89
IN VITRO ANTITUMOR SCREENING OF SOME
POLYSUBSTITUTED PYRAZOLE ANALOGS
Mohammed S. Al-Saadi, Sherif A. F. Rostom* and Hassan M. Faid-Allah
‫ك ربوكسضضيليأشيدضضيدشهيدرولويضضدشوم ض ش ض ش‬-3- ‫بيضضزولو‬-‫يضضد‬1‫شهيدروكس ض ش‬-4-‫شكلوروفيني ض )ش‬-4(‫ ش‬-1‫بعضضمشتق ض ش‬
‫ش–شووكسض يي لوالي شووم ض شدضتشش قضييده ش‬4,2,1‫ش–ش زوي لواليض شوش‬4,2,1‫ششتثض ش‬3‫تج وع شإحالميةشتخ لفضةشفض شوم و ض ش‬
‫وإجزوءشوم يضي شوم تضد شمنقض ا شوم ثض شفض شإي ض اشع ضوشومعديضدشتض شومخاليض شومسضز عيةشفض شوم عاضدشومضو ن شملسضز ش‬
‫وذمأشف شوحدةشومغزبلةشومخ صةشب ض يو شومخاليض شومسضز عيةشوم ع ليضةشوم وجاضةشمل ضزقدششودضدشوجضدشفض شومسض ي ش ض ش‬
‫شدضضدشيراضضز شف عليضضةشتضض يةشوودضضعةشوم ضضدخشملخاليض ش‬3-1‫وألوميضضةشم ليض شومخليضضةشفض شوم عاضضدشي شمالمضضةشتض شوم زكتض شهض ش‬
‫ومسز عيةش دشتج شوود شتض ش وضو شومخاليض شومتقضزيةشوم خ لفضةشوذمضأشفض ش سض شتناض مشوهضت شوم زكتض ش ض شو ي رهض ش‬
‫بوودوةشوم عادشومو ن شمت وثشومسز شمي شإجزوءشغزبلةش أكيديةشعليا شي صدشتنا ش يي شإتك عي شوم ج ربشوم ع ليضةش‬
‫وم ضض يةشملسضز دششو ضنشتن دقضةشتفصضضلةشألفضض شع ض بشوم جض ربشوم ع ليضةشمل ضضأميزشوم ضض يشملخاليض شومسضز عيةشماضضت ش‬
‫وم زكت ض شومنقضضوةشوم ض ش ض شوم صضضو شعليا ض شت ض شومتزو وكضضوال شومثالمضضةشوم ع دتضضةشومخ صضضةشب م عاضضدشومضضو ن شألب ض ثش‬
‫شم ض ش ضضدوينا شف ض شهضضت شوم مضضةشودضضدشيراضضز شوم زكت ض شومفع مضضةشومثالمضضةشعنضضدشوم زكي ض شوألود ض شوم ثضضت شملن ضضوش‬
‫ومسضضز‬
‫د ش‬1>2>‫ش‬3‫ شت شيرجةشف عليةشت ق باةش زيتششش‬LD50‫ شو زكي شيود شت ينش‬TGI‫تس وي ش ثتي شع وشكل ش‬GI50
‫ش‬
‫ش‬
Certain 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid hydrazide derivatives,
carrying various substituents at position 3- such as 1,2,4-triazolyl and 1,2,4-oxadiazolyl moieties
have been previously synthesized and preliminarily evaluated for their antitumor activity at the
National Cancer Institute’s (NCI) in vitro disease-oriented antitumor screen unit. In the primary
60 cell line assay, three compounds (1-3) revealed potential broad spectrum antitumor activity
against a wide range of different human cell lines of nine tumor subpanels. These compounds
were further selected by the NCI for carrying out confirmatory screening procedures in order to
assess their exact in vitro antitumor potentialities. A detailed discussion of the best in vitro
antitumor results of these active analogs obtained from the three consecutive NCI procedures is
reported in this paper. The active three compounds at the GI50 level exhibited TGI and LC50 levels
with nearly the same order of activity; 3> 2> 1.
Key words: 4-Hydroxy-1H-pyrazoles, 1,2,4-Triazole, 1,2,4-Oxadiazole, Antitumor screening
Introduction
Research and development of new pyrazoles for
cancer chemotherapy have been one of a major focus
in anticancer drug design. In this respect, the
discovery of the natural antibiotic pyrazofurin; 4hydroxy -3 β-D-ribofuranosyl -1H-pyrazole-5-carboxamide; having a potent antitumor efficacy in some
Division of Medicinal Chemistry, Faculty of Medicine, King
Abdul-Aziz University, P.O. Box 80205, Jeddah 21589, Saudi
Arabia.
*To whom correspondence should be addressed.
Saudi Pharmaceutical Journal, Vol. 13, No. 2-3 April-July 2005
cancer cases (1) lead to intensive investigations of
numerous pyrazoles carrying different functionalities
for their anticancer (2-4), antiviral (5-7) as well as
antimicrobial (8-10) potentials. During our ongoing
studies aimed at the discovery of new heterocycles
endowed with antitumor activity (11-13), we have
presented the synthesis and the primary anticancer
evaluation of several new 1-(4-chlorophenyl)-4hydroxy-1H-pyrazole-3-carboxylic acid hydrazide
derivatives (13), according to the protocol of the
National Cancer Institute’s (NCI) in vitro diseaseoriented antitumor screen unit. We have also
emphasized the role of incorporating substituents at
90
AL-SAADI ET AL
position 3- of the pyrazole ring such as triazolyl and
oxadiazolyl moieties on the antitumor potency,
where they showed an interesting activity often
associated with high or moderate selectivity for
certain human tumor cell lines. As a consequence,
three of these compounds (1-3) were further selected
by the NCI’s biological committee for subsequent
confirmatory screening procedures in order to assess
their exact antitumor potentialities. These tests
include the repetition of the testing in the primary
screen, referring to the Biological Evaluation
Committee and a final review by the Biological
Evaluation Committee. In the current NCI anticancer
screen, each candidate is tested over a broad
concentration range against every cell line in the
panel (14-16). Active compounds are selected for
further testing based on several criteria: disease-type
specificity in the in vitro assay, unique structure,
potency and demonstration of a unique pattern of
cellular cytotoxicity or cytostasis, indicating a
unique mechanism of action or intracellular target
(17). Secondary in vitro studies to optimize the
exposure time to an agent and to define its potential
mechanism of action are useful for determining the
necessity of the subsequent in vivo studies (17). In
this paper, the best data obtained from the
previously-mentioned three NCI in vitro screening
procedures with a discussion of the antitumor
activities of compounds (1-3) are presented.
Materials and Methods
Source of Compounds:
The 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazole3-carboxylic acid hydrazide derivatives investigated
in the present study were previously synthesized and
characterized (13). Their chemical names are:
-5-(1-(4-Chlorophenyl)-4-hydroxy-1H-pyrazol-3yl)-4-cyclohexyl-1,2,4-triazolin-3-thione (1)
-5-(1-(4-Chlorophenyl)-4-hydroxy-1H-pyrazol-3yl)-1,3,4-oxadiazol-2-one (2)
-5-(1-(4-Chlorophenyl)-4-hydroxy-1H-pyrazol-3yl)-2-phenyl-1,3,4-oxadiazole (3)
In vitro Antitumor Testing and Data Analysis:
Compounds 1-3 were subjected to the NCI in
vitro disease-oriented human cells screening panel
assay to screen their antitumor activities (14-16).
About 60 cell lines of nine tumor subpanels,
including leukemia, non-small cell lung, colon,
CNS, melanoma, ovarian, renal, prostate and breast
Saudi Pharmaceutical Journal, Vol. 13, No. 2-3 April-July 2005
cancer cell lines, were incubated with five
concentrations (0.01-100 μM) for each compound
and were used to create log concentration - %
growth inhibition curves. Three response parameters
(GI50, TGI, and LC50) were calculated for each cell
line. The GI50 value (growth inhibitory activity)
corresponds to the concentration of the compounds
causing 50% decrease in net cell growth, the TGI
value (cytostatic activity) is the concentration of the
compounds resulting in total growth inhibition and
the LC50 value (cytotoxic activity) is the
concentration of the compounds causing net 50%
loss of initial cells at the end of the incubation period
(48h). Subpanel and full panel mean-graph midpoint
values (MG-MID) for certain agents are the average
of individual real and default GI50, TGI, or LC50
values of all cell lines in the subpanel or the full
panel, respectively (14). The NCI antitumor drug
discovery was designed to distinguish between broad
spectrum antitumor compounds and tumor or
subpanel-selective agents.
Results and Discussion
The selected three pyrazoles 1-3 revealed
distinctive potential patterns of activity against some
individual tumor cell lines (Table 1), as well as a
broad spectrum of antitumor activity (Tables 2-4).
Regarding the sensitivity against some
individual cell lines, they proved to be very sensitive
towards most of the tested subpanel tumor cell lines
with significantly low GI50 values ranging between
<0.01 – 59.8 μM. Compound 1 revealed sensitivity
towards about 9 different cancer cell lines with GI 50
values lying in the nanomolar concentration range
(GI50 values < 0.01 μM). Moreover, it showed a
remarkable sensitivity against most of the tested
subpanel tumor cell lines (GI 50 values <0.01 – 6.05
μM) with special effect on the leukemia and breast
cancer cell lines (GI50 values <0.01 – 0.39 and 2.94
μM, respectively). Few exceptions were reported in
table 1, where a small number of tumor cell lines
showed a relative lower sensitivity towards the same
compound (GI50 values range 10.0-59.8 μM). As
concerns compound 2, it exhibited a distinctive
activity against most of tested subpanel tumor cell
lines with GI50 values ranging between <0.01-3.25
μM. On the other hand, the analog 3 showed an
overall potential antitumor activity against all the
tested cancer cell lines (GI50 values ranging between
<0.01-16.1 μM). About 26 different cancer cell lines
IN VITRO ANTITUMOR SCREENING OF PYRAZOLES
showed obvious sensitivity pattern towards this
compound, with GI50 values lying in the nanomolar
concentration range (GI50 values < 0.01 μM) (Table
1).
Concerning the broad spectrum of antitumor
activity, the tested compounds 1-3 displayed
effective growth inhibition GI 50 (MG-MID) values of
0.65, 0.19 and 0.08 μM, respectively, beside a
cytostatic activity TGI (MG-MID) values of 16.9,
11.7 and 15.8 μM, respectively (Tables 2 and 3). In
addition, they exhibited some cytotoxic activity with
LC50 (MG-MID) values of 95.5, 87.1 and 64.6 μM,
respectively (Table 4).
Compound 3; 5-(1-(4-chlorophenyl)-4-hydroxy1H-pyrazol-3-yl)-2-phenyl-1,3,4-oxadiazole; having
GI50, TGI, and LC50 MG-MID values of 0.08, 15.8
91
and 64.6 μM, respectively, proved to be the most
active member in this study. It revealed potential
activity against all the tested subpanel tumor cell
lines with special high potency on the leukemia and
breast cancer subpanels at both the GI50 (0.03 and
0.04 μM, respectively) and the TGI levels (27.9 and
26.2 μM, respectively) (Tables 2 and 3).
Furthermore, the compound showed almost the
same level of antitumor activity against the colon,
CNS and prostate cancer subpanels at both the GI50
(0.2, 0.3 and 0.34 μM, respectively) and the TGI
levels (11.6, 28.4 and 61.3 μM, respectively) (Tables
2 and 3). It should be pointed out that, this
compound revealed a moderate cytotoxic activity
against all the tested subpanel tumor cell lines with
LC50 values ranging between 45.3-94.4 μM (Table 4).
Table 1: Growth inhibitory concentration (GI50, μM) values of the in vitro tumor cell lines a.
Cell Lines
1
2
3
CCRF-CEM
HL-60 (TB)
K-562
MOLT-4
PRMI-8226
SR
Non-Small Cell Lung Cancer
0.25
NTb
<0.01
0.39
0.23
<0.01
0.23
0.03
0.04
0.05
0.12
0.03
1.47
<0.01
<0.01
0.02
0.09
<0.01
A 549 / ATCC
EKVX
HOP-62
HOP-92
NCI – H226
NCI – H23
NCI – H322M
NCI – H460
NCI – H522
Colon Cancer
0.93
14.2
0.47
38.7
59.8
0.32
0.33
0.24
0.37
0.05
0.03
0.09
0.15
0.07
0.07
NT
0.04
0.55
<0.01
0.13
<0.01
16.1
<0.01
0.01
0.02
<0.01
0.14
COLO 205
HCC – 2998
HCT – 116
HCT – 15
HT29
KM12
SW - 620
CNS Cancer
SF-268
48.1
2.33
0.61
0.15
23.9
0.39
0.47
3.25
0.24
0.06
0.08
0.20
0.11
0.45
0.40
0.33
<0.01
<0.01
0.25
<0.01
0.51
11.8
0.08
<0.01
Leukemia
Saudi Pharmaceutical Journal, Vol. 13, No. 2-3 April-July 2005
92
a
b
AL-SAADI ET AL
SF-295
SF-539
SNB-19
SNB-75
U251
Melanoma
<0.01
0.31
0.33
0.16
0.47
0.05
0.03
0.19
0.23
0.02
<0.01
<0.01
0.11
5.11
<0.01
LOX IMVI
MALME-3M
M14
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian Cancer
0.28
<0.01
0.68
27.3
0.52
0.23
0.87
<0.01
0.11
<0.01
0.13
0.54
12.0
0.11
0.43
0.10
1.63
8.34
<0.01
12.9
5.48
<0.01
0.51
0.23
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
Renal Cancer
24.2
<0.01
19.0
2.17
0.29
0.34
0.12
0.47
0.92
0.41
0.23
0.39
<0.01
0.03
3.85
0.66
<0.01
4.15
786-0
A498
ACHN
CAKI-1
RXF-393
SN12C
TK-10
UO-31
Prostate Cancer
0.54
0.25
NT
0.39
6.05
0.84
0.41
13.5
0.50
0.09
0.10
0.16
0.11
0.05
0.01
0.23
<0.01
4.90
<0.01
<0.01
0.28
<0.01
0.05
<0.01
PC-3
DU-145
Breast Cancer
10.0
0.33
0.35
0.06
0.36
0.32
MCF7
NCI/ADR-RES
MDA-MB-231/ATCC
HS 578T
MDA-MB-435
BT-549
T-47D
<0.01
<0.01
1.19
0.26
<0.01
2.94
0.48
0.33
0.08
3.19
0.05
0.01
0.01
0.22
0.01
0.03
1.90
0.01
0.01
2.58
0.16
The best data obtained from NCI’s in vitro disease-oriented human tumor cell screen.
NT = Not Tested.
Saudi Pharmaceutical Journal, Vol. 13, No. 2-3 April-July 2005
IN VITRO ANTITUMOR SCREENING OF PYRAZOLES
93
Table 2: Median growth inhibitory concentrations (GI50, μM) of in vitro subpanel tumor cell linesa.
Subpanel Tumor Cell Linesb
Cpd.
MG-
No.
I
II
III
IV
V
VI
VII
VIII
IX
MIDc
1
0.23
6.60
11.3
2.89
4.17
8.13
6.1
5.16
4.81
0.65
2
0.09
0.23
0.15
0.13
2.24
0.54
0.22
0.21
0.62
0.19
3
0.03
2.45
0.20
0.30
4.06
5.10
1.49
0.34
0.04
0.08
The best data obtained from NCI’s in vitro disease-oriented human tumor cell screen.
I, Leukemia; II, non-small cell lung cancer; III, colon cancer; IV, CNS cancer; V, melanoma; VI, ovarian cancer; VII,
renal cancer; VIII, prostate cancer; IX, breast cancer.
c GI (μM) full panel mean-graph mid point (MG-MID) = the average sensitivity of all cell lines towards the test agent.
50
a
b
Table 3: Median total growth inhibitory concentrations (TGI, μM) of in vitro subpanel tumor cell linesa.
Subpanel Tumor Cell Linesb
Cpd.
MGMIDc
No.
I
II
III
IV
V
VI
VII
VIII
IX
1
36.8
75.1
66.4
37.1
77.4
52.1
78.4
28.1
55.0
26.9
2
28.1
31.8
57.8
80.0
47.6
82.5
40.0
50.2
39.5
11.7
3
27.9
22.2
11.6
28.4
19.5
36.8
23.3
61.3
26.2
15.8
The best data obtained from NCI’s in vitro disease-oriented human tumor cell screen.
For subpanel tumor cell lines, see footnote (b) of table 2.
c TGI (μM) full panel mean-graph mid point (MG-MID) = the average sensitivity of all cell lines towards the test agent.
a
b
Table 4: Median lethal concentration 50 (LC50, μM) values of in vitro subpanel tumor cell linesa.
Subpanel Tumor Cell Linesb
Cpd.
MGMIDc
No.
I
II
III
IV
V
VI
VII
VIII
IX
1
---d
94.6
96.6
37.1
85.9
---
---
---
94.7
95.5
2
89.1
90.7
95.6
94.6
73.3
---
---
96.6
85.5
87.1
3
94.4
69.4
45.3
81.6
57.9
80.3
72.0
82.4
68.9
64.4
The best data obtained from NCI’s in vitro disease-oriented human tumor cell screen.
For subpanel tumor cell lines, see footnote (b) of table 2.
c
LC50 (μM) full panel mean-graph mid point (MG-MID) = the average sensitivity of all cell lines towards the
test agent.
d
Subpanel LC50 value > 100 μM.
a
b
Saudi Pharmaceutical Journal, Vol. 13, No. 2-3 April-July 2005
94
AL-SAADI ET AL
H
OH
HO
N
HO
HO
N
HO
O
S
N
O
NH2
N N
N
N
H
PYRAZOFURIN
Cl
1
H
N
N
O
N
N
O
HO
O
HO
N
N
Cl
2
On the other hand, compound 2 namely; 5-(1-(4chlorophenyl)-4-hydroxy-1H-pyrazol-3-yl)-1,3,4oxadiazol-2-one; showed nearly the same pattern of
activity as 3 but to a lesser extent. It showed
remarkable growth inhibitory, cytostatic and
cytotoxic activities against the nine subpanel tumor
cell lines as evidenced by their GI50 (MG-MID), TGI
(MG-MID) and LC50 (MG-MID) values (0.19, 11.7
and 87.1 μM, respectively) (Tables 2-4). Particular
activity have been shown against the leukemia
subpanel at both the GI50 and TGI levels (0.09 and
28.1 μM, respectively) (Tables 2 and 3). Moreover,
the compound proved to be almost equipotent
Saudi Pharmaceutical Journal, Vol. 13, No. 2-3 April-July 2005
N
N
Cl
3
towards the non-small cell lung, colon, CNS, renal
and prostate cancer subpanels at the GI50 level (0.23,
0.15, 0.13, 0.22 and 0.21 μM, respectively) (Table
2). In addition, the overall cytotoxic activity of this
compound (LC50 (MG-MID) 87.1 μM) was far away
from that of compound 3. Meanwhile, it is devoid of
any cytotoxic potency on the ovarian and renal
cancer subpanels (Table 4).
Finally, compound 1; 5-(1-(4-chlorophenyl)-4hydroxy-1H- pyrazol-3-yl)-4- cyclohexyl-1,2,4-triazolin-3-thione; displayed relatively weaker growth
inhibition, cytostatic and cytotoxic patterns when
compared with 2 and 3 (GI50, TGI and LC50 MG-
IN VITRO ANTITUMOR SCREENING OF PYRAZOLES
MID values 0.65, 26.9 and 95.5 μM, respectively)
(Tables2-4). Except for the pronounced activity
against the leukemia subpanel (GI50 value 0.23 μM),
table 2 reflected that this compound has almost the
same potency against the other 8 subpanels with GI50
value ranging between 2.89 and 11.3 μM. The same
range of activity was nearly maintained on the
cytostatic level (TGI values 36.8-78.4 μM) (Table
3). Moreover, except for the CNS cancer subpanel,
compound 1 revealed marginal cytotoxic activity
and was devoid of such effect on the leukemia,
ovarian, renal and prostate cancer subpanels (Table
4).
The ratio obtained by dividing the full panel
MG-MID (μM) of the compounds by their individual
subpanel MG-MID (μM) is considered as a measure
of compound selectivity. Ratios between 3 and 6
refer to moderate selectivity, ratios greater than 6
indicate high selectivity towards the corresponding
cell line, while compounds not meeting either of
these criteria are rated non-selective (15). All the
active compounds in the present study proved to be
non-selective with broad spectrum antitumor activity
against the nine tumor subpanels tested with ratios
ranging between 0.01-2.83 for the GI50 and 0.151.36 for the TGI. At the GI50 level, compounds 2 and
3 revealed mild selectivity towards the leukemia
subpanel with selectivity ratios near 3 (2.83 and
2.67, respectively).
The broad spectrum antitumor activity as well as
the potential cytostatic and cytotoxic effects of such
type of 4-hydroxypyrazoles will be of interest for
future derivatization in the hope of finding more
active anticancer lead compound(s) in the nanomolar
concentration level or less.
Acknowledgment
The authors are very grateful to the staff
members of the Department of Health and Human
Services, National Cancer Institute (NCI), Bethesda,
Maryland, U.S.A., for carrying out the antitumor
screening.
References
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2.
3.
4
Conclusion
In conclusion, the aim of the present
investigation was to present and discuss the in vitro
antitumor activity of some new 4-hydroxy-1Hpryazoles carrying either the 4-substituted-1,2,4triazolin-3-thione (compound 1) or the 2-substituted1,3,4-oxadiazole (compounds 2 and 3) counterparts
that are structurally related to the natural 4hydroxypyrazole; pyrazofurin. The obtained results
after subjection to the consecutive three NCI
screening procedures confirmed the pronounced
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analog 1. The proposed relationship between the
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biological activity has been previously discussed
(13). These active three compounds at the GI 50 level
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Saudi Pharmaceutical Journal, Vol. 13, No. 2-3 April-July 2005
95
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