Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group
The aim was analysis of 4-thiazolidinones and related heterocyclic systems anticancer activity data and formation of some rational design directions of potential anticancer agents. Synthetic research carried out in Danylo Halytsky Lviv National Medical University (DH LNMU) allowed us to propose a w...
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irk-123456789-1537072019-06-15T01:30:22Z Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group Lesyk, R. B. Zimenkovsky, B. S. Kaminskyy, D. V. Kryshchyshyn, A. P. Havryluk, R. B. LD. Ya. Atamanyuk, D. V. Subtel’na, I. Yu. Khyluk, D. V. Structure and Function of Biopolymers The aim was analysis of 4-thiazolidinones and related heterocyclic systems anticancer activity data and formation of some rational design directions of potential anticancer agents. Synthetic research carried out in Danylo Halytsky Lviv National Medical University (DH LNMU) allowed us to propose a whole number of new molecular design directions of biological active 4-thiazolidinones and related heterocyclic systems, as well as obtain directed library that numbers over 5000 of novel compounds. At the present time in vitro anticancer activity screening was carried out for more than 1000 compounds (US NCI protocol (Developmental Therapeutic Program), among them 167 compounds showed high antitumor activity level. For the purpose of optimization and rational design of highly active molecules with optimal «drug-like» characteristics and discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were carried out. The ultimate aim of the project is creating of innovative synthetic drug with special mechanism of action and sufficient pharmacological and toxicological features. Some aspects of structure–activity relationships were determined and structure design directions were proposed. The series of active compounds with high anticancer activity and/or selectivity levels were selected. Key words: synthesis, 4-thia(imida)zolidinones, thiopyrano[2,3-d]thiazoles, anticancer activity, (Q)SAR. Метою роботи був аналіз результатів дослідження протипухлинної активності 4-азолідонів і споріднених гетероциклічних сполук та формування деяких напрямків раціонального дизайну потенційних протипухлинних агентів. Синтетичні дослідження, проведені у ЛНМУ імені Данила Галицького, дозволили запропонувати низку нових спрямувань молекулярного дизайну біологічно активних 4-тіазолідинонів та споріднених гетероциклічних систем, а також одержати сфокусовану бібліотеку, яка нараховує понад 5000 нових сполук. На цей час здійснено in vitro скринінг протипухлинної активності понад 1000 сполук (US NCI протокол Developmental Therapeutic Program), з-поміж яких 167 ідентифіковано як такі, що мають високу протиракову активність. Для оптимізації і раціонального дизайну високоактивних молекул з оптимальними «лікоподібними» характеристиками та визначення можливого механізму біологічної дії проведено SAR- і QSAR-аналіз і молекулярний докінг. Кінцевою метою проекту є створення інноваційного синтетичного лікарського препарату з оригінальним механізмом дії та достатнім фармакологічним і токсикологічним профілем. Ключові слова: синтез, 4-тіа(іміда)золідинони, тіопірано[2, 3-d]тіазоли, протипухлинна активність, (Q)SAR. Цель работы состояла в анализе результатов исследования противоопухолевой активности 4-азолидонов и родственных гетероциклических систем и формировании некоторых направлений рационального дизайна потенциалных противоопухолевых агентов. Синтетические исследования, проведенные в ЛНМУ имени Данила Галицкого, позволили предложить ряд новых направлений молекулярного дизайна биологически активных 4-тиазолидинонов и родственных гетероциклических систем, а также получить сфокусированную библиотеку, насчитывающую более 5000 новых соединений. На данный момент осуществлен in vitro скрининг противоопухолевой активности (US NCI протокол Developmental Therapeutic Program) более 1000 соединений, позволивший идентифицировать 167 соединений с высоким противораковым эффектом. Для оптимизации и рационального дизайна высокоактивных молекул с оптимальными «drug-like» характеристиками и установления вероятного механизма биологического действия проведен SAR- и QSAR-анализ и молекулярный докинг. Конечная цель проекта – создание инновацинного синтетического лекарственного сресдтва с оригинальным механизмом действия, достаточным фармакологическим и токсикологическим профилем. Ключевые слова: синтез, 4-тиа(имида)золидиноны, тиопирано[2,3-d]тиазолы, противоопухолевая активность, (Q)SAR. 2011 Article Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group / R. B. Lesyk, B. S. Zimenkovsky, D. V. Kaminskyy, A. P. Kryshchyshyn, D. Ya. Havryluk, D. V. Atamanyuk, I. Yu. Subtel’na, D. V. Khyluk // Вiopolymers and Cell. — 2011. — Т. 27, № 2. — С. 107-117. — Бібліогр.: 49 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000089 http://dspace.nbuv.gov.ua/handle/123456789/153707 615.012.1.076:547.789.1 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
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| topic |
Structure and Function of Biopolymers Structure and Function of Biopolymers |
| spellingShingle |
Structure and Function of Biopolymers Structure and Function of Biopolymers Lesyk, R. B. Zimenkovsky, B. S. Kaminskyy, D. V. Kryshchyshyn, A. P. Havryluk, R. B. LD. Ya. Atamanyuk, D. V. Subtel’na, I. Yu. Khyluk, D. V. Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group Вiopolymers and Cell |
| description |
The aim was analysis of 4-thiazolidinones and related heterocyclic systems anticancer activity data and formation of some rational design directions of potential anticancer agents. Synthetic research carried out in
Danylo Halytsky Lviv National Medical University (DH LNMU) allowed us to propose a whole number of
new molecular design directions of biological active 4-thiazolidinones and related heterocyclic systems, as
well as obtain directed library that numbers over 5000 of novel compounds. At the present time in vitro anticancer activity screening was carried out for more than 1000 compounds (US NCI protocol (Developmental
Therapeutic Program), among them 167 compounds showed high antitumor activity level. For the purpose
of optimization and rational design of highly active molecules with optimal «drug-like» characteristics and
discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were carried out.
The ultimate aim of the project is creating of innovative synthetic drug with special mechanism of action and
sufficient pharmacological and toxicological features. Some aspects of structure–activity relationships
were determined and structure design directions were proposed. The series of active compounds with high
anticancer activity and/or selectivity levels were selected.
Key words: synthesis, 4-thia(imida)zolidinones, thiopyrano[2,3-d]thiazoles, anticancer activity, (Q)SAR. |
| format |
Article |
| author |
Lesyk, R. B. Zimenkovsky, B. S. Kaminskyy, D. V. Kryshchyshyn, A. P. Havryluk, R. B. LD. Ya. Atamanyuk, D. V. Subtel’na, I. Yu. Khyluk, D. V. |
| author_facet |
Lesyk, R. B. Zimenkovsky, B. S. Kaminskyy, D. V. Kryshchyshyn, A. P. Havryluk, R. B. LD. Ya. Atamanyuk, D. V. Subtel’na, I. Yu. Khyluk, D. V. |
| author_sort |
Lesyk, R. B. |
| title |
Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group |
| title_short |
Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group |
| title_full |
Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group |
| title_fullStr |
Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group |
| title_full_unstemmed |
Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group |
| title_sort |
thiazolidinone motif in anticancer drug discovery. experience of dh lnmu medicinal chemistry scientific group |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
2011 |
| topic_facet |
Structure and Function of Biopolymers |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/153707 |
| citation_txt |
Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group / R. B. Lesyk, B. S. Zimenkovsky, D. V. Kaminskyy, A. P. Kryshchyshyn, D. Ya. Havryluk, D. V. Atamanyuk, I. Yu. Subtel’na, D. V. Khyluk // Вiopolymers and Cell. — 2011. — Т. 27, № 2. — С. 107-117. — Бібліогр.: 49 назв. — англ. |
| series |
Вiopolymers and Cell |
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| fulltext |
Thiazolidinone motif in anticancer drug discovery.
Experience of DH LNMU medicinal
chemistry scientific group
R. B. Lesyk, B. S. Zimenkovsky, D. V. Kaminskyy, A. P. Kryshchyshyn,
D. Ya. Havryluk, D. V. Atamanyuk, I. Yu. Subtel’na, D. V. Khyluk
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University
69, Pekarska St., Lviv, Ukraine, 79010
dr_r_lesyk@org.lviv.net; dankaminskyy@gmail.com
The aim was analysis of 4-thiazolidinones and related heterocyclic systems anticancer activity data and for-
mation of some rational design directions of potential anticancer agents. Synthetic research carried out in
Danylo Halytsky Lviv National Medical University (DH LNMU) allowed us to propose a whole number of
new molecular design directions of biological active 4-thiazolidinones and related heterocyclic systems, as
well as obtain directed library that numbers over 5000 of novel compounds. At the present time in vitro anti-
cancer activity screening was carried out for more than 1000 compounds (US NCI protocol (Developmental
Therapeutic Program), among them 167 compounds showed high antitumor activity level. For the purpose
of optimization and rational design of highly active molecules with optimal «drug-like» characteristics and
discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were carried out.
The ultimate aim of the project is creating of innovative synthetic drug with special mechanism of action and
sufficient pharmacological and toxicological features. Some aspects of structure–activity relationships
were determined and structure design directions were proposed. The series of active compounds with high
anticancer activity and/or selectivity levels were selected.
Key words: synthesis, 4-thia(imida)zolidinones, thiopyrano[2,3-d]thiazoles, anticancer activity, (Q)SAR.
Introduction. Thiazolidinone derivatives are well
known class of biological active substances [1–3] that
became basic for the whole number of innovative
medicinal agents, such as hypoglycemic thiazolidine-
diones (Pioglitazone and its analogues) [4], aldose re-
ductase inhibitors (Epalrestat) [5], dual inhibitors of
COX-2/5-LOX (Darbufelon) [6], modern diuretics
(Etozoline) [7], Mur family inhibitors (UDP-MurNAc/
L-Ala ligases) etc. [8]. Recently thiazolidinone rese-
arch area unexpectedly became interesting and promi-
sing for oncology. In-depth study of PPARs allowed to
put forward and validate the concept of anticancer po-
tential existence of PPAR agonists including thiazoli-
dinediones [9, 10]. In addition, inhibitors of antiapop-
totic proteins Bcl-XL and ВН3 [11] which contribute to
modulation of programmed cell death (apoptosis), as
well as inhibitors of tumor necrosis factor TNFα [12],
necroptosis inhibitors [13], integrin antagonists [14],
inhibitors of JSP-1 [15], Pim-2 and Рim-1 protein kina-
ses [16], COX-2 [17] etc. were identified among 4-thia-
zolidinones.
Biological active thiazolidinones and related hete-
rocycles refer to one of the most successful scientific
projects in the area of pharmacy of DH LNMU (Fig. 1).
It is based on three strategic vectors: а) organic syn-
thesis; b) pharmacological research; c) rational design
of «drug-like» molecules (virtual screening: QSAR-
analysis, molecular docking etc.) [1, 18].
107
ISSN 0233–7657. Biopolymers and Cell. 2011. Vol. 27. N 2. P. 107–117
Institute of Molecular Biology and Genetics NAS of Ukraine, 2011
In the starting stages of the project anti-inflamma-
tory [19–21], antimicrobial [22, 23], anticonvulsant,
choleretic [24] and antioxidant [25] activities were
identified. In spite of the series of perspective results,
progress of the project brings to some research direc-
tions changes, notably it has focused on the search of
new anticancer agents. Taking into account global
processes in the world science and the necessity of
planning the tactics of narrowly defined groups deve-
lopment in competition environment of the biological
active molecules market, screening research are carried
out within the National Cancer Institute (NCI) of Nati-
onal Institute of Health (NIH) scientific programs (De-
velopmental Therapeutic Program, Bethezda, USA,
http:/dtp.nci.nih.gov) [26–30]. The ultimate aim of the
project is creating of innovative synthetic drug with
special mechanism of action and sufficient pharmaco-
logical and toxicological features.
Results and discussion. Synthetic research in the
area of 4-thiazolidinones derivatives. Synthetic stra-
tegy consists in structure modification of azolidinone
ring formed in different [2 + 3]-cyclocondensation re-
actions and modifying it in the positions 2, 3, 4 and 5.
Six key types of the reactions were generally used
(Knoevenagel reaction, [2 + 3]-cyclocondensation, N-
alkylation, acylation, heterodiene synthesis, «domino»
reactions) that allowed to obtain directed library with
over 5000 new thiazolidinones and related heterocyclic
systems (Fig. 2) [1, 21, 23, 31–40].
While applying the research strategy through the
past few years we succeeded in gaining a number of in-
teresting synthetic results that make possible to extend
the field of the chemistry of thiazolidinone and related
heterocycles, especially in the scope of «drug-like»
molecules design.
Anticancer activity evaluation of 4-thiazolidi-
nones and related heterocyclic systems and efficient
approaches to interpretation of «structure–activi-
ty» correlation. Obtained real library of heterocyclic
compounds became an object for study concerning an-
ticancer activity identifying according to the standard
NCI procedure. On the first stage high-performance in
vitro prescreening was held on 3 tumor cell lines (NCI-
H460, MCF-7 and SF-268) in concentration 10–4 М.
108
LESYK R. B. ET AL.
Synthetic
investigation
Chemical library
(over 5000 compounds)
Pharmacological
study
Early stages of research
anti-inflammatory, antioxidant, antimicrobial,
anticonvulsant and choleretic activities
Modern project stage
NCI DTP
anticancer screening
QSAR-analysis, docking etc
In silico approaches in
"drug-like" molecules design
testing in single concentration 10–4M
(MCF-7, NCI-H460, SF-268 cell lines)
482 compounds
testing in single concentration 10–5 M
(60 cancer cell lines)
594 compounds
testing in range of
concentration 10–4 – 10–8M
(60 cancer cell lines)
402 compounds
Biological Evaluation
Committee NCI
14 lead-compounds
In-depth preclinical investigation
7 lead-compounds
since 2005
I phase
II phase
III phase
IV phase
167 hit-
compounds
Fig. 1. Scheme of the De-
partment of Pharmaceu-
tial, Organic and Bioor-
gaic Chemistry project
design
Since 2005 the prescreening criteria became strict and
the procedure of prescreening consists in testing of
compounds activity on 60 tumor cell lines in con-
centration 10–5 M. On the second stage of prescre-
ening active compounds are tested in vitro at 10-fold
dilutions of five concentrations (10–4–10–8M) on 60 tu-
mor cell lines including lines of leukemia, non-small
sell lung cancer, colon cancer, CNS cancer, melanoma,
ovarian cancer, prostate cancer and breast cancer. In
this assay three dose-response parameters are obtained:
1) growth inhibition of 50 % – GI50; 2) total growth
inhibition – TGI; 3) LC50. Whereas the GI50 may be vie-
wed as a growth-inhibitory level of effect, the TGI
signifies a «total growth inhibition» or cytostatic level
of effect. The LC50 is the lethal concentration, «net cell
killing» or cytotoxity parameter. If the tested parame-
ters (pGI50, pTGI and pLC50) specified in negative
log10 units are less then < 4.00 these compounds are
assigned as active.
Now among 1076 tested compounds 402 (37.4 %)
have successfully passed prescreening phase (Fig. 1).
After passing the second testing phase 14 compounds
were submitted for consideration of NCI Biological
Committee, among them 7 compounds are affirmed for
the in-depth in vivo preclinical trials as potential anti-
cancer agents. Tested compounds introduce all the sub-
libraries (Fig. 2) of obtained derivatives and accor-
ding to the data of NCI specialists most of the highly
active compounds don’t belong to any class of known
anticancer agents that is weighty argument for their in-
depth investigation.
When analyzing the in-depth in vitro research re-
sults [18] it is worth to mention that in the anticancer
selectivity rating the most sensitive to 4-thiazolidino-
nes and related heterocyclic systems was the line of
leukemia. Level of selectivity on the cell lines of non-
small sell lung cancer, CNS cancer and breast cancer
are approximately the same. Series of cell lines, such as
leukemia lines (CCRF-CEM, HL-60(TB), RPMI-
8226, SR, K-562, MOLT-4), CNS cancer line (U251),
non-small cell lung cancer line (HOP-92), renal cancer
cell lines (UO-31, 786-O), colon cancer line (HCT-
116) as well as breast cancer line (MDA-MB 231) have
been found to be the most sensitive to testing com-
pounds. The ranking is given in decreasing order of
high antitumor effect frequency for tested compounds.
Thus based on the obtained results the hypotheses of
specific anti-leukemia activity of heterocycles contai-
ning «thiazolidinone matrix» may be put forward.
Obtained results allowed to form a number of struc-
ture-anticancer activity relations and outline the ratio-
nal design directions. SAR analysis was carried out wi-
thin each of the presented sub-libraries of azolidinone
derivatives (Fig. 3–5).
109
THIAZOLIDINONE MOTIF IN ANTICANCER DRUG DISCOVERY
X
N
HS
N
S
Y
R
N
A
O
R
Y
O
N
N
O
R2
R1
N
O R
R2
R1N
O N
H
S
R
N
N
O
R2
R1
S
N
NN
O
N N
Y
O
O
O
R
N
N
R
R2
R1
O
X
O
X
Y
H
R
X
O
R O
X
O
X
Y
N
NHR
X
Y
O(N)H
R
N
H
N
HO
O
S
N
HO
O
S
N
HO
S
S
N
HS
O
X = S, NH
A
Y = O, NH
Y = O, S
Hydantoin
2,4-Thiazolidinedione
Rhodanine
Isorhodanine
Fig. 2. Structure of compounds sub-libraries, synthesized at the Department of Pharmaceutical, Organic and Bioorganic Chemistry
Anticancer effect realization of 2-substituted 4-
thiazolidinones (1, 2) (Fig. 3) depends on the nature of
substituents in the positions С2 and N3, moreover rela-
tion between activity levels of the derivatives 2 and 3
wasn’t established. Retrospective analysis of these
compounds showed that anticancer activity increases
while transition from cycloalkyl moiety to heteryl moi-
ety in position C2 and the moieties of amino acid or
aromatic amine are eligible in position N3. Instead of
this compounds of row 1 with the 2-imino fragment are
characterized by the higher activity, while presence of
substituent in the position N3 is not always desirable
(3). Imidazolidinone isosters (X = NH) of sub-libraries
1, 3 posses lower activity level than compounds based
on thiazolidinone (X = S) [39]. Suggested and confir-
med by us hypotheses about the crucial role of the pre-
sence and the nature of the substituent in the position
C5 in anticancer effects realization [1, 36] is abso-
lutely confirmed in the case of 2-substituted 4-thiazoli-
done derivatives 4. In this number of heterocycles the
compounds with aryl(heteryl)idene fragments are cha-
racterized by the maximum level of anticancer activity.
One of the effective and frequently used directions
of new biological active substances research in modern
medical chemistry is the direction based on the phar-
macophore hybrid approach usage [41]. This approach
110
LESYK R. B. ET AL.
3711
O
N
(CH2)nCONR
N
Ar
N
Het
X = S X = NH
A + B = Het
A = H, B = Ar
A + B = CyclAlk
R2 = H, R1 = Ar
R2 + R1 = Het
or
X
O
R2
R1 4
X
N
N
H
Ar (Het)
3
Desirable molecular fragment Increase of activity level
X
N
O
N (NH)
1
Ar (Het)
Ar (Het)
N
S S
O
N
H
S
N
N
S
O
N
H
N
S
S
N
N
N
Ar
Ph
O
N
S
O
N
N
Ar
Ar'
S
O
S
Ar
S
N N
N
O
S
NO
N
R
N S
N
H O
N
H
S
O
X N
S
O
N
H
S
N
N
H O
R
R
Modification of C5 position -
most effective direction
8
9
10
5
6
S
N
O
A
B
2
Ar (Het)
Fig. 3. Some features of structure–anticancer activity relationships in synthesized 2,3-disubstituted-4-thiazolidinones and heterylsubstituted
thiazolidinones sub-libraries
provides combination of different pharmacophore cyc-
les with equal biological activity and affinity to diffe-
rent biotargets in one molecule. Such combination of-
ten allows to reach the potantiation of action (synergic
effect). The results of our research work confirm this
hypothesis and help us to identify high antitumor effect
of heteryl substituted 2(4)-thiazolidinones.
Study of the «structure–anticancer activity» rela-
tionship makes possible to establish that antimitotic ef-
fect displaying depends on the nature of heterocyclic
fragment. Moving from non-condensed bis-thiazolidi-
nones 5 to 2-pyrazolin substituted 10 and 2-benzthia-
zolamine-4-thiazolidinones 6 is characterized by the
increasing of activity [35, 38]. It is worth to mention
that position of heterocyclic fragment relative to the ba-
sic (thiazolidinone) cycle has ambiguous influence on
the activity appearance. In the row of non-condensed
systems with thiazolidinone and benzthiazole frag-
ments moderate activity intension is traced when chan-
ging the position of benzthiazole cycle from С2 (6) to
N3 (7), while changing the position of pyrazoline cycle
from С2 (10) to С4 (9) doesn’t influence the antimitotic
effect realization [37]. It is established that 4-pyrazo-
line substituted 2-thiazolidones 9 are more active than
4-arylamine-2-thiazolidinones 8, at the same time 2-
arylamine-4-thiazolidinones isomers 3 possess higher
or equal activity than 2-heteryl substituted derivatives
6, 10. In general, structure of the substituent in position
C5 of thiazolidinone cycle is determinative for the anti-
cancer activity realization for all the heteryl substitu-
ted thiazolidinones. That’s why modification of men-
tioned position is the key concept of directed synthesis
of novel anticancer agents in described class of com-
pounds. When moving from thiazolidinone scaffold to
condensed thiazolo[3,2-b][1,2,4]triazol-6-one system
light activity increasing occurs [32], though C5-sub-
stituent remains the determining factor.
The group of 4-thiazolidinone-3(5)-alkanecarbo-
xylic acids is one of the most studied groups of thiazoli-
dinone derivatives with the determined molecular me-
chanism of biological activity realization, including
anticancer activity [42]. Comparison of anticancer acti-
vity of 4-thia(imida)zolidinone-5-carboxylic acids (12)
and 4-thia(imida)zolidinone-3-carboxylic acids (13)
indicates that the latter show higher antitumor activity
level (Fig. 4). In the series of presented derivatives the-
re is no significant difference between the levels of an-
titumor activity of thiazolidinone (X = O) and rhoda-
nine (X = S) derivatives. However, the substitution of a
sulfur atom in thiazolidinone cycle for the atom of nit-
rogen (transition from 2,4-thiazolidinediones to 2,4-
imidazolidinediones) in compounds 13 contributes to
the intensification of anticancer activity and appea-
rance of selectivity of 4-imidazolidinone-3-carboxylic
acids effects. Thus for the hydantoin-3-acetic acids the
significant effect on the leukemia lines was observed,
though there was almost no influence on the other can-
cer cell lines [36]. This fact allows to consider 5-aryl-
idene-2,4-imidazolidinedione-3-acetic acids amides as
«hit-structures» for the anti-leukemia agents search. Si-
multaneous presence of substituents in the positions C5
and N3 of the basic heterocycle is desirable and is pro-
ved by the higher anticancer activity level of 4-thiazo-
lidinone-3,5-alkanecarboxylic acids (14, 15) and 5-
arylidene-4-thiazolidinone-3-alkanecarboxylic acids
(16) [43]. Comparison of the activity of the compounds
14–16 points an advantage of ylidene moiety, namely
the aryl(heteryl)idene fragment. Also, it is found that
amides are more active than esters and free acids ir-
respective of the presented acids series they belong to.
Antitumor activity evaluation of 5-ylidenerhodani-
ne-3-succinic acids (17) proved presented relation and
allowed us to make a suggestion that 3-(4-oxo-2-thi-
oxothiazolidine-3-yl)-pyrrolidine-2,5-dione fragment
is probable pharmacophore for this series of compo-
unds [44]. The position C-5 of rhodanine cycle and nit-
rogen atom of pyrrolidine cycle are considered to be the
main directions of its chemical modification. Utiliza-
tion of thiazolidinone-alkanecarboxylic acids for the
structure optimization of other scaffolds is effective
approach in novel antitumor agents design; it is eluci-
dated by the example of triterpenoid structure modifi-
cation (18) and may be taken as the variant of hybrid
pharmacophore approach.
Annealing of heterocyclic fragments as widespread
method used for conformational flexibility limitation,
is perspective and not sufficiently studied direction of
biological active substances search. Possibility of fu-
sed thiazole heterocyclic systems 20 (Fig. 5) to imitate
some biophore fragments of their synthetic precursors,
namely 5-ylidene-4-thiazolidinones 19, allowed us to
put forward the hypothesis about activity remaining in
111
THIAZOLIDINONE MOTIF IN ANTICANCER DRUG DISCOVERY
their condensed derivatives [31, 34]. Based on antitu-
mor activity retrospective analysis we established that
activity level, mainly, depends on the surroundings of
thiopyrane fragment. Basing on the comparison of
thiopyrano[2,3-d]thiazoles derivatives activity we
can’t determine precise structure–activity relation-
ship. Though it should be noted that antitumor effect
increases when moving from isothiochromeno[4a,4-d]
[1,3]thiazole derivatives (21) to chromeno[4',3':4,5]
thiopyrano[2,3-d]thiazoles (22), the same tendency is
observed in the series 23–25 and 26–28. The optimal
surroundings of thiopyrane fragment in thiopyrano
[2,3-d]thiazole-2-ones is naphtoquinone moiety (25) or
unsubstituted norbornane fragment (28). In all series of
mentioned derivatives isorhodanine isosters (Х = О)
are more active than thiorhodanine derivatives (X = S)
and the main direction of highly active anticancer
agents rational design is introduction of the substituent
in position N3. Realization of this method presented by
the example of chromeno[4',3':4,5]thiopyrano[2,3-d]
thiazoles (22) [45, 46] allows achieving significant in-
creasing of the level and/or selectivity of studied sub-
stances anticancer activity in comparison with N-un-
substituted analogues, moreover presence of N-aryl-
acetamide fragments is desirable. The optimal mole-
cular fragments that cause increasing of the activity le-
vel of thiopyrano[2,3-d]thiazole-2-ones and fragments
are presented at the Fig. 5.
The Fig. 6 presents «hit-compounds» from diffe-
rent groups that possess high antimitotic effect in vitro
in submicromolar concentrations (10–5–10–7 М) and are
characterized by the low in vivo toxicity level.
In silico method of anticancer activity data ana-
lysis. The COMPARE analysis was performed for the
active compounds in order to investigate the similarity
of their cytotoxicity pattern (mean graph fingerprints)
with those of known anticancer standard agents, NCI
active synthetic compounds and natural extracts, which
are present in public available databases. Such in silico
analysis consists in the comparison of the patterns of
112
LESYK R. B. ET AL.
Desirable molecular fragment Increase of activity level
Y
N
H
N
O
X
A
O
R H
A
N O
R
O
O
O
X = O; Y = S, N
X = S, O; Y = S
12 13
Y
N
O
X
A
N
O
R
14
Y
N
O
X
A
N
H
O
R
S
N
O
O
A N
H
O
N
H
O
Ar
R
O
O
R
O
N
R
S
N
S or O N
N
O
O
OH
Y
N
HO
X
X = S, O; Y = S, N
Comparison of acids row
Modification of triterpenoids
15
16
X O
N N
O
O
A OH
O
A
Ar (Het)
N
S
O
N
O
R
X = O, S
Chain elongation or
branching
N
O
OS
N
O
X
1817
Ar (Het)
Ar (Het)
H
Y
N
H
XA
N O
R
H H
H
HH
H
Fig. 4. Some features of structure–anticancer activity relationships in sub-library of synthesized azolidinone-carboxylic acids derivatives
differential growth inhibition for cultured cell lines and
can potentially gain insight into the mechanism of the
cytotoxic action. It is accessible for the practical usage
on the web portal of NCI (USA, http://dtp.nci.nih.gov/
docs/compare/compare.html) [47, 48] and may indi-
rectly indicates possible mechanism of cytotoxic acti-
on. If the data pattern correlates well with that of com-
pounds belonging to a standard agent database (Pear-
son’s correlation coefficient (PCC) >0.6), the compo-
und of interest may have the same mechanism of ac-
tion. On the other hand, if the activity pattern does not
correlate with any standard agent, it is possible that the
compound has a novel/another mechanism of action.
Standard COMPARE analysis was performed at the
GI50 and TGI levels.
For synthesized heterocyclic substances was estab-
lished correlation with the inhibitors of tubulin poly-
merization, RNA polymerase, p-glycoprotein or topo-
isomerase II, inductors of apoptosis, activators of cas-
pases, that allow prediction of mentioned mechanism
of anticancer action for 4-thiazolidinone derivatives
and related heterocyclic systems. It is worth to mention
interesting fact of significant values of correlation co-
efficients of thiazolidinone derivatives from different
sub-libraries [35, 39] to the S-trityl-L-cysteine (NSC
83265, r = 0.702), aminoacyl-tRNA synthetases inhibi-
tor with antiproliferative effect against leukemia [49].
In silico methods, such as molecular docking and
QSAR-analysis are widely used in our research work
for rational design of potential anticancer agents. Cur-
rently for highly active substances from different gro-
ups is performed flexible molecular docking (using
Glide and Fred programs) to «classical» for 4-thia-
zolidinones biotargets, such as PPARγ (codes 1FM6
and 1NYX), protein complex Bcl-XL-BH3 (1BXL) and
tubulin (1SA1). We chose tubulin because of high va-
lues of Pearson’s correlation coefficient of synthesized
compounds and classical tubulin polymerization inhi-
bitors. QSAR-analysis of antitumor activity parameter
lgGI50 with the usage of docking scoring functions and
molecular descriptors (Mr, lgP, TPSA, HOMO and
LUMO, µ, qmin, and qmax) allowed obtaining series of re-
113
THIAZOLIDINONE MOTIF IN ANTICANCER DRUG DISCOVERY
S
N
O
R1
X
R
R2
S
N
S
R
X
R2
R1
S
H
H
H R
S
O
O H R
S
N
O
O
H
H
R
H
H
H R
S
H R
N
O
O
R
SN
H
S
O
R R
S
O
H
H
S
H
Me
R
S
R
OHC
R
S
S
N
O
N
H
O
R
S
S
N
O
O
O R
X = S X = O
-CH2CO-
Modification of N3 position -
most effective direction
25
24
23
22
21
20
26
27
28
19
Direction of chemical modification
Hal- Aryl, Het
Fig. 5. Some features of structure–anticancer activity relationships in sub-library of synthesized thiopyrano[2.3-d]thiazole derivatives
liable QSAR models. So, in the case of thiopyrano[2, 3-
d]thiazole-2-ones, models 1–4 indicate the highest cor-
relation of lgGI50 parameter for leukemnia, prostate and
CNS cancer cell lines with LUMO (energy of the low-
est unoccupied molecular orbital) and scoring func-
tions values to tubulin molecules and protein complex
Bcl-XL-ВН3 which may be used as potential targets for
the anticancer agents design and virtual screening [31]:
lgGI50 (Breast Cancer /T-47D) = 34.787 ⋅ LUMO + 0.002 ⋅ ZB
(tubuline) (1)
N = 11; r2 = 0.91; S = 0.13; F = 43; q2 = 0.82;
lgGI50 (Breast Cancer/T-47D) = 35.259 ⋅ LUMO – 0.015 ⋅ PLP
(1BLX) – 0.029 ⋅ CS (1BLX) (2)
N = 11; r2 = 0.93; S = 0.11; F = 33; q2 = 0.88;
lgGI50 (Colon Cancer/HCT-116) = 0.611 ⋅ µ – 2.294 ⋅ qmin +
+ 0.046 ⋅ CS (1FM6) (3)
N = 10; r2 = 0.93; S = 0.07; F = 32; q2 = 0.81;
lgGI50 (CNS Cancer/SNB-19) = –0.388 ⋅ lgP – 5.008 ⋅ qmin –
– 0.035 ⋅ PLP (1BLX) (4)
N = 11; r2 = 0.91; S = 0.09; F = 24; q2 = 0.81.
Series of valid QSAR models 5–8 were calculated
for 5-ylidene-2-thioxo-4-oxothiazolidinone-3-succinic
acids derivatives [44]:
lgGI50 (Lung Cancer/NCI-H322M) = –0,507 ⋅ lgP – 18.598 ×
× LUMO – 0,046 ⋅ ZB (1FM6) (5)
N = 10; r2 = 0.96; S = 0.05; F = 48; q2 = 0.91;
lgGI50 (Lung Cancer/HOP-92) = –0,636 ⋅ qmax + 0,006 ⋅ ZB
(1SA1) (6)
N = 13; r2 = 0.95; S = 0.20; F = 95; q2 = 0.91;
lgGI50 (Lung Cancer/A549/ATCC) = –0,003 ⋅ MW + 0.012 ×
× TPSA + 0,052 ⋅ ZB (1BXL) (7)
N = 13; r2 = 0.93; S = 0.09; F = 40; q2 = 0.86;
lgGI50 (Ovarian Cancer/MD_mean) = –0,185 ⋅ lgP + 0,064 ×
× ZB (1BXL) – 0,004 ⋅ SG (1BXL) (8)
N = 13; r2 = 0.93; S = 0,07; F = 40; q2 = 0,86.
Docking functions comparison in the model range
5–8 shows that the best is correlation of Zapbind func-
tions values (Fred) and E-model (Glide). In determined
models values of lgP, LUMO, HOMO and docking
114
LESYK R. B. ET AL.
S
N
O
S
N
H
S
N
Cl
ONH
O
O
CH
3
N
H
N
O
O
N
H
O
F
FF
Cl S N
N
N+
O−
O
N
O
O
CH
3
Ph
N
S
O
N
H
OH
N+
O−
O
Cl S
N
O
N
H O
Cl
N
N
S
N
H
O
O
NH
S
S
O
Cl
Cl
O
N
O
OF
F
F
NS
S
O
OH
H
H
H
H
S
N N
N
O
N
H
O
N
S
S
O
O
O
N
F
F
F
NCS 745159
pGI50 = 5,27 – 5,81
NCS 731910
pGI50 = 4,47 – 5,78
NCS 740765
pGI50 = 6,06 – 6,53 (Leukemia)
NCS 740763
pGI50 = 4,22 – 6,10
NCS 745116
pGI50 = 4,30 – 6,34
NCS 728398
pGI50 = 4,72 – 6,74
pTGI = 4,13 – 6,36
pLC50 = 4,12 – 5,98
NCS 741029
pGI50 = 4,00 – 5,41
NCS 729567
pGI50 = 4,14 – 6,94
pTGI = 4,07 – 7,04
pLC50 = 4,01 –5,23
NCS 735629
pGI50 = 4,84 – 5,67
H
H
H
H
H
H
H
H
Fig. 6. Structures of some synthesized hit-compounds with high in vitro antitumor level
ratings to Bcl-XL-BH3 protein complex, PPARγ, as
well as to tubulin protein predominate. However, it
should be noted that if there is docking function for
Bcl-XL-BH3 protein complex in the model, its partial
contribution in the PLS model is more essential, than if
docking is performed to other biotargets. In consequ-
ence of performed studies in silico it can be assumed
that the most probable mechanism of anticancer activi-
ty of 5-ylidene-4-thiazolidinone-3-succinic acids may
be binding with the anti-apoptotic protein complex
Bcl-XL-BH3.
Thus, based on the complex use of molecular do-
cking, COMPARE analysis and QSAR analysis we put
forward a hypothesis about probable 4-thiazolidinones
and related heterocycles influence on the apoptotic
bisystem. Currently we continue with complex studies
using molecular biology methods to confirm our
hypothesis.
Project outline. The ultimate aim of scientific pro-
ject of the DH LNMU department of pharmaceutical,
organic and bioorganic chemistry is creating of drug
prototype with unique mechanism of action for the in-
depth preclinical and clinical trials. So, besides going
on with synthetic and pharmacological studies such
tasks are privileged for our group:
optimization of «hit-compounds» biopharmaceuti-
cal characteristics;
«hit-compounds» improvement using rational de-
sign methods;
experimental confirmation and identification of
biotargets to anticancer 4-thiazolidinones and related
heterocyclic systems;
usage of modern delivery systems (drug delivery
system) for the drug candidates as actual approach in
drug technology and biopharmacy.
Conclusions. Novel methods for sulfur- and nitro-
gen containing heterocycles synthesis are worked out
that allow to obtain over 5000 of new substances for
pharmacological screening, as well as broaden out the
field of thiazolidinone and related heterocycles stu-
dying in the context of original «drug-like» molecules
design.
Based on systematic combination of pharmacolo-
gical screening methods and in silico data the antican-
cer activity is determined as privileged for thiazolidi-
nones and related heterocyclic systems that allowed
identification of «hit-compounds» series.
Some aspects of structure–activity relationships
were determined and structure rational design directi-
ons were proposed. Among tested compounds 167
samples showed high antitumor activity level and their
in-depth preclinical studies are in progress.
Acknowledgements. We are grateful to Dr. V. L. Na-
rayanan from Drug Synthesis and Chemistry Branch,
National Cancer Institute, Bethesda, MD, USA, for in
vitro evaluation of anticancer activity.
Р. Б. Ле сик, Б. С. Зімен ко вський, Д. В. Камінський,
А. П. Кри щи шин, Д. Я. Гав ри люк, Д. В. Атаманюк,
І. Ю. Суб тель на, Д. В. Хи люк
Тіазоліди но ни як лей тмо тив у ство ренні про ти ра ко вих
ліка рських за собів. Досвід на уко вої гру пи
з ме дич ної хімії ЛНМУ імені Да ни ла Га лиць ко го
Ре зю ме
Ме тою ро бо ти був аналіз ре зуль татів досліджен ня про ти пух -
лин ної ак тив ності 4-азолідонів і спорідне них ге те ро циклічних
спо лук та фор му ван ня де я ких на прямків раціональ но го диз ай ну
по тенційних про ти пух лин них агентів. Син те тичні досліджен -
ня, про ве дені у ЛНМУ імені Да ни ла Га лиць ко го, доз во ли ли за -
про по ну ва ти низ ку но вих спря му вань мо ле ку ляр но го диз ай ну
біологічно ак тив них 4-тіазоліди нонів та спорідне них ге те ро -
циклічних сис тем, а та кож одер жа ти сфо ку со ва ну бібліот е -
ку, яка на ра хо вує по над 5000 но вих спо лук. На цей час здійсне но
in vitro скринінг про ти пух лин ної ак тив ності по над 1000 спо лук
(US NCI про то кол Developmental Therapeutic Program), з-по-
між яких 167 іден тифіко ва но як такі, що ма ють ви со ку про -
ти ра ко ву ак тивність. Для оптимізації і раціональ но го диз ай ну
ви со ко ак тив них мо ле кул з опти маль ни ми «ліко подібни ми» ха -
рак те рис ти ка ми та виз на чен ня мож ли во го ме ханізму біоло-
гічної дії про ве де но SAR- і QSAR-аналіз і мо ле ку ляр ний докінг.
Кінце вою ме тою про ек ту є ство рен ня інно ваційно го син те -
тич но го ліка рсько го пре па ра ту з оригіна льним ме ханізмом дії
та дос татнім фар ма ко логічним і ток си ко логічним профілем.
Клю чові сло ва: син тез, 4-тіа(іміда)золіди но ни, тіопірано[2,
3-d]тіазо ли, про ти пух лин на ак тивність, (Q)SAR.
Р. Б. Ле сык, Б. С. Зи мен ков ский, Д. В. Ка мин ский,
А. П. Кри щи шин, Д. Я. Гав ри люк, Д. В. Атаманюк,
И. Ю. Суб тель ная, Д. В. Хи люк
Ти а зо ли ди но ны как лей тмо тив в со зда нии
про ти во о пу хо ле вых ле ка рствен ных средств. Опыт на учной
груп пы ме ди цин ской хи мии ЛНМУ имени Да ни ла Га лиц ко го
Ре зю ме
Цель ра бо ты со сто я ла в ана ли зе ре зуль та тов ис сле до ва ния
про ти во о пу хо ле вой ак тив нос ти 4-азо ли до нов и ро дствен ных
ге те ро цик ли чес ких сис тем и фор ми ро ва нии не ко то рых на -
прав ле ний ра ци о наль но го диз ай на по тен ци ал ных про ти во о пу -
хо ле вых аген тов. Син те ти чес кие ис сле до ва ния, про ве ден ные в
ЛНМУ име ни Да ни ла Га лиц ко го, по зво ли ли пред ло жить ряд но -
вых на прав ле ний мо ле ку ляр но го диз ай на би о ло ги чес ки ак тив -
ных 4-ти а зо ли ди но нов и ро дствен ных ге те ро цик ли чес ких сис-
115
THIAZOLIDINONE MOTIF IN ANTICANCER DRUG DISCOVERY
тем, а так же по лу чить сфо ку си ро ван ную биб ли о те ку, на счи -
тыва ю щую бо лее 5000 но вых со е ди не ний. На дан ный мо мент
осу ще ствлен in vitro скри нинг про ти во о пу хо ле вой ак тив нос ти
(US NCI про то кол Developmental Therapeutic Program) бо лее
1000 со е ди не ний, по зво лив ший иден ти фи ци ро вать 167 со е ди -
не ний с вы со ким про ти во ра ко вым эф фек том. Для опти ми за -
ции и ра ци о наль но го диз ай на вы со ко ак тив ных мо ле кул с опти-
маль ны ми «drug-like» ха рак те рис ти ка ми и уста нов ле ния ве ро -
ят но го ме ха низ ма би о ло ги чес ко го де йствия про ве ден SAR- и
QSAR-ана лиз и мо ле ку ляр ный до кинг. Ко неч ная цель проекта –
со зда ние ин но ва цин но го син те ти чес ко го ле ка рствен но го
сресдтва с ори ги наль ным ме ха низ мом де йствия, до ста точ -
ным фар ма ко ло ги чес ким и ток си ко ло ги чес ким про фи лем.
Клю че вые сло ва: син тез, 4-тиа(ими да)зо ли ди но ны, ти о пи ра -
но[2,3-d]ти а зо лы, про ти во о пу хо ле вая ак тив ность, (Q)SAR..
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UDC 615.012.1.076:547.789.1
Received 10.01.11
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