Cинтез та протипухлинна активність 5-сульфонільних похідних 1,3-оксазол-4-карбоксилатів
A series of new 2-aryl 5-sulfonyl-1,3-oxazole-4-carboxylates for NCI anticancer screening protocol against 60 cancer cell lines were synthesized. Screening was performed in vitro on 60 cell lines of lungs, kidneys, CNS, ovaries, prostate, and breast cancer, leukemia, and melanoma. Methyl 5-benzylsul...
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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_ | 1871193572016914432 |
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| author | Pilyo, Stepan G. Kozachenko, Оlexandr P. Zhirnov, Victor V. Kachaeva, Maryna V. Kobzar, Oleksandr L. Vovk, Andriy I. Brovarets, Volodymyr S. |
| author_facet | Pilyo, Stepan G. Kozachenko, Оlexandr P. Zhirnov, Victor V. Kachaeva, Maryna V. Kobzar, Oleksandr L. Vovk, Andriy I. Brovarets, Volodymyr S. |
| author_institution_txt_mv | [
{
"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": "Оlexandr P. Kozachenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Victor V. Zhirnov",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"author": "Maryna V. Kachaeva",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine"
},
{
"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": "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": "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_sort | Pilyo, Stepan G. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:53Z |
| description | A series of new 2-aryl 5-sulfonyl-1,3-oxazole-4-carboxylates for NCI anticancer screening protocol against 60 cancer cell lines were synthesized. Screening was performed in vitro on 60 cell lines of lungs, kidneys, CNS, ovaries, prostate, and breast cancer, leukemia, and melanoma. Methyl 5-benzylsulfonyl-2-phenyl-1,3-oxazole-4-carboxylate 15 exhibited potent and broad range of cytotoxic activity against tested human cancer cells with average GI50, TGI, and LC50 values of 5.37·10-6, 1.29·10-5 and 3.6·10-5 mol/L respectively. Molecular docking was used to evaluate the possible interaction of compound 15 with tubulin as well as a complex formation with CDK2 |
| doi_str_mv | 10.15407/bioorganica2020.02.013 |
| first_indexed | 2025-07-17T12:19:39Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
UDC 547.787.1
DOI: https://doi.org/10.15407/bioorganica2020.02.013
13
RESEARCH ARTICLE
Synthesis and anticancer activity of 5-sulfonyl derivatives
of 1,3-oxazole-4-carboxylates
Stepan G. Pilyo, Оlexandr P. Kozachenko, Victor V. Zhirnov, Maryna V. Kachaeva,
Oleksandr L. Kobzar, Andriy I. Vovk and Volodymyr S. Brovarets*
V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
Abstract: A series of new 2-aryl 5-sulfonyl-1,3-oxazole-4-carboxylates for NCI anticancer screening protocol against 60 cancer cell lines
were synthesized. Screening was performed in vitro on 60 cell lines of lungs, kidneys, CNS, ovaries, prostate, and breast cancer, leukemia,
and melanoma. Methyl 5-benzylsulfonyl-2-phenyl-1,3-oxazole-4-carboxylate 15 exhibited potent and broad range of cytotoxic activity
against tested human cancer cells with average GI50, TGI, and LC50 values of 5.37·10-6, 1.29·10-5 and 3.6·10-5 mol/L respectively.
Molecular docking was used to evaluate the possible interaction of compound 15 with tubulin as well as a complex formation with CDK2.
Keywords: 5-sulfonyl-1,3-oxazole-4-carboxylates; synthesis; anticancer activity; selectivity; molecular docking.
Introduction
During the last years, the search for new biologically
active compounds, in particular anticancer agents, among
1,3-oxazole-4-carboxylates has stimulated considerable
synthetic efforts [1-3]. Oxazoles I-VIII containing
arylsulfonyl [4] or sulfonamide [5-6] moiety displayed
considerable cytotoxicity and selectivity towards diverse
cancer subpanels with sub-micromolar GI50 values
(Figure 1). It has been proposed that possible ways of
anticancer influence of sulfonamide derivatives are
associated with inhibition of the tubulin polymerization,
similar to E7010 [5], DNA damage, BCL6, and NSD2
inhibition [6]. So, previous works [4-6] have focused
mostly on 4-cyano-substituted 1,3-oxazoles.
In the present work, we replaced the nitrile with an ester
group in oxazole derivatives and synthesized new
5-sulfonyl derivatives of 1,3-oxazole-4-carboxylate,
investigated their anticancer screening and elucidated the
Received:
Revised:
Accepted:
Published online:
14.10.2020
16.10.2020
29.10.2020
30.12.2020
Corresponding author. Tel.: +380-44-573-2596;
e-mail: brovarets@bpci.kiev.ua (V. S. Brovarets)
ORCID: 0000-0001-6668-3412
Figure 1. 5-Sulfonyl-substituted 1,3-oxazoles with anticancer
activity.
© Pilyo S. G. 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:brovarets@bpci.kiev.ua
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
14
possible mechanism of their action by molecular docking
approaches.
Although the nitrile group is quite robust and, in most
cases, is not readily metabolized, there are some confirmed
facts of its cleavage and modification leading to increased
cytotoxicity [7]. Ester group in comparison with nitrile is
less cytotoxic for normal cells and it is perspective moiety
for the introduction in 1,3-oxazole-5-sulfonamide pharma-
cophore for the new anticancer drugs search.
Accordingly, in this study, we report the synthesis,
characterization and biological activity of novel molecules
combined 2-aryl-1,3-oxazole-4-carboxylate and sulfonami-
de scaffolds.
Results and Discussion
Chemistry
The synthesis of target compounds was accomplished by
the reaction sequence illustrated in Scheme 1 and 2. The
previously described in the literature [8] dichloroacrylates
1a,b were chosen as the starting materials.
1,3-Oxazole-5-sulfonamides 3-12 were prepared from
methyl 5-chlorosulfonyl-2-phenyloxazole-4-carboxylate (2)
by refluxing with appropriate amines [9].
The preparation of arylsulfonyl derivatives 17 and 18
involves the reaction sequences as in Sheme 2. The starting
methyl 2-(benzoylamino)-3,3-dichloroacrylate (1a) was
reacted with sodium sulfide to yield methyl 5-mercapto-2-
phenyl-1,3-oxazole-4-carboxylate (13), which was conver-
ted into methyl 5-(benzylsulfonyl)-2-phenyl-1,3-oxazole-4-
carboxylate (15) by alkylation with benzyl chloride and
oxidation with hydrogen peroxide [10].
5-((3-Methoxyphenyl)sulfonyl)-2-(4-methylphenyl)-1,3-
oxazole-4-carbonitrile (18) was synthesized following the
transformation sequence 1b → 16 → 17 → 18 in Sheme 2.
Reaction of methyl 3,3-dichloro-2-((4-methylbenzoyl)-
amino)acrylate (1b) with benzenemethanethiol in the
presence of triethylamine yielded methyl 3,3-bis((3-
methoxyphenyl)thio)-2-((4-methylbenzoyl)amino)acrylate
(16), that was cyclized in the presence of silver carbonate to
form methyl 5-((3-methoxyphenyl)thio)-2-(4-methyl-
phenyl)-1,3-oxazole-4-carboxylate (17). The latter was
converted into the corresponding sulfonyl derivative 18 by
oxidation with hydrogen peroxide [10].
The structure and composition of all obtained
compounds 3-12, 15, and 18 have been in good agreement
with IR, NMR (1H and 13C NMR) spectroscopy,
chromato‐mass spectrometry (LC-MS), and elemental
analysis data. The CH-protons of the methoxy group at the
4th position of the oxazole ring of synthesized compounds
appear as a singlet at 3.61-3.93 ppm. All CH2 and CH-
proton signals of sulfamides 3-12 are visible in the 1H NMR
spectra. The signal of the OH group of 6 and 7 is located in
1H NMR at 4.80-4.68 ppm. The signal at 8.32 ppm belongs
to NH group of compound 3. The strong absorption bands
of SO2 group appeared at 1152 to 1192 сm-1 and 1353 to
1386 cm-1 in the IR spectra of all compounds. Also, the
broad strong bands at 1731 to 1732 cm-1 corresponded to
C═O bond of esters.
In vitro evaluation of the anticancer activity
The synthesized 5-sulfonyl-1,3-oxazole-4-carboxylates
were screened on human cancer cell lines at the NIH,
Bethesda, Maryland, USA, under the drug discovery
program of the NCI. Results for each compound were
reported as a mean graph of the percent growth (GP%) of
the treated cells when compared to the untreated control
cells and one-dose screening data are summarized in
Table 1.
Scheme 1. Synthesis of 5-sulfamide derivatives of 2-phenyl-1,3-oxazole-4-carboxylate 3-12. Reagents and conditions: (a) 2.5 eq. NaSH;
(b) BnCl; (c) Cl2, AcOH, H2O; (d) amine, Et3N.
S. G. Pilyo, О. P. Kozachenko, V. V. Zhirnov et al.
15
Scheme 2. Synthesis of 5-aryl-1,3-oxazole-4-carboxylates 15, 18. Reagents and conditions: (a) 2.5 eq. Na2S; HCl; (b) PhCH2Cl, Et3N;
(c) H2O2, AcOH; (d) 2 eq. 3-MeOC6H4SH, 2 eq. Et3N; (e) 2.5 eq. Ag2CO3; (f) H2O2, AcOH, reflux.
The synthesized compounds showed differential
anticancer activity pattern against different types of cancer
and cell lines according to the primary one-dose anticancer
assay [11-15]. The most active methyl 5-(benzylsulfonyl)-
2-phenyl-1,3-oxazole-4-carboxylate (15) had anticancer
activity range from -78.70 to 109.63%. Thus, com-
pound 15 revealed high cytotoxic effect on leukemia
CCRF-CEM (GP = -6.08%), MOLT-4 (GP = -9.29%), SR
(GP = -11.55%), colon cancer COLO 205 (GP = -42.98%),
melanoma MALME-3M (GP = -78.70%), renal cancer
ACHN (GP = -35.00%) cell lines.
Since compound 15 possessed a significant anticancer
effect against several cell lines, it was tested additionally in
the fifth-dose assay (10-4-10-8 M) [13, 16] (Table 2). Three
dose-dependent values were extrapolated from
concentration-response curves for each cell line:
GI50 – the drug concentration of the compound that
inhibited 50% net cell growth; TGI – concentration of
tested compound with total cell growth inhibition,
LC50 – concentration of compound leading to 50% net cell
death.
Compound 15 exhibited a potent and broad range of
cytotoxic activity against tested human cancer cells with
average GI50, TGI, and LC50 5.37·10-6, 1.29·10-5, and
3.6·10-5 mol/L respectively. GI50 values were ranged from
1.48 μM (renal cancer UO‐31 cell line) to 70.2 μM (ovarian
cancer SK-OV‐3 cell line), TGI ‒ from 3.12 μM (non‐small
cell lung cancer NOP‐92 cell line) to >100 μM (CNS
Cancer SF‐395 cell line, and Ovarian cancer SK-OV-3 cell
line), and LC50 ‒ from 5.45 μM (renal cancer UO‐31 cell
line) to >100 μM (leukemia panel, non‐small cell lung
cancer A549/ATCC cell line, ovarian cancer SK-OV‐3,
breast cancer MCF7, HS 578T, T-47D).
Table 1. Anticancer NCI one-dose screening data (10-5 M)
for compounds 3-12, 15, 18
Compd
NSC
Mean
growth,
%
Range
of
growth,
%
Most sensitive cell line
growth, %
3
802758
65.66 from
-21.00 to
120.90
-21.00 (CCRF-CEM/Leukemia)
4.12 (HL-60(TB)/Leukemia)
13.37 (K-562/Leukemia)
7.96 (MOLT-4/ Leukemia)
7.86 (RPMI-8226/ Leukemia)
1.88 (SR/ Leukemia)
23.78 (NCI-H522/ Non-small cell
lung cancer)
18.71 (SW-620 / Colon cancer)
31.67 (MCF7/Breast cancer)
29.94 (MDA-MB-468/ Breast cancer)
4
802759
66.95 from
-19.22 to
116.57
-19.22 (CCRF-CEM/Leukemia)
17.47 (HL-60(TB)/Leukemia)
9.15 (K-562/Leukemia)
1.79 (MOLT-4/ Leukemia)
20.02 (RPMI-8226/ Leukemia)
-3.58 (SR/ Leukemia)
25.60 (NCI-H522/ Non-small cell
lung cancer)
5
802760
93.48 from
67.00 to
136.78
67.00 (SR/ Leukemia)
67.05 (MDA-MB-468/ Breast cancer)
6
802761
65.83 from
-24.58 to
112.08
16.16 (CCRF-CEM/Leukemia)
-24.58 (HL-60(TB)/Leukemia)
22.17 (K-562/Leukemia)
6.31 (MDA-MB-468/ Breast cancer)
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
16
Table 1. (Contd.)
Compd
NSC
Mean
growth,
%
Range
of
growth,
%
Most sensitive cell line
growth, %
7
802781
72.07 from
0.92 to
110.17
1.21 (CCRF-CEM/Leukemia)
14.99 (HL-60(TB)/Leukemia)
17.71 (K-562/Leukemia)
6.09 (MOLT-4/ Leukemia)
0.92 (SR/ Leukemia)
28.58 (NCI-H522/ Non-small cell
lung cancer)
29.19 (MDA-MB-468/ Breast cancer)
8
802782
58.77 from
-33.25 to
110.68
-3.72 (CCRF-CEM/Leukemia)
-33.25 (HL-60(TB)/Leukemia)
14.77 (K-562/Leukemia)
1.95 (MOLT-4/ Leukemia)
-3.16 (SR/ Leukemia)
0.81 (NCI-H522/ Non-small cell lung
cancer)
20.64 (COLO 205/Colon cancer)
25.38 (SW-620 / Colon cancer)
16.19 (OVCAR-3/Ovarian cancer)
23.15 (TK-10/Renal cancer)
-14.59 (MDA-MB-468/ Breast cancer)
9
802797
69.91 from
12.35 to
113.24
12.35 (CCRF-CEM/Leukemia)
22.72 (K-562/Leukemia)
23.59 (MOLT-4/ Leukemia)
17.56 (NCI-H522/ Non-small cell
lung cancer)
38.26 (SW-620 / Colon cancer)
16.19 (OVCAR-3/Ovarian cancer)
10
802783
91.60 from
61.48 to
111.90
61.48 (CCRF-CEM/Leukemia)
62.10 (SR/ Leukemia)
11
802784
72.26 from
-11.85 to
121.22
-11.85 (CCRF-CEM/Leukemia)
21.81 (HL-60(TB)/Leukemia)
20.41 (K-562/Leukemia)
-1.38 (SR/ Leukemia)
22.65 (MDA-MB-468/ Breast cancer)
12
802796
74.57 from
4.91 to
111.22
4.91 (CCRF-CEM/Leukemia)
15
802778
69.01 from
-78.70 to
109.63
-6.08 (CCRF-CEM/Leukemia)
2.87 (K-562/Leukemia)
-9.29 (MOLT-4/ Leukemia)
-11.55 (SR/ Leukemia)
-42.98 (COLO 205/Colon cancer)
-78.70 (MALME-3M/ Melanoma)
-35.00 (ACHN/ Renal cancer)
5.41 (TK-10/Renal cancer)
18
802780
78.38 from
-12.30 to
109.75
-9.09 (CCRF-CEM/Leukemia)
11.58 (K-562/Leukemia)
-7.44 (MOLT-4/ Leukemia)
0.69 (SR/ Leukemia)
-8.96 (COLO 205/Colon cancer)
-12.30 (MALME-3M/ Melanoma)
Table 2. Anticancer NCI five-dose-response parameters for
compound 15.
Panel Cell line GI50, M TGI, M LC50, M
Leukemia CCRF-CEM 2.91·10-6 8.41·10-6 >1.00·10-4
HL-60(TB) 2.30·10-6 6.22·10-6 >1.00·10-4
K-562 2.07·10-6 5.29·10-6 >1.00·10-4
MOLT-4 2.11·10-6 5.57·10-6 >1.00·10-4
Non-Small
Cell Lung
Cancer
HOP-92 1.61·10-6 3.12·10-6 6.06·10-6
NCI-H522 1.52·10-6 3.29·10-6 7.13·10-6
Colon
Cancer
COLO 205 1.84·10-6 3.66·10-6 7.30·10-6
HCT-116 2.58·10-6 6.23·10-6 2.16·10-5
HCT-15 1.79·10-6 3.58·10-6 7.15·10-6
SW-620 2.05·10-6 4.14·10-6 8.33·10-6
Melanoma MALME-3M 1.73·10-6 3.44·10-6 6.85·10-6
Ovarian
Cancer
OVCAR-3 1.94·10-6 3.52·10-6 6.40·10-6
OVCAR-4 1.82·10-6 3.40·10-6 6.32·10-6
Renal
Cancer
ACHN 1.77·10-6 3.15·10-6 5.62·10-6
CAKI-1 1.84·10-6 3.42·10-6 6.37·10-6
RXF 393 1.87·10-6 3.50·10-6 6.55·10-6
TK-10 1.74·10-6 3.19·10-6 5.86·10-6
UO-31 1.48·10-6 2.84·10-6 5.45·10-6
Breast
Cancer
MDA-MB-
468
1.85·10-6 4.02·10-6 8.75·10-6
Average values 5.37·10-6 1.29·10-5 3.6·10-5
Previously, anticancer activity of 2-substituted
5-arylsulfonyl-4-cyano-1,3-oxazoles was proposed to be
related to the inhibition of tubulin polymerization [5].
Given the interest in microtubule-targeting agents [17], as
well as to possible inhibitors of oncogenic signaling
pathways [18], two series of molecular docking simulations
for the 5-sulfonyl-1,3-oxazole-4-carboxylates were carried
out in this paper. The compounds were docked into
colchicine binding site of tubulin (PDB code 1SA0 [19])
and ATP-binding sites of cyclin-dependent kinases CDK1,
CDK2, CDK7 and CDK9 (PDB codes 4Y72 [20], 3QQJ,
1UA2 [21], 4BCF [22], respectively). The highest affinity
of compound 15 was observed towards CDK2.
The molecular docking of 5-benzylsulfonyl derivative of
1,3-oxazole-4-carboxylate 15 into colchicine binding site of
αβ-tubulin heterodimer structure showed calculated binding
affinity of -8.0 kcal/mol. According to the obtained model
(Figure 2A), the 5-(benzylsulfonyl)oxazole fragment of
ligand provided electrostatic, van der Waals, and
hydrophobic interactions with amino acids residues Val238,
Leu248, Leu255, Lys352, and Ile378 of β-tubulin subunit
(B chain). The complex exhibited hydrogen bond of methyl
acetate moiety of ligand with backbone amino group of
Ala250 (B chain). The 5-benzylsulfonyl fragment of the
S. G. Pilyo, О. P. Kozachenko, V. V. Zhirnov et al.
17
ligand was located near amino acids residue Asn101,
Thr179, Ala180, and Val181, which belong to α-tubulin
subunit (A chain).
Binding mode of compound 15 into ATP-binding
site of cyclin-dependent kinase 2 with binding affinity
-9.2 kcal/mol is shown in Figure 2B. In this model,
5-(benzylsulfonyl)-oxazole fragment of ligand was located
in hydrophobic pocket and had electrostatic, Wan der
Waals, and hydrophobic interaction with amino acids
residues Val18, Ile10, Ala31, Val64, Phe80, Leu83,
Leu134, and Ala144 as well as showed π-stacking
interaction with Phe82. The sulfonyl group of
5-benzylsulfonyl moiety was adjacent to Gln85, Asp86, and
Lys89 residues.
Figure 2. Possible binding modes of 5-benzylsulfonyl derivative
of 1,3 oxazole-4-carboxylate 15 into colchicine binding site of
tubulin (A) and ATP-binding site of CDK2 (B).
Conclusions
All the reported in this paper substances showed
significant inhibitory activity and selectivity over 60 cell
lines. Leukemia and non-small cell lung cancer NCI-H522
cell lines were particularly sensitive to all synthesized
compounds except 5 and 10. Colon cancer COLO 205 cell
line was sensitive to compounds 15, 18, and 8. Melanoma
MALME-3M cell line appeared to be sensitive to
compounds 15 and 18.
The study of the antitumor activity of 5-sulfonyl
derivatives of 1,3-oxazole-4-carboxylates towards the
NCI 60 human cancer cell lines revealed «leader com-
pound» – methyl 5-benzylsulfonyl-2-phenyl-1,3-oxazole-4-
carboxylate (15). The Non-Small Cell Lung Cancer, Colon
Cancer, Melanoma, Ovarian, Renal and Breast Cancer cell
lines showed a significant sensitivity to this compound with
sub-micro molar LC50 values.
The results of NCI screening make the reported
1,3-oxazole-4-carboxylate derivatives not only interesting
for further chemical optimization but also for the
elucidation of their mechanism of action. In this regard,
molecular docking approaches were used to evaluate the
possible interaction between compound 15 and tubulin as
well as in silico binding to CDK2.
Experimental section
Chemistry
All reagents and solvents used in synthetic procedures
were purchased from Aldrich and used as received.
Reaction progress was monitored by TLC on Merck Silica
gel 60 F254 aluminium sheets. Melting points were
determined on a Fisher-Johns apparatus. FT-IR (KBr pellet)
spectra were performed on a Bruker VERTEX 70 spectro-
meter and only the most representative frequencies were
reported. Absorption bands are reported in cm-1. 1H and 13C
NMR spectra were recorded on a Bruker Avance DRX 500
(500 and 125 MHz, respectively) or Varian Mercury 400
(400 MHz) spectrometers in DMSO-d6 taking its residual
protons signal as a standard. Mass spectra were recorded on
an Agilent 1200 LCMSD SL instrument (chemical
ionization (APCI), electrospray ionization (ESI)).
Combustion elemental analysis was performed in the
V.P. Kukhar Institute of Bioorganic Chemistry and
Petrochemistry analytical laboratory, their results were
found to be in good agreement (±0.4%) with the calculated
values. The carbon and hydrogen contents were determined
using the Pregl gravimetric method, nitrogen – using the
Duma's gasometrical micromethod, sulfur – by the
Scheininger titrimetric method, chlorine – by the
mercurometric method.
General procedure for preparation of compounds (3-12).
A mixture of a solution of 0.001 mol of methyl 5-(chlo-
rosulfonyl)-2-phenyl-1,3-oxazole-4-carboxylate (2), 15 ml
of anhydrous dioxane, 0.001 mol of the corresponding
amine, and 0.001 mol of Et3N was refluxed for 2 h. Then
the mixture was incubated at 20-25 °C during 12 h; the
precipitate was filtered off, and the solvent was removed in
vacuum. The residue was treated with water, filtered off,
dried, and recrystallized.
Methyl 5-(((2-(4-chlorophenyl)-2-morpholin-4-ylethyl)-
amino)sulfonyl)-2-phenyl-1,3-oxazole-4-carboxylate (3).
Yield: 0.36 g, 71%; mp 172-174 °C. 1H NMR
(500 MHz, DMSO-d6) δ 8.32 (s, 1H, NH), 8.01-7.98 (m,
2H, Ar), 7.64-7.58 (m, 3H, Ar), 7.29-7.25 (m, 2H, Ar),
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
18
7.18-7.15 (m, 3H, Ar), 3.88 (s, 3H, OCH3), 3.67-3.63 (m,
1H, CH), 3.57-3.55 (m, 1H, CH), 3.43-3.40 (m, 5H, CH,
CH2), 2.52 (br s, 1H, CH), 2.24 (m, 2H, CH2), 2.16 (m, 2H,
CH2). IR (KBr) ν, 2817, 1718 (C=O), 1552, 1486, 1400,
1342 (SO2), 1237, 1161, 1113, 1073, 1056, 852, 714, 688.
LC/MS (CI) m/z 505.9 (M+1)+. Anal. Calcd. for
C23H24ClN3O6S: C, 54.60; H, 4.78; Cl, 7.01; N, 8.30;
S, 6.34. Found: C, 54.58; H, 4.76; Cl, 7.14; N, 8.45; S, 6.52.
Methyl 5-(((2-(4-chlorophenyl)-2-piperidin-1-ylethyl)-
amino)sulfonyl)-2-phenyl-1,3-oxazole-4-carboxylate (4).
Yield: 0,37 g, 73%; mp 134-136 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.01-7.98 (m, 2H, Ar), 7.65-7.57 (m, 3H, Ar),
7.27-7.24 (m, 2H, Ar), 7.15-7.11 (m, 2H, Ar), 3.87 (s, 3H,
OCH3), 3.65-3.58 (m, 2H, CH2), 2.53 (br s, 1H, CH), 2.24
(br s, 2H, CH, CH2), 2.04 (br s, 2H, CH2), 1.33 (br s, 4H,
CH2), 1.15 (br s, 2H, CH2). IR (KBr) ν, 3198 (NH), 2935,
2797, 1718 (C=O), 1558, 1490, 1397, 1340 (SO2), 1245,
1188, 1158, 1069, 820, 714, 689. LC/MS (CI) m/z 504.0
(M+1)+. Anal. Calcd. for C24H26ClN3O5S: C, 57.19; H,
5.20; Cl, 7.03; N, 8.34; S, 6.36. Found: C, 57.16; H, 5.18;
Cl, 7.19; N, 8.45; S, 6.26.
Methyl 5-(((2-hydroxyethyl)amino)sulfonyl)-2-phenyl-
1,3-oxazole-4-carboxylate (5).
Yield: 0,25 g, 76%; mp 108-110 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.41 (br s, 1H, NH), 8.03-7.99 (m, 2H, Ar),
7.65-7.56 (m, 3H, Ar), 4.71-4.68 (m, 1H, OH), 3.86 (s, 3H,
CH3), 3.43-3.37 (m, 2H, CH2), 3.14-3.09 (m, 2H, CH2).
IR (KBr) ν, 3538 (OH), 3213 (NH), 2955, 2887, 1726
(C=O), 1556, 1484, 1354, 1338 (SO2), 1235, 1179, 1153,
1056, 820, 710, 616. LC/MS (CI) m/z 326.3 (M+1)+. Anal.
Calcd. for C13H14N2O6S: C, 47.85; H, 4.32; N, 8.58; S, 9.83.
Found: C, 47.82; H, 4.31; N, 8.68; S, 9.93.
Methyl 5-(((2-hydroxyethyl)(methyl)amino)sulfonyl)-2-
phenyl-1,3-oxazole-4-carboxylate (6).
Yield: 0,26 g, 75%; mp 119-121 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.02-8.01 (m, 2H, Ar), 7.65-7.57 (m, 3H, Ar),
4.80-4.79 (m, 1H, OH), 3.87 (s, 3H, OCH3), 3.54-3.53 (m,
2H, CH2), 3.00 (s, 3H, NCH3), 2.52 (br s, 2H, CH2).
IR (KBr) ν, 3434 (OH), 2950, 2873, 1742 (C=O), 1557,
1486, 1375 (SO2), 1297, 1224, 1173, 1082, 1069, 987, 924,
814, 714, 598. LC/MS (CI) m/z 340.4 (M+1)+. Anal. Calcd.
for C13H14N2O6S: C, 49.41; H, 4.74; N, 8.23; S, 9.42.
Found: C, 49.38; H, 4.76; N, 8.33; S, 9.52.
Methyl 5-((3-methylpiperidin-1-yl)sulfonyl)-2-phenyl-
1,3-oxazole-4-carboxylate (7).
Yield: 0,27 g, 73%; mp 100-102 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.05-8.01 (m, 2H, Ar), 7.69-7.61 (m, 3H, Ar),
3.90 (s, 3H, OCH3), 3.69 (dd, J 22,1 Hz, J 11,6 Hz, 1H,
CH), 2.88 (t, J 12 Hz, 1H, CH), 2.59-2.54 (m, 1H, CH),
1.75-1.61 (m, 3H, CH, CH2), 1.52-1.43 (m, 1H, CH), 1.06-
0.98 (m, 1H, CH), 0.87 (d, J 6,8 Hz, 3H, CH3). 13C NMR
(125 MHz, DMSO-d6): δ 161.8, 160.4, 147.0, 134.8, 133.0,
129.9, 127.5, 125.3, 53.3, 52.6, 46.4, 31.5, 30.7, 24.7, 19.0.
IR (KBr) ν, 2954, 2929, 1749 (C=O), 1545, 1481, 1374
(SO2), 1363, 1224, 1179, 1144, 1070, 1053, 1008, 930, 818,
749, 716, 621, 581. LC/MS (CI) m/z 364.4 (M+1)+. Anal.
Calcd. for C17H20N2O5S: C, 56.03; H, 5.53; N, 7.69; S, 8.80.
Found: C, 56.00; H, 5.50; N, 7.79; S, 8.89.
Methyl 5-((4-(aminocarbonyl)piperidin-1-yl)sulfonyl)-2-
phenyl-1,3-oxazole-4-carboxylate (8).
Yield: 0,28 g, 77%; mp > 210 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.05 (d, J 7.6 Hz, 2H, Ar), 7.69-7.60 (m, 3H,
Ar), 7.17 (s, 1H, C(O)NH2), 6.70 (s, 1H, C(O)NH2), 3.91 (s,
3H, OCH3), 3.83 (d, J 12,4 Hz, 2H, CH2), 2.98 (t, J 10.8 Hz,
2H, CH2), 2.26 (t, J 10.8 Hz, 1H, CH), 1.84 (d, J 10.4 Hz,
2H, CH2), 1.62-1.53 (m, 2H, CH2). IR (KBr) ν, 3380
(NHamide), 3192, 2943, 1749 (C=O), 1651, 1552, 1449, 1372
(SO2), 1336, 1299, 1221, 1178, 1148, 1067, 1054, 954, 815,
720, 714, 675, 610, 582. LC/MS (CI) m/z 364.4 (M+1)+.
Anal. Calcd. for C17H19N3O6S: C, 56.03; H, 5.53; N, 7.69;
S, 8.80. Found: C, 51.90; H, 4.87; N, 10.68; S, 8.15.
Methyl 5-((4-methylpiperidin-1-yl)sulfonyl)-2-phenyl-
1,3-oxazole-4-carboxylate (9).
Yield: 0,28 g, 78%; mp 102-104 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.04 (d, J 7.6 Hz, 2H, Ar), 7.67-7.60 (m, 3H,
Ar), 3.90 (s, 3H, OCH3), 3.78 (d, J 12,4 Hz, 2H, CH2), 2.89
(t, J 12 Hz, 2H, CH2), 1.71 (d, J 13,2 Hz, 2H, CH2), 1.48
(br s, 1H, CH), 1.14 (dd, J 23.6 Hz, J 13.2 Hz, 2H, CH2),
0.88 (d, J 6.4 Hz, 3H, CH3). IR (KBr) ν, 2942, 1746 (C=O),
1547, 1449, 1371 (SO2), 1337, 1221, 1157, 1049, 927, 815,
726, 689, 617, 592. LC/MS (CI) m/z 365.2 (M+1)+. Anal.
Calcd. for C17H20N2O5S: C, 56.03; H, 5.53; N, 7.69; S, 8.80.
Found: C, 55.90; H, 5.50; N, 7.58; S, 8.19.
Methyl 2-phenyl-5-((4-phenylpiperazin-1-yl)sulfonyl)-
1,3-oxazole-4-carboxylate (10).
Yield: 0,31 g, 73%; mp 119-121 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.01 (d, J 8 Hz, 2H, Ar), 7.66-7.57 (m, 3H,
Ar), 7.19 (t, J 7 Hz, 2H, Ar), 6.92 (d, J 7.5 Hz, 2H, Ar),
6.79 (t, J 7.5 Hz, 1H, Ar), 3.90 (s, 3H, OCH3), 3.48 (br s,
4H, 2CH2), 3.25 (br s, 4H, 2CH2). 13C NMR (125 MHz,
DMSO-d6): δ 161.6, 159.9, 150.4, 146.1, 134.9, 132.5,
129.5, 129.0, 127.1, 125.0, 119.7, 116.2, 52.9, 48.2, 45.6.
IR (KBr) ν, 2842, 1737 (C=O), 1598, 1555, 1495, 1451,
1380 (SO2), 1322, 1225, 1181, 1149, 1069, 1052, 953, 816,
771, 713, 698, 688, 596. LC/MS (CI) m/z 427.5 (M+1)+.
Anal. Calcd. for C21H21N3O5S: C, 59.00; H, 4.95; N, 9.83;
S, 7.50. Found: C, 59.03; H, 4.91; N, 9.70; S, 7.62.
Methyl 5-((4-(4-methoxyphenyl)piperazin-1-yl)sulfonyl)-
2-phenyl-1,3-oxazole-4-carboxylate (11).
Yield: 0,34 g, 74%; mp 119-121 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.02 (d, J 7 Hz, 2H, Ar), 7.66-7.58 (m, 3H,
Ar), 6.88 (d, J 9 Hz, 2H, Ar), 6.82-6.79 (m, 2H, Ar), 3.90
(s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.47 (br s, 4H, 2CH2),
3.11 (br s, 4H, 2CH2). 13C NMR (125 MHz, DMSO-d6):
δ 161.6, 160.3, 153.6, 146.0, 144.7, 134.9, 132.6, 129.5,
129.0, 127.1, 125.0, 118.3, 114.4, 55.2, 52.9, 49.6, 45.8.
IR (KBr) ν, 2832, 1747 (C=O), 1552, 1513, 1485, 1449,
1374 (SO2), 1323, 1270, 1249, 1224, 1180, 1151, 1116,
1034, 1052, 951, 818, 732, 716, 688, 614, 601. LC/MS (CI)
m/z 457.5 (M+1)+. Anal. Calcd. for C22H23N3O6S: C, 57.76;
H, 5.07; N, 9.18; S, 7.01. Found: C, 57.78; H, 5.04; N, 9.26;
S, 7.13.
S. G. Pilyo, О. P. Kozachenko, V. V. Zhirnov et al.
19
Methyl 5-((4-(3-chlorophenyl)piperazin-1-yl)sulfonyl)-2-
phenyl-1,3-oxazole-4-carboxylate (12).
Yield: 0,34 g, 75%; mp 119-121 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.00 (d, J 7 Hz, 2H, Ar), 7.66-7.58 (m, 3H,
Ar), 6.88-6.79 (m, 4H, Ar), 3.87 (s, 3H, OCH3), 3.61 (s, 3H,
OCH3), 3.42 (br s, 4H, 2CH2), 3.15 (br s, 4H, 2CH2).
13C NMR (125 MHz, DMSO-d6): δ 162.0, 160.3, 151.9,
146.4, 135.3, 134.3, 133.0, 130.9, 130.0, 127.5, 125.4,
119.2, 115.7, 114.7, 53.3, 47.9, 45.8. IR (KBr) ν, 2849,
1738 (C=O), 1596, 1556, 1484, 1450, 1380 (SO2), 1320,
1220, 1181, 1147, 954, 856, 786, 724, 712, 687, 599, 543.
LC/MS (CI) m/z 461.9 (M+1)+. Anal. Calcd. for
C21H20ClN3O5S: C, 54.60; H, 4.36; N, 9.10; S, 6.94. Found:
C, 54.62; H, 4.38; N, 9.19; S, 6.99.
Synthesis of methyl 5-(benzylsulfonyl)-2-phenyl-1,3-
oxazole-4-carboxylate (15).
To a suspension of 0.01 mol of methyl 2-benzoylamino-
3,3-dichloroacrylate (1a) in 40 ml of methanol 0.025 mol of
sodium sulfide was added while stirring, the suspension was
mixed for 2-3 h, then kept for 12 h at 20-25 °C. The
precipitate was filtered off. The filtrate was diluted with
water, acidified with hydrochloric acid to pH < 7, to form
red precipitate 13.
A mixture of methyl 5-mercapto-2-phenyl-1,3-oxazole-
4-carboxylate (13, 0.01 mol), chloromethylbenzene (0.01
mol) and triethylamine (0.01 mol) was refluxed for 2-3 h.
The precipitate was filtered off, the solvent was removed in
vacuo, the residue was treated with water, filtered off, and
dried to form compound 14.
A solution of 0.01 mol of methyl 5-benzylthio-2-phenyl-
1,3-oxazole-4-carboxylate (14) in 40 ml of glacial acetic
acid was heated to reflux, then H2O2 was added in three
portions during 2 h, then the reaction mixture was left for
12 h at room temperature. The mixture was kept for 8 h at
20-25 °C, and the precipitate was filtered off and purified
by recrystallization from ethanol to form compound 15.
Yield: 0,26 g, 72%; mp 143-145 °C. 1H NMR (400 MHz,
DMSO-d6) δ 7.95 (d, J 7.6 Hz, 1H, Ar), 7.84 (d, J 6.4 Hz,
1H, Ar), 7.68-7.58 (m, 1H, Ar), 7.41-7.35 (m, 7H, Ar), 5.05
(s, 2H, CH2), 3.93 (s, 3H, OCH3). IR (KBr) ν, 2954, 1739
(C=O), 1614, 1545, 1494, 1345 (SO2), 1318, 1301, 1237,
1180, 1140, 1085, 1062, 825, 776, 736, 696, 652, 640, 540,
522. LC/MS (CI) m/z 357.4 (M+1)+. Anal. Calcd. for
C18H15NO5S: C, 60.49; H, 4.23; N, 3.92; S, 8.97. Found: C,
60.46; H, 4.21; N, 3.99; S, 8.85.
Synthesis of 5-((3-methoxyphenyl)sulfonyl)-2-(4-
methylphenyl)-1,3-oxazole-4-carbonitrile (18).
A mixture of 3,3-dichloro-2-((4-methylbenzoyl)-
amino)acrylate (1b, 0.01 mol), triethylamine (0.02 mol) and
the corresponding 3-methoxybenzenethiol (0.02 mol) in 30
ml of acetonitrile was stirred on a magnetic stirrer at
20-25 °C C for 8 h. The precipitate was filtered off, the
solvent was removed in vacuo, the residue was treated with
water, filtered and dried. The mixture of formed N-(1-
cyano-2,2-bis((3-methoxyphenyl)thio)vinyl)-4-methylbenz-
amide (16, 0.01 mol) and dried silver carbonate (0.025 mol)
in 40 ml of acetonitrile was stirred on a magnetic stirrer at
reflux for 8-10 h, then left at 20-25 °C for 8 h. The
precipitate was filtered off, the solvent was removed in
vacuo, the residue was washed with water, filtered off, dried
and purified by recrystallization.
The formed 5-((3-methoxyphenyl)thio)-2-(4-methyl-
phenyl)-1,3-oxazole-4-carbonitrile (19, 0.01 mol) was
heated to boiling in glacial acetic acid (20 ml), then 30%
H2O2 was added in three 2 ml portions over 2 hours. The
mixture was left at 20-25 ºC for 8 hours. The precipitate
formed was filtered off, dried and recrystallized from
ethanol. Yield: 0,27 g, 70%; mp 93-95 °C. 1H NMR
(400 MHz, DMSO-d6) δ 7.91 (d, J 7.6 Hz, 2H, Ar), 7.71-
7.61 (m, 3H, Ar), 7.40-7.37 (m, 3H, Ar), 3.90 (s, 3H,
CH3O), 3.86 (s, 3H, CH3O), 2.39 (s, 4H, 2CH2). IR (KBr) ν,
3530, 1742 (C=O), 1597, 1496, 1482, 1353 (SO2), 1333,
1291, 1251, 1227, 1172, 1144, 1036, 821, 734, 702, 677,
642, 618, 534. LC/MS (CI) m/z 387.4 (M+1)+. Anal. Calcd.
for C19H17NO6S: C, 58.91; H, 4.42; N, 3.62; S, 8.28. Found:
C, 58.93; H, 4.40; N, 3.70; S, 8.39.
In vitro anticancer assay
In vitro screening methodology, screening interpretation
information and cancer cell growth calculation method is
described in details at the NCI Development Therapeutics
Program site [23].
Molecular docking calculation
Molecular docking was carried out by Autodock Vina
software [24]. Before the calculation, ligands, water
molecules and amino acids conformers were removed from
crystal structures of tubulin (PDB code 1SA0 [18]), CDK1,
CDK2, CDK7, and CDK9 (PDB codes 4Y72 [20], 3QQJ,
1UA2 [21], and 4BCF [22], respectively), which were
downloaded from PDB server (https://www.rcsb.org) [25].
The structure of 5-benzylsulfonyl derivative of 1,3 oxazole-
4-carboxylate 15 was drawn using MarvinSketch [26] and
optimized with the AM1 semi-empirical quantum
mechanical method in MOPAC software [27]. Files for
docking were prepared by using AutoDockTools (version
1.5.6) [28]. Analysis of models was performed in program
Discovery Studio 3.5 Visualizer (Accelrys Inc., San Diego,
CA, USA).
Notes
Acknowledgments and finances. We would like to
thank US Public Health Service and National Cancer
Institute, USA, for in vitro evaluation of anticancer activity
(providing the NCI-60 cell testing) within the
framework of Developmental Therapeutic Program [23],
and Enamine Ltd. for the material and technical support.
We also thank the National Research Foundation of Ukraine
(NRFU competition "Science for the safety of human and
society", Grant No. 2020.01/0075) for financial support.
The authors declare no conflict of interest.
https://www.rcsb.org/
ISSN 1814-9758. Ukr. Bioorg. Acta, 2020, Vol. 15, N 2
20
Author contributions. S. G. P.: synthesis of
compounds, investigation, formal analysis. O. P. K.:
synthesis of compounds, investigation, formal analysis.
V. V. Z.: COMPARE analysis. M. V. K.: writing most of
the manuscript. O. L. K.: analysis of literature and
molecular docking calculation. A. I. V.: conceptualization,
writing, review. V. S. B.: conceptualization, supervision,
writing - review & editing.
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http://scholar.google.com/scholar?cluster=3281289866994742613&hl=en&oi=scholarr
http://scholar.google.com/scholar?cluster=3281289866994742613&hl=en&oi=scholarr
https://dtp.cancer.gov/discovery_development/nci-60/default.htm
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http://openmopac.net/
S. G. Pilyo, О. P. Kozachenko, V. V. Zhirnov et al.
21
Cинтез та протипухлинна активність 5-сульфонільних похідних
1,3-оксазол-4-карбоксилатів
С. Г. Пільо, О. П. Козаченко, В. В. Жирнов, М. В. Качаєва, О. Л. Кобзар, А. І. Вовк, В. С. Броварець*
Інститут біоорганічної хімії та нафтохімії ім. В. П. Кухаря НАН України, вул. Мурманська, 1, Київ, 02094, Україна
Резюме: На основі попередніх досліджень протипухлинної активності 5-сульфонілзаміщених 1,3-оксазолів було синтезовано ряд нових 2-арил-5-
сульфоніл-1,3-оксазол-4-карбоксилатів для проведення скринінгу щодо 60 ракових клітинних ліній NCI: недрібноклітинного раку легень
(A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460, NCI-H522), раку нирок (786-0, A498, ACHN, CAKI-1, RXF
393, SN12C, TK-10, UO-31), ЦНС (SF-268, SF-295, SF-539, SNB-19, SNB-75, U251), яєчників (IGROV1, OVCAR-3, OVCAR-4, OVCAR-5,
OVCAR-8, NCI/ADR-RES, SK-OV-3), простати (PC-3, DU-145), товстого кишкивніка (COLO 205, HCC-2998, HCT-116, HCT-15, HT29, KM12,
SW-620), молочної залози (MCF7, MDA-MB-231/ATCC, HS 578T, BT-549, T- 47D, MDA-MB-468), лейкемії (CCRF-CEM, HL-60 (TB), K-562,
MOLT-4, RPMI-8226, SR) та меланоми (LOX IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62).
Серед досліджуваних речовин «сполукою-лідером» виявився метил 5-бензилсульфоніл-2-феніл-1,3-оксазол-4-карбоксилат (15), який показав
значну цитотоксичність на багатьох лініях досліджених ракових клітин людини із середнім значенням GI50, TGI та LC50 5,37·10-6, 1,29·10-5 та
3,6·10-5 моль/л відповідно. Молекулярний докінг було використано для oцінки взаємодій між сполукою 15 і тубуліном, а також для моделювання
комплексів сполуки 15 з СDK2, енергія зв’язування в якому становила -9.2 ккал/моль. Cеред нових похідних 1,3-оксазолу знайдено перспективні
сполуки для подальшого дослідження протиракової активності щодо різних ліній.
Ключові слова: 5-сульфоніл-1,3-оксазол-4-карбоксилати; синтез; протипухлинна активність; селективність; молекулярний докінг.
Notes
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| id | oai:ojs2.bioorganica.com.ua:article-36 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:00:50Z |
| publishDate | 2020 |
| 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/f9/6194f43b7e0d57967fdca2df7e3844f9.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-362026-07-19T14:56:53Z Synthesis and anticancer activity of 5-sulfonyl derivatives of 1,3-oxazole-4-carboxylates Cинтез та протипухлинна активність 5-сульфонільних похідних 1,3-оксазол-4-карбоксилатів Pilyo, Stepan G. Kozachenko, Оlexandr P. Zhirnov, Victor V. Kachaeva, Maryna V. Kobzar, Oleksandr L. Vovk, Andriy I. Brovarets, Volodymyr S. 5-sulfonyl-1,3-oxazole-4-carboxylates synthesis anticancer activity selectivity molecular docking 5-сульфоніл-1,3-оксазол-4-карбоксилати синтез протипухлинна активність селективність молекулярний докінг A series of new 2-aryl 5-sulfonyl-1,3-oxazole-4-carboxylates for NCI anticancer screening protocol against 60 cancer cell lines were synthesized. Screening was performed in vitro on 60 cell lines of lungs, kidneys, CNS, ovaries, prostate, and breast cancer, leukemia, and melanoma. Methyl 5-benzylsulfonyl-2-phenyl-1,3-oxazole-4-carboxylate 15 exhibited potent and broad range of cytotoxic activity against tested human cancer cells with average GI50, TGI, and LC50 values of 5.37·10-6, 1.29·10-5 and 3.6·10-5 mol/L respectively. Molecular docking was used to evaluate the possible interaction of compound 15 with tubulin as well as a complex formation with CDK2 На основі попередніх досліджень протипухлинної активності 5-сульфонілзаміщених 1,3-оксазолів було синтезовано ряд нових 2-арил-5-сульфоніл-1,3-оксазол-4-карбоксилатів для проведення скринінгу щодо 60 ракових клітинних ліній NCI: недрібноклітинного раку легень (A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460, NCI-H522), раку нирок (786‑0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, UO-31), ЦНС (SF-268, SF-295, SF-539, SNB-19, SNB-75, U251), яєчників (IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, NCI/ADR-RES, SK-OV-3), простати (PC-3, DU-145), товстого кишкивніка (COLO 205, HCC-2998, HCT-116, HCT-15, HT29, KM12, SW-620), молочної залози (MCF7, MDA-MB-231/ATCC, HS 578T, BT-549, T- 47D, MDA-MB-468), лейкемії (CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226, SR) та меланоми (LOX IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62). Серед досліджуваних речовин «сполукою-лідером» виявився метил 5-бензилсульфоніл-2-феніл-1,3-оксазол-4-карбоксилат (15), який показав значну цитотоксичність на багатьох лініях досліджених ракових клітин людини із середнім значенням GI50, TGI та LC50 5,37·10-6, 1,29·10-5 та 3,6·10-5 моль/л відповідно. Молекулярний докінг було використано для oцінки взаємодій між сполукою 15 і тубуліном, а також для моделювання комплексів сполуки 15 з СDK2, енергія зв’язування в якому становила -9.2 ккал/моль. Cеред нових похідних 1,3-оксазолу знайдено перспективні сполуки для подальшого дослідження протиракової активності щодо різних ліній V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2020-12-30 Article Article application/pdf application/pdf https://bioorganica.com.ua/index.php/journal/article/view/36 10.15407/bioorganica2020.02.013 Ukrainica Bioorganica Acta; Vol. 15 No. 2 (2020): Ukrainica Bioorganica Acta; 13-21 Ukrainica Bioorganica Acta; Том 15 № 2 (2020): Ukrainica Bioorganica Acta; 13-21 1814-9766 1814-9758 10.15407/bioorganica2020.02 en https://bioorganica.com.ua/index.php/journal/article/view/36/34 https://bioorganica.com.ua/index.php/journal/article/view/36/35 Copyright (c) 2020 Stepan G. Pilyo, Оlexandr P. Kozachenko, Victor V. Zhirnov, Maryna V. Kachaeva, Oleksandr L. Kobzar, Andriy I. Vovk, Volodymyr S. Brovarets https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | 5-сульфоніл-1,3-оксазол-4-карбоксилати синтез протипухлинна активність селективність молекулярний докінг Pilyo, Stepan G. Kozachenko, Оlexandr P. Zhirnov, Victor V. Kachaeva, Maryna V. Kobzar, Oleksandr L. Vovk, Andriy I. Brovarets, Volodymyr S. Cинтез та протипухлинна активність 5-сульфонільних похідних 1,3-оксазол-4-карбоксилатів |
| title | Cинтез та протипухлинна активність 5-сульфонільних похідних 1,3-оксазол-4-карбоксилатів |
| title_alt | Synthesis and anticancer activity of 5-sulfonyl derivatives of 1,3-oxazole-4-carboxylates |
| title_full | Cинтез та протипухлинна активність 5-сульфонільних похідних 1,3-оксазол-4-карбоксилатів |
| title_fullStr | Cинтез та протипухлинна активність 5-сульфонільних похідних 1,3-оксазол-4-карбоксилатів |
| title_full_unstemmed | Cинтез та протипухлинна активність 5-сульфонільних похідних 1,3-оксазол-4-карбоксилатів |
| title_short | Cинтез та протипухлинна активність 5-сульфонільних похідних 1,3-оксазол-4-карбоксилатів |
| title_sort | cинтез та протипухлинна активність 5-сульфонільних похідних 1,3-оксазол-4-карбоксилатів |
| topic | 5-сульфоніл-1,3-оксазол-4-карбоксилати синтез протипухлинна активність селективність молекулярний докінг |
| topic_facet | 5-sulfonyl-1,3-oxazole-4-carboxylates synthesis anticancer activity selectivity molecular docking 5-сульфоніл-1,3-оксазол-4-карбоксилати синтез протипухлинна активність селективність молекулярний докінг |
| url | https://bioorganica.com.ua/index.php/journal/article/view/36 |
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