Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
Aim. To study anticancer activity of a series of new thiopyrano[2,3-d]thiazoles with a norbornane fragment in the molecules. The search for trypanocidal properties of target compounds. Methods. Organic synthesis, analytical and spectral methods, pharmacological screening, COMPARE and SAR analysis. R...
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irk-123456789-1529262019-06-14T01:26:09Z Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety Kryshchyshyn, A.P. Atamanyuk, D.V. Kaminskyy, D.V. Grellier, Ph. Lesyk, R.B. Bioorganic Chemistry Aim. To study anticancer activity of a series of new thiopyrano[2,3-d]thiazoles with a norbornane fragment in the molecules. The search for trypanocidal properties of target compounds. Methods. Organic synthesis, analytical and spectral methods, pharmacological screening, COMPARE and SAR analysis. Results. Fused thiopyrano[2,3-d]thiazoles bearing the norbornane moiety were synthesized and modified at the C9 and N5 positions of the main core in order to obtain the compounds with a satisfactory pharmacological profile. A number of compounds with significant level of cancer cells growth inhibition were identified; they include a hit-compound N1-(4-chlorophenyl)-2-{2-[6-oxo-5,9-dithia-7-azatetracyclo [9.2.1.02,10.04,8]tetradec-4(8)-en-3-yl]phenoxy}acetamide IId that selectively inhibited Leukemia cell lines at submicromolar concentrations. Moreover, a series of thiopyrano[2,3-d]thiazoles showed a moderate antitrypanosomal activity. Conclusions. New thiopyrano[2,3-d]thiazoles with the norbornane fragment as well as their analogues with different substituents at the N5 and C9 position were designed and synthesized. The compounds showed significant levels of anticancer activity towards the selected cancer cell lines and may be used for further optimization. The compounds with a high antitumor activity inhibited the growth of Trypanosoma brucei brucei in in vitro tests. The combined anticancer and antitrypanosomal effect of compounds is the basis for further modification and search for a possible mode of action of the target compounds. Мета. Вивчення протипухлинної та трипаноцидної активності серії нових тіопірано[2,3-d]тіазолів з норборнановим фрагментом у молекулах. Методи. органічний синтез, аналітичні та спектральні методи, фармакологічний скринінг, COMPARE та SAR аналізи. Результати. Для одержання сполук з відповідним фармакологічним профілем синтезовано нові конденсовані похідні тіопірано[2,3-d]тіазолу з норборнановим фрагментом у молекулах, які модифіковані за положеннями С9 та N5 базового гетероциклу. Ідентифіковано ряд сполук з суттєвим рівнем інгібування росту ракових клітин, серед яких сполука-хіт N1-(4-хлорофеніл)-2-{2-[6-оксо-5,9-дитіа-7-азатетрацикло[9.2.1.02,10.04,8]тетрадец-4(8)-ен-3-іл]фенокси}ацетамід IId, що селективно інгібує лінії клітин лейкемії в субмікромолярних концентраціях. Крім того, ряд тіопірано[2,3-d]тіазолів також проявляють перспекти-вну протитрипаносомну активність. Висновки. Синтезовано нові тіопірано[2,3-d]тіазоли з норборнановим фрагментом у молекулах а також їх похідні з різноманітними субституентами в положеннях N5 та C9 базової гетероцик-лічної системи. Сполуки проявили суттєвий рівень протипухлинної активності і можуть бути використані для по-дальшої оптимізації структури як потенційні протиракові агенти. Окрім того, сполуки з високим рівнем протипух-линного ефекту in vitro інгібують ріст Trypanosoma brucei brucei. Поєднання протиракової та протитрипаносомної активності синтезованих сполук є основою для наступної структурної модифікації та пошуку імовірних механізмів реалізації їх біологічної активності. Цель. Изучение антиопухолевой и трипаноцидной активности серии новых тиопирано[2,3-d]тиазолов из нор-борнановым фрагментом в молекулах. Методы. органический синтез, аналитические и спектральные методы, фармакологический скрининг, COMPARE и SAR анализы. Результаты. Для получения соединений с соответствующим фармакологическим профилем синтезированы новые производные тиопирано[2,3-d]тиазола с норборнановым фрагментом в молекулах, которые модифицированы по положениям С9 и N5 базового гетероцикла. Идентифицирован ряд соединений с существенным уровнем ингибирования роста раковых клеток, среди которых соединение-хит N1-(4-хлорфенил)-2-{2-[6-оксо-5,9-дитиа-7-азатетрацикло[9.2.1.02,10.04,8]тетрадец-4(8)-ен-3-ил]фенокси}ацетамид IId, который селективно ингибирует линии клеток лейкемии в субмикромолярных концентрациях. Кроме того, некоторые тіопірано[2,3-d]тіазолы также проявляют перспективную протитрипаносомную активность. Выводы. Синтезированы новые тиопирано[2,3-d]тиазолы с норборнановым фрагментом у молекулах, а также их производные с различными заместителями в положениях N5 и C9 базовой гетероциклической системы. Соединения проявили существенный уровень противоопухолевой активности и могут быть использованы для дальнейшей структурной оптимизации как потенциальные противораковые агенты. Кроме того, соединения с высоким уровнем противоопухолевого эффекта in vitro ингибируют рост Trypanosoma brucei brucei. Сочетание антираковой и противотрипаносомной активности синтезированных соединений может быть основой для дальнейшей оптимизации структуры и поиска возможных механизмов реализации их биологической активности. 2017 Article Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety / A.P. Kryshchyshyn, D.V. Atamanyuk, D.V. Kaminskyy, Ph. Grellier, R.B. Lesyk // Вiopolymers and Cell. — 2017. — Т. 33, № 3. — С. 183-205. — Бібліогр.: 40 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00094F http://dspace.nbuv.gov.ua/handle/123456789/152926 615.012.1.076:547.789.6 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 Kryshchyshyn, A.P. Atamanyuk, D.V. Kaminskyy, D.V. Grellier, Ph. Lesyk, R.B. Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety Вiopolymers and Cell |
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Aim. To study anticancer activity of a series of new thiopyrano[2,3-d]thiazoles with a norbornane fragment in the molecules. The search for trypanocidal properties of target compounds. Methods. Organic synthesis, analytical and spectral methods, pharmacological screening, COMPARE and SAR analysis. Results. Fused thiopyrano[2,3-d]thiazoles bearing the norbornane moiety were synthesized and modified at the C9 and N5 positions of the main core in order to obtain the compounds with a satisfactory pharmacological profile. A number of compounds with significant level of cancer cells growth inhibition were identified; they include a hit-compound N1-(4-chlorophenyl)-2-{2-[6-oxo-5,9-dithia-7-azatetracyclo [9.2.1.02,10.04,8]tetradec-4(8)-en-3-yl]phenoxy}acetamide IId that selectively inhibited Leukemia cell lines at submicromolar concentrations. Moreover, a series of thiopyrano[2,3-d]thiazoles showed a moderate antitrypanosomal activity. Conclusions. New thiopyrano[2,3-d]thiazoles with the norbornane fragment as well as their analogues with different substituents at the N5 and C9 position were designed and synthesized. The compounds showed significant levels of anticancer activity towards the selected cancer cell lines and may be used for further optimization. The compounds with a high antitumor activity inhibited the growth of Trypanosoma brucei brucei in in vitro tests. The combined anticancer and antitrypanosomal effect of compounds is the basis for further modification and search for a possible mode of action of the target compounds. |
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Article |
| author |
Kryshchyshyn, A.P. Atamanyuk, D.V. Kaminskyy, D.V. Grellier, Ph. Lesyk, R.B. |
| author_facet |
Kryshchyshyn, A.P. Atamanyuk, D.V. Kaminskyy, D.V. Grellier, Ph. Lesyk, R.B. |
| author_sort |
Kryshchyshyn, A.P. |
| title |
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety |
| title_short |
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety |
| title_full |
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety |
| title_fullStr |
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety |
| title_full_unstemmed |
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety |
| title_sort |
investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety |
| publisher |
Інститут молекулярної біології і генетики НАН України |
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2017 |
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Bioorganic Chemistry |
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http://dspace.nbuv.gov.ua/handle/123456789/152926 |
| citation_txt |
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety / A.P. Kryshchyshyn, D.V. Atamanyuk, D.V. Kaminskyy, Ph. Grellier, R.B. Lesyk // Вiopolymers and Cell. — 2017. — Т. 33, № 3. — С. 183-205. — Бібліогр.: 40 назв. — англ. |
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Вiopolymers and Cell |
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183
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy
© 2017 A. P. Kryshchyshyn et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf
of Biopolymers 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 615.012.1.076:547.789.6
Investigation of anticancer and anti-parasitic activity
of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
A. P. Kryshchyshyn1, D. V. Atamanyuk1,2, D. V. Kaminskyy1, Ph. Grellier3, R. B. Lesyk1
1 Danylo Halytsky Lviv National Medical University
69, Pekarska Str., Lviv, Ukraine, 79010
2 Emanine Ltd
23, A. Matrosova Str., Kyiv, Ukraine, 01103
3 National Museum of Natural History, UMR 7245 CNRS MCAM, Sorbonne Universités
CP 52, 57 Rue Cuvier, Paris 75005, France
dr_r_lesyk@org.lviv.net
Aim. To study anticancer activity of a series of new thiopyrano[2,3-d]thiazoles with a norbornane
fragment in the molecules. The search for trypanocidal properties of target compounds. Methods.
Organic synthesis, analytical and spectral methods, pharmacological screening, COMPARE and SAR
analysis. Results. Fused thiopyrano[2,3-d]thiazoles bearing the norbornane moiety were synthesized
and modified at the C9 and N5 positions of the main core in order to obtain the compounds with a
satisfactory pharmacological profile. A number of compounds with significant level of cancer cells
growth inhibition were identified; they include a hit-compound N1-(4-chlorophenyl)-2-{2-[6-oxo-
5,9-dithia-7-azatetracyclo [9.2.1.02,10.04,8]tetradec-4(8)-en-3-yl]phenoxy}acetamide IId that selec-
tively inhibited Leukemia cell lines at submicromolar concentrations. Moreover, a series of
thiopyrano[2,3-d]thiazoles showed a moderate antitrypanosomal activity. Conclusions. New
thiopyrano[2,3-d]thiazoles with the norbornane fragment as well as their analogues with different
substituents at the N5 and C9 position were designed and synthesized. The compounds showed
significant levels of anticancer acti vi ty towards the selected cancer cell lines and may be used for
further optimization. The compounds with a high antitumor activity inhibited the growth of Trypanosoma
brucei brucei in in vitro tests. The combined anticancer and antitrypanosomal effect of compounds is
the basis for further modification and search for a possible mode of action of the target compounds.
K e y w o r d s: Thiopyrano[2,3-d]thiazoles, norbornane, synthesis, anticancer activity, anti-
trypanosomal activity, SAR.
Introduction
Thiopyranothiazole core is a good scaffold for
design of new pharmacologically interesting
molecules [1–6]. The most efficient method
for their synthesis is based on hetero-Diels-
Alder reaction of 5-ene-4-thioxo-2-thiazolidi-
nones (5-eneisorhodanines). Thus, thiopyrano-
Bioorganic Chemistry ISSN 1993-6842 (on-line); ISSN 0233-7657 (print)
Biopolymers and Cell. 2017. Vol. 33. N 3. P 183–205
doi: http://dx.doi.org/10.7124/bc.00094F
mailto:mail@mail.com
184
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
thiazoles are the derivatives of widely inves-
tigated 4-thiazolidinones. There are a number
of drug candidates and approved drugs based
on 4-thiazolidinone core, such as hypoglyce-
mic glytazones – PPARsγ agonists –
Rosiglitazone, Pioglitazone (2,4-thiazolidinone
derivatives) [7] and aldose reductase inhibi-
tor – Epalrestat (rhodanine derivative) [8];
anti-inflammatory dual inhibitor of COX-2/5-
LOX – Darbufelon (2-aminothiazolidinone
derivative) [9]; diuretic Etozoline (2-ylidene-
4-thiazolidinone derivative) [10]; anticonvul-
sant Ralitoline (2-ylidene-4-thiazolidinone
derivative) etc. [11]. Despite this, modern me-
dicinal chemistry is still interested in the 4-thi-
azolidinone derivatives as a source of new
drugs and a lot of research have been done in
this area [12, 13]. Though, there are also com-
ments of some scientists claiming the 4-thia-
zolidinones, namely 5-ene-4-thiazolidinones
(one of the most powerful subtypes of men-
tioned heterocycles), as pan assay interference
compounds (PAINS) due to their possible
Michael acceptor functionality, wide spectrum
of biological activities and low selectivity [14,
15]. The issues of PAINS remain controver-
sial [12, 13]. Thiopyranothiazoles are hypoth-
esized as biomimetics of the pharmacologi-
cally active 5-ene-4-thiazolidinones (synthetic
precursors of thiopyranothiazoles) without
mentioned Michael acceptor functionality [1,
2, 6]. Taking into account the results of bio-
logical activities study of thiopyranothiazoles
one can conclude that these compounds might
have good pharmacological profile but reveal
different chemical and physical properties. The
pharmacological activities associated with
thiopyranothiazole core are antitumor [1, 2, 5,
6, 16, 17], antitrypanosomal [18–20], antioxi-
dant and anti-inflammatory [21] etc. Moreover,
our previous findings showed that introduction
of norbornane fragment in thiopyranothiazole
molecules contributed to their antitumor acti-
vi ty with selectivity towards lung, renal, breast,
leukemia and melanoma cancer types [1, 2].
A search for new anticancer agents among
thiopyranothiazoles seems to be promising,
and the target compounds of this work are
shown in Fig. 1.
A number of hypotheses has been put for-
ward in order to explain possible modes of
antitumor action of the thiazolidinone deriva-
tives and speculatively thiopyranothiazoles.
For example, a mitochondria-depended pro-
apoptic mode of action related with G0/G1
arrest and an activation of ROS production;
the caspase-depended and Bcl-depended path-
ways are the most discussed [13, 22].
The present work is an extension of our
ongoing efforts towards a search for new thi-
azolidinone-based anticancer agents. Another
objective of the study was to discover wheth-
er there is any correlation between anticancer
and antitrypanosomal activity as the latter was
shown for a series of related thiopyranothia-
zoles [20]. A repurposing approach is one of
the currently used methods to discover new
active antitrypanosomal agents [18, 23]. For
example, anticancer drug Bortezomid showed
excellent results in in vitro test against
Trypanosome brucei inhibiting the parasites
growth at nanomolar concentrations [24]. The
DNA topoisomerase inhibitors (aclarubicin,
doxorubicin and mitoxantrone) were also test-
ed against bloodstream forms of Trypanosoma
brucei and their trypanocidal activities were
comparable with those of commercial antitry-
panosomal drugs [25].
185
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
Here we addressed the screening of anti-
cancer and antitrypanosomal effects in vitro of
new thiopyrano[2,3-d]thiazoles with norbor-
nane core and their N-3 derivatives.
Materials and Methods
Chemistry
All chemicals were of the analytical grade and
commercially available. All reagents and sol-
vents were used without further purification
and drying. The starting 5-eneisorhodanines
(I) [1] and 2,4-thiazolidinedione-5-acetic acid
[26] were synthesized as described previously.
NMR spectra were determined with Varian
Mercury 400 (400 MHz) spectrometer, in
DMSO-d6 using tetramethylsilane as an inter-
nal standard. Elemental analyses (C, H, N)
were performed on a Perkin-Elmer 2400 CHN
analyzer and were within ± 0.4% from the
theoretical values. Mass spectra were obtained
using electrospray ionization (ESI) techniques
on an Agilent 1100 Series LCMS. The purity
of the compounds was checked by thin-layer
chromatography performed with Merck Silica
Gel 60 F254 aluminum sheets.
General procedure for the synthesis of
9-aryl(heteryl)-3,7-dithia-5-azatetracyc-
lo[9.2.1.02,10.04,8]tetradecen-4(8)-ones-6 (II).
A mixture of 5-ene-4-thioxo-2-thiazolidinone
I (5 mmol), 2-norbornene (6 mmol), cata-
lytic amounts of hydroquinone and acetic
acid (15 mL) was heated under reflux during
1 hour and then cooled. Obtained solid prod-
ucts were filtered off, dried and recrystallized
from the mixture of DMF/EtOH (1:2) or
acetic acid.
9 - ( 2 - P y r i d y l ) - 3 , 7 - d i t h i a - 5 -
azatetracyclo[9.2.1.02,10.04,8]tetradec-4(8)-en-
6-one (IIa). Yield 68 %, mp 226–228 °C. 1H
NMR (DMSO-d6) d: 1.14 m, 1.23 (d, J =
9.8 Hz), 1.35 m, 1.45 m, 1.62 m, 1.95 m,
2.10 m, 2.24 m (9H, norbornane fragment),
3.42–3.48 (m, 2H, ArCH, SCH), 7.67 (m, 1H,
arom.), 7.86 (d, 1H, J = 6.8 Hz, arom.), 8.57
(s, 1H, arom.), 8.75 (d, 1H, J = 5.0 Hz, arom.),
11.05 (s, 1H, NH). LCMS (ESI) m/z 317
(97 %, (M+H+). Calcd. for C16H16N2OS2: C,
S
S
NO
O
H
H
R1
R
N
H
S
S
ON
O
O
H
R
HHAr
S
S
N
H
O
O Ar
O
H
S
S
N
H
Ar
O
S
S
N
H
Ar
O
S
S
N
Ar
O
R
Target compounds
[2][6][5]
Modification directions
Anticancer agents
Fig. 1. Structure of active thiopyra-
no[2,3-d]thiazoles and target com-
pounds
186
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
60.73; H, 5.10; N, 8.85; Found: C, 60.00; H,
8.90; N, 9.00.
9-(4-Methyloxycarboxyphenyl)-3,7-dithia-
5-azatetracyclo[9.2.1.02,10.04,8]tetradec-4(8)-
en-6-one (IIb). Yield 70 %, mp 243-245 °C.
1H NMR (DMSO-d6) d: 1.05 m, 1.18 (d, J =
10.2 Hz), 1.32 m, 1.38 m, 1.58 m, 1.89 m,
2.11(d, J = 10.1 Hz), 2.24 m (9H, norbornane
fragment), 3.44 (d, 1H, J = 7.6 Hz, ArCH),
3.56 (d, 1H, J = 10.2 Hz, SCH), 3.85 (s, 3H,
CH3), 7.54 (d, 2H, J = 8.0 Hz, arom.), 7.974
(d, 2H, J = 8.0 Hz, arom.), 11.53 (s, 1H, NH).
LCMS (ESI) m/z 374 (98 %, (M+H+). Calcd.
for C19H19NO3S2: C, 61.10; H, 5.13; N, 3.75;
Found: C, 61.00; H, 5.00; N, 4.00
9-(3,5-Dimethoxy-4-hydroxyphenyl)-3,7-
dithia-5-azatetracyclo-[9.2.1.02,10.04,8]tetra-
dec-4(8)-en-6-one (IIc). Yield 75 %, mp
>250 °C. 1H NMR (DMSO-d6) d: 1.11 m, 1.22
(d, J = 10.0 Hz), 1.33 m, 1.44 m, 1.64 m,
1.98 m, 2.16 m, 2.23 m (9H, norbornane frag-
ment), 3.30 (d, 1H, J = 7.9 Hz, ArCH), 3.37
(d, 1H, J = 10.1 Hz, SCH), 3.84 (s, 6H,
2*CH3), 7.32 (brs, 2H, arom), 9.08 (s, 1H,
OH), 11.26 (s, 1H, NH). Calcd. for
C19H21NO4S2: C, 58.29; H, 5.41; N, 3.58;
Found: C, 58.40; H, 5.60; N, 3.40.
N1-(4-Chlorophenyl)-2-{2-[6-oxo-5,9-
dithia-7-azatetracyclo [9.2.1.02,10.04,8]tetra-
dec-4(8)-en-3-yl]phenoxy}acetamide (IId).
Yield 78 %, mp 194-196°C. 1H NMR
(DMSO-d6) d: 1.16 m, 1.31 m, 1.44 m, 1.63 m,
1.92 brs, 2.10 m, 2.21 m, 2,31 m (9H, norbor-
nane fragment), 3.39 (d, 1H, J = 7.8 Hz,
ArCH), 4.00 (d, 1H, J = 10.2 Hz, SCH), 4.68
(s, 2H, OCH2), 6.99 (m, 2H, arom.), 7.26–7.40
(m, 4H, arom.), 7.59 (d, 2H, J = 8.0 Hz, arom.),
10.02 (s, 1H, NH), 11.30 (s, 1H, NH). LCMS
(ESI) m/z 499/501 (96 %, (M+H+). Calcd. for
C25H23ClN2O3S2: C, 60.17; H, 4.65; N, 5.61;
Found: C, 60.00; H, 4.60; N, 5.80.
9-(4-N-Dimethylaminophenyl)-3,7-dithia-
5-azatetracyclo[9.2.1.02,10.04,8]tetradec-4(8)-
en-6-one (IIe). Yield 72 %, mp 246–248 °C.
1H NMR (DMSO-d6) d: 1.13 (m, 1H, norbor-
nane fragment), 1,16 (t, 6H, J = 6.9 Hz,
2*CH3), 1.20 m, 1.31 m, 1.47 m, 1.64 m, 2.11
m, 2.12 (d, J = 10.0 Hz), 2.21 (d, J = 3,9 Hz)
(8H, norbornane fragment), 3.17 (d, 1H, J =
7.8 Hz, ArCH), 3.34 (m, 4H, 2*CH2), 3.37 (m,
1H, SCH), 6.56 (d, 2H, J = 8.2 Hz, arom.),
7.01 (d, 2H, J = 8.2 Hz, arom.), 11.10 (s, 1H,
NH). LCMS (ESI) m/z 387 (95.6 %, (M+H+).
Calcd. for C21H26N2O2S2: C, 65.25; H, 6.78;
N, 7.25; Found: C, 65.35; H, 6.85; N, 7.10.
9- (Th iophen-2 -y l ) -3 ,7 -d i th ia -5 -
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6 (IIf). Analytical and spectral data are
described [1].
9-(4-Chlorophenyl)-3,7-di thia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6 (IIg). Analytical and spectral data are
described [1].
9-(4-(3,5-Diphenyl-4,5-dihydro-pyrazol-1-
yl)-phenyl)-3,7-dithia-5-azatetracyc-
lo-[9.2.1.02,10.04,8]tetradecen-4(8)-one-6 (IIh).
Yield 76 %, mp 133–135 °C. 1H NMR
(DMSO-d6) d: 1.14 m, 1.28 m, 1.39 m, 1.62 m,
1.86 m, 2.10 m, 2.23 m, 2,32 m (9H, norbor-
nane fragment), 3.39 (d, 1H, J = 7.8 Hz, ArCH),
3.48 (m, 1H, CH2CH), 3.85 (m, 1H, CH2CH),
3.94 (d, 1H, J = 10.2 Hz, SCH), 5.76 (m, 1H,
CH2CH), 6.84–6.92 (m, 2H, arom.), 7.21–7.28
(m, 4H, arom.), 7.56–7.62 (m, 4H, arom.),
7.69–7.73 (brs, 4H, arom), 11.02 (s, 1H, NH).
LCMS (ESI) m/z 536 (96.2 %, (M+H+). Calcd.
for C32H29N3OS2: C, 71.74; H, 5.46; N, 7.84;
Found: C, 72.00; H, 5.70; N, 7.60.
187
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
9-(4-Metoxyphenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6 (IIi). Analytical and spectral data are
described [1].
9-(4-Hydroxyphenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6 (IIj). Analytical and spectral data are
described [1].
9-(5-Nitro-2-(2-chlorobenzyloxyphenyl)-
3,7-dithia-5-azatetracyclo-[9.2.1.02,10.04,8]
tetradecen-4(8)-one-6 (IIk). Yield 63 %, mp
232–233 °C. 1H NMR (DMSO-d6) d: 1.07 m,
1.21 (d, J = 9.6 Hz), 1.28 m, 1.39 m, 1.58 m,
1.92 m, 2.20 m, 2.38 m, (9H, norbornane frag-
ment), 3.42 (m, 1H, ArCH), 3.99 (d, 1H, J =
9.7 Hz, SCH), 5.28 (s, 2H, OCH2), 7.22–7.24
(m, 2H,arom.), 7.30–7.40 (m, 2H, arom.), 7.90
(m, 2H, arom.), 8.22 (s, 1H, arom.), 11.54 (s,
1H, NH). LCMS (ESI) m/z 501/503 (95.6 %,
(M+H+). Calcd. for C24H21ClN2O4S2: C, 57.54;
H, 4.22; N, 5.59; Found: C, 57.80; H, 4.30; N,
5.40.
9-(2-Hydroxy-3-metoxyphenyl)-3,7-dithia-
5-azatetracyclo-[9.2.1.02,10.04,8]tetradecen-
4(8)-one-6 (IIl). Yield 75 %, mp 215-216 °C.
1H NMR (DMSO-d6) d: 1.05 m, 1.20 (d, J =
9.2 Hz), 1.31 m, 1.42 m, 1.60 m, 1.92 brs, 2.08
(d, J = 7.8 Hz), 2.20 brs, 2.27 m, (9H, norbor-
nane fragment), 3.41 (d, 1H, J = 7.8 Hz, ArCH),
3.47 (d, 1H, J = 10.1 Hz, SCH), 3.82 (s, 3H,
CH3), 6.80–6.84 (m, 1H, arom,) 6.86–6.93 (m,
2H, arom.), 8.78 (s, 1H, OH), 11.40 (s, 1H,
NH). LCMS (ESI) m/z 362 (97.8 %, (M+H+).
Calcd. for C18H19NO3S2: C, 59.81; H, 5.30; N,
3.87; Found: C, 60.00; H, 5.50; N, 3.70.
9 - ( 2 - N i t r o p h e n y l ) - 3 , 7 - d i t h i a - 5 -
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6 (IIm). Yield 75 %, mp 236–238 °C. 1H
NMR (DMSO-d6) d: 1.12m, 1.20 (d, J =
10.1 Hz), 1.32 m, 1.47 m, 1.65 m, 2.06 m,
2.12 m, 2.22 m (9H, norbornane fragment),
3.22 (d, 1H, J = 7.6 Hz, ArCH), 3.35 (d, 1H,
J = 10.4 Hz, SCH), 7.22–7.28 (m, 3H,
arom.),7.92 (brs, 1H, arom.), 11.12 (s, 1H,
NH). LCMS (ESI) m/z 361 (96 %, (M+H+).
Calcd. for C17H16N2O3S2: C, 56.65; H, 4.47;
N, 7.77; Found: C, 56.85; H, 4.65; N, 7.50.
9-(3,4-Dimethoxyphenyl)-3,7-dithia-5-
azatetracyclo[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6 (IIn). Yield 69 %, mp 242–243 °C. 1H
NMR (DMSO-d6) d: 1.08m, 1.17 (d, J = 10.2
Hz), 1.35 m, 1.44 m, 1.60 m, 1.97 brs, 2.06 m,
2.22 m (9H, norbornane fragment), 3.40 (d,
1H, J = 7.9 Hz, ArCH), 3.47 (d, 1H, J = 10.1
Hz, SCH), 3.76 (s, 3H, CH3), 3.78 (s. 3H,
CH3), 6,94 (d, 1H, J = 8.2 Hz, arom.), 6.96 (d,
1H, J = 8.3 Hz, arom.), 6.98 (s, 1H, arom.),
11.45 (s, 1H, NH). LCMS (ESI) m/z 376
(97 %, (M+H+). Calcd. for C19H21NO3S2: C,
60.77; H, 5.64; N, 3.73; Found: C, 60.50; H,
5.50; N, 5.80.
9-(3-Methoxy-4-hydroxyphenyl)-3,7-
dithia-5-azatetracyclo[9.2.1.02,10.04,8]-tetra-
decen-4(8)-one-6 (IIo). Analytical and spectral
data are described [1].
General procedure for the synthesis of
2-(9-aryl(heteryl)-3,7-dythia-5-azatetracyc-
lo-[9.2.1.02,10.04,8]tetradecen-4(8)-one-6-yl-5)
acetic acid amides and ester (III).
The mixture of appropriate compound II
(3 mmol), pottasium hydroxide (3 mmol), ap-
propriate N-substituted chloroacetamide or
ethylchloroacetate (3.3 mmol) and catalytic
amounts of KI in the medium of methanol /
DMF (2:1) was heated under reflux for 3 hours
and cooled. Formed precipitate was filtered
and recrystallized from buthanol, acetic acid
or mixture of DMF/methanol (1:1).
188
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
2-(9-(4’-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-phenyl-acetamide (IIIa). Yield
71 %, mp 105–107 °C. 1H NMR (DMSO-d6)
d: 1.11 m, 1.16 (d, J = 10.0 Hz), 1.32 m,
1.41 m, 1.62 m, 2.07 m, 2.21 m, (9H, norbor-
nane fragment), 3.38 (d, 1H, J = 7.8 Hz,
ArCH), 3.52 (d, 1H, J = 10.1 Hz, SCH), 4.58
(brs, 2H, CH2CO), 6.72–6.78 (m, 4H, arom.),
6.94–7.05 (m, 3H, arom.), 7.12–7.15 (m, 2H,
arom.), 10.98 (s, 1H, NH). LCMS (ESI) m/z
483/485 (95.6 %, (M+H+). Calcd. for
C25H23ClN2O2S2: C, 62.16; H, 4.80; N, 5.80;
Found: C, 62.40; H, 5.00; N, 4.60.
2-(9-(4-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-3-methylphenyl-acetamide
(IIIb). Yield 71 %, mp 164–166 °C. 1H NMR
(DMSO-d6) d: 1.20 m, 1.31 m, 1.51 m, 1.62 m,
2.12 m, 2.24 m, (9H, norbornane fragment),
2.33 (s, 3H, CH3), 3.39 (d, 1H, J = 7.8 Hz,
ArCH), 3.70 (d, 1H, J = 10.2 Hz, SCH), 4.58
(m, 2H, CH2CO), 7.35 (d, 2H, J = 8.2 Hz,
arom.), 7.42 (d, 2H, J = 8.2 Hz, arom.), 7.50–
7.56 (m, 3H, arom), 7.68 (brs, 1H, arom.),
10.52 (s, 1H, NH). LCMS (ESI) m/z 497/498
(95.6 %, (M+H+). Calcd. for C26H25ClN2O2S2:
C, 62.82; H, 5.07; N, 5.64; Found: C, 63.00;
H, 5.20; N, 5.50.
2-(9-(4-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-3-trifluoeromethylphenyl-acet-
amide (IIIc). Yield 65 %, mp 176–178 °C. 1H
NMR (DMSO-d6) d: 1.17 (t, J = 10.2 Hz), 1.23
(d, J = 9.8 Hz), 1.33 (t, J = 10.2 Hz), 1.49 (t,
J = 10.0 Hz), 1.64 m, 2.06 m, 2.24 m, (9H,
norbornane fragment), 3.32 (d, 1H, J = 7.8 Hz,
ArCH), 3.55 (d, 1H, J = 10.1 Hz, SCH), 4.47
(d, 1H, J = 16.0, Hz, CH2CO), 4.60 (d, 1H, J =
16.0, Hz, CH2CO), 7.23 (d, 2H, J = 8.1 Hz,
arom.), 7.61 (d, 2H, J = 8.1 Hz, arom.), 7.34–
7.37 (m, 3H, arom.), 10.16 (s, 1H, NH). LCMS
(ESI) m/z 551/553 (97.2 %, (M+H+). Calcd.
for C26H22ClF3N2O2S2: C, 56.67; H, 4.02; N,
5.08; Found: C, 56.50; H, 3.90; N, 5.30.
2-(9-(4-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-4-chlorophenyl-acetamide
(IIId). Yield 68 %, mp 138–140 °C. 1H NMR
(DMSO-d6) d: 1.16 m, 1.22 m, 1.36 m, 1.52 m,
2.01 m, 2.14 m, 2.23 m (9H, norbornane frag-
ment), 3.37–3.43 (m, 2H, ArCH, SCH), 4.94
(d, 1H, J = 16.0 Hz, CH2CO), 5.02 (d, 1H, J =
16.0 Hz, CH2CO), 7.30 (d, 2H, J = 8.6 Hz,
arom.), 7.34 (d, 2H, J = 8.6 Hz, arom.), 7.52
(d, 2H, J = 8.6 Hz, arom.), 7.62 (d, 2H, J = 8.6
Hz, arom.), 10.67 (s, 1H, NH). LCMS (ESI)
m/z 517/518/519 (95.6 %, (M+H+). Calcd. for
C25H22Cl2N2O2S2: C, 58.02; H, 4.29; N, 5.41;
Found: C, 58.20; H, 4.50; N, 5.30.
2-(9-(4-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-4-methylphenyl-acetamide
(IIIe). Yield 76 %, mp 189–191 °C. 1H NMR
(DMSO-d6) d: 1.21 m, 1.27 m, 1.38 m, 1.52 m,
2.14 m, 2.23 m (9H, norbornane fragment),
2.31 (s, 3H, CH3), 3.34 (m, 1H, ArCH) 3.92
(d, 1H, J = 10.2 Hz, SCH), 4.92 (d, 1H, J =
16.2 Hz, CH2CO), 4.96 (d, 1H J = 16.2, Hz,
CH2CO), 7.28 (d, 2H, J = 8.2 Hz, arom.), 7.32
(d, 2H, J = 8.0 Hz, arom.), 7.38 (d, 2H, J =
8.2 Hz, arom.), 7.54 (d, 2H, J = 8.0 Hz, arom.),
10.57 (s, 1H, NH). LCMS (ESI) m/z 497/498
(97.0 %, (M+H+). Calcd. for C26H25ClN2O2S2:
C, 62.82; H, 5.07; N, 5.64; Found: C, 63.00;
H, 5.20; N, 5.40.
2-(9-(4-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
189
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
one-6-yl-5)-N-2-methylphenyl-acetamide
(IIIf). Yield 74 %, mp 215–217 °C. 1H NMR
(DMSO-d6) d: 1.22 m, 1.28 m, 1.34 m, 1.51 m,
2.14 m, 2.23 m (9H, norbornane fragment),
2.33 (s, 3H, CH3), 3.32 (d, 1H, J = 7.8 Hz,
ArCH), 3.91 (d, 1H, J = 10.4 Hz, SCH), 4.87
(d, 1H, J = 16.0 Hz, CH2CO), 4.96 (d, 1H, J =
16.0 Hz, CH2CO), 7.32 (d, 2H, J = 8.4 Hz,
arom.), 7.36 (d, 2H, J = 8.3 Hz, arom.), 7.42
(d, 1H, J = 8.3 Hz, arom.), 7.52–7.56 (m, 3H,
arom.), 10.60 (s, 1H, NH). LCMS (ESI) m/z
497/499 (97.0 %, (M+H+). Calcd. for
C26H25ClN2O2S2: C, 62.82; H, 5.07; N, 5.64;
Found: C, 62.70; H, 5.00; N, 5.60.
2-(9-(4-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-4-methoxyphenyl-acetamide
(IIIg). Yield 78 %, mp 132–134 °C. 1H NMR
(DMSO-d6) d: 1.18 m, 1.22 m, 1.33 m, 1.51 m,
2.12 m, 2.31 m (9H, norbornane fragment),
3.30 (d, 1H, J = 7.6 Hz, ArCH), 3.81 (s, 3H,
CH3), 3.87 (d, 1H, J = 10.2 Hz, SCH), 4.52 (d,
1H, J = 16.0, Hz, CH2CO), 4.62 (d, 1H, J =
16.0, Hz, CH2CO), 7.30 (d, 2H, J = 8.4 Hz,
arom.), 7.34 (d, 2H, J = 8.3 Hz, arom.), 7.52
(d, 2H, J = 8.3 Hz, arom.), 7.56 (d, 2H, J =
8.3 Hz, arom.), 10.57 (s, 1H, NH). LCMS
(ESI) m/z 513/515 (97.0 %, (M+H+). Calcd.
for C26H25ClN2O3S2: C, 60.87; H, 4.91; N,
5.46; Found: C, 61.00; H, 5.10; N, 4.70.
2-(9-(Thiophen-2-yl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-4-methylphenyl-acetamide
(IIIh). Yield 73 %, mp 230–232 °C. 1H NMR
(DMSO-d6) d: 1.24 m, 1.30 (t, J = 9.2 Hz),
1.53 m, 1.64 m, 2.13m, 2.23 m (9H, norbor-
nane fragment), 2.27 (s, 3H, CH3), 3.33 (d, 1H,
J = 7.6 Hz, ArCH), 3.91 (d, 1H, J = 10.6 Hz,
SCH), 4.46 (d, 1H, J = 16.0 Hz, CH2CO), 4.51
(d, 1H, J = 16.0, Hz, CH2CO), 7.10 (m, 4H,
arom.), 7,41 (d, 2H, J = 8.2 arom.), 7.45 (d,
1H, J = 6.8 Hz, arom.), 10.16 (s, 1H, NH).
LCMS (ESI) m/z 469 (97 %, (M+H+). Calcd.
for C24H24N2O2S3: C, 61.51; H, 5.16; N, 5.98;
Found: C, 61.70; H, 5.30; N, 6.10.
2-(9-(Thiophen-2-yl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-2-trifluoriphenyl-acetamide
(IIIi). Yield 69 %, mp 153–155 °C. 1H NMR
(DMSO-d6) d: 1.24 m, 1.32 m, 1.54 m, 1.63 m,
2.18 m, 2.23 m (9H, norbornane fragment),
3.34 (d, 1H, J = 7.6 Hz, ArCH), 3.71 (d, 1H,
J = 7.8 Hz, SCH), 4.52 (d, 1H, J = 16.0 Hz,
CH2CO), 4.54 (d, 1H, J = 16.0, Hz, CH2CO),
7.05–7.10 (m, 2H, arom.), 7.25–7.30 (m, 2H,
arom.), 7.36 (m, 2H, arom.), 7.40 (d, 1H, J =
7.5 Hz, arom.), 9.81 (s, 1H, NH). LCMS (ESI)
m/z 523 (98.2 %, (M+H+). Calcd. for
C24H21F3N2O2S3: C, 55.16; H, 4.05; N, 5.36;
Found: C, 55.30; H, 4.30; N, 5.50.
2-(9-(Thiophen-2-yl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-4-chlorophenyl-acetamide
(IIIj). Yield 74 %, mp 232–234 °C. 1H NMR
(DMSO-d6) d: 1.23 m, 1.28 m, 1.58 m, 1.64 m,
2.21 m, 2.24 m (9H, norbornane fragment),
3.34 (d, 1H, J = 7.2 Hz, ArCH), 3.93 (d, 1H,
J = 8.8 Hz, SCH), 4.42 (d, 1H, J = 16.0 Hz,
CH2CO), 4.46 (d, 1H, J = 16.0 Hz, CH2CO),
7.05 (brs, 1H, arom.), 7.12 (brs, 1H, arom.),
7.39 (d, 2H, J = 8.0 Hz, arom.), 7.60 (d, 1H,
J = 4.0 Hz, arom.), 7.96 (d, 2H, J = 7.4 Hz,
arom), 10.35 (s, 1H, NH). LCMS (ESI) m/z
489/491 (97.0 %, (M+H+). Calcd. for
C23H21ClN2O2S3: C, 56.48; H, 4.33; N, 5.73;
Found: C, 56.70; H, 4.50; N, 5.50.
2-(9-(Thiophen-2-yl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
190
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
one-6-yl-5)-N-4-metoxyphenyl-acetamide
(IIIk). Yield 75 %, mp 264–266 °C. 1H NMR
(DMSO-d6) d: 1.26 (d, J = 9.5 Hz) 1.35 m,
1.55 (t, J = 8.9 Hz), 1.68 m, 2.21 m, 2.38 m
(9H, norbornane fragment), 3.10 (s, 3H, CH3),
3.37 (d, 1H, J = 7.7 Hz, ArCH), 3.92 (d, 1H,
J = 10.7 Hz, SCH), 4.55 (d, 1H, J = 16.0 Hz,
CH2CO), 4.57 (d, 1H, J = 16.0, Hz, CH2CO),
7.06 (t, 1H, J = 4.2 Hz, arom.), 7.13 (brs, 1H,
arom.), 7.42 (d, 1H, J = 4.8 Hz, arom.), 7.73
(d, 2H, J = 8.2 Hz, arom.), 7.93 (d, 2H, J =
8.3 Hz, arom), 10.35 (s, 1H, NH). LCMS (ESI)
m/z 485 (98.0 %, (M+H+). Calcd. for
C24H24N2O3S3: C, 59.48; H, 4.99; N, 5.78;
Found: C, 59.70; H, 5.10; N, 5.50.
2-(9-(Thiophen-2-yl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-3-trifluorophenyl-acetamide
(IIIl). Yield 68 %, mp 182–184 °C. 1H NMR
(DMSO-d6) d: 1.26 m, 1.36 m, 1.56 m, 1.68 m,
2.21 m, 2.28 (9H, norbornane fragment), 3.38
(d, 1H, J = 7.7 Hz, ArCH), 3.92 (d, 1H, J =
10.6 Hz, SCH), 4.54 (d, 1H, J = 16.0 Hz,
CH2CO), 4.57 (d, 1H, J = 16.0, Hz, CH2CO),
7.06 (m, 1H, arom.), 7,13 (brs, 1H, arom.),
7.35 (t, 1H, J = 8.3 Hz, arom.), 7.40 (d, 1H,
J = 4.8 Hz, arom.), 7.51 (t, 1H, J = 7.9 Hz,
arom), 7.76 (d, 1H, J = 7.9 Hz. arom.), 8.07
(s, 1H, arom), 10.57 (s, 1H, NH). LCMS (ESI)
m/z 523 (97.0 %, (M+H+). Calcd. for
C24H21F3N2O3S3: C, 55.16; H, 4.05; N, 5.36;
Found: C, 55.00; H, 3.90; N, 5.50.
2-(9-(Thiophen-2-yl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-N-3,4-dichlorophenyl-acetamide
(IIIm). Yield 72 %, mp 219–221 °C. 1H NMR
(DMSO-d6) d: 1.26 (d, J = 9.7 Hz), 1.38 (t, J =
9.3 Hz), 1.56 (t, J = 9.8 Hz), 1.68 m, 2.18 m,
2.28 (9H, norbornane fragment), 3.36 (d, 1H,
J = 7.3 Hz, ArCH), 3.90 (d, 1H, J = 10.4 Hz,
SCH), 4.52 (d, 1H, J = 16.7 Hz, CH2CO), 4.56
(d, 1H, J = 16.0 Hz, CH2CO), 7.06 (d, 1H, J =
4.7 Hz, arom.), 7.11 (brs, 1H, arom.), 7.40 (d,
1H, J = 4.73 Hz, arom.), 7.42 (m, 2H, arom.),
7.96 (s, 1H, arom), 10.51 (s, 1H, NH). LCMS
(ESI) m/z 523/524/525 (96.0 %, (M+H+).
Calcd. for C23H20Cl2N2O2S3: C, 52.77; H, 3.85;
N, 5.35; Found: C, 52.90; H, 4.00; N, 5.20.
2-(9-(4’-Chlrophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-acetic acid ethyl ester (IIIn).
Yield 78 %, mp 178–180 °C. 1H NMR
(DMSO-d6) d: 1.16 m, 1.26 (d, J = 9.2 Hz),
1.32 m, 1.30 (t, 3H, J = 7.2 Hz, CH3),1.50 (t,
J = 8.2 Hz), 1.67 (t, J = 9.0 Hz), 2.07 m, 2.21
m (9H, norbornane fragment), 3.31 (d, 1H, J
= 17.6 Hz, SCH), 3.50 (d, 1H, J = 10.2 Hz,
ArCH), 4.21 (q, 2H, J = 7.2 Hz, CH2CH3),
4.37 (s, 2H, CH2CO), 7.33–7.36 (m, 4H,
arom.). LCMS (ESI) m/z 436/438 (96 %,
(M+H+). Calcd. for C21H22ClNO3S2: C, 57.85;
H, 5.09; N, 3.21; Found: C, 58.00; H, 5.20; N,
4.90.
2-(9-(4’-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-acetic acid hydrazide (IIIo). A
mixture of IIIn (3 mmol) and hydrazine hy-
drate (4 mmol) in ethanol (20 mL) was heate
under reflux for 5 h. The precipitate was fil-
tered off and recrystallized from acetic acid.
Yield 60 %, mp 219–221 °C. 1H NMR
(400 MHz, DMSO-d6) d: 1.14 m, 1.23 (d, J =
10.3 Hz), 1.31 (t, J = 10.7 Hz), 1.48 m, 1.66 m,
2.02 m, 2.20 m, 2.26 m (9H, norbornane frag-
ment), 3.32 (d, 1H, J = 7.9 Hz, ArCH), 3.52
(d, 1H, J = 9.7 Hz, SCH), 4.31 (d, 1H, J =
16.3 Hz, CH2CO), 4.41 (d, 1H, J = 16.0 Hz,
CH2CO), 7.37 (m, 4H, arom.), 8.10 (brs, 1H,
191
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
NH), 9.60 (brs, 2H, NH2). LCMS (ESI) m/z
422/424 (98%, (M+H+). Calcd for
C19H20ClN3O2S2: C, 54.08; N, 9.96; S, 15.20.
Found: C, 54.10; N, 9.98; S, 15.25.
4-[9-(4’-Chlorophenyl)-6-oxo-3,7-dithia-
5-azatetracyclo-[9.2.1.02,10.04,8]-tetradec-4(8)-
ene-5-yl]-acetyl-1-phenyl-thiosemicarbazide
(IIIt) The mixture of IIIo (3 mmol), pheny li-
so thiacyanate (4 mmol) in ethanol (20 mL)
was heated under reflux during 1 h and then
cooled. Solid product was filtered off, washed
with ethanol, diethyl eter and recrystallized
from ethanol. Yield, 64 %, mp 188–190 ºC. 1H
NMR (400 MHz, DMSO-d6): 1.18 m, 1.23 m,
1.37 m, 1.52 m, 2.12 m, 2.22 m, (9H, norbor-
nane fragment), 3.31 (d, 1H, J = 7.8 Hz,
ArCH), 3.62 (d, 1H, J = 10.7 Hz, SCH), 4.32
(d, 1H, J = 16.3 Hz, CH2CO), 4.36 (d, 1H, J =
16.3 Hz, CH2CO), 7.32 (d, 2H, J = 8.2 Hz,
arom.), 7.38 (d, 2H, J = 8.2 Hz, arom.), 7.48–
7.52 (m, 5H, arom.), 8.11 (brs, 1H, NH), 9.62
(brs, 2H, NH2). LCMS (ESI) m/z 558/560
(96 %, (M+H+). Calcd for C26H25ClN4O2S3:
C, 56.05; N, 10.06; S, 17.26. Found: C, 56.15;
N, 10.10; S, 17.20.
Dihydrazide of 2-(9-(4’-chlorophenyl)-3,7-
dithia-5-azatetracyclo-[9.2.1.02,10.04,8]-tetra-
decen-4(8)-one-6-yl-5)-acetic acid and
2,4-thiazolidinedione-5-acetic acid (IIIp). The
solution of 2,4-thiazolidinedione-5-acetic acid
chloride (3 mmol) in dioxane (3 mL) was
added to the solution of IIIo (3 mmol) and
triethylamine (3 mmol) in dioxane (12 mL).
The mixture was heated at 80 °C during 15 min
and cooled. The product of the reaction was
precipitated with water. Solid precipitate was
filtered off and recrystallized from ethanol.
Yield 81 %, mp. 192–194 ºC (dec.). 1H NMR
(400 MHz, DMSO-d6) d: 1.09 m, 1.21 m,
1.31 m, 1.45 m, 1.64 m, 1.97 m, 2.18 m, 2.25
m (9H, norbornane fragment), 3.33 (d, 1H, J =
7,7 Hz, ArCH), 3.54 (d, 1H, J = 10.5 Hz,
SCH), 2.85 (dd, 1H, J = 16.5, 8.7 Hz, CH2CH),
3.06 (dd, 1H, J = 8.7, 4.0 Hz, CH2CH), 4.36
(m, 2H, CH2CO), 4.58 (dd, 1H, J = 3.6, 9.0 Hz,
CHCH2), 7.38–7.43 (m, 4H, arom.), 10.26 (s,
1H, NH), 10.37 (s, 1H, NH). LCMS (ESI)
m/z 580/582 (95 %, (M+H+). Calcd for
C24H23ClN4O5S3: C, 49.78; N, 9.67; S, 16.61.
Found: C, 49.85; N, 9.70; S, 16.60.
5-(1-Phenyl-2-mercapto-1,3,4-triazolil-
methylene)-9-(4’-chlorophenyl)-3,7-dithia-
5-azatetracyclo-[9.2.1.02,10.04,8]tetradecen-
4(8)-one-6 (IIIu). The mixture of IIIt
(2.5 mmol) and 10 mL of 2 % sodium hydro-
xi de solution was heated under reflux during
2 h. After cooling the reaction mixture was
acidified with the HCl, pH=5 and then the
solid product was filtered off. The precipitate
was recrystallized from the DMF : EtOH (1:2)
mixture. Yield 72 %, mp > 250 ºC. 1H NMR
(400 MHz, DMSO-d6) d: 1.11 m, 1.20 (d, J =
9.0 Hz), 1.30 m, 1.44 m, 1.63 m, 1.95 m,
2.15 m, 2.23 m, (9H, norbornane fragment),
3.25 (d, 1H, J = 7.6 Hz, ArCH), 3.49 (d, 1H,
J = 10.5 Hz, SCH), 4,74 (d, 1H, J = 16.9 Hz,
CH2CO), 4.78 (d, 1H, J = 16.9, Hz, CH2CO),
7.40–75 (m, 5H, arom), 7.56–7.60 (m, 4H,
arom), 13.90 (s 1H, SH). LCMS (ESI) m/z
539/541 (96 %, (M+H+). Calcd for
C26H23ClN4OS3: C, 57.92; N, 10.39; S, 17.84.
Found: C, 58.03; N, 10.41; S, 17.80.
General procedure for the synthesis of
2 - (9-ary l -3 ,7-di thia-5-azate tracyc -
lo-[9.2.1.02,10.04,8]tetradecen-4(8)-one-6-yl-5)-
acetic acid (2-oxo-1,2-dihydro-indol-
3-ylidene)-hydrazides (IIIq-s). A mixture of
hydrazide IIIo (3 mmol), appropriate isatin
192
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
(3 mmol) in ethanol (20 mL) in the presence
of acetic acid (2 mL) was heated under reflux
during 5 h and then cooled. Obtained solid
products were filtered off, dried and recrystal-
lized from the mixture of DMF/EtOH (1:2) or
acetic acid.
2-(9-(4’-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-acetic acid (2-oxo-1,2-dihydroin-
dol-3-ylidene)-hydrazide (IIIq). Yield 76 %,
mp. 272–274 ºC. 1H NMR (400 MHz,
DMSO-d6) d: 1.15 m, 1.23 (d, J = 9.7 Hz),
1.33 m, 1.47 m, 1.68 m, 2.02 m, 2.18 m,
2.25 m (9H, norbornane fragment), 3.34 (d,
1H, J = 6,7 Hz, ArCH), 3.56 (d, 1H, J = 9.9 Hz,
SCH), 4.92 (d, 1H, J = 17.6 Hz, CH2CO), 5.02
(d, 1H, J = 17.6 Hz, CH2CO), 6.94 (d, 1H, J =
7.2 Hz, arom.), 7.06 (t, 1H, J = 7.7 Hz, arom.),
7.34 (t, 1H, J = 7.7 Hz, arom.), 7.41 (brs, 4H,
arom.), 7.57 (d, 1H, J = 6.7 Hz, arom.), 11.26
(s, 1H, NH), 12.76 (s, 1H, NH). LCMS (ESI)
m/z 552/554 (96 %, (M+H+). Calcd for
C27H23ClN4O3S2: C, 58.85; H, 4.21; N, 10.17;
Found: C, 59.00; H, 4.40; N, 10.00.
2-(9-(4’-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-acetic acid (2-oxo-1,2-dihydro-
5-bromoindol-3-ylidene)-hydrazide (IIIr).
Yield 78 %, mp. > 250 ºC. 1H NMR (400 MHz,
DMSO-d6) d: 1.16 m, 1.24 m, 1.34 m, 1.48 m,
1.66 m, 2.03 m, 2.19 m, 2.23 m (9H, norbor-
nane fragment), 3.34 (d, 1H, J = 7,1 Hz,
ArCH), 3.54 (d, 1H, J = 10.3 Hz, SCH), 4.94
(d, 1H, J = 16.6 Hz, CH2CO), 5.02 (d, 1H, J =
16.9 Hz, CH2CO), 6.91 (d, 1H, J = 6.9 Hz,
arom.), 7.41 (brs, 4H, arom.), 7.47 (d, 1H, J =
7.8 Hz, arom.), 7.72 (s, 1H, arom.), 11.47 (s,
1H, NH), 12.69 (s, 1H, NH). LCMS (ESI) m/z
629/631/632/633 (98 %, (M+H+). Calcd for
C27H22BrClN4O3S2: C, 51.48; H, 3.52; N, 8.89;
Found: C, 51.60; H, 3.70; N, 8.70.
2-(9-(4’-Chlorophenyl)-3,7-dithia-5-
azatetracyclo-[9.2.1.02,10.04,8]tetradecen-4(8)-
one-6-yl-5)-acetic acid (2-oxo-1,2-dihydro-
5-chloroindol-3-ylidene)-hydrazide (IIIs).
Yield 72 %, mp. > 250 ºC. 1H NMR (400 MHz,
DMSO-d6) d: 1.16 m, 1.24 (d, J = 9.7 Hz),
1.34 m, 1.48 m, 1.62 m, 2.03 m, 2.19 (d, J =
9.6 Hz), 2.25 m (9H, norbornane fragment),
3.33 (d, 1H, J = 7,3 Hz, ArCH), 3.56 (d, 1H,
J = 10.3 Hz, SCH), 4.98 (m, 2H, CH2CO), 6.94
(d, 1H, J = 8.0 Hz, arom.), 7.33 (d, 1H, J =
7.6 Hz, arom.), 7.41 (brs, 4H, arom.), 7.58 (s,
1H, arom.), 11.38 (s, 1H, NH), 12.67 (s, 1H,
NH). LCMS (ESI) m/z 586/588 (95%, (M+H+).
Calcd for C27H22Cl2N4O3S2: C, 55.39; H, 3.79;
N, 9.57; Found: C, 55.60; H, 4.00; N, 9.40.
Pharmacology
Anticancer activity screening. In vitro cell line
screening of anticancer activity of the synthe-
sized compounds was carried out at the
National Cancer Institute within Developmental
Therapeutic Program (www.dtp.nci.nih.gov).
Anticancer assays were performed according
to the US NCI protocol, which was described
elsewhere [27–29].
Antitrypanosomal activity screening.
Bloodstream forms of Trypanosoma brucei
brucei (Tbb) strain 90-13 were cultured in
HMI9 medium supplemented with 10 % FCS
at 37 °C in an atmosphere of 5 % CO2 [30]. In
all experiments, log-phase cell cultures were
harvested by centrifugation at 3000×g and im-
mediately used. Drug assays were based on
the conversion of a redox-sensitive dye (resa-
zurin) to a fluorescent product by viable
cells [31]. Drug stock solutions were prepared
193
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
in DMSO. Tbb bloodstream forms (105 cells/
mL) were cultured in 96-well plates either in
the absence or in the presence of different
concentrations of inhibitors in a final volume
of 200 ml. After the 72 h incubation, resa-
zurin solution was added in each well at the
final concentration of 45 mM and fluorescence
was measured at 530 nm and 590 nm absor-
bance after further 4 h incubation. The percent-
age of inhibition of parasite growth rate was
calculated by comparing the fluorescence of
parasites maintained in the presence of drug
to that in the absence of drug. DMSO was used
as a control. Concentration inhibiting 50% of
parasite growth (IC50) value was given as the
mean +/- the standard deviation of three inde-
pendent experiments.
Results and Discussion
Chemistry
An approach to the target compounds synthesis
was based on the developed protocol utili zing
5-eneisorhodanines as heterodienes and nor-
bornene as dienophile in the hetero-Diels-Alder
reaction following our previous fin dings [1, 2].
This approach was proved to be an efficient
regio- and stereoselective tool for the function-
alized thiazolothiopyrane core formation [4,
32]. One of the promising directions of thia-
zolothiopyrane optimization is modification of
the C5-fragment of the starting 5-ene-
isorhodanines [5]. For this purpose different
5-eneisorhodanines with bulky benzylidene
fragment and heterocyclic fragments at C5 po-
sition, including substances bearing substituted
phenolic OH group [33, 34] (Scheme 1), have
been used. Hetero-Diels-Alder reaction of start-
ing 5-ene-4-thioxothiazolidin-2-ones (I) and
norbonene led to the target 9-aryl(heteryl)-3,7-
dithia-5-azatetracyclo[9.2.1.02,10.04,8]tetradecen-
4(8)-ones-6 (II) with high yields.
Introduction of a variety of substituents at
the N3 position of the thiazole ring is another
efficient approach to the thiazolothiopyrane
core modification in order to obtain new bio-
S
N
HS
Ar(Het)
O S
N
HS
O
H Ar(Het)
H
H
N
N Ph
Ph
O
N
H
O
Cl
O
Cl
O2N
I
Ar(Het)
IIa pyridin-2-yl
IIb 4-MeOOCC6H4
IIc 3,5-(MeO)2-4-OH-C6H2
IId A
IIe 4-Et2N-C6H4
IIf Thiophen-2-yl
IIg 4-Cl-C6H4
IIh B
IIi 4-OMe-C6H4
IIj 4-OH-C6H4
IIk C
IIl 3-(MeO)-2-OH-C6H3
IIm 3-NO2-C6H4
IIn 3,4-(MeO)2-C6H3
IIo 4-OH-3-OEt-C6H3
B
II
A
C
Scheme.1. General scheme of the target 9-aryl(heteryl)-3,7-dithia-5-azatetracyclo[9.2.1.02,10.04,8]tetradecen-4(8)-
ones-6 (II) synthesis
194
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
logically active analogues [26, 35]. One more
argument in favor of this approach is a de-
creased toxicity of the N-substituted structur-
ally related 4-thiazolidinones [36]. This goal
was achieved via the alkylation reaction and
further modification of the exocyclic func-
tional groups. Synthetic protocol included in
situ 9-aryl(heteryl)-3,7-dithia-5-azatetracyc-
lo[9.2.1.02,10.04,8]tetradecen-4(8)-ones-6
N-potassium salts formation. A series of
N-substituted chloroacetamides were used as
alkylating agents.
Modification of carboxylic group at N3 of
thiazolidinone fragment yielded compounds
IIIo, IIIp and IIIu. N-(4-Chlorophenyl)-2-(9-
(4-chlorophenyl)-3,7-dythia-5-azatetracyc-
lo-[9.2.1.02,10.04,8]tetradecen-4(8)-one-6-yl-5)
acetic acid hydrazide IIIo was synthesized in
the reaction of appropriate ester IIIn with
hydrazine hydrate in the ethanol medium. IIIp
S
N
HS
O
H Ar(Het)
H
H S
NS
O
H Ar(Het)
H
H
N
H
O
Cl
N
H
O
R
R
Cl
S
Cl
O S
NH
O
O
Cl
O
O
S
NS
O
H
H
H
O
O
Cl
S
NS
O
H
H
H
N
H
O
NH2
Cl
S
N
S
OH
H
H
N
H
O
N
Cl
N
HO
R
S
NS
O
H
H
H
N
H
O
N
H
Cl
O
S NH
O
O
S
N
S
O
H
H
H
N
H
O
N
H
Cl
N
H
S Ph
S
NS
O
H
H
H
Cl
N N
N SH
KOH
III
A
B
KOH
2795
NH2-NH2
PhNCS
NaOH
IIIu
Ar(Het) R
IIIa A H
IIIb A 3-Me
IIIc A 3-CF3
IIId A 4-Cl
IIIe A 4-Me
IIIf A 2-Me
IIIg A 4-MeO
IIIh B 4-Me
IIIi B 2-CF3
IIIj B 4-Cl
IIIk B 4-OMe
IIIl B 3-CF3
IIIm B 3,4-Cl2
IIIn
R
IIIq H
IIIr Br
IIIs Cl
IIIo IIIp
II
IIIt
Scheme.2. General scheme of the N-substituted 9-aryl(heteryl)-3,7-dithia-5-azatetracyclo[9.2.1.02,10.04,8]tetradecen-
4(8)-ones-6 synthesis
195
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
was synthesized in acylation reaction of hy-
drazide IIIo by 2,4-thiazolidinedione-5-acetic
acid chloride. Compound IIIu was obtained
based on hydrazide IIIo in the reaction with
phenylisothiocyanate yielding 4-[9-(4’-chlo-
ro phenyl)-6-oxo-3,7-dithia-5-azatetracyclo-
[9.2.1.02,10.04,8]-tetradecen-4(8)-ene-5-yl]-
acetyl-1-phenyl-thiosemicarbazide via known
approach. Phenylthiosemicarbazide fragment
in the basic medium was cyclized giving com-
pound IIIu with 1,3,4-triazole fragment at N5
position of the thiopyranothiazole core.
Compounds IIIq-IIIs were synthesized in the
reaction of hydrazide IIIo with isatins in eth-
anol medium.
The purity and structure of synthesized
compounds were confirmed by the analytical
and spectral data. 1H NMR spectra of the syn-
thesized compounds showed classic system of
doublets, triplets and multiplets at δ 1.10–
3.30 ppm characteristic for norbornane frag-
ment. A signal of the CH-group’s proton linked
to the aromatic ring shows doublet at δ 3.36–
3.98 ppm and is often overlapped with the
norbornane proton signals. In the most cases,
signal of the N-CH2-CO group corresponds to
two doublets of the diastereotopic methylene
protons with the spin-spin coupling constant
~16.0 Hz that is caused by the diastereotopi-
ci ty of the protons of methylene group. The
AMX-system in the form of 3 doublets of
doublets is characteristic for CH2-CH group
(compounds IIIp and IIi).
Anticancer activity
Compounds IIb, IIh, IIIh were selected for
primary screening on three tumor cell lines:
NCI-H460 (Lung cancer), MCF7 (Breast can-
cer), SF-268 (CNS cancer) at 10-4M concentra-
tion. These compounds did not show signifi-
cant growth inhibition of mentioned cancer
cell lines. Moreover, the derivative with thio-
phene ring in the molecule even increased
tumor cell growth (data not shown).
The compounds IIc, IIe, IIIn and IIIu were
evaluated at one dose assay towards approxi-
mately 60 cell lines (concentration 10-5 M).
The human tumor cell lines represent all forms
of cancer (such as, non-small cell lung cancer,
colon cancer, breast cancer, ovarian cancer,
leukemia, renal cancer, melanoma, prostate
cancer). In the screening protocol, each cell
line was inoculated and pre-incubated for 24–
48 h on a microtiter plate. Test agents were
then added at a single concentration and the
culture was incubated for further 48 h. The end
point determinations were made with a protein
binding dye, sulforhodamine B. The results for
each test agent were reported as the percent
growth (GP) of the treated cells compared to
the untreated control cells. The screening re-
sults are shown in Table 1.
All the tested compounds showed rather
good growth inhibition levels against Leukemia
cell lines. The best growth inhibition results
against Leukemia panel were observed for IIe:
cell lines CCRF-CEM (GI = 8.12 %) and HL-
60(TB) (GI = –44.16 %) and for IIc cell lines
CCRF-CEM (GI = 7.01 %). These data cohere
with our previously findings about leukemia
selective action of the related thiazolidi-
nones [13]. The latter compound also inhib-
ited Non-small cell lung cancer line NCI-H522
(GI = 8.12 %). Compound IIIn inhibited
growth of Leukemia cell lines and showed
cytostatic effect on HCT-15 line of Colon can-
cer (GI = –100 %). Complication of the basic
core with triazole cycle did not influence the
196
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
activity level, so IIIu showed only moderate
anti-tumor activity with the best GI against
renal cancer cell line UO-31 (GI = 29.35 %).
Finally, the compounds IIIn and IIIu were
selected for an advanced assay against a pa nel
of approximately sixty tumor cell lines at 10-
fold dilutions of five concentrations (0.01–
100 mM). Additionally, compounds IIa, IId,
IIId, IIIg, were involved into the study with-
out prescreening. The percentage of growth
was evaluated spectrophotometrically versus
controls not treated with test agents after 48-h
exposure and using SRB protein assay to es-
timate cell viability or growth. The dose-re-
sponse parameters were calculated for each
cell line: GI50 – molar concentration of the
compound that inhibits 50 % net cell growth;
TGI – molar concentration of the compound
leading to the total inhibition; and LC50 – mo-
lar concentration of the compound leading to
50 % net cell death. Furthermore, a mean
graph midpoints (MG_MID) were calculated
Table 1. Anticancer screening data (one dose assay, 10 μM).
Comp. Mean growth.
% Range of growth % The most sensitive cell lines GP% of the most
sensitive cell lines
Positive
cytostatic effecta
IIc 82.30 7.01 to 112.94
CCRF-CEM /L
HL-60(TB) /L
NCI-H522 /NscLC
HOP-92 /NscLC
HS 578T /BC
7.01
53.79
–5.03
40.77
53.61
3/56
IIe 89.71 -44.16 to 136.08
HL-60(TB) /L
CCRF-CEM /L
SR /L
K-562 /L
–44.16
8.12
37.85
52.77
3/57
IIIn 63.53 -100.00 to 92.68
CCRF-CEM /L
K-562 /L
HCT-116 /CC
HCT-15 /CC
HT-29 /CC
SK-MEL-5 /M
CAKI-1 /Rc
UO-31 /Rc
PC-3 /PC
T-47D /BC
13.40
29.06
38.78
–100.00
50.49
41.34
22.75
50.33
42.85
38.85
8/59
IIIu 77.84 29.35 to 116.31
SF-295 /CNSC
IGROV1 /OC
UO-31 /Rc
MCF7 /BC
33.33
50.21
29.35
46.73
3/59
a Ratio between number of cell lines with percent growth from 0 to 50 and total number of cell lines.
L – Leukemia; NscLC- Non-Small Cell Lung Cancer; BC – Breast cancer; CC – Colon Cancer; OC – Ovarian Cancer;
RC – Renal Cancer; M – Melanoma; CNSC – CNS Cancer
197
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
for GI50, giving an average activity parameter
over all cell lines for the tested compound. The
meanings of the GI50 at the range of concentra-
tions for the tested compounds are given in the
table 2. Compound IIa with pyridine fragment
at the C9 position and unsubstituted N5 posi-
tion didn’t show significant levels of logGI50
(from –4.00 to –4.48) and was the less active
compound among tested. Better results were
observed for the compounds bearing p-Cl-
phenyl fragment at the C9. Compound IIIg
selectively inhibited growth of Leukemia cell
lines with the best logGI50 level of –5.36
against SR line. Derivatives IIId and IIIu
showed significant cytostatic effects towards
all tested cell lines with the MID of –4.98 and
–5.09 respectively. Though, the ester IIIn, in
general, did not inhibit the cancer cell lines’
growth, except some Leukemia lines: HL-
60(TB) (logGI50 = –5,06) and RPMI-8226 (log
GI50= –4,81). The highest cytostatic effect was
observed for the compound IId, which selec-
tively inhibited Leukemia cell lines at submi-
cromolar concentrations: logGI50= –6.03 (HL-
60(TB) line), logGI50= –7.37 (SR line), log-
GI50= < –8.00 (MOLT-4 line).
Table 2. Total values of the in-depth in vitro anticancer activity screening in 5 concentrations (10−4–
10−8 M).
Cancer cell Concentration of the compound that inhibits 50 % net cell growth, logGI50
lines IIa IId* IIIg IIId IIIu IIIn
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT- 4
RPMI-8226
SR
ND
-4.44
-4.43
-4.48
-4.19
-4.30
ND/-4.20
-6.03/-4.60
-4.57/-4.38
<-8.00/-4.55
-4.61/-4.24
-7.37/-4.72
-4.03
-4.26
-4.50
-4.46
-4.49
-5.36
-5.35
-5.23
-5.52
-5.23
-5.50
-5.72
-5.48
-4.86
-5.32
-5.25
-5.30
-5.48
-4.11
-5.06
>-4.00
>-4.00
-4.81
>-4.00
NSC lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H522
NCI-H460
-4.18
>-4.00
ND
-4.21
>-4.00
>-4.00
>-4.00
>-4.00
-4.12
-4.16/-4.26
-4.51/-4.10
ND>/-4.00
-4.76/-4.59
>-4.00/>-4.00
>-4.00>-4.00
>-4.00/-4.47
-4.29/-4.44
-4.18/-4.06
>-4.00
>-4.00
>-4.00
-4.99
>-4.00
>-4.00
>-4.00
>-4.00
ND
-4.67
-4.75
-4.91
-5.36
-4.71
-5.35
-5.45
-5.45
-4.86
-5.04
-5.27
-4.70
-5.21
-5.02
-5.04
-4.92
ND
-5.28
-4.08
>-4.00
>-4.00
-4.42
>-4.00
-4.20
>-4.00
-4.21
-4.21
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
-4.08
>-4.00
-4.24
-4.21
-4.34
>-4.00
>-4.00
>-4.00/-4.55
>-4.00/>-4.00
-4.43/-4.39
-4.21/-4.17
-4.04/-4.07
-4.07/-4.37
>-4.00/>-4.00
>-4.00
ND
-4.78
>-4.00
-4.21
>-4.00
>-4.00
-5.22
ND
-5.67
-4.83
-5.58
-5.29
-5.30
-4.83
-5.17
-5.05
-5.11
-4.91
-5.09
-4.86
-4.03
ND
-4.42
>-4.00
-4.32
-4.14
>-4.00
198
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
>-4.00
-4.08
>-4.00
>-4.00
-4.44
-4.05
>-4.00/-4.26
>-4.00/-4.16
>-4.00/>-4.00
>-4.00/>-4.00
-4.18/-4.53
-4.25/-4.15
>-4.00
>-4.00
>-4.00
>-4.00
-4.07
>-4.00
-4.56
-5.19
-5.33
-4.99
>-4.00
-4.84
-4.99
-5.47
-5.09
-4.87
-5.33
-5.26
>-4.00
-4.08
>-4.00
>-4.00
-4.27
>-4.00
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
-4.14
>-4.00
ND
>-4.00
>-4.00
-4.37
-4.47
>-4.00
-4.28
-4.04/>-4.00
>-4.00/-4.33
ND/-4.07
>-4.00/-4.17
>-4.00/>-4.00
>-4.00/>-4.00
-4.37/>-4.00
>-4.00/>-4.00
-4.26/-4.27
>-4.00
>-4.00
-4.36
>-4.00
>-4.00
>-4.00
>-4.00
>-4.00
>-4.00
-5.28
>-4.00
-5.52
-5.40
-4.34
-4.89
-4.98
-4.32
-5.36
-4.98
-4.74
ND
-5.24
-4.94
-4.99
-5.30
-4.92
-5.65
-4.18
-4.17
>-4.00
>-4.00
>-4.00
-4.77
-4.47
-4.13
>-4.00
Ovarian Cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
>-4.00
-4.15
-4.34
>-4.00
>-4.00
>-4.00
>-4.00
>-4.00/-4.69
>-4.00/-4.35
>-4.00/-4.26
>-4.00/>-4.00
>-4.00/>-4.00
>-4.00/>-4.00
>-4.00/>-4.00
>-4.00
>-4.00
-4.33
-4.63
>-4.00
-4.20
>-4.00
-5.05
-4.47
-4.37
-5.91
-4.52
-4.99
>-4.00
-4.95
-4.92
-5.09
-4.66
-4.76
-4.94
-4.70
>-4.00
>-4.00
-4.40
>-4.00
>-4.00
-4.20
>-4.00
Renal Cancer
786-0
A498
ACHN
CAKI-1
RXF 393
SN12C
TK-10
UO-31
>-4.00
>-4.00
-4.10
-4.14
ND
>-4.00
-4.12
-4.28
>-4.00/>-4.00
>-4.00/>-4.00
>-4.00/>-4.00
>-4.00/-4.32
-4.34/-4.13
>-4.00/-4.12
>-4.00/-4.23
-4.00/-4.35
>-4.00
>-4.00
>-4.00
>-4.00
>-4.00
>-4.00
>-4.00
>-4.00
-5.12
-4.01
-4.88
-4.72
-4.43
-4.99
-5.57
-4.63
-5.19
-5.03
-4.85
-5.42
-5.72
-5.32
-4.57
-5.13
>-4.00
>-4.00
>-4.00
>-4.00
-4.09
>-4.00
>-4.00
>-4.00
Breast Cancer
MCF7
MDA-MB-231/ATCC
HS 578T
BT-549
-4.08
-4.07
-4.17
-4.25
-4.15
-4.09/>-4.00
-4.49/-4.53
>-4.00/>-4.00
>-4.00/>-4.00
-4.04/-5.10
>-4.00
-4.69
>-4.00
>-4.00
>-4.00
-4.93
-5.66
>-4.00
-4.72
-4.82
-5.30
-4.92
-4.96
-5.34
-5.16
-4.13
>-4.00
-4.24
-4.10
-4.42
Prostate Cancer
PC-3
DU-145
-4.06
-4.03
-4.55/-4.56
-4.64/>-4.00
-4.71
ND
-5.15
ND
-5.43
-4.82
ND
>-4.00
Quantity of the
“sensitive lines”a
33/56
(59%)
25/56/36/59
(45%)/(61%)
16/57
(28%)
53/57
(93%)
57/57
(100%)
26/57
(46%)
* data of two independent studies; ND – not investigated
a s/t – ratio of sensitive lines (logGI50<−4.00) to the total number of tested lines.
199
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
COMPARE analysis
The obtained results of the tested compounds’
antitumor activity led us to establishing a pos-
sible mode of their action. For this purpose
COMPARE analysis was performed. NCI’s
COMPARE algorithm [37, 38] allows estab-
lishing possible biochemical mechanisms of
action of the novel compounds on the basis of
their in vitro activity profiles when comparing
with those of standard agents. We performed
COMPARE computations for the compounds
IIa, IIc, IId, IIe, IIId, IIIg, IIIn, and IIIu
against the NCI “Standard Agents” database
at the GI50 level (Table 3).
Unfortunately, the calculated Pearson cor-
relation coefficients (PCC) did not indicate
cytotoxicity mechanisms of the tested com-
pounds with high probability. The highest cor-
relation at the GI50 level was observed for the
compound IId (PCC = 0.661) with alkylating
agent fluorodopan. Interestingly, other
4-azolidinone derivatives also have significant
value of correlation coefficients to the above-
mentioned substance [26, 39–40]. Pearson
correlation coefficients exceeding 0.6 were
also calculated for the IIId (PCC = 0.631) with
hydroquinone ansamycin antibiotic macbecin
II, and for IIe (PCC = 0.603) with hydroxyurea
which is the ribonucleotide reductase inhibitor
and belongs to the class of antimetabolites.
Probably, the PCC < 0.5 for the hit-compound
IIIu indicates other molecular mechanisms
underlying its anticancer effect.
Antitrypanosomal activity
Antitrypanosomal activity of a series of
9-aryl(heteryl)-3,7-dithia-5-azatetracyc-
lo[9.2.1.02,10.04,8]tetradecen-4(8)-ones and
N-substituted analogues was evaluated in the
in vitro assay against Trypanosoma brucei
brucei. All compounds were first tested at a
range of concentrations. IC50 values were
further derived from the dose-response
curves.
Most of the tested compounds showed mo-
de ra te trypanocidal activity at micromolar
range of concentrations. Though, some sub-
stituents in the 9th position of the main scaffold
increased the activity, e.g. ether moiety with
the nitrophenyl fragment in IIk (IC50 =
Table 3. COMPARE analysis results
Comp. PCC Target Mode of actiona
IIa 0.482 thalicarpine p-glycoprotein inhibitor, arrests cancer cells at the G2/M and
G1 phase
IIc 0.584 fluorodopan alkylating agent
IId 0.661 fluorodopan alkylating agent
IIe 0.603 hydroxyurea ribonucleotide reductase inhibitor
IIId 0.631 macbecin II antitumor antibiotic
IIIg 0.538 CCNU alkylating agent
IIIn 0.45 trimethyltrimethylolmelamin -
IIIu 0.499 methyl-CCNU alkylating agent
a Putative mechanisms of action were identified with the use of literature sources; PCC – Pearson correlation coeffi-
cients
200
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
Table 4. IC50 values against Trypanosoma brucei brucei
Compound
S
S
N
O
Ar
R
H
IC50, µM
Ar R
IIi OMe H 21.99
IIj O H 20.52
IIk O
Cl
N+
O
O
H 4.17
IIl
OH OMe
H 22.68
IIm
N+
O
O
H 23.45
IIn
OMe
OMe H 20.24
IIb
O
OMe
H 14.46
IIo O
OEt
H 17.84
4.17 µM) or p-chlorophenyl substituent in IIg
(IC50 = 3.72 µM). p-Oxomethyl- (IIf) and
p-oxophenyl (IIj) substituents negatively influ-
ence trypanocidal properties.
Anticancer activity levels were also low
for these compounds, but they were highly
active towards selected cancer cell lines (IIf:
log GI50 = –7.01 melanoma SK-MEL-2; IIj:
log GI50 = <–8.00 renal cancer RXF-393). An
interesting situation was observed for the
compounds IIf with thiophene fragment, in-
troduction of which led to the significant
antitrypanosomal activity decrease; whilst its
N-substituted derivatives inhibited the para-
201
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
site growth at the concentrations 10 times
lower.
Comparing anticancer profile of the tested
compounds, it is worth to mention that IIg
selectively inhibited growth of the Leukemia
cell lines (log GI50 = –5.16, –5.59) as well as
its N-substituted derivative IIIg; and both have
shown trypanocidal effects.
Conclusions
A series of novel thiopyranothiazole deriva-
tives were synthesized and their anticancer
activity was investigated. Being moderately
active towards approximately 60 tumor cell
lines, all tested compounds showed rather good
growth inhibition against Leukemia cell lines.
Chemical structures of the identified hit-com-
IIf
S
H 53.81
IIIh
O
N
H
Me
7.47
IIIi
O
N
H
CF3
6.31
IIIj
O
N
H
Cl
7.16
IIIk
O
N
H
OMe
4.13
IIIl
O
N
H
CF3
7.65
IIIm
O
N
H
Cl
Cl
7.64
IIg
Cl
H 3.72
IIIg
O
N
H
OMe
3.9
IIIs
O
N
H
N
N
HO
Cl
13.32
202
A. P. Kryshchyshyn, D. V. Atamanyuk, D. V. Kaminskyy et al.
pounds IId and IIIu indicate that the presence
of the arylidene and heterocyclic fragments in
the basic system enhances the antitumor effect
of such compounds. To establish possible bio-
chemical mechanisms of the action of novel
compounds the COMPARE analysis was per-
formed showing correlation at the GI50 level
for IId (PCC = 0.661) with alkylating agent
fluorodopan. A number of 9-aryl(heteryl)-3,7-
dithia-5-azatetracyclo-[9.2.1.02,10.04,8]-tetra-
decen-4(8)-ones were tested in vitro against
Trypanosoma brucei brucei. Thiopyra no thi-
azo les with different arylidene fragments in
the N5 position showed higher inhibition le vel
than their N-unsubstituted analogues. Inte res-
ting is dual antitumor and antitrypanosomal
effect observed for some compounds that may
be used for establishing molecular modes of
action for this class of compounds.
Acknowledgement
We thank Dr. V.L. Narayanan from the Drug
Synthesis and Chemistry Branch, National
Cancer Institute, Bethesda, MD, USA, for in
vitro evaluation of anticancer activity. This
work was partially supported by the Ministry
of Education and Science of Ukraine
(Ukrainian-France program “Dnipro” M/188-
2015; M/71-2016).
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Вивчення протиракової та протипаразитарної
активності тіопірано[2,3-d]тіазолів
з норборнановим фрагментом
А. П. Крищишин, Д. В. Атаманюк,
Д. В. Камінський, Ф. Грельє, Р. Б. Лесик
Мета. Вивчення протипухлинної та трипаноцидної
активності серії нових тіопірано[2,3-d]тіазолів з нор-
борнановим фрагментом у молекулах. Методи: орга-
нічний синтез, аналітичні та спектральні методи, фар-
макологічний скринінг, COMPARE та SAR аналізи.
Результати. З метою одержання сполук з відповідним
фармакологічним профілем синтезовано нові конден-
совані похідні тіопірано[2,3-d]тіазолу з норборнановим
фрагментом у молекулах, які модифіковані за поло-
женнями С9 та N5 базового гетероциклу. Іденти фі ко-
ва но ряд сполук з суттєвим рівнем інгібування росту
ракових клітин, серед яких сполука-хіт N1-(4-
х л о р о ф е н і л ) - 2 - { 2 - [ 6 - о кс о - 5 , 9 - д и т і а - 7 -
азатетрацикло[9.2.1.02,10.04,8]тетрадец-4(8)-ен-3-іл]
фенокси}ацетамід IId, що селективно інгібує лінії
клітин лейкемії в субмікромолярних концентраціях.
Крім того, ряд тіопірано[2,3-d]тіазолів також проявля-
ють перспективну протитрипаносомну активність.
Висновки. Синтезовано нові тіопірано[2,3-d]тіазоли
з норборнановим фрагментом у молекулах а також їх
похідні з різноманітними субституентами в положен-
нях N5 та C9 базової гетероциклічної системи. Сполуки
проявили суттєвий рівень протипухлинної активності
і можуть бути використані для подальшої оптимізації
структури як потенційні протиракові агенти. Окрім
того, сполуки з високим рівнем протипухлинного
ефекту in vitro інгібують ріст Trypanosoma brucei brucei.
Поєднання протиракової та протитрипаносомної ак-
тивності синтезованих сполук є основою для наступної
структурної модифікації та пошуку імовірних механіз-
мів реалізації їх біологічної активності.
К л юч ов і с л ов а: тіопірано[2,3-d]тіазоли, норбор-
нан, синтез, протиракова активність, протитрипано-
сомна активність, SAR.
Изучение противораковой и противо парази-
таной активности тиопирано[2,3-d]тиазолов
из норборнановым фрагментом
А. П. Крищишин, Д. В. Атаманюк,
Д. В. Каминский, Ф. Грэлье, Р. Б. Лесык
Цель. Изучение противоопухолевой и трипаноцидной
активности серии новых тиопирано[2,3-d]тиазолов из
норборнановым фрагментом в молекулах. Методы:
органический синтез, аналитические и спектральные
методы, фармакологический скрининг, COMPARE и
SAR анализы. Результаты. С целью получения сое-
динений с соответстующим фармакологическим про-
филем синтезированы новые производные тиопира-
205
Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety
но[2,3-d]тиазола из норборнановым фрагментом в
молекулах, которые модифицированы по положеннях
С9 и N5 базового гетероцикла. Идентифицировано ряд
соединений с существенным уровнем ингибирования
роста раковых клеток, среди которых соединение-хит
N1-(4-хлорфенил)-2-{2-[6-оксо-5,9-дитиа-7-
азатетрацикло[9.2.1.02,10.04,8]тетрадец-4(8)-ен-3-ил]
фенокси}ацетамид IId, который селективно інгиби-
рует линии клеток лейкемии в субмикромолярных
концентрациях. Кроме того, некоторые тіопірано[2,3-d]
тіазолы также проявляют перспективную протитрипа-
носомную активность. Выводы. Синтезорованы новые
тиопирано[2,3-d]тиазолы из норборнановым фрагмен-
том у молекулах, а также их производные из различ-
ными заместителями в положениях N5 и C9 базовой
гетероциклической системы. Соединения проявили
существенный уровень противоопухолевой активности
и могут быть использованы для дальнейшей структур-
ной оптимизации как потенциальные противораковые
агенты. Кроме того, соединения с високим уровнем
противоопухолевого эффекта in vitro ингибируют рост
Trypanosoma brucei brucei. Сочетание противораковой
и противотрипаносомной активности синтезированых
соединений может быть основой для дальнейшей
оптимизации структуры и поиска возможных механиз-
мов пеализации их биологической активности.
К л юч е в ы е с л ов а: тиопирано[2,3-d]тиазолы, нор-
борнан, синтез, противораковая активность, проти-
вотрипаносомная активность, SAR.
Received 02.04.2017
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