюгом інгібують активність PTP1B, MEG1, MEG2 та VE-PTP, а також GST з печінки коня та людську рекомбінантну GSTA1-1 зі значеннями IC50 у низькому мікромолярному діапазоні. Інгібувальний ефект на активність протеїнтирозинфосфатаз залежав від замісника в 2 положенні тіазолового кільця, тоді як природа замісників у положенні 2 та 4 мала незначний вплив на інгібувальну активність сполук щодо глутатіон-S-трансфераз. Найкраща сполука, 11-(5-{[2-(4-хлорфеніл)-1,3-тіазол-5-іл]метиліден}}-4-оксо-2-сульфаніліден-1,3-тіазолідин-3-іл)ундеканова кислота, продемонструвала конкурентний тип інгібування VE-PTP. У випадку GST з печінки коня сполука виявилась змішаним інгібітором при використанні GSH як субстрату та неконкурентним інгібітором у разі CDNB. Результати молекулярного докінгу вказують на те, що інгібітор може займати активний центр протеїнтирозинфосфатази VE-PTP, тоді як інгібування людської рекомбінантної GSTA1-1 може бути пояснено розташуванням похідної роданіну між С- та N-кінцевими доменами однієї з субодиниць ферменту V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2020-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/39 10.15407/bioorganica2020.02.033 Ukrainica Bioorganica Acta; Vol. 15 No. 2 (2020): Ukrainica Bioorganica Acta; 33-40 Ukrainica Bioorganica Acta; Том 15 № 2 (2020): Ukrainica Bioorganica Acta; 33-40 1814-9766 1814-9758 10.15407/bioorganica2020.02 en https://bioorganica.com.ua/index.php/journal/article/view/39/38 Copyright (c) 2020 Oleksandr L. Kobzar, Vitaliy O. Sinenko, Yuriy V. Shulha, Vladyslav M. Buldenko, Diana M. Hodyna, Stepan G. Pilyo, Volodymyr S. Brovarets, Andriy I. Vovk https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | роданін тіазол протеїнтирозинфосфатаза глутатіон-S-трансфераза інгібування ферменту молекулярний докінг Kobzar, Oleksandr L. Sinenko, Vitaliy O. Shulha, Yuriy V. Buldenko, Vladyslav M. Hodyna, Diana M. Pilyo, Stepan G. Brovarets, Volodymyr S. Vovk, Andriy I. Синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів протеїнтирозинфосфатаз та глутатіон-S-трансфераз |
| title | Синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів протеїнтирозинфосфатаз та глутатіон-S-трансфераз |
| title_alt | Synthesis and evaluation of new thiazole-containing rhodanine-3-alkanoic acids as inhibitors of protein tyrosine phosphatases and glutathione S-transferases |
| title_full | Синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів протеїнтирозинфосфатаз та глутатіон-S-трансфераз |
| title_fullStr | Синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів протеїнтирозинфосфатаз та глутатіон-S-трансфераз |
| title_full_unstemmed | Синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів протеїнтирозинфосфатаз та глутатіон-S-трансфераз |
| title_short | Синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів протеїнтирозинфосфатаз та глутатіон-S-трансфераз |
| title_sort | синтез та оцінка нових тіазоловмісних роданін-3-алканових кислот як інгібіторів протеїнтирозинфосфатаз та глутатіон-s-трансфераз |
| topic | роданін тіазол протеїнтирозинфосфатаза глутатіон-S-трансфераза інгібування ферменту молекулярний докінг |
| topic_facet | rhodanine thiazole protein tyrosine phosphatase glutathione S-transferase enzyme inhibition molecular docking роданін тіазол протеїнтирозинфосфатаза глутатіон-S-трансфераза інгібування ферменту молекулярний докінг |
| url | https://bioorganica.com.ua/index.php/journal/article/view/39 |
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