Antineoplastic activity of novel thiazole derivatives
The development of novel efficient substances for anticancer chemotherapy is an important problem of medicinal chemistry. Aim. To evaluate the level of cytotoxic action of novel thiazole derivatives towards tumor cell lines of different origin. Methods. Four N acylated 2-amino-5-benzyl-1,3-thiazoles...
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Інститут молекулярної біології і генетики НАН України
2017
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irk-123456789-1529192019-06-14T01:28:09Z Antineoplastic activity of novel thiazole derivatives Finiuk, N.S. Hreniuh, V.P. Ostapiuk, Yu.V. Matiychuk, V.S. Frolov, D.A. Obushak, M.D. Stoika, R.S. Babsky, A.M. Bioorganic Chemistry The development of novel efficient substances for anticancer chemotherapy is an important problem of medicinal chemistry. Aim. To evaluate the level of cytotoxic action of novel thiazole derivatives towards tumor cell lines of different origin. Methods. Four N acylated 2-amino-5-benzyl-1,3-thiazoles (5a–d) were synthesized by reaction of 2-amino-5-R-benzyl-1,3-thiazoles with acid chlorides in the presence of triethylamine in the dioxane medium. Anticancer screening of the synthesized thiazoles was performed by the MTT assay. Results. Thiazole derivatives were shown to exert antineoplastic activity towards different types of tumor cells. The anti-glioma and anti-melanoma selectivity of these derivatives action was demonstrated. The compound 5a was found to be the most toxic for human glioblastoma U251 cells and human melanoma WM793 cells. At the same time, the created compounds possessed low toxicity towards pseudo-normal cells. Conclusion. The novel thiazole derivative 5a was the most toxic against human glioblastoma and melanoma cells. Створення нових ефективних субстанцій для використання у протипухлинній хіміотерапії є актуальним напрямком медичної хімії. Мета. Дослідити цитотоксичну дію нових похідних тіазолу щодо пухлинних клітин різного тканинного походження. Мето-ди. Чо-ти-ри нові N-ацильованих 2-аміно-5-бензил-1,3-тіазолів (субстанції 5a‑d) були синтезовані взаємодією 2-аміно-5-R-бензил-1,3-тіазолів з ацилхлоридами у середовищі діоксану за наявності триетиламіну. Для дослідження протипухлинної активності похідних тіазолу використовували МТТ-тест. Результа-ти. Вста-новлено, що деякі похідні тіазолу мають антинеопластичну активність щодо пухлинних клітин різного тканинного походження. Показано селективну антигліомну та антимеланомну дію досліджуваних сполук. Речовина 5а має найбільш виражену цитотоксичну дію щодо клітин лінії U251 гліобластоми людини і лінії WM793 меланоми людини. Синтезовані сполуки мають низьку токсичність щодо псевдонормальних ембріональних клітин нирки. Висновок. Нове похідне тіазолу (речовина 5а) є перспективним цитотоксичним чинником для дії на клітини гліобластоми і меланоми. Разработка и синтез новых производных тиазола являются перспективным направлением медицинской химии и противоопухолевой терапии. Цель. Изучение цитотоксического действия новых производных тиазола в отноше-нии злокачественных клеток различного тканевого происхождения. Методы. Четыре новых N-ацилированных 2-амино-5-бензил-1,3-тиазола (5a–d) были синтезированы взаимодействием 2-амино-5-R-бензил-1,3-тиазолов с ацилхлоридами в присутствии триэтиламина в среде диоксана. Исследование противоопухолевой активности тиа-золов проводили с использованием МТТ-анализа. Результаты. Уста-нов-лено, что производные тиазола оказывают противоопухолевое действие на некоторые типы опухолей. Было подтверждено селективное антиглиомное и ан-тимеланомное действие соединений. Соединение 5а проявляет наиболее выраженное цитотоксическое действие на опухолевые клетки U251 глиобластомы человека и WM793 меланомы человека. Исследованные соединения обла-дают низкой токсичностью по отношению к псевдо-нормальным эмбриональным клеткам почек. Вывод. Соедине-ние 5а является перспективным токсическим агентом для клеток глиобластомы и меланомы. 2017 Article Antineoplastic activity of novel thiazole derivatives / N.S. Finiuk, V.P. Hreniuh, Yu.V. Ostapiuk, V.S. Matiychuk, D.A. Frolov, M.D. Obushak, R.S. Stoika, A.M. Babsky // Вiopolymers and Cell. — 2017. — Т. 33, № 2. — С. 135-ХХ146 — Бібліогр.: 35 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00094B http://dspace.nbuv.gov.ua/handle/123456789/152919 547.789.1; 57.085.23; 615.277.3 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
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Bioorganic Chemistry Bioorganic Chemistry |
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Bioorganic Chemistry Bioorganic Chemistry Finiuk, N.S. Hreniuh, V.P. Ostapiuk, Yu.V. Matiychuk, V.S. Frolov, D.A. Obushak, M.D. Stoika, R.S. Babsky, A.M. Antineoplastic activity of novel thiazole derivatives Вiopolymers and Cell |
| description |
The development of novel efficient substances for anticancer chemotherapy is an important problem of medicinal chemistry. Aim. To evaluate the level of cytotoxic action of novel thiazole derivatives towards tumor cell lines of different origin. Methods. Four N acylated 2-amino-5-benzyl-1,3-thiazoles (5a–d) were synthesized by reaction of 2-amino-5-R-benzyl-1,3-thiazoles with acid chlorides in the presence of triethylamine in the dioxane medium. Anticancer screening of the synthesized thiazoles was performed by the MTT assay. Results. Thiazole derivatives were shown to exert antineoplastic activity towards different types of tumor cells. The anti-glioma and anti-melanoma selectivity of these derivatives action was demonstrated. The compound 5a was found to be the most toxic for human glioblastoma U251 cells and human melanoma WM793 cells. At the same time, the created compounds possessed low toxicity towards pseudo-normal cells. Conclusion. The novel thiazole derivative 5a was the most toxic against human glioblastoma and melanoma cells. |
| format |
Article |
| author |
Finiuk, N.S. Hreniuh, V.P. Ostapiuk, Yu.V. Matiychuk, V.S. Frolov, D.A. Obushak, M.D. Stoika, R.S. Babsky, A.M. |
| author_facet |
Finiuk, N.S. Hreniuh, V.P. Ostapiuk, Yu.V. Matiychuk, V.S. Frolov, D.A. Obushak, M.D. Stoika, R.S. Babsky, A.M. |
| author_sort |
Finiuk, N.S. |
| title |
Antineoplastic activity of novel thiazole derivatives |
| title_short |
Antineoplastic activity of novel thiazole derivatives |
| title_full |
Antineoplastic activity of novel thiazole derivatives |
| title_fullStr |
Antineoplastic activity of novel thiazole derivatives |
| title_full_unstemmed |
Antineoplastic activity of novel thiazole derivatives |
| title_sort |
antineoplastic activity of novel thiazole derivatives |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
2017 |
| topic_facet |
Bioorganic Chemistry |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/152919 |
| citation_txt |
Antineoplastic activity of novel thiazole derivatives / N.S. Finiuk, V.P. Hreniuh, Yu.V. Ostapiuk, V.S. Matiychuk, D.A. Frolov, M.D. Obushak, R.S. Stoika, A.M. Babsky // Вiopolymers and Cell. — 2017. — Т. 33, № 2. — С. 135-ХХ146 — Бібліогр.: 35 назв. — англ. |
| series |
Вiopolymers and Cell |
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135
N. S. Finiuk, V. P. Hreniuh, Yu. V. Ostapiuk
© 2017 N. S. Finiuk et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Bio-
polymers and Cell. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium,
provided the original work is properly cited
UDC 547.789.1; 57.085.23; 615.277.3
Antineoplastic activity of novel thiazole derivatives
N. S. Finiuk1,2, V. P. Hreniuh2, Yu. V. Ostapiuk3, V. S. Matiychuk3, D. A. Frolov3,
M. D. Obushak3, R. S. Stoika1, A. M. Babsky2
1 Institute of Cell Biology, NAS of Ukraine
14/16, Drahomanov Str., Lviv, Ukraine, 79005
2 Biology Faculty, Ivan Franko National University of Lviv
4, Hrushevskoho Str., Lviv, Ukraine, 79005
3 Chemistry Faculty, Ivan Franko National University of Lviv
6, Kyrylo and Mefodiy Str., Lviv, Ukraine, 79005
andriy.babsky@lnu.edu.ua
The development of novel efficient substances for anticancer chemotherapy is an important
problem of medicinal chemistry. Aim. To evaluate the level of cytotoxic action of novel thia-
zole derivatives towards tumor cell lines of different origin. Methods. Four N acylated
2-amino-5-benzyl-1,3-thiazoles (5a–d) were synthesized by reaction of 2-amino-5-R-ben-
zyl-1,3-thiazoles with acid chlorides in the presence of triethylamine in the dioxane medium.
Anticancer screening of the synthesized thiazoles was performed by the MTT assay. Results.
Thiazole derivatives were shown to exert antineoplastic activity towards different types of
tumor cells. The anti-glioma and anti-melanoma selectivity of these derivatives action was
demonstrated. The compound 5a was found to be the most toxic for human glioblastoma U251
cells and human melanoma WM793 cells. At the same time, the created compounds possessed
low toxicity towards pseudo-normal cells. Conclusion. The novel thiazole derivative 5a was
the most toxic against human glioblastoma and melanoma cells.
K e y w o r d s: thiazole derivatives, 2-amino-5-benzyl-1,3-thiazoles, anticancer activity, leu-
kemia, glioblastoma, melanoma.
Introduction
The discovery and development of the con-
ventional anticancer drugs have been mainly
focused on the cytotoxic agents [1]. The per-
spective antineoplastic agents are expected to
inhibit, delay or reverse the progression of
cancer development through their cytotoxicity
or apoptosis-inducing properties [2]. Cytotoxic
drugs prevent the rapid growth and division
(mitosis) of tumor cells [1]. However, many
anticancer drugs do not possess enough selec-
tivity towards their targets. Thus, their applica-
tion for cancer treatment is associated with
Bioorganic Chemistry ISSN 1993-6842 (on-line); ISSN 0233-7657 (print)
Biopolymers and Cell. 2017. Vol. 33. N 2. P 135–146
doi: http://dx.doi.org/10.7124/bc.00094B
mailto:andriy.babsky@lnu.edu.ua
136
N. S. Finiuk, V. P. Hreniuh, Yu. V. Ostapiuk et al.
numerous negative side effects in the orga-
nism [3, 4]. Drugs demonstrate cytotoxicity
toward different normal cells and organs, in-
cluding bone marrow cells, reproductive
glands, mucous layer of the intestine and hair
follicles. These effects limit significantly ap-
plication of some drugs and lead to the devel-
opment of novel drugs.
Thiazole derivatives have attracted the in-
terest of medicinal chemists due to a variety
of their biological activities including anti-
bacterial, anti-fungal, anti-HIV, anti-hyperten-
sion, anti-inflammatory, anti-cancer, anti-con-
vulsive and anti-depressant [5–10]. The mech-
anisms of 1,3-thiazole derivatives antitumor
activity may be associated with DNA interca-
lation [11, 12], PRL-3, SHP-2 and JSP-1 inhi-
bition [13–16], tumor necrosis factor
(TNFα) [17], anti-apoptotic bio-complex Bcl-
XL-BH3 [18], integrin avb3 [19], others.
Thiazole ring belongs to the privileged scaf-
folds in modern medicinal chemistry [11, 20,
21], particularly at discovering new anticancer
agents.
Herein, we described novel N-acylated
2-amino-5-benzyl-1,3-thiazoles and discovered
N2
+ -
O
CuCl2 Cl
Cl
O NH2 NH2
S
S
N
NH2
R R
R
EtOH, t
NEt3, dioxane
R1 Cl
O
S
N
N
H
R1
OR
acetone/H2O
1a-d
1, 2, 3: R = H (a), 4-Et (b), 4-Br (c), 3,4-Cl2 (d)
3a-d2a-d
5a-d
4a-d
Entry Compounds Entry Compounds
5a
S
N
N
H
O O
S
N
N
H
Et
O
S
O
S
N
N
HBr
O O
S
N
N
HCl
OCl
O
5c
S
N
N
H
O O
S
N
N
H
Et
O
S
O
S
N
N
HBr
O O
S
N
N
HCl
OCl
O
5b
S
N
N
H
O O
S
N
N
H
Et
O
S
O
S
N
N
HBr
O O
S
N
N
HCl
OCl
O
5d
S
N
N
H
O O
S
N
N
H
Et
O
S
O
S
N
N
HBr
O O
S
N
N
HCl
OCl
O
Fig. 1. General scheme of synthesis of thiazole derivatives
137
Antineoplastic activity of novel thiazole derivatives
anticancer activity of the obtained amides. The
synthesis of the target acylated 5-R-benzyl-
1,3-thiazol-2-amines 5 is presented in Fig. 1.
At the first step, the acrolein reacts with arene-
diazonium salts (1a–d) in the presence of
copper(II) chloride under the Meerwein aryla-
tion conditions. 3-Aryl-2-chloropropanals
(2a–d) react with the thiourea in ethanol at
refluxing and form 2-amino-5-R-benzyl-1,3-
thiazoles (3a–d) with good yield [22, 23].
Previously, we have discussed the synthetic
possibilities of 5-benzyl-2-aminothiazoles du-
ring the synthesis of 2-[(5-benzyl-1,3-thiazol-
2-yl)imino]-1,3-thiazolidin-4-ones as potential
biologically active compounds [24, 25]. In this
paper, we described N-acylated 2-amino-
5-benzyl-1,3-thiazoles (5a–d) obtained by the
reaction of 2-amino-5-R-benzyl-1,3-thiazoles
3a–d with acid chlorides 4a–d in the presence
of trietylamine in the dioxane medium.
The present study was addressed on the
synthesis of thiazole derivatives containing
some heterocyclic cores and the evaluation of
their anticancer activity towards tumor cell
lines of different tissue origin.
Materials and Methods
Thiazole derivatives
A 10 mM stock solution of thiazole derivatives
was prepared in the dimethyl sulfoxide
(DMSO, Sigma-Aldrich, USA), and addition-
ally dissolved in a culture medium prior to
addition to the cell culture.
General Procedure for the Synthesis
of 3-aryl-2-chloropropanales 2a–d [23]
A three-necked flask equipped with a dropping
funnel, a stirrer, and a gas-outlet tube attached
to a bubble counter was charged with acrolein
(0.2 mol or 13.5 cm3), CuCl2·2H2O (10 g), and
acetone (50 cm3). Then, cold aqueous solution
of arenediazonium chloride 1a–d prepared by
diazotization of aniline (0.2 mol) was added
drop-wise to the flask under vigorous stirring.
The temperature of the mixture was kept with-
in 10–30 °C. The organic phase was separated
when the reaction was completed, and the
aqueous phase was extracted with chloroform.
The extract was combined with the previous
organic phase, dried over magnesium sulfate,
evaporated, and the residue was distilled under
reduced pressure.
General Procedure for the Synthesis
of 2-amino-5-arylmethylthiazoles 3a–d
A mixture of 8 g of thiourea and 0.1 mol of
3-aryl-2-chloropropanal 2a–d in 50 cm3 of
ethanol was heated for 2 h under reflux. Then,
it was cooled, diluted with 300 cm3 of water,
and alkaline pH (~ 9) was achieved by adding
aqueous ammonia. The precipitate was filtered
off and recrystallized from carbon tetrachlo-
ride. 5-Benzyl-1,3-thiazol-2-amine 3a has been
described earlier [22, 23].
5-(4-Ethylbenzyl)-1,3-thiazol-2-amine
3b.Yield 86 %. M.p. 105–106 °C. 1H NMR
(400 MHz, DMSO-d6), δ: 7.11 (d, J = 7.8 Hz,
2H), 7.08 (d, J = 7.8 Hz, 2H), 6.64 (s, 1Н),
6.60 (s, 2Н), 3.81 (s, 2H), 2.58 (q, J = 7.7 Hz,
2H), 1.19 (t, J = 7.6 Hz, 3H). Calculated, %:
C 66.02, Н 6.46, N 12.83. C12H14N2S. Found:
C 65.85, Н 6.33, N 12.58.
5-(4-Bromobenzyl)-1,3-thiazol-2-amine 3c.
Yield 84 %. M.p. 123–125 °C. 1H NMR
(400 MHz, DMSO-d6), δ: 7.42 (d, 2Н, J =
8.1 Hz), 7.15 (d, 2Н, J= 8.1 Hz), 6.61 (s, 2Н),
6.64 (s, 1Н), 3.86 (s, 2Н). Calculated, %:
138
N. S. Finiuk, V. P. Hreniuh, Yu. V. Ostapiuk et al.
44.62, Н 3.37, N 10.41. C10H9BrN2S. Found:
C 44.34, Н 3.32, N 10.25.
5-(3,4-Dichlorobenzyl)-1,3-thiazol-2-amine
3d. Yield 83%. M.p. 92–94°C. 1H NMR
(400 MHz, DMSO-d6), δ: 7.47 (d, 1Н,
J=8.4 Hz), 7.40 (d, 1Н, J=1.8 Hz), 7.17 (dd,
1Н, 4J=1.8 Hz, 3J=8.4 Hz), 6.67 (br. s, 3Н),
3.90 (s, 2Н). Calculated, %: C 46.35, Н 3.11,
N 10.81. C10H8Cl2N2S. Found: C 46.22,
Н 3.08, N 10.69.
General Procedure for the Synthesis
of compounds 5a–d
5 mmol of 2-amino-5-arylmethylthiazole 3a–d
was dissolved in the mixture of 5 ml dioxane
and 5 mmol triethylamine. Solution of 5 mmol
acid chloride 4a–d in 3 ml dioxane was added
drop-wise to the reaction mixture under vigor-
ous stirring. Mixture was stirred for 2 h, and
diluted with 50 cm3 of water. The precipitate
was filtered off and recrystallized from mixture
EtOH/DMF.
N-(5-Benzyl-1,3-thiazol-2-yl)-3,5-dimethyl-
1-benzofuran-2-carboxamide 5a. Yield 75 %.
M.p. 198 °C. 1H NMR (400 MHz, DMSO-d6),
δ: 12.42 (s, 1H), 7.54 (s, 1H), 7.49 (d, 1H, J =
8.5 Hz,), 7.35–7.26 (m, 6H), 7.25–7.21 (m,
1H), 4.10 (s, 2H), 2.54 (s, 3H), 2.42 (s, 3H).
13C NMR (100 MHz, DMSO-d6), δ: 152.10,
142.44, 140.64, 133.87, 133.04, 131.92,
131.80, 129.66, 129.55, 129.07, 129.01,
128.89, 126.98, 124.10, 121.23, 111.93, 32.54,
21.36, 9.39. Calculated, %: C, 69.59; H, 5.01;
N, 7.73. C21H18N2O2S. Found: C, 69.29; H,
4.94; N, 7.63.
N-[5-(4-Ethylbenzyl)-1,3-thiazol-2-yl]-1-
oxo-1H-isothiochromene-3-carboxamide 5b.
Yield 83 %. M.p. 190 °C. 1H NMR (400 MHz,
DMSO-d6), δ: 13.09 (s, 1H), 8.36 (s, 1H), 8.18
(d, 1H, J = 7.9 Hz), 7.99–7.88 (m, 2H), 7.77
(t, 1H, J = 7.1 Hz), 7.33 (s, 1H), 7.19 (d, 2H,
J = 7.7 Hz), 7.16 (d, 2H, J = 8.1 Hz), 4.02 (s,
2H), 2.56 (q, 2H J = 7.7 Hz), 1.15 (t, 3H, J =
7.5 Hz). 13C NMR (101 MHz, DMSO-d6),δ: =
187.30, 156.46, 155.32, 146.97, 142.55,
137.57, 136.91, 135.26, 132.92, 131.54,
129.01, 128.86, 128.77, 128.55, 128.48,
128.46, 125.67, 32.43, 28.26, 16.11. Calculated,
%: C, 65.00; H, 4.46; N, 6.89. C22H18N2O2S2.
Found: C, 64.57; H, 4.39; N, 6.75.
N-[5-(4-Bromobenzyl)-1,3-thiazol-2-yl]-2-
(2,4-dimethylphenoxy)acetamide 5c. Yield
80 %. M.p. 150°C. 1H NMR (400 MHz,
DMSO-d6), δ: 12.15 (s, 1H), 7.49 (d, 2H,J =
8.2 Hz), 7.26 (s, 1H), 7.21 (d, 2H, J = 8.2 Hz),
6.95 (s, 1H), 6.89 (d, 1H, J = 8.2 Hz), 6.66 (d,
1H, J = 8.2 Hz), 4.77 (s, 2H), 4.06 (s, 2H),
2.17 (s, 3H), 2.16 (s, 3H). 13C NMR (101 MHz,
DMSO-d6), δ:162.19, 162.12, 154.31, 140.20,
135.40, 131.90, 131.82, 131.47, 131.09,
130.06, 127.46, 126.33, 120.03, 111.72, 66.91,
31.65, 20.52, 16.48. Calculated, %: C, 55.69;
H, 4.44; N, 6.49. C20H19BrN2O2S. Found: C,
55.32; H, 4.39; N, 6.33.
N-[5-(3,4-Dichlorobenzyl)-1,3-thiazol-2-
yl]-2H-chromene-2-carboxamide 5d. Yield
85%. M.p. 216°C. 1H NMR (400 MHz,
DMSO-d6), δ: 12.32 (s, 1H), 7.69 (s, 1H), 7.57
(d, 2H, J = 8.3 Hz), 7.33 (s, 1H), 7.31–7.22
(m, 3H), 6.99–6.95 (m, 1H), 6.86 (d, 1H, J =
8.0 Hz), 4.98 (s, 2H), 4.12 (s, 2H). 13C NMR
(101 MHz, DMSO-d6), δ: = 154.88, 142.01,
132.33, 132.22, 131.50, 131.47, 131.19,
131.14, 130.84, 130.76, 129.58, 129.50,
129.46, 129.33, 129.27, 122.44, 121.38,
116.28, 64.44, 31.21. Calculated, %: C, 57.56;
H, 3.38; N, 6.71. C20H14Cl2N2O2S. Found: C,
57.30; H, 3.31; N, 6.62.
139
Antineoplastic activity of novel thiazole derivatives
Cell culture
Human breast adenocarcinoma cells of MCF-
7 line, lung adenocarcinoma cells of A549 line,
glioblastoma cells of U251 line, myeloid
leukemia cells of K562 line, acute T-cell leuke-
mia cells of Jurkat line, and embryonic kidney
cells of HEK293 line were obtained from Cell
Collection of R.E. Kavetsky Institute of
Experimental Pathology, Oncology and
Radiology (Kyiv, Ukraine). Human melanoma
cells of WM793 line were provided by Dr. O.
Stasyk (Institute of Cell Biology, National
Academy of Sciences of Ukraine, Lviv,
Ukraine). Cells were grown in the RPMI (APP,
Austria) or DMEM (Sigma-Aldrich, USA)
culture medium supplemented with 10 % fetal
bovine serum (FBS, APP, Austria). Cells were
cultivated in the CO2-thermostate at 37oC in
atmosphere of 95 % air and 5 % CO2.
Cell proliferation assay
Antineoplastic activity of the synthesized
compounds towards cancer cell lines was mea-
sured by the MTT (3-(4,5-Dimethylthiazole-
2-yl)-2,5-diphenyl-tetrazolium bromide) test
(Sigma-Aldrich, USA) [26]. The antitumor
drug doxorubicin (Pharmachemie B.V., the
Netherlands) was used as a reference drug
control. Tumor cells were seeded for 24 h in
96-well plates in 100 μl at the concentration
of 5,000 cells/well (substrate-dependent cells)
or 10,000 cells/well (suspension cells). After
that, cells were incubated for next 72 h with
various additions of the synthesized com-
pounds or doxorubicin (0–100 μM). MTT was
added to the cells according to the manufac-
turer’s protocol (Sigma-Aldrich, USA). The
results of the reaction were determined by an
Absorbance Reader BioTek ELx800 (BioTek
Instruments, Inc., USA). The IC50 of tested
compounds was calculated as a lethal concen-
tration of drug killing 50 % of the cells in
comparison with an untreated culture.
Statistical analysis
All data are presented as the mean ± standard
deviation. The results were analyzed and il-
lustrated with GraphPad Prism (version 6;
GraphPad Software, USA). Statistical analysis
was performed using two-way ANOVA tests.
P-value of <0.05 was considered as statisti-
cally significant.
Results
The synthesis of different derivatives of
2-amino-5-arylmethylthiazoles is described
in the Materials and Methods section. The
compounds under study were added to the
cultured human tumor and pseudo-normal
cells in different final concentrations (0; 1;
10; 50 μM) for 72 h. Doxorubicin was used
as a reference positive control. The obtained
results were expressed as IC50 and presented
in Figures 2–4. The synthesized thiazoles
were shown to possess diverse anti-prolifer-
ative action towards tumor cells of different
tissue origin.
In the first set of experiments, the antican-
cer effect of compounds was studied towards
adenocarcinoma cells, namely human breast
adenocarcinoma cells of MCF-7 line and hu-
man lung adenocarcinoma cells of A549 line.
Doxorubicin demonstrated a much stronger
cytotoxicity for MCF-7 cells comparing to
the A549 cells (Fig. 2). However, both cell
lines were relatively not sensitive to the ac-
tion of studied thiazoles used in doses up to
50 μM.
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140
N. S. Finiuk, V. P. Hreniuh, Yu. V. Ostapiuk et al.
The antineoplastic effect of the thiazole
derivatives was also studied using human glio-
blastoma cells of U251 line and human mela-
noma cells of WM793 line. The concentration-
dependent cytotoxicity effect of the thiazoles
was found when the glioblastoma cells were
treated. The synthesized 5c, 5d and 5b dis-
played a weak activity towards glioblastoma
U251 cells (IC50 for 5c was 40.0±2.46 μM;
IC50 for 5d was 36.5±1.96 μM and IC50 for 5b
was 40.0±2.82 μM), and demonstrated cyto-
toxicity only when used in high dose (50 μM).
At the same time, the 5a compound was high-
ly toxic for the glioblastoma cells (IC50 =
9.8±0.82 μM), and even more toxic than the
doxorubicin (IC50 = 21.0±1.64 μМ) that is
considered to be a “golden standard” in the
anticancer chemotherapy (Fig. 3).
The general pattern of the cytotoxic activ-
ity of 5a–d thiazoles and doxorubicin towards
human melanoma cells of WM793 line was
similar to that described above for human
glioblastoma U251 cells. IC50 for 5c was
32.3±2.15 μM, IC50 for 5d was 34.6±2.24 μM,
Fig. 2. Characteristics of cytotoxicity of thiazole derivatives (5a–d) and doxorubicin (Dox) towards human breast
adenocarcinoma MCF-7 cells and human lung adenocarcinoma A549 cells.
Fig. 3. Characteristics of cytotoxicity of thiazole derivatives (5a–d) and doxorubicin (Dox) towards human glioblas-
toma U251 cells and human melanoma WM793 cells.
141
Antineoplastic activity of novel thiazole derivatives
and IC50 for 5b was 28.5±2.06 μM, whereas
the 5a compound was highly toxic for the
melanoma cells (IC50 = 7.2±0.48 μM), and the
toxicity of doxorubicin was similar to such
effect of the 5a compound (IC50 = 6.1±0.38 μM)
(Fig. 3).
As four human tumor cell lines used above
belong to the substrate-dependent type of cells,
it was reasonable to study the effect of 5a–d
thiazoles and doxorubicin on the inhibition of
growth of the leukemia cells in suspension.
Thus, human myeloid leukemia cells of K562
line and human acute T-cell leukemia cells of
Jurkat line were treated in vitro with the doxo-
rubicin and experimental anticancer agents.
We have found that 5c and 5b compounds
possessed a moderate toxicity for leukemia
K-562 cells (IC50 for 5c was 40.0±2.65 μM
and IC50 for 5b was 44.7±3.15μM). 5d and 5a
compounds were relatively non-toxic for the
leukemia K-562 cells in the concentration up
to 50 μM (Fig. 4), whereas the toxicity of
doxorubicin was much higher comparing to
the effect of thiazoles and IC50 for doxorubicin
was 15.2±1.14 μM.
It was found that 5c, 5a and 5b did not
demonstrate significant toxicity for human
acute T-cell leukemia cells of Jurkat line
(IC50 for 5a was 27.0±2.13 μM, IC50 for 5c
was 32.3±2.73 μM, and IC50 for 5b was
33.0± 2.85 μM). The 5d was poorly active
towards the Jurkat leukemia cells in dose to
50 μM, whereas the doxorubicin was ex-
tremely to xic for these cells (IC50 =
0.7±0.05 μM) (Fig. 4).
Fig. 4. Characteristics of cytotoxicity of thiazole derivatives (5a–d) and doxorubicin (Dox) towards human myeloid
leukemia cells of K562 line and human acute T-cell leukemia cells of Jurkat line.
Fig. 5. Characteristics of cytotoxicity of thiazole deriva-
tives (5a–d) and doxorubicin (Dox) towards human em-
bryonic kidney cells of HEK 293 line.
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142
N. S. Finiuk, V. P. Hreniuh, Yu. V. Ostapiuk et al.
Thus, the tested thiazole derivatives showed
a broad spectrum of the growth inhibition
activity against human tumor cells of different
tissue origin and the melanoma and glioma
cells appeared to be more sensitive to the ac-
tion of these derivatives comparing to human
leukemia cells.
Finally, we have studied the cytotoxic effect
of the novel thiazoles towards non-tumor pseu-
do-normal cells – human embryonic kidney
cells of HEK293 line (Fig. 5). Notably, these
cells demonstrated the resistance to the cyto-
toxic action of the thiazoles in dose up to
50 μM, whereas doxorubicin showed signifi-
cant cytotoxicity with the IC50 = ~20 μM.
Discussion
The tumor targeting technologies are focused
on creating novel agents that effectively in-
hibit, reverse or delay carcinogenesis [27]
through selective affecting tumor cells mostly
by impairing their antioxidant potential [28]
or inducing apoptosis [29, 30]. Additionally,
the potential drugs should combat tumor cells
of the advanced stages of malignancy (metas-
tasis) that is a major cause of patients’ morta-
lity [1].
We have screened the anti-proliferative ac-
tivity of the novel synthesized thiazoles 5a–d
towards human tumor cells of various tissue
origin. The MTT assay-based evaluation of the
survival of treated human breast adenocarci-
noma cells of MCF-7 line and human lung
adenocarcinoma cells of A549 line showed that
these cells were sensitive to the cytotoxic ac-
tion of the thiazoles used only in high doses
(up to 50 μM). At the same time, these com-
pounds possessed a distinct antineoplastic ac-
tivity towards the human glioblastoma cells of
U251 line and human melanoma cells of
WM793 line, whereas the human myeloid
leukemia cells of K562 line and human acute
T-cell leukemia cells of Jurkat line were less
sensitive to the cytotoxic action of the experi-
mental anticancer agents. The ranking of the
toxic action of thiazoles and doxorubicin to-
wards the glioblastoma U251 cells was as
following: 5a > doxorubicin > 5d > 5c ≈ 5b.
IC50 of 5a for the glioblastoma cells equaled
9.8±0.82 μM, whereas doxorubicin was less
toxic for these cells (IC50 = 21.0±1.64 μМ).
Obviously, the amides endowed with the ben-
zofuran moiety (5a) possess a higher antican-
cer activity [31, 32]. Glass et al. (2000) showed
an inhibition of growth in human glioblastoma
cell lines by the farnesyltransferase inhibitor
SCH66336. However, the concentration of that
inhibitor, which is required to achieve 50 %
inhibition (IC50) ranged from 30 µM (single
24 h treatment) to 10 µM (5 day treatment).
This is a higher dose compared to the dose
required for distinct effect of 5a used in our
study.
Malignant melanoma is a disease with a
high mortality rate caused by rapid metastasis.
Ciołczyk-Wierzbicka et al. [35] showed the
inhibition of proliferation of human melanoma
cells by using specific siRNA for silencing the
N-cadherin gene. Its silencing arrests the cell
growth at the G1-phase of cell cycle and in-
hibits the cell entry into the S-phase. Note wor-
thy, there are no effective chemotherapies for
the melanoma treatment [33]. The immuno-
modulating approaches used in clinics are still
very costly and possess high general toxi-
city [34].
During studying the anti-proliferative activ-
ity of the synthesized thiazoles towards the
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143
Antineoplastic activity of novel thiazole derivatives
human melanoma WM793 cells, we have
found that 5a was also the most cytotoxic agent
(IC50 = 7.2±0.48 μM) the action of which was
comparable with the action of doxorubicin
(IC50 = 6.1±0.38 μM). The toxicity rank of
thiazoles and doxorubicin for the melanoma
WM793 cells was: doxorubicin ≈ 5a > 5b >
5c > 5d.
The synthesized thiazoles were also found
to be toxic for leukemia cells ‒ the human
myeloid leukemia cells of K562 line and the
human acute T-cell leukemia cells of Jurkat
line, however, demonstrated their cytotoxicity
only at high doses. The ranking of the toxic
action of thiazoles and doxorubicin on the
leukemia K562 cells was the following: doxo-
rubicin (15.2±1.14 μM) > 5c (40.0±2.65 μM)
> 5b > 5d > 5a. Thus, the rank of toxicity of
the 5a for these leukemia cells growing only
in suspension is opposite to the rank found for
the glioblastoma and melanoma cells growing
in the monolayer culture. Thus, the role of
silencing N-cadherin (participates in cell at-
tachment) for the inhibition of melanoma cells
should be reminded here [35]. Doxorubicin
was the most effective inhibitor of growth of
the human acute T-cell leukemia cells of Jurkat
line, and the rank of inhibitory effects dropped
in the following manner: doxorubicin (IC50 =
0.7±0.05 μM) > 5a (IC50 = 27.0±2.13 μM) >
5c > 5b >5d. Obviously, amides 5 endowed
with benzofuran moiety (5a) have a higher
anticancer activity [31, 32].
It was also shown that thiazoles were not
toxic for human embryonic kidney HEK293
cells, while doxorubicin had high cytotoxity
towards these cells (IC50 was 5.7±0.42 μM).
The tested thiazole derivatives showed a
broad spectrum of the anti-proliferative acti-
vi ty against human tumor cells of different
tissue origin and the melanoma and glioma
cells appeared to be more sensitive to the ac-
tion of these derivatives comparing to human
leukemia cells.
Conclusion
Four novel thiazole derivatives were synthe-
sized and screened for their anticancer acti-
vi ty in vitro. These derivatives selectively
inhibited the growth of human tumor cells,
and 5a was the most potent agent demonstrat-
ing a selective action towards the glioma and
melanoma cells, comparing to the leukemia
cells. Thus, the thiazole derivatives are a
perspective source of the innovative antican-
cer agents.
Acknowledgments
The authors thank Dr. O. Stasyk (Institute of
Cell Biology, National Academy of Sciences
of Ukraine, Lviv, Ukraine) for providing hu-
man melanoma cells of WM793 line. This
work was partially financed by the grant
№ 0116U001533 from the Ukrainian govern-
ment.
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Антинеопластична активність нових похідних
тіазолів
Н. С. Фінюк, В. П. Гренюх, Ю. В. Остап’юк,
В. С. Матійчук, Д. А. Фролов, М. Д. Обушак,
Р. С. Стойка, А. М. Бабський
Створення нових ефективних субстанцій для викорис-
тання у протипухлинній хіміотерапії є актуальним
напрямком медичної хімії. Мета. Дослідити цитоток-
сичну дію нових похідних тіазолу щодо пухлинних
клітин різного тканинного походження. Мето ди. Чо-
ти ри нові N-ацильованих 2-аміно-5-бензил-1,3-тіазолів
(субстанції 5a-d) були синтезовані взаємодією 2-аміно-
5-R-бензил-1,3-тіазолів з ацилхлоридами у середовищі
діоксану за наявності триетиламіну. Для дослідження
протипухлинної активності похідних тіазолу викорис-
товували МТТ-тест. Результа ти. Вста новлено, що
146
N. S. Finiuk, V. P. Hreniuh, Yu. V. Ostapiuk et al.
деякі похідні тіазолу мають антинеопластичну актив-
ність щодо пухлинних клітин різного тканинного по-
ходження. Показано селективну антигліомну та анти-
меланомну дію досліджуваних сполук. Речовина 5а
має найбільш виражену цитотоксичну дію щодо клітин
лінії U251 гліобластоми людини і лінії WM793 мела-
номи людини. Синтезовані сполуки мають низьку
токсичність щодо псевдонормальних ембріональних
клітин нирки. Висновок. Нове похідне тіазолу (речо-
вина 5а) є перспективним цитотоксичним чинником
для дії на клітини гліобластоми і меланоми.
К л юч ов і с л ов а: похідні тіазолу, 2-аміно-5-бензил-
1,3-тіазоли, протипухлинна активність, лейкоз, гліо-
бластома, меланома.
Антинеопластическая активность новых
производных тиазола
Н. C. Финюк, В. П. Гренюх, Ю. В. Остапюк,
В. С. Матийчук, Д. А. Фролов, M. Д. Обушак,
Р. С. Стойка, А. М. Бабский
Разработка и синтез новых производных тиазола яв-
ляются перспективным направлением медицинской
химии и противоопухолевой терапии. Цель. Изучение
цитотоксического действия новых производных тиа-
зола в отношении злокачественных клеток различно-
го тканевого происхождения. Методы. Четыре новых
N-ацилированных 2-амино-5-бензил-1,3-тиазола (5a–
d) были синтезированы взаимодействием 2-ами-
но-5-R-бензил-1,3-тиазолов с ацилхлоридами в при-
сутствии триэтиламина в среде диоксана. Исследо ва-
ние противоопухолевой активности тиазолов прово-
дили с использованием МТТ-анализа. Результаты.
Уста нов лено, что производные тиазола оказывают
противоопухолевое действие на некоторые типы опу-
холей. Было подтверждено селективное антиглиомное
и антимеланомное действие соединений. Соединение
5а проявляет наиболее выраженное цитотоксическое
действие на опухолевые клетки U251 глиобластомы
человека и WM793 меланомы человека. Исследованные
соединения обладают низкой токсичностью по отно-
шению к псевдо-нормальным эмбриональным клеткам
почек. Вывод. Соединение 5а является перспектив-
ным токсическим агентом для клеток глиобластомы
и меланомы.
К л юч е в ы е с л ов а: производные тиазола, 2-амино-
5-бензил-1,3-тиазолы, противоопухолевая активность,
лейкоз, глиобластома, меланома.
Received 10.03.2017
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