Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives
The aim of present research was investigation of anticancer activity of 4-azolidinone-3-carboxylic acids derivatives, and studies of structure–activity relationships (SAR) aspects. Methods. Organic synthesis; spectral methods; anticancer screening was performed according to the US NCI protocol (Deve...
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irk-123456789-1538712019-07-06T20:27:47Z Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives Kaminskyy, D.V. Lesyk, R.B. Bioorganic Chemistry The aim of present research was investigation of anticancer activity of 4-azolidinone-3-carboxylic acids derivatives, and studies of structure–activity relationships (SAR) aspects. Methods. Organic synthesis; spectral methods; anticancer screening was performed according to the US NCI protocol (Developmental Therapeutic Program). Results. The data of new 4-thiazolidinone-3-alkanecarboxylic acids derivatives in vitro anticancer activity were described. The most active compounds which belong to 5-arylidene-2,4- thia(imida)zolidinone-3-alkanecarboxylic acids; 5-aryl(heteryl)idenerhodanine-3-succinic acids derivatives were selected. Determination of some SAR aspects which allowed to determine directions in lead-compounds structure optimization, as well as desirable molecular fragments for design of potential anticancer agents based on 4-azolidinone scaffold were performed. 5-Arylidenehydantoin-3-acetic acids amides were identified as a new class of significant selective antileukemic agents. Possible pharmacophore scaffold of 5-ylidenerhodanine-3-succinic acids derivatives was suggested. Conclusions. The series of active compounds with high anticancer activity and/or selectivity levels were selected. Some SAR aspects were determined and structure design directions were proposed. Мета даного дослідження полягала у вивченні протиракової активності 4-азолідон-3-карбонових кислот та їхніх похідних, встановленні особливостей взаємозв’язку «структура–активність». Методи. Органічний синтез, спектральні методи, скринінг протипухлинної активності (US NCI-методології, Developmental Therapeutic Program). Результати. Представлено результати тестування in vitro протиракової активності нових похідних 4-азолідон-3-алканкарбонових кислот. Виділено високоактивні сполуки, які належать до похідних 5-ариліден-2,4-тіа(іміда)золідон-3-алканкарбонових кислот та 5-арил(гетерил)іденроданін-3-сукцинатних кислот. Встановлені закономірності залежності «структура–активність» дозволяють окреслити напрямки оптимізації структур-лідерів і ідентифікувати молекулярні фрагменти для дизайну потенційних протиракових агентів на основі 4-азолідонового скаффолду. Аміди 5-ариліденгідантоїн-3-оцтових кислот визначено як новий клас протилейкемічних агентів. Для 5-іліденроданін-3-сукцинатних кислот ідентифіковано ймовірний фармакофор. Висновки. Одержано низку активних сполук з високим рівнем протиракової активності та/або селективності. Запропоновано напрямки дизайну структури потенційних протиракових агентів на основі встановлених закономірностей «структура–активність». Цель данного исследования состояла в изучении противоопухолевой активности 4-азолидон-3-карбоновых кислот и их производных, а также в установлении некоторых особенностей взаимосвязи «структура–активность». Методы. Органический синтез, спектральные методы, скрининг противоопухолевой активности (US NCI-методология, Developmental Therapeutic Program). Результаты. Представлены результаты тестирования in vitro противоопухолевой активности новых производных 4-азолидон-3-аланкарбоновых кислот. Отобраны наиболее активные соединения, которые относятся к производным 5-арилиден-2,4-тиа(имида)золидон-3-алканкарбоновых кислот и 5-арил(гетерил)иденроданин-3-сукцинатных кислот. На основании выявленных закономерностей взаимосвязи «структура–активность» определены направления оптимизации структур-лидеров, идентифицированы молекулярные фрагменты для дизайна потенциальных противоопухолевых агентов на основании 4-азолидонового скаффолда. Амиды 5- арилиденгидантоин-3-уксусных кислот рассматриваются как новый класс противолейкемических агентов. Для ряда 5-илиденроданин-3-сукцинатных кислот установлен вероятный фармакофор. Выводы. Выделен ряд активных соединений с высоким уровнем противоопухолевой активности и/или селективности. Предложены направления дизайна структуры потенциальных противоопухолевых агентов на основе установленных закономерностей «структура–активность». 2010 Article Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives / D.V. Kaminskyy, R.B. Lesyk // Вiopolymers and Cell. — 2010. — Т. 26, № 2. — С. 136-145. — Бібліогр.: 35 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000150 http://dspace.nbuv.gov.ua/handle/123456789/153871 615.012.1.076:547.789.1 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 Kaminskyy, D.V. Lesyk, R.B. Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives Вiopolymers and Cell |
| description |
The aim of present research was investigation of anticancer activity of 4-azolidinone-3-carboxylic acids derivatives, and studies of structure–activity relationships (SAR) aspects. Methods. Organic synthesis; spectral methods; anticancer screening was performed according to the US NCI protocol (Developmental Therapeutic Program). Results. The data of new 4-thiazolidinone-3-alkanecarboxylic acids derivatives in vitro anticancer activity were described. The most active compounds which belong to 5-arylidene-2,4- thia(imida)zolidinone-3-alkanecarboxylic acids; 5-aryl(heteryl)idenerhodanine-3-succinic acids derivatives were selected. Determination of some SAR aspects which allowed to determine directions in lead-compounds structure optimization, as well as desirable molecular fragments for design of potential anticancer agents based on 4-azolidinone scaffold were performed. 5-Arylidenehydantoin-3-acetic acids amides were identified as a new class of significant selective antileukemic agents. Possible pharmacophore scaffold of 5-ylidenerhodanine-3-succinic acids derivatives was suggested. Conclusions. The series of active compounds with high anticancer activity and/or selectivity levels were selected. Some SAR aspects were determined and structure design directions were proposed. |
| format |
Article |
| author |
Kaminskyy, D.V. Lesyk, R.B. |
| author_facet |
Kaminskyy, D.V. Lesyk, R.B. |
| author_sort |
Kaminskyy, D.V. |
| title |
Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives |
| title_short |
Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives |
| title_full |
Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives |
| title_fullStr |
Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives |
| title_full_unstemmed |
Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives |
| title_sort |
structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives |
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Інститут молекулярної біології і генетики НАН України |
| publishDate |
2010 |
| topic_facet |
Bioorganic Chemistry |
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http://dspace.nbuv.gov.ua/handle/123456789/153871 |
| citation_txt |
Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives / D.V. Kaminskyy, R.B. Lesyk // Вiopolymers and Cell. — 2010. — Т. 26, № 2. — С. 136-145. — Бібліогр.: 35 назв. — англ. |
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Вiopolymers and Cell |
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| fulltext |
BIOORGANIC CHEMISTRY
Structure–anticancer activity relationships among
4-azolidinone-3-carboxylic acids derivatives
D. V. Kaminskyy, R. B. Lesyk
Danylo Halytsky Lviv National Medical University
69, Pekarska, Lviv, Ukraine, 79010
dr_r_lesyk@org.lviv.net; dankaminskyy@gmail.com
The aim of present research was investigation of anticancer activity of 4-azolidinone-3-carboxylic acids
derivatives, and studies of structure–activity relationships (SAR) aspects. Methods. Organic synthesis;
spectral methods; anticancer screening was performed according to the US NCI protocol (Developmental
Therapeutic Program). Results. The data of new 4-thiazolidinone-3-alkanecarboxylic acids derivatives in
vitro anticancer activity were described. The most active compounds which belong to 5-arylidene-2,4-
thia(imida)zolidinone-3-alkanecarboxylic acids; 5-aryl(heteryl)idenerhodanine-3-succinic acids deriva-
tives were selected. Determination of some SAR aspects which allowed to determine directions in lead-
compounds structure optimization, as well as desirable molecular fragments for design of potential
anticancer agents based on 4-azolidinone scaffold were performed. 5-Arylidenehydantoin-3-acetic acids
amides were identified as a new class of significant selective antileukemic agents. Possible pharmacophore
scaffold of 5-ylidenerhodanine-3-succinic acids derivatives was suggested. Conclusions. The series of
active compounds with high anticancer activity and/or selectivity levels were selected. Some SAR aspects
were determined and structure design directions were proposed.
Keywords: 4-azolidinone-3-carboxylic acids, anticancer activity, SAR.
Introduction. Design of «small molecules» as innova-
tive anticancer agents based on well-known scaffolds is
one of the most commonly employed approaches in
drug discovery. Nowadays the anticancer potential of
4-azolidinone-3-carboxylic acids (derivatives of rho-
danine, 2,4-thiazolidindione or hydantoin with carbo-
xylic acids in position N3) realized via influence on
various metabolic pathways of cancer cells is described
based on traditional and high-throughput screening [1,
2] (Fig. 1). The large group of mentioned heterocycles
with known pharmacological activity (such as antioxi-
dant, anti-inflammatory, hypoglycemic, immunomo-
dulative, etc.) was established as promising anticancer
agents as well. Another approach to search of anti-
cancer substances is target-oriented drug design, which
allows to identify anticancer hit-compounds among
4-azolidinone-3-carboxylic acids derivatives [6]. Con-
sequently, the row of 4-azolidinone-3-carboxylic acids
derivatives with high affinity to «anticancer biotar-
gets» was discovered. 5-Arylidenerhodanine-3-carbo-
xylic acids are known as inhibitors of antiapoptic pro-
tein–protein interaction between Bcl-2 and Bax family
and their interaction with receptors’ domains [7–10];
inhibitors of JSP-1 – «atypical» dual-specific phospha-
tases family member (JNK-stimulating phosphatase-1)
[11]. Among 4-azolidinone-3-carboxylic acids COX
inhibitors are selected [12] because of their potential
anticancer activity [6]. Hydantoin-carboxylic acids are
inhibitors of Ras farnesyl transferase [13] and are con-
sidered to be perspective anticancer agents [14]. The
ligands of neuroimunofiline FK506-binding protein
(FKBP) are structurally analogous to mentioned series
136
ISSN 0233-7657. Biopolymers and Cell. 2010. Vol. 26. N 2
Ó Institute of Molecular Biology and Genetics NAS of Ukraine, 2010
of compounds. Functionalized 4-imidazolidinone-3-
alkancarboxylic acids belong to a new group of non-
covalent inhibitors of Human Leukocyte Elastase [16] .
There is known antiproliferative potential of 5-
substituted N-derivatives of hydantoin [17] and 5-ary-
lidene-2,4-imidazolidinediones [18], which are related
to EGFR-kinase (epidermal growth factor receptor)
inhibition [19–21]. Among amides of latter acids the
inhibitors of cyclin-depended kinase (CDK2/Cyclin A)
[22] are selected. One of the discovered molecular me-
chanisms of 4-azolidinone-3-carboxylic acids is anta-
gonism to avb3-receptors. Inhibitor possibility was im-
proved based on correlation between expression fac-
tor progression and cancer development [23].
Also anticancer activity of 5-substituted 4-azoli-
dinone-carboxylic acids are associated with p53 depen-
dent pathways of apoptotic and neoplastic trans-
formation [24] and inhibition of necroptosis (regulated
caspase-independent cell death mechanism) [25].
Extensive research has been directed towards hypoxia-
based strategies for anticancer agents [6]. 5-Ylidene-
rhodanines, which may be interpreted as synthetic pre-
cursors of rhodanine-3-carboxylic acids, modulate pro-
liferation and apoptosis of cancer cells via influence on
NO-related pathways [5]. There is an interesting fact of
combined anti-inflammatory, antioxidant, and other
related activities established for some compounds [26,
27], which is extremely important within the classical
progression triad: stress–inflammation–cancer.
In the light of search for new 4-azolidinone-3-
carboxylic acids derivatives as potential anticancer
agents the present work was aimed to investigation of
anticancer activity of newly synthesized compounds
and studies of some structure-activity relationships
aspects.
Materials and methods. For anticancer activity
screening the library of 4-azolidinone-3-carboxylic
acids was previously synthesized [1, 28–30] using kno-
wn synthetic methods. Synthetic approaches to target
compounds differed and depended on nature of core
heterocycles (rhodanine, 2,4-thiazolidinedione, hydan-
toin). Compounds of rhodanine row were synthesized
by modification of rhodanine-3-carboxylic acids. Deri-
vatives of acids belonged to 2,4-thia(imida)zolidinedi-
one series were synthesized on the assumption of 2,4-
thiazolidinedione or hydantoin rings. 5-Ylidenederiva-
tives of mentioned compounds were obtained by dif-
ferent modifications of Knoevenagel reaction (Fig. 2).
The structures and purity of synthesized compo-
unds were elucidated by spectral data (1H NMR, IR, EI-
MS, LC-MS).
Newly synthesized compounds were selected by
the National Cancer Institute (NCI) Developmental
Therapeutic Program (www.dtp.nci.nih.gov) for the in
137
STRUCTURE-ANTICANCER ACTIVITY OF 4-AZOLIDINONE-3-CARBOXYLIC ACIDS DERIVATIVES
SS
N
O
OH
O
Ar
Me
Me
S
N
O
S
COOH
NH
N
Cl
O
O
N
H
N
R
O
O
N
H
R1
N
N
O
O
N
NO
O
Et
X
N
O A OH
O
Y
Inhibitors of interaction
of Bcl-Xl and BH3 protein [7, 8]
JSP-1 inhibitors [11] EGFR inhibitor [16]
Necroptosis inhibitors [24] Farnesyl tranferase inhibitor [12]
X = S, NH;
Y = S, O
Direction of chemical
modification
Lead-compounds among 4-azolidineone-carboxylic acids
derivatives with anticancer activity
General structure of target compounds
Fig. 1. Structure of 4-azolidinone derivatives with anticancer activity
138
KAMINSKYY D. V., LESYK R. B.
N
S
N
+
S
O
O
O
O
Cl
OH
N
S S
N
H
O
O
SO
2
NH
2
N
S O
O
O
N
H
CF
3
N
S O
O
O
N
H
S
N
N
S O
O
O
N O
NS
O
O
O
Me
O
Me
OMe
N
H
O
SO
2
NH
2
N
N
H
O
O
N
H
O
O
Me F
3
C
N
H
N
N
H
O
O
O
O
Me
CF
3
Cl
N
H
N
N
H
O
O
O
O
Me
O
Me
N
S
O
S
N
OH
O
OH
O
N
S
O
S
Me N
O
O
OH
O
N
S
O
S
N
O
O
N
H
O
SO
2
NH
2
N
S
O
N
O
O
N
H
OS
OH
N
S
O
S
N
O
O
N
H
O
OH
N
S
O
S
N
O
O
NH
O
SO
2
NH
2
N
S
O
S
Me
N
O
O
SO
2
NH
2
N
S
O
S
N
O
O
OH
O
N
S
O
S
N
O
O
OH
O
N
S
O
S
N
O
O
OH
O
N
S
O
S
N
O
O
Me
Me
OH
O
N
N
H
O
O
N
H
O
Cl
Cl
NS
O
O
Me
N
H
O
F
N
N
H
O
O
N
H
O
N
N
H
O
O
Cl
N
H
O
CF3
N
NH
O
O
N
H
O
CF3
Cl
1
2
3
4
5
7
10
11
12
15
18
19
20
21
22
16
17
23
24
25
9
6
13
14
8
Fig. 3. Structure of selected samples for advanced anticancer screening (against the full panel of about 60 human tumor cell lines at 10-fold
dilutions of five concentrations ranging from 10–4 to 10–8 M)
X
O
O
N
H
O
ClR
X
N
HO
O
R2
R1
X
NO
O
A
N
H
O
R
R1
R2
N
H
O
ClR
A N
H
O
R
X
O
O
N
A OH
OS
O
Y
N
A
OH
O
S
O
Y
N
R1
R2
O
S
N
N
O
O
R
S
N
O
O
N
S
N
N
N
R
N
N
N
NH2
HS
R
2. R-NH2
1. KOH
2.
1. KOH
2.
X = S, NH
DCC, THF
1. SOCl2
Y = S, O
X = S, NH
Y = S, O
A = CHCH2COOH
1. POCl3
2.
1. SOCl2
R1 = H; R2 = Ar, Het, PhCHCH; R1 = R2 = CH3; R1 + R2 = (CH2)n; R = Ar; (CH2)nCOOH; A = (CH2)n
R-NH2
2. R-NH2
N
H
Fig. 2. General synthetic scheme
vitro cell line screening to investigate their anticancer
activity. Anticancer assays were performed according
to the US NCI protocol as described elsewhere [31–
34]. The compounds were first evaluated at one dose
primary anticancer assay towards three cell lines (panel
consisting of three types of human cancers: breast
(MCF7), lung (NCI-H460) and CNS (SF-268) – con-
centration 10–4 M) or towards approximately 60 cell li-
nes (concentration 10–5 M). The human tumor cell lines
were derived from nine different cancer types: leuke-
mia, melanoma, lung, colon, CNS, ovarian, renal, pro-
state and breast cancers. 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. End point determinations were made with a
protein binding dye, sulforhodamine B (SRB). Re-
sults for each test agent were reported as the percent
growth of the treated cells when compared to the un-
treated control cells. A 48 h continuous drug exposure
protocol was used with a SRB protein assay to estimate
cell viability and growth.
The cytotoxic and/or growth inhibitory effects of
the most active selected compounds were tested in vitro
against the full panel of about 60 human tumor cell
lines at 10-fold dilutions of five concentrations ranging
from 10–4 to 10–8 M. Using the seven absorbance measu-
rements [time zero (Tz), control growth in the absence
of drug (C), and test growth in the presence of drug at
the five concentration levels (Ti)], the percentage gro-
wth was calculated at each of the drug concentrations
levels. Percentage growth inhibition was calculated as:
[Ti – Tz/C – Tz] × 100 for concentrations for which Ti ³ Tz;
[Ti – Tz/Tz] × 100 for concentrations for which Ti < Tz.
Three dose response parameters were calculated for
each compound. Growth inhibition of 50 % (GI50) was
calculated from [(Ti – Tz)/(C – Tz)] × 100 = 50, which is
the drug concentration resulting in a 50 % lower net
protein increase in the treated cells (measured by SRB
staining) as compared to the net protein increase seen in
the control cells. The drug concentration resulting in
total growth inhibition (TGI) was calculated from Ti =
= Tz. The LC50 (concentration of drug resulting in a
50 % reduction in the measured protein at the end of the
drug treatment as compared to that at the beginning)
indicating a net loss of cells following treatment was
calculated from [(Ti – Tz)/Tz] × 100 = –50. Values were
calculated for each of these three parameters if the level
of activity is reached; however, if the effect was not
reached or was exceeded, the value for that parameter
was expressed as greater or less than the maximum or
minimum concentration tested. The lgGI50, lgTGI,
lgLC50 were then determined, defined as the mean of
the log’s of the individual GI50, TGI, LC50 values. The
lowest values are obtained with the most sensitive cell
lines. Furthermore, mean graph midpoints (MG_MID)
were calculated for each of the parameters, giving an
average activity parameter over all cell lines for each
compound. For the calculation of the MG_MID, in-
sensitive cell lines were included with the highest
concentration tested.
Results and discussion. During the first step of
screening (using one concentration) on 3 cancer cell
lines (MCF7, NCI-H460, SF-268) 49 compounds were
tested. For mentioned samples different levels of anti-
mitotic activity were established, thought in the
majority of cases the maximum influence was observed
against NCI-H460 line Non-small cell lung cancer line.
32 Compounds were tested using 60 cancer cell lines
panel. Average values of panel cancer lines growth per-
cent lay within 100 %, which provides evidence that
nonspecific antimitotic action for studied 4-thiazoli-
dinone derivatives. However, tested compounds pos-
sessed specific influence on some individual cell lines
without influencing others. This fact may be related to
effect on some metabolic pathways or biotarget of
certain cell lines (www.dtp.nci.nih.gov; http://www.lg
cpromochem-atcc.com). UO-31 and 786-O renal can-
cer cell lines have been found to be the most sensitive to
testing compounds. For example 3-[3-(3-trifluoro-
methylphenyl)-[1,2,4]-triazolo-[3,4-b][1,3,4]-thiadia-
zol-6-yl-methyl]-thiazolidine-2,4-dione, 2-[2,4-dioxo-
5-(3,4,5-trimethoxybenzylidene)-thiazolidin-3-yl]-N-
(4-sulfamoylphenyl)-acetamide, 3-[5-(4-methoxyben-
zylidene)-4-oxo-2-thioxothiazolidin-3-yl]-1-(3-triflu-
oromethylphenyl)-pyrrolidine-2,5-dione and 2-(4-ben-
zylidene-2,5-dioxoimidazolidin-1-yl)-N-(4-chloro-
phenyl)-acetamide provided not only growth inhibition
but also death of UO-31 cells. The same effect was ob-
139
STRUCTURE-ANTICANCER ACTIVITY OF 4-AZOLIDINONE-3-CARBOXYLIC ACIDS DERIVATIVES
140
KAMINSKYY D. V., LESYK R. B.
Com-
pound
logGI50 logGI50 logGI50
N 1 Rangea MG_MID N 2 Rangea MG_MID N 3 Rangea MG_MID
1 2 3 4 5 6 7 8 9 10
1 50 <–8.00 ̧–5.17 –6.26 50 –6.85 ̧–4.70 –5.31 29 –5.73 ̧–4.08 –4.37
Most sensitive cell lines (logGI50/logTGI): MOLT-4 –7,80/–6,85; SR < –8,00/–6,85 (L); SW-620 < –8,00/–6,57 (CC);
SF 539 < –8,00/–6,57 (CNS)
2 28 –5.22 ̧–4.36 4.60 9 –4.63 ̧> –4.30 –4.34 – > –4.30 4.30
Most sensitive cell lines (logGI50/logTGI): HL-60 (TB) –5.22/–4.32; K-562 –5.16/–4.59; RPMI-8226 –5.10/–4.47 (L);
NCI-H460 –5.20/–4.49; NCI-H522 –5.12/> –4.30 (NSCLC); KM12 –5.07/> –4.30 (CC); LOX IMVI –5.00/–4.51 (M);
OVCAR-3 –5.14/–4.50 (OC); MDA-MB-435 –5.02/–4.51 (BC)
3 28 –6.21 ̧> –4.30 –4.64 4 –5.39 ̧> –4.30 –4.35 – > –4.30 –4.30
Most sensitive cell lines (logGI50/logTGI): A549/ATTC –5.41/> –4.30; NCI-H460 –5.30/> –4.30 (NSCLC);
HCT-116 –5.38/> –4.30 (CC); U251 –5.36/> –4.30 (CNS); SK-MEL5 –6.21/–5.39 (M); ACHN –5.08/> –4.30;
SN12C –5.20/> –4.30 (RC); MCF-7 –5.06/> –4.30; MDA-MB-231/ATTC –5.19/> –4.30 (BC)
4 46 –5.88 ̧> –4.30 –4.77 17 –5.53 ̧> –4.30 –4.38 1 –4.43 ̧> –4.30 –4.30
Most sensitive cell lines (logGI50/ logTGI): CCRF-CEM –4.95/> –4.30 (L); SF 539 –5.88/–5.53; U251 –5.34/–4.74 (CNS);
LOX IMVI –5.10/–4.48; SK-MEL2 –5.25/–4.52; UACC62 –5.02/–4.46 (M); OVCAR-8 –5.05/> –4.30 (OC);
ACHN –5.00/–4.45; UO31 –5.01/–4.36 (RC); DU-145 –5.03/> –4.30 (PC); MDA-MB-231/ATTC –5.09/–4.57 (BC)
5 49 <–8.30 ̧> –4.30 –4.78 24 –6.45 ̧> –4.30 –4.42 4 –4.62 ̧> –4.30 –4.31
Most sensitive cell lines (logGI50/logTGI): RPMI-8226 –4.99/> –4.30 (L); NCI-H23 –4.97/–4.69;
NCI-H522 –4.90/–4.56 (NSCLC); HCT-116 –4.94/–4.58 (CC); U251 –4,95/> –4.30 (CNS); SK-MEL5 < –8.30/–6.45 (M);
OVCAR-8 –4.92/–4.47 (OC); ACHN –4.99/–4.69 (RC)
6 19 –6.08 ̧> –4.30 –4.55 5 –5.79 ̧> –4.30 –4.36 – > 4.30 –4.30
Most sensitive cell lines(logGI50/logTGI): SR –5.21/> –4.30 (L); NCI-H23 –5.09/–4.35 (NSCLC);
U-251 –4.82/> –4.30 (CNS); LOX IMVI –5.93/–5.53 (M); UO-31 –6.08/–5.79 (RC)
7 38 –6.17 ̧–4.02 –4.47 17 –5.41 ̧–4.18 –4.14 8 –4.30 ̧–4.05 –4.03
Most sensitive cell lines (logGI50/logTGI): CCRF-CEM –5.36/–5.41; RPMI8226 –6.17/–5.41; MOLT-4 –5.41/–4.00 (L);
OVCAR-8 –5.16/> –4.00 (OC)
8
8
10*
–6.05 ̧–4.01
–7.71 ̧–4.10*
–4.26
–4.17*
5
3*
–5.85 ̧–4.01
–5.51 ̧–4.62*
–4.09
–4.05*
3
2*
–5.02 ̧–4.53
–4.28 ̧–4.09*
–4.05
–4.01*
Most sensitive cell lines (logGI50/logTGI): CCRF-CEM –6.06 (5.92*)/> –4.00 (–5.51*); HL-60 (TB) –6.53/––5.70;
K-562 –5.68 (–5.27*)/> –4.00 (> –4.00*); MOLT-4 –6.52 (–5.34*)/–5.49 (–4.62*); SR –6.51 (–7.71*)/–5.85 (–4.90*) (L);
HOP-92 –4.74/–4.01 (NSCLC)
9 53 –5.15 ̧–4.04 –4.57 29 –4.55 ̧–4.09 –4.16 6 –4.22 ̧–4.14 –4.01
Most sensitive cell lines (logGI50/logTGI): CCRF-CEM –4.83/–4.50; HL-60 (TB) –4.71/–4.33; MOLT-4 –4.96/–4.55;
RPMI-8226 –4.68/–4.17; SR –5.15/–4.47 (L); HOP-62 –4.82/–4.36; HOP-92 –4.76/–4.38; NCI-H226 –4.80/–4.35 (NSCLC);
SF-268 –4.98/–4.53, SF-539 –4.78/–4.41: SNB –4.88/–4.44; U251 –4.83/–4.53 (CNS); LOX-IMVI –4.81/–4.49 (M);
OVCAR-4 –4.88/–4.19; SK-OV-3 –4.71/–4.29 (OC); SN-12C –4.77/–4.32; TK-10 –4.77/–4.37 (RC); MDA-MB-231/ATTC
–4.79/–4.37; HS-578T –4.97/–4.42 (BC)
10 16 –5.55 ̧–4.11 –4.12 5 –4.23 ̧–4.02 –4.01 0 – –4.00
Most sensitive cell lines (logGI50/logTGI): NCI NCI-H23 –4.58/–4.05 (NSCLC); HCT-116 –4.52/> –4.00 (CC);
U251 –4.59/–4.16 (CNS); OVCAR-3 –4.51/–4.02 (OC); MCF-7 –5.55/> –4.00; MDA-MB-231/ATTC –4.63/–4.23 (BC)
Summary of anticancer activity of the compounds in different concentrations (10–4–10–8 M) towards 60 cancer cell lines
141
STRUCTURE-ANTICANCER ACTIVITY OF 4-AZOLIDINONE-3-CARBOXYLIC ACIDS DERIVATIVES
1 2 3 4 5 6 7 8 9 10
11 22 –5.57 ̧–4.07 –4.28 7 –4.78 ̧–4.04 –4.04 2 –4.31 ̧–4.16 –4.01
Most sensitive cell lines (logGI50/logTGI): CCRF-CEM –4.66/> –4.00; SR –5.14/–4.70 (L); HOP-92 –5.22/–4.62;
NCI-H226 –4.58/> –4.00 (NSCLC); SF-295 –4.51/> –4.00; SNB-75 –5.57/–4.78; U251 –5.03/–4.20 (CNS);
SK-OV-3 –4.71/–4.09 (OC); 786-O –4.66/> –4.00 (RC); MDA-MB-231/ATTC –4.80/> –4.00; HS-578 –4.73/–4.04 (BC)
12 11 –6.71 ̧–4.15 –4.11 1 – –4.00 0 – 4.00
Most sensitive cell lines (logGI50/logTGI): CCRF-CEM –6.71/> –4.00 (L); U251 –4.51/> –4.00 (CNS)
13 20 –4.66 ̧> –4.06 –4.13 2 –4.43 ̧–4.28 –4.01 1 –4.11 ̧–4.00 –4.00
Most sensitive cell lines (logGI50/logTGI): SR –4,47/> –4.00 (L); NCI-H23 –4.50/> –4.00; A-498 –4.75/–4.43 (NSCLC);
MDA-MB-231/ATTC –4.58/> –4.00; HS-578T –4.66/–4.28 (BC)
14 36 –8.00 ̧–4.03 –4.53 11 –5.16 ̧–4.11 –4.10 4 –4.55 ̧–4.05 –4.02
Most sensitive cell lines (logGI50/ logTGI): CCRF-CEM –4.87/> –4.00; MOLT–4 –5.60/> –4.00; RPMI-8226 –8.00/–5.16
(L); A549/ATTC –4.97/> –4.00; HOP-62 –4.90/–4.53. HOP-92 –5.27/–4.54; NCI-H226 –4.88/–4.33 (NSCLC);
HCT-116 –4.86/–4.18 (CC); M14 –4.84/> –4.00 (M); 786-O –4.86/–4.45; ACHN –4.84/–4.54. SN12C –4.92/–4.46 (RC);
MDA-MB-231/ATTC –5.34/–4.64; HS578T –4.98/–4.11 (BC)
15 1 –8.00 ̧–4.00 –4.07 1 –4.02 –4.00 – – –4.00
Most sensitive cell lines (logGI50/logTGI): HOP-92 < –8.00/–4.02 (NSCLC)
16 48 –5.55 ̧–4.30 –4.66 36 –4.65 ̧–4.30 –4.26 18 –4.33 ̧–4.03 –4.07
Most sensitive cell lines (logGI50/logTGI): NCI-H522 –5.55/> –4.00 (NSCLC); U251 –4.91/–4.61(CNS);
PC-3 –4.87/–4.52 (PC)
17 40 –5.39 ̧–4.20 –4.41 13 –4.30 ̧–4.06 –4.04 1 –4.26 ̧–4.00 –4.00
Most sensitive cell lines (logGI50/logTGI): CCRF-CEM –5.39/> –4.00; K-562 –5.04/> –4.00; MOLT-4 –5.33/> –4.00 (L)
18 46 –6.30 ̧–4.06 –4.55 23 –4.55 ̧–4.04 –4.16 8 –4.27 ̧–4.10 –4.03
Most sensitive cell lines (logGI50/logTGI): NCI-H23 –4.89/–4.55 (NSCLC); NCI-H522 –6.30/> –4.00
19 8 –4.54 ̧–4.16 –4.04 – – –4.00 – – –4.00
Most sensitive cell lines (logGI50/logTGI): MALME-3M –4.54/> –4.00 (M)
20 55 –4.78 ̧–4.10 –4.56 31 –4.39 ̧–4.07 –4.13 5 –4.19 ̧–4.03 –4.01
Most sensitive cell lines (logGI50/logTGI): SK-MEL-5 –4.78/–4.48; UACC-62 –4.74/–4.39 (M)
21 56 –5.78 ̧–4.87 –5.31 52 –5.38 ̧–4.02 –4.67 22 –4.80 ̧–4.04 –4.12
Most sensitive cell lines (logGI50/ logTGI): HL-60(TB) –5.66/–5.23; K-562 –5.43/–4.77 (L); NCI-H522 –5.78/–5.38
(NSCLC); KM12 –5.62/–5.18 (CC)
22 56 –5.29 ̧–4.03 –4.74 43 –4.63 ̧–4.12 –4.28 13 –4.18 ̧–4.04 –4.03
Most sensitive cell lines (logGI50/ logTGI): CCRF-CEM –5.18/–4.34; SR –5.18/–4.49 (L); KM12 –5.11/–4.63 (CC); U251
–5.10/–4.61 (CNS); ÐÑ-3 –5.29/–4.56 (PC)
23 21 –4.90 ̧–4.30 –4.42 3 –4.47 ̧–4.30 –4.31 – > –4.30 –4.30
Most sensitive cell lines (logGI50/ logTGI): EKVX –4.83/–4.39; NCI-H23 –4.75/> –4.30 (NSCLC); SF-268 –4.86/–4.32
(CNS); LOX IMVI –4.90/–4.47 (M)
8
Continuation of Table
served for 6-[5-(4-nitrobenzylidene)-4-oxo-2-thioxo-
thiazolidin-3-yl]-hexanoic acid, 2-(5-isopropylidene-
2,4-dioxothiazolidin-3-yl)-N-(3-trifluoromethylphe-
nyl)-acetamide influence on 786-O cell. Moreover,
high sensitivity of all leukemia cell lines to studied 4-
azolidinone derivatives was detected.
As the next step 25 compounds were selected for
advanced assays on 60 cell lines panel (at five 10-fold
dilutions – concentrations ranging from 10–4 to 10–8 M)
(Fig. 3). Tested compounds belonged to the following
groups (5-aryl(heteryl)idenerhodanine-3-alkanemo-
no(di)carboxylic acids, 5-arylidene-2,4-thiazolidinedi-
one-3-alkanecarboxylic acids and 5-arylidene-2,4-imi-
dazolidinedione-3-acetic acids) and showed different
strength of anticancer activity – from practically absent
to expressive action on all tested cell lines (Table). Ob-
tained data allowed us to summarize some aspects of
structure – anticancer activity relationships in testing
row of 4-azolidinone derivatives. The presence of yli-
dene moiety in position 5 of core heterocycles plays
142
KAMINSKYY D. V., LESYK R. B.
1 2 3 4 5 6 7 8 9 10
24 47 –5.32 ̧–4.16 –4.55 20 –4.35 ̧–4.16 –4.13 8 –4.21 ̧–4.02 –4.02
Most sensitive cell lines (logGI50/ logTGI): NCI-H522 –5.32/> –4.00 (NSCLC); SN12C –5.14/–4.08 (RC)
25 45 –5.24 ̧–4.44 –4.88 32 –4.88 ̧–4.34 –4.50 12 –4.56 ̧–4.34 –4.33
Most sensitive cell lines (logGI50/ logTGI): SR –5.16/–4.72 (L); NCI-H322M –5.03/–4.53; NCI-H522 –5.01/–4.55 (NSCLC);
UACC-62 –5.12/–4.84 (M); OVCAR-8 –5.14/–4.67 (OC); MDA-MB-435 –5.07/–4.74; MDA-MB-231/ATTC –5.16/–4.64; BT-549
–5.24/–4.88 (BC)
Ending of Table
aThe value > –4.00 (or > –4.30) was excluded; *data of double assay; N 1, N 2, N 3 – number of sensitive cell lines; L – Leukemia; CC –
Colon Cancer; CNS – CNS Cancer; NSCLC – Non–Small Cell Lung Cancer; M – Melanoma; OC – Ovarian Cancer; BC – Breast Cancer;
RC – Renal Cancer; PC – Prostate Cancer.
NCI-H460 – 99 %
MCF6 – 100 %
SF-268 – 110 %
NCI-H460 – 1 %
MCF6 – 7 %
SF-268 – 39 %
NCI-H460 – 108 %
MCF6 – 92 %
SF-268 – 98 %
NCI-H460 – 4 %
MCF6 – 58 %
SF-268 – 108 %
N
N
H
O
O
N
H
O
ClN
S
O
O
N
H
O
Cl
N
H
N
O
O
O
N
HCl
F
FF
14
S
N
O
O
O
N
HCl
F
FF
S
N
O
O
O
N
HCl
Cl
N
H
N
O
O
O
N
HCl
Cl
9
N
H
N
O
O
O
N
H
CF
3
N
H
N
O
O
O
N
H
F3C
Cl
N
H
N
O
O
O
N
H
F3C
OMe 10
14
NCI-H460 – 106 %
MCF6 – 111 %
SF-268 – 113 %
NCI-H460 – 4 %
MCF6 – 58 %
SF-268 – 108 %
NCI-H460 – 5 %
MCF6 – 6 %
SF-268 – 30 %
Fig. 4. Some structure-anticancer activity relationships aspects (in square grow percent for definite cancer cell lines)
crucial role for achieving anticancer activity (Fig. 4).
Presence of certain arylidene or phenylpropenylidene
fragments is also desirable. This confirms our hypo-
thesis about critical influence of the moiety in position
5 of core heterocycles on realization of biological ef-
fects, as it was previously established for another gro-
ups of 4-azolidinone and related heterocyclic systems
derivatives [1, 28]. Comparison of anticancer activity
of free acids and their derivatives (namely amides)
shows that latter are more active than corresponding
acids as well as the results of [35]. CF3-Substituted
anilines and sulfanilamide moieties are desirable as
«privileged» fragments.
Comparison of anticancer activity of isosters of
rhodanine and 2,4-thiazolidinedione derivatives or
homologs of mentioned substances didn’t allow us to
establish any relation. However, substitution of S-atom
of thiazolidinone ring for N-atom (transfer from 2,4-
thiazolidinedione to 2,4-imidazolidinedione) contribu-
tes to increase in anticancer activity and appearing of
selectivity. Hydantoin-3-acetic acids derivatives (14,
8, 9, 11, 12) possess the distinct selective influence on
Leukemia cell lines comparing to the other groups of
cancer cell lines. This fact allows us to interpret the 5-
arylidene-2,4-imidazolidinedione-3-acetic acids ami-
des as lead-compounds in search of antileukemic
agents. In addition, mentioned group is more active in
comparison to other 2,4-thia(imida)zolidinedione deri-
vatives [28].
Analysis of anticancer activity data of 5-ylide-
nerhodanine-3-succinic acids derivatives allowed to
summarize some structure-activity correlations (Fig.
5). Modification of free dicarboxylic acids to their
diamides caused increase in anticancer activity, which
was the most prominent for cyclic imides. Based on the
interpretation of obtained data 3-(4-oxo-2-thioxothia-
143
STRUCTURE-ANTICANCER ACTIVITY OF 4-AZOLIDINONE-3-CARBOXYLIC ACIDS DERIVATIVES
N
N
H
SO2NH2
O
N
S
O
S
O
O
N
N
H
SO2NH2
O
S
O
S
22
2
N N
O
O
OH
O
N N
O
O
OH
O
N
N
O
O
OH
O
N N
O
O
Me
Me
OH
O
17
23
24
25
Combining of thiazolidinone and
pyrrolidinedione cycles
Desirable elongation or complicate of carbonic chain in N of
pyrrolidinedione moiety
N
S
O
S
N
O
O
Possible «pharmacophore»
Direction of optimization
Direction of optimization
Fig. 5. Directions of lead optimization among 5-ylidenerhodanine-3-succinic acids derivatives
zolidine-3-yl)-pyrrolidine-2,5-dione fragment was as-
sumed as possible pharmacophore within investigated
samples row [29]. Consequently, we showed the direc-
tions of this fragment chemical modification aimed at
structure optimization, namely: position C5 of rhodani-
ne cycle and N-atom of pyrrolidine.
Conclusion. The present study describes in vitro
anticancer activity of new 5-ylidene-4-thiazolidinone-
3-alkanecarboxylic acids derivatives. The series of
active compounds with high activity and/or selectivity
levels were selected. Some aspects of structure–an-
ticancer activity relationships were determined and
structure design directions were proposed. 5-Ary-
lidenehydantoin-3-acetic acids derivatives were iden-
tified as a new class of potent antileukemic agents.
Possible pharmacophore scaffold of 5-ylidenerhoda-
nine-3-succinic acids derivatives was suggested.
Acknowledgements. We are grateful to Dr. V. L.
Narayanan from Drug Synthesis and Chemistry
Branch, National Cancer Institute, Bethesda, MD,
USA, for in vitro evaluation of anticancer activity.
Ä. Â. Êàìiíñüêèé, Ð. Á. Ëå ñèê
Âçàºìîç â’ÿ çîê «ñòðóê òó ðà–ïðî òè ðà êî âà àê òèâí³ñòü» â ðÿäó 4-
àçîë³äîí-3-êàð áî íî âèõ êèñ ëîò òà ¿õí³õ ïîõ³äíèõ
Ðå çþ ìå
Ìåòà äà íî ãî äîñë³äæåí íÿ ïî ëÿ ãà ëà ó âèâ ÷åíí³ ïðî òè ðà êî âî¿
àê òèâ íîñò³ 4-àçîë³äîí-3-êàð áî íî âèõ êèñ ëîò òà ¿õí³õ ïîõ³äíèõ,
âñòà íîâ ëåíí³ îñîá ëè âîñ òåé âçàºìîç â’ÿç êó «ñòðóê òó ðà–àê -
òèâí³ñòü». Ìå òî äè. Îðãàí³÷íèé ñèí òåç, ñïåê òðàëüí³ ìå òî äè,
ñêðèí³íã ïðî òè ïóõ ëèí íî¿ àê òèâ íîñò³ (US NCI-ìå òî äî ëî㳿,
Developmental Therapeutic Program). Ðå çóëü òà òè. Ïðåä ñòàâ -
ëå íî ðå çóëü òà òè òåñ òó âàí íÿ in vitro ïðî òè ðà êî âî¿ àê òèâ -
íîñò³ íî âèõ ïîõ³äíèõ 4-àçîë³äîí-3-àë êàí êàð áî íî âèõ êèñ ëîò.
Âèä³ëåíî âè ñî êî àê òèâí³ ñïî ëó êè, ÿê³ íà ëå æàòü äî ïîõ³äíèõ
5-àðèë³äåí-2,4-ò³à(³ì³äà)çîë³äîí-3-àë êàí êàð áî íî âèõ êèñ ëîò
òà 5-àðèë(ãå òå ðèë)³äåí ðî äàí³í-3-ñóê öè íàò íèõ êèñ ëîò. Âñòà -
íîâ ëåí³ çà êî íîì³ðíîñò³ çà ëåæ íîñò³ «ñòðóê òó ðà–àê òèâí³ñòü»
äîç âî ëÿ þòü îêðåñ ëè òè íà ïðÿì êè îïòèì³çàö³¿ ñòðóê òóð-
ë³äåð³â ³ ³äåí òèô³êó âà òè ìî ëå êó ëÿðí³ ôðàã ìåí òè äëÿ äèç àé íó
ïî òåíö³éíèõ ïðî òè ðà êî âèõ àãåíò³â íà îñíîâ³ 4-àçîë³äî íî âî ãî
ñêàô ôîë äó. Àì³äè 5-àðèë³äåíã³äàí òî¿í-3-îöòî âèõ êèñ ëîò âè-
çíà ÷å íî ÿê íî âèé êëàñ ïðî òè ëåé êåì³÷íèõ àãåíò³â. Äëÿ 5-³ë³äåí -
ðî äàí³í-3-ñóê öè íàò íèõ êèñ ëîò ³äåí òèô³êî âà íî éìîâ³ðíèé
ôàð ìà êî ôîð. Âèñ íîâ êè. Îäåð æà íî íèç êó àê òèâ íèõ ñïî ëóê ç âè -
ñî êèì ð³âíåì ïðî òè ðà êî âî¿ àê òèâ íîñò³ òà/àáî ñå ëåê òèâ íîñò³.
Çàï ðî ïî íî âà íî íà ïðÿì êè äèç àé íó ñòðóê òó ðè ïî òåíö³éíèõ ïðî -
òè ðà êî âèõ àãåíò³â íà îñíîâ³ âñòà íîâ ëå íèõ çà êî íîì³ðíîñ òåé
«ñòðóê òó ðà–àê òèâí³ñòü».
Êëþ ÷îâ³ ñëî âà: 4-àçîë³äîí-3-êàð áî íîâ³ êèñ ëî òè, ïðî òè ðà êî âà
àê òèâí³ñòü, âçàºìîç â’ÿ çîê «ñòðóê òó ðà–àê òèâí³ñòü».
Ä. Â. Êà ìèí ñêèé, Ð. Á. Ëå ñûê
Âçà è ìîñ âÿçü «ñòðóê òó ðà–ïðî òè âî î ïó õî ëå âàÿ àê òèâ íîñòü» â
ðÿäó 4-àçî ëè äîí-3-êàð áî íî âûõ êèñ ëîò è èõ ïðî èç âîä íûõ
Ðå çþ ìå
Öåëü äàí íî ãî èñ ñëå äî âà íèÿ ñî ñòî ÿ ëà â èç ó÷å íèè ïðî òè âî î ïó -
õî ëå âîé àê òèâ íîñ òè 4-àçî ëè äîí-3-êàð áî íî âûõ êèñ ëîò è èõ ïðî -
èç âîä íûõ, à òàê æå â óñòà íîâ ëå íèè íå êî òî ðûõ îñî áåí íîñ òåé
âçà è ìîñ âÿ çè «ñòðóê òó ðà–àê òèâ íîñòü». Ìå òî äû. Îðãà íè ÷åñ -
êèé ñèí òåç, ñïåê òðàëü íûå ìå òî äû, ñêðè íèíã ïðî òè âî î ïó õî ëå -
âîé àê òèâ íîñ òè (US NCI-ìå òî äî ëî ãèÿ, Developmental The-
rapeutic Program). Ðå çóëü òà òû. Ïðåä ñòàâ ëå íû ðå çóëü òà òû
òåñ òè ðî âà íèÿ in vitro ïðî òè âî î ïó õî ëå âîé àê òèâ íîñ òè íî âûõ
ïðî èç âîä íûõ 4-àçî ëè äîí-3-àëàí êàð áî íî âûõ êèñ ëîò. Îòîá ðà íû
íà è áî ëåå àê òèâ íûå ñî å äè íå íèÿ, êî òî ðûå îò íî ñÿò ñÿ ê ïðî èç -
âîä íûì 5-àðè ëè äåí-2,4-òèà(èìè äà)çî ëè äîí-3-àë êàí êàð áî íî -
âûõ êèñ ëîò è 5-àðèë(ãå òå ðèë)èäåí ðî äà íèí-3-ñóê öè íàò íûõ
êèñ ëîò. Íà îñíî âà íèè âû ÿâ ëåí íûõ çà êî íî ìåð íîñ òåé âçà è ìîñ -
âÿ çè «ñòðóê òó ðà–àê òèâ íîñòü» îïðå äå ëå íû íà ïðàâ ëå íèÿ îïòè -
ìè çà öèè ñòðóê òóð-ëè äå ðîâ, èäåí òè ôè öè ðî âà íû ìî ëå êó ëÿð íûå
ôðàã ìåí òû äëÿ äèç àé íà ïî òåí öè àëü íûõ ïðî òè âî î ïó õî ëå âûõ
àãåí òîâ íà îñíî âà íèè 4-àçî ëè äî íî âî ãî ñêàô ôîë äà. Àìèäû 5-
àðè ëè äåí ãè äàí òî èí-3-óêñóñ íûõ êèñ ëîò ðàñ ñìàò ðè âà þò ñÿ êàê
íî âûé êëàññ ïðî òè âî ëåé êå ìè ÷åñ êèõ àãåí òîâ. Äëÿ ðÿäà 5-èëè -
äåí ðî äà íèí-3-ñóê öè íàò íûõ êèñ ëîò óñòà íîâ ëåí âå ðî ÿò íûé
ôàð ìà êî ôîð. Âû âî äû. Âû äå ëåí ðÿä àê òèâ íûõ ñî å äè íå íèé ñ âû -
ñî êèì óðîâ íåì ïðî òè âî î ïó õî ëå âîé àê òèâ íîñ òè è/èëè ñå ëåê -
òèâ íîñ òè. Ïðåä ëî æå íû íà ïðàâ ëå íèÿ äèç àé íà ñòðóê òó ðû
ïî òåí öè àëü íûõ ïðî òè âî î ïó õî ëå âûõ àãåí òîâ íà îñíî âå óñòà -
íîâ ëåí íûõ çà êî íî ìåð íîñ òåé «ñòðóê òó ðà–àê òèâ íîñòü».
Êëþ ÷å âûå ñëî âà: 4-àçî ëè äîí-3-êàð áî íî âûå êèñ ëî òû, ïðî -
òè âî î ïó õî ëå âàÿ àê òèâ íîñòü, âçà è ìîñ âÿçü «ñòðóê òó ðà–àê òèâ -
íîñòü».
REFERENCES
1. Lesyk R. B., Zimenkovsky B. S. 4-Thiazolidones: Centenarian
history, current status and perspectives for modern organic
and medicinal chemistry // Curr. Org. Chem.–2004.–8,
N 16.–P. 1547–1577.
2. Prabhakar Y. S., Solomon V. R., Gupta M. K., Katti S. B.
QSAR studies on thiazolidines: biologically privileged scaf-
fold // Top. Heterocycl. Chem.–2006.–4.–P. 161–249.
3. Ottana R., Carotti S., Maccari R., Landini I., Chiricosta G.,
Caciagli B., Vigorita M. G., Mini E. In vitro antiproliferative
activity against human colon cancer cell lines of represen-
tative 4-thiazolidinones. Part I // Bioorg. Med. Chem. Lett.–
2005.–15, N 17.–P. 3930–3933.
4. Shih M. H., Ke F. Y. Synthesis and evaluation of antioxidant
activity of sydnonyl substituted thiazolidinone and thiazoline
derivatives // Bioorg. Med. Chem.–2004.–12, N 17.–P. 4633–
4643.
5. Kesel A. S., Sonnenbicher I., Polborn K., Gurtler L., Klinkert
W. E. F., Modolell M., Nussler A. K., Oberthur W. A new anti-
oxidative vitamine B6-analogue modulates pathophysiolo-
gical cell proliferation and demage // Bioorg. Med. Chem.–
1999.–7, N 2.–P. 359–367.
6. Avendano C., Menendez J. C. Medicinal chemistry of anti-
cancer drugs.–Amsterdam: Elsevier, 2008.–400 p.
144
KAMINSKYY D. V., LESYK R. B.
7. Liu W. J., Bulgaru A., Haigentz M., Stein C. A., Perez-Soler
R., Mani S. The BCL2-family of protein ligands as cancer
drugs: the next generation of therapeutics // Curr. Med.
Chem. Anti Cancer Agents.–2003.–3, N 3.–P. 217–223.
8. Degterev A., Lugovskoy A., Cardone M., Mulley B., Wagner
G., Mitchison T., Yuan J. Identification of small-molecule in-
hibitors of interaction between the BH3 domain and Bcl-xl //
Nat. Cell Biol.–2001.–3, N 2.–P. 173–182.
9. Lugovskoy A. A., Degterev A. I., Fahmy A. F., Zhou P., Gross
J. D., Yuan J., Wagner G. A Novel approach for characteri-
zing protein ligand complexes: molecular basis for specificity
of small-molecule Bcl-2 inhibitors // J. Am. Chem. Soc.–
2002.–124, N 7.–P. 1234–1240.
10. Xing C., Wang L., Tang X. H., Sham Y.Y. Development of se-
lective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-
1 // Bioorg. Med. Chem.–2007.–15, N 5.–P. 2167–2176.
11. Cutshall N. S., O’Day C., Prezhdo M. Rhodanine derivatives
as inhibitors of JSP-1 // Bioorg. Med. Chem. Lett.–2005.–15,
N 14.–P. 3374–3379.
12. Look G. C., Shuilck J. R., Holmes Ch. P., Chinn J. P., Gordon
E. M., Gallop M. A. The identification of cyclooxygenase-1
inhibitors from 4-thiazolidinone combinatorial library // Bio-
org. Med. Chem. Lett.–1996.–6, N 6.–P. 707–712.
13. Lee J., Kim J., Koh J. S., Chung H. H., Kim K. H. Hydantoin
derivatives as non-peptidic inhibitors of Ras farnesyl trans-
ferase // Bioorg. Med. Chem. Lett.–2006.–16, N 7.–P. 1954–
1956.
14. Mazieres J., Pradines A., Favre G. Perspectives on farnesyl
transferase inhibitors in cancer therapy // Cancer Lett.–
2004.–206, N 2.–P. 159–164.
15. Zhao L., Huang W., Liu H., Wang L., Zhong W., Xiao J., Hu
Y., Li S. FK506-binding protein ligands: structure-based des-
ign, synthesis, and neurotrophic/neuroprotective properties
of substituted 5,5-dimethyl-2-(4-thiazolidine) carboxylates //
J. Med. Chem.–2006.–49, N 14.–P. 4059–4071.
16. Liuqing W., Gan X., Zhong J., Alliston K. R., Groutas W. C.
Noncovalent inhibitors of human leukocyte elastase based on
the 4-imidazolidinone scaffold // Bioorg. Med. Chem.–
2003.–11, N 23.–P. 5149–5153.
17. Carmi C., Cavazzoni A., Zuliani V., Lodola A., Bordi F.,
Plazzi P. V., Alfieri R. R., Petronini P. G., Mor M. 5-Benzyli-
dene-hydantoins as new EGFR inhibitors with antiproliferati-
ve activity // Bioorg. Med. Chem. Lett.–2006.–16, N 15.–
P. 4021–4025.
18 Rajic Z., Zorc B., Raic-Malic S., Ester K., Kralj M., Pavelic
K., Balzarini J., Clercq E. D., Mintas M. Hydantoin derivati-
ves of L- and D-amino acids: synthesis and evaluation of their
antiviral and antitumoral activity // Molecules.–2006.–11,
N 11.–P. 837–848.
19. Gibbs J. B., Oliff A. The potential of farnesyltransferase inhi-
bitors as cancer chemotherapeutics // Ann. Rev. Pharmacol.
Toxicol.–1997.–37.–P. 143–166.
20. Haluska P., Dy G. K., Adjei A. A. Farnesyl transferase inhibi-
tors as anticancer agents // Eur. J. Cancer.–2002.–38, N 13.–
P. 1685–1700.
21. Lv P. C., Zhou C. F., Chen J., Liu P. G., Wang K. R., Mao W.
J., Li H. Q., Yang Y., Xiong J., Zhu H. L. Design, synthesis
and biological evaluation of thiazolidinone derivatives as po-
tential EGFR and HER-2 kinase inhibitors // Bioorg. Med.
Chem.–2010.–18, N 1.–P. 314–319.
22. Pevarello P., Brasca M. G., Orsini P., Traquandi G., Longo
A., Nesi M., Orzi F., Piutti C., Sansonna P., Varasi M., Came-
ron A., Vulpetti A., Roletto F., Alzani R., Ciomei M., Albanese
C., Pastori W., Marsiglio A., Pesenti E., Fiorentini F.,
Bischoff J. R., Mercurio C. 3-Aminopyrazole inhibitors of
CDK2/cyclin A as antitumor agents. 2. Lead optimization // J.
Med. Chem.–2005.–48, N 8.–P. 2944–2956.
23. Dayam R., Aiello F., Deng J., Wu Y., Garofalo A., Chen X.,
Neamati N. Discovery of small molecule integrin avb3 anta-
gonists as novel anticancer agents // J. Med. Chem.–2006.–
49, N 15.–P. 4526–4534.
24. Pat. US2003/0119894, IPC A 61K31/404, N 09/9106291.
Methods for treatment of cancer or neoplastic disease and for
inhibiting growth of cancer cells and neoplastic cellsmurthy /
M. S. R. Murthy, G. C. Shore, J. Bajorath, F. L. Stahura //
Publ. 26.06.2003.
25. Teng X., Degterev A., Jagtap P., Xing X., Choi S., Denu R.,
Yuan J., Cuny G. D. Structure-activity relationship study of
novel necroptosis inhibitors // Bioorg. Med. Chem. Lett.–
2005.–15, N 22.–P. 5039–5044.
26. Lesyk R., Zimenkovsky B., Lukyanchuk V., Atamanyuk D.,
Vovk O. Chemistry and ðharmacology of 4-thiazolidone de-
rivatives // Ann. Polish Chem. Soc.–2003.–2.–P. 293–298.
27. Zimenkovsky B. S., Lesyk R. B. Purposeful synthesis of biolo-
gical active compound base on 4-azolidinone // J. Org.
Pharm. Chem.–2003.–1, N 1–2.–P. 24–30 (in Ukrainian).
28. Kaminskyy D., Zimenkovsky B., Lesyk R. Synthesis and in vit-
ro anticancer activity of 2,4-azolidinedione-acetic acids deri-
vatives // Eur. J. Med. Chem. – 2009.–44, N 9.–P. 3627–3636.
29. Kaminskyy D. V., Roman O. M., Atamanyuk D. V., Lesyk R. B.
5-Ylidene-2-thioxo-4-thiazolidinone-3-succinic acids and
their derivatives: synthesis, anticancer activity, QSAR-ana-
lysis // J. Org. Pharm. Chem.– 2006.–4, N 1(13).–P. 41–48.
30. Êaminskyy D. V., Lesyk R. B. Synthesis and biological activi-
ty of 4-thiazolidinone-3-acetic acids derivatives // Farma-
cevt. Zhur. (Kyiv).–2008.–3.–P. 70–78.
31. Monks A., Scudiero D., Skehan P., Shoemaker R., Paull K.,
Vistica D., Hose C., Langley J., Cronise P., Vaigro-Wolff A.,
Gray-Goodrich M., Campbell H., Mayo J., Boyd M. Feasibi-
lity of a high-flux anticancer drug screen using a diverse pa-
nel of cultured human tumor cell lines // J. Nat. Cancer
Inst.–1991.–83, N 11.–P. 757–766.
32. Boyd M. R., Paull K. D. Some practical considerations and
applications of the national cancer institute in vitro anticancer
drug discovery screen // Drug Develop. Res.–1995.–34, N 2.–
P. 91–109.
33. Boyd M. R. Anticancer drug development guide: preclinical
screening, clinical trials, and approval in: cancer drug disco-
very and development / Ed. A. Teicher.–Totowa: Humana
Press, 1997.–P. 23–43.
34. Shoemaker R. H. The NCI60 human tumour cell line antican-
cer drug screen // Nat. Rev. Cancer.–2006.–6, N 10.–P. 813–
823.
35. Gududuru V., Hurh E., Dalton J. T., Miller D. D. Synthesis
and antiproliferative activity of 2-aryl-4-oxo-thiazolidin-3-
yl-amides for prostate cancer // Bioorg. Med. Chem. Lett.–
2004.–14, N 21.–P. 5289–5293.
UDC 615.012.1.076:547.789.1
Received 10.01.10
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STRUCTURE-ANTICANCER ACTIVITY OF 4-AZOLIDINONE-3-CARBOXYLIC ACIDS DERIVATIVES
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