Synthesis and antitumor activity of substituted triazolo[4,3-a]pyrimidin-6-sulfonamide with an incorporated thiazolidinone moiety

Article abstract of DOI:10.1016/j.bmcl.2009.05.126

Chlorosulfonation of 3-methyl[1,2,4]triazolo[4,3-a]pyrimidine with chlorosulfonic acid in the presence of thionyl chloride was studied. When triazolo[4,3-a]pyrimidines are used as substrates, the substitution occurs at C-6. Also the reactivity of the hydr

Full text of DOI:10.1016/j.bmcl.2009.05.126

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4143–4147
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antitumor activity of substituted triazolo[4,3-a]pyrimidin-
6-sulfonamide with an incorporated thiazolidinone moiety
*
Hend N. Hafez , Abdel-Rahman B. A. El-Gazzar
National Research Centre, Photochemistry Department (Heterocyclic & Nucleoside Unit), Dokki, 12622 Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Chlorosulfonation of 3-methyl[1,2,4]triazolo[4,3-a]pyrimidine with chlorosulfonic acid in the presence of
thionyl chloride was studied. When triazolo[4,3-a]pyrimidines are used as substrates, the substitution
occurs at C-6. Also the reactivity of the hydrazides (7) towards aldehydes, thioglycolic acid and amines
were studies. The newly prepared compounds 10a,d and 11a,d demonstrated inhibitory effects on the
Received 26 February 2009
Revised 15 May 2009
Accepted 30 May 2009
Available online 6 June 2009
growth of a wide range of cancer cell lines generally at 10ꢀ5 M level and in some cases at 10ꢀ7
concentrations.
M
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Triazolo[4,3-a]pyrimidine
Thioglycolic acid
Thiazolidinone
Anti-tumor
Cancer encompasses many disease states generally character-
ized by abnormally proliferating cell and is a major and often fatal
disease. A variety of anticancer drugs are currently in clinical use.
Some of these compounds can be applied successfully for the treat-
ment of several neoplastic diseases such as leukemias or testicular
cancer. However, the effect of anticancer drugs on solid tumors has
been poor. Because the response of solid tumors to available anti-
cancer chemotherapy has been reduced, new drugs with improved
efficacy are desired.
Pyrimidines nucleus are a pharmacophoric scaffold and repre-
sents a class of heterocyclic compounds with a wide range of bio-
logical applications. Many of them are widely used as anti-
convulsant,1 analgesic,2 sedative,3 anti-depressive,4 anti-pyretic
agents.5 Some heterocycles containing pyrimidine moiety were re-
ported to possess anti-inflammatory,6 antiviral,7 anti-HIV-1,8 anti-
microbial,9 and anti-tumor activities.10,11 Other than their biologi-
cal importance, pyrimidine derivatives are valuable for the prepa-
ration of fused ring compounds, such as triazolopyrimidines,12
thieno-pyrimidines,13 thiazolo-pyrimidines,14 and pyridopyrimi-
dines.15 It has been noticed that introduction of an additional ring
to the pyrimidines core tends to exert profound influence in con-
ferring novel biological activities in these molecules. Although
many methods for synthesizing triazolopyrimidines ring systems
have been reported, they continue to receive a great deal atten-
tion.16–18
exhibit useful pharmacological properties and clinical applications.
In addition to these considerable biological applications, triazolo-
pyrimidines are important intermediates and final products in or-
ganic synthesis. In the course of our research and as part of our
program involving the synthesis of heterocyclic compounds having
potential biological interest, we have already reported the synthe-
sis of many pyridopyrimidine,20 pyrimido[4,5-b]quinoline and its
tricyclic derivatives.21–23
In pursuance of our interests for investigating the reactivity of
pyrimidine-2-thione towards electrophile reagents we now extend
the scope of this reactivity towards other active reagents. Also, sul-
fochlorination reactions are widely used in organic chemistry. Sul-
fonyl chlorides are intermediates in syntheses of active and
dispersible dyes, herbicides, and fungicides.24 Among six-mem-
bered heterocyclic compounds containing two nitrogen atoms, a
prominent place is occupied by pyrimidine derivatives used as
drugs (sulfamide drug such as sulfadimethoxine, sulfamono-
methoxine; antitumor agent fluorouracil; antibiotic Amecytin,
etc.).25 Moreover, triazolo[4,3-a]pyrimidin-6-sulfonoamide deriva-
tives were utilized as new pharmacophoric tool for the develop-
ment of more efficacious antitumor agent. On the basis of the
above observations, the development of novel heteroaromatic sul-
fonamide as potential antitumor agents is very attractive.
Synthetic pathway depicted in Scheme 1 outlines the chemistry
of the present work. The key intermediate 7-amino-3-methyl-5H-
[1,2,4]triazolo[4,3-a]pyrimidin-5-one (3) was prepared by treating
of 2-hydrazino-6-aminopyrimidin-4(4H)-one (2) with glacial ace-
tic acid. The latter 2-hydrazino compound 2 was obtained from
the action of hydrazine hydrate on 2-aminothiouracil (1). The reac-
tion of compound 3 with aromatic aldehydes in ethanol and cata-
Another class of heterocyclic compounds used as scaffold in
medicinal chemistry is devoted to sulfonamide derivatives.19 They
* Corresponding author.
E-mail address: hendnagah2000@yahoo.com (H.N. Hafez).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.126

4144
H. N. Hafez, Abdel-Rahman B. A. El-Gazzar / Bioorg. Med. Chem. Lett. 19 (2009) 4143–4147
O
O
O
C
H3
N
HN
HN
(i)
AcOH
N
N
(ii)
N
NH2
N
NH2
NH2NH
N
H
NH2
O
S
H
3
2
1
(iii)
ArCHO
O
H3C
N
O
O
H3C
N
S
ClSO3H
N
N
Cl
(iv)
N
N
N
Ar
N
N
N
Ar
H
H
4a-c
5a-c
4,5 a, Ar = 4-CH3OC6H4
4,5 b, Ar = 4-ClC6H4
4,5 c, Ar = C6H5
Scheme 1. Reagents and conditions: (i) EtOH (100 mL), NH2.NH2 (25 mL, 99%), 12 h; (ii) AcOH (30 mL), 16 h; (iii) Ar-CHO, EtOH (30 mL), AcOH (1 mL), 4 h; (iv) ClSO3H,
stirring at rt (20–30 min), heated at 75–85 °C for 5–6 h, cooled to 0 °C.
lytic amount of acetic acid yielded triazolo[4,3-a]pyrimidine (4a–
c). According to the literature, the data on chlorosulfonation of
pyrimidines are relatively few. As shown in the chemical ab-
stract,26 uracil and substituted pyrimidines react with a tenfold ex-
cess of chlorosulfonic acid to form uracil-6-sulfonyl chloride and 6-
methyluracil-5-chlorosulfonyl. We reported here a develop and
more efficient procedure for preparation of 7-aryl-methyleneami-
no-3-methyl-6-chlorosulfonyl[1,2,4]triazolo[4,3-a]pyrimidin-5-
one (5a–c). Chlorosulfonic acid in combination with thionyl chlo-
ride (1.5:1) considerably increases the rate of formation and yields
of (5a–c).
Compounds (5a–c) were synthesized by chlorosulfonation of 7-
arylmethylene-amino-3-methyl[1,2,4]triazolo[4,3-a]pyrimidin-
5-one (4a–c). C-Sulphonyl chloride in position 6 of the triazolopyr-
imidine ring was performed at atmospheric pressure by treatment
of 4 with chlorosulphonic acid and thionyl chloride (1.5:1).
Treatment of compound 5a with aryl amine in dry benzene under
reflux afforded 7-(4-methoxyphenylmethyleneamino)-3-methyl-
triazolo[4,3-a]pyrimidin-6-N-aryl-sulfonoamide (6a–c), (Scheme
2). Postulated structures of the newly synthesized compounds 3,
4, 5 and 6 are in agreement with their IR, 1H NMR spectral and
elemental analysis data.
methoxy groups, showed also the aromatic protons at d 7.52 (d, 2H,
J = 8.01 Hz), 7.80 (d, 2H, J = 8.00 Hz), 8.22 (d, 2H, J = 8.01 Hz) and
8.38 (d, 2H, J = 8.00 Hz), the two azomethain protons (–N@CH–)
appear at d 8.81, 8.96 ppm, finally two broad bands corresponding
to 2 NH at d 9.50 and 11.40 which are D2O exchangeable.
The syntheses of 3-methyltriazolo[4,3-a]pyrimidin-6-sulfono[(4-
methylpiperazine/or morpholine-1-yl-methyl)-4-oxo-2-(arylthiaz-
olidin-3-yl]amide derivatives (10 and 11) were carried out as shown
in Scheme 3. The intermediate compounds 9a–d was synthesized by
the nucleophilic cycloaddition of thioglycolic acid in dry benzene un-
der reflux in a water-bath. The structure of 9 was assigned to the iso-
lated products 9a–d on the basis of elemental analysis, IR and in
particular NMR spectra: the latter compound revealed the absence
of –CH@N– and appeared the absorption signal corresponding to
the methylene proton around d 4.40 ppm and the singlet signal due
to the N–CH–S of thiazolidine proton around d 8.80 ppm.
6-(4-Methylpiprazin or morpholin)-1-yl-methyl)-derivatives
were prepared by the reaction of intermediate 9 with a mixture
of paraformaldehyde and N-methyl piperazine or morpholine in
absolute ethanol. The mixture was refluxed for 7–10 h and left it
at room temperature under stirring for 3 days. The structure of
compounds 10a–d and 11a–d were conformed on the basis of their
correct elemental analyses as well as compatible spectral data
(general).31 The 1H NMR spectra of compounds 10 and 11 revealed
the absence of the –CH2– absorption signal of thiazolidine ring and
appeared the multiplet absorption signals of the methylene pro-
tons (4–CH2) of piperazine and morpholine.
Simultaneously, the reaction of compound 5a with hydrazine
hydrate (99%) was completed in 5 h, the pure sulphonyl hydrazide
7 was obtained in good yield. The latter hydrazide was treated with
aryl aldehydes at room temperature in absolute ethanol affording
the corresponding aryl hydrazone derivatives 8a–d (Scheme 3).
The NMR spectrum of 8a, as an example showed three singlet sig-
nals at d 2.31, 3.93 and 4.00 corresponding to the methyl and two
Evaluation of anticancer activity on thiazolopyrimidines 6–11
was performed at the National Cancer Institute (NCI). First, all
O
O
O
O
O
O
H3C
C
H3
S
S
Ar'
Ar
Ar'NH2
N
N
Cl
N
N
H
N
N
N
OMe
a, Ar' =
b, Ar' =
c, Ar' =
N
N
Ar
N
N
H
H
Cl
5a
6a-c
Ar = 4-CH3OC6H4
Me
Scheme 2. Reagents and conditions: Ar0-NH2, dry benzene (50 mL), reflux 3 h.

H. N. Hafez, Abdel-Rahman B. A. El-Gazzar / Bioorg. Med. Chem. Lett. 19 (2009) 4143–4147
4145
O
O
O
O
O
O
H3C
N
H
3C
S
N
S
NH2
R
N
N
N
(ii)
N
H
H
N
a, R =
b, R =
c, R =
d, R =
OMe
Cl
N
N
N
N
Ar
N
N
Ar
H
H
7
8a-d
(iii)
Ar = 4-CH3OC6H4
CH
S
(i)
R
O
N
O
O
S
H
3C
5a
S
N
(iv)
N
N
H
N
(v)
O
N
N
Ar
O
H
9a-d
H3C
R
R
O
O
O
O
S
O
S
H
3C
CH3
N
O
S
S
N
N
N
N
N
N
N
N
H
H
N
N
O
O
N
N
N
N
Ar
N
N
Ar
H
H
10a-d
11a-d
Scheme 3. Reagents and conditions; (i) NH2NH2 (5 mL, 99%), EtOH (30 mL), 5 h; (ii) Ar-CHO, EtOH, (25 mL), rt 48 h; (iii) SHCH2COOH, dry benzrne (25 mL), water-bath 80 °C,
10–14 h.; (iv) N-methylpiprazine, HCHO (15 mL), EtOH (25 mL), 30–45 min, then reflux for 7–10 h.; (v) morpholine, HCHO (15 mL), EtOH (25 mL), 30–45 min, then reflux for
7–10 h.
thiazolopyrimidines were evaluated in primary anticancer assay at
10ꢀ4 M concentration against NCI-H460 (Lung), MCF7 (Breast), and
SF-268 (CNS) cell lines (Table 1).
centrations at 10-fold dilution against every cell line in the panel. A
48 h continuous drug exposure protocol is used and a sulforhoda-
mine B (SRB) protein assay is used to estimate cell viability or
growth.29 The anticancer activity of each compound is deduced
from dose response curves and is presented in three different ta-
bles according to the data provided by NCI.30 The response param-
eters GI50, TGI and LC50 (Table 2) refer to the drug concentration
that produce 50% inhibition, total growth inhibition, and 50% cyto-
toxicity, respectively, and are expressed in 10ꢀ5 molar concentra-
tions. In the tables we report only the activity of those
For NCI criteria, compounds, which reduce the growth of any
one of the cell lines to approximately 32% or less, are passed on
for evaluation in the full panel of cell lines over a 5-log dose range.
Sulfonamide derivatives 10a,d and 11a,d, which meet these crite-
ria, were evaluated for their anticancer activity following the
known in vitro disease-oriented antitumor screening program,
which is based upon use of a multiple panels of 60 human tumor
cell lines.27,28 Each compound is tested at a minimum of five con-
compounds which exhibited GI50, TGI, and LC50 less than
10 ꢁ 10ꢀ5 M.
The GI50 data reported in Table 2 indicate that all selected com-
pounds 10a,d and 11a,d showed a good level of cytostatic activity
at 10ꢀ5 M and in some cases at 10ꢀ7 M concentrations against all
subpanel cell lines. Compound 10a displayed a significant growth
inhibitory activity on all the 60 cell lines showing GI50 values be-
tween 5.89 and 37.1 ꢁ 10ꢀ6 M, and total growth inhibitory activity
on 56 cell lines at 2.1–8.94 ꢁ 10ꢀ5 M concentrations. Compound
10a showed cytotoxic activity against 31 cell lines with particular
selectivity against all renal cancer and prostate cancer cell lines.
Compound 10d totally inhibited the growth of 20 cell lines at
0.318–9.73 ꢁ 10ꢀ5 M concentrations, showing a good selectivity
on the leukemia panel. In addition, it was not cytotoxic, except
for three cell lines of this panel (HL-60TB, K-562, and SR). Com-
pound 11a showed cytotoxic activity on four leukemia cell lines
with LC50 values between 7.15 and 8.68 ꢁ 10ꢀ5 M. Furthermore,
11d produced 50% growth inhibition of 26 cell lines at micromolar
concentrations. The same compound inhibited totally the growth
of 24 cell lines at 10ꢀ5 M concentrations exhibiting high potency
against leukemia SR cell line (TGI value 3.18 ꢁ 10ꢀ6 M and LC50 va-
lue 9.20 ꢁ 10ꢀ6 M). Compound 11d is cytotoxic against HCC-2998
cell line of colon cancer only (LC50 value 6.48 ꢁ 10ꢀ5 M).
Table 1
Aniproliferative activity of triazolo[4,3-a]pyrimidines 6–11 at 10ꢀ4 M concentration
expressed in growth percentage
Compd No.
Cell lines
NCI-H460
MCF7
SF-268
6a
6b
6c
7
8a
8b
8c
8d
9a
9b
9c
9d
10a
10b
10c
10d
11a
11b
11c
11d
86
87
83
43
83
93
87
66
91
90
72
89
9
102
55
46
64
94
67
24
82
102
89
45
55
73
83
13
118
88
67
106
0
86
109
24
16
68
63
13
91
87
85
55
85
101
93
62
94
84
63
98
18
106
102
58
75
95
82
56
Theactivity appears to berelated to somestructural requirements,
as the 6-substituent on the 3-methyl-triazolo[4,3-a]pyrimidin-6-
sulfonoamide ring. In fact, the presence of an 4-methylpiprazin/or

4146
H. N. Hafez, Abdel-Rahman B. A. El-Gazzar / Bioorg. Med. Chem. Lett. 19 (2009) 4143–4147
Table 2
GI50 values, TGI values and LC50 values of compounds 10a,d and 11a,d
R'
O
R'
O
O
H3C
N
S
S
CH3
S
O
N
N
H
R
N
N
N
N
N
R =
;
N
O
N
N
Ar
O
H
10a, R' = 4-CH3OC6H4
10d, R' = 2-C4H3S
11a, R' = 4-CH3OC6H4
11d, R' = 2-C4H3S
Ar = 4-CH3OC6H4
Panel/cell line
Type of test
10a
10d
11a
11d
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
LC50
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
1.72
2.82
1.30
1.78
1.41
0.772
4.92
8.68
2.87
5.89
3.90
2.75
n.t
—
6.33
—
—
8.49
0.352
0.341
0.287
0.288
0.256
0.079
1.61
n.t
2.58
0.98
1.30
1.36
1.64
1.17
7.89
2.72
3.23
3.44
4.43
2.89
n.t
0.627
n.t.
0.234
0.408
0.386
0.110
—
n.t.
1.13
4.06
2.62
0.32
n.t
n.t.
—
—
—
0.704
0.675
1.83
0.821
0.303
3.13
6.82
—
—
1.31
7.43
8.05
8.68
—
7.15
0.920
Nn-small cell lung cancer
A549/AT CC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
1.34
2.59
2.02
1.78
1.24
2.05
2.11
1.64
2.19
5.08
6.03
4.09
3.64
3.06
4.81
5.11
4.67
4.77
n.t
n.t
8.26
7.42
7.57
n.t
n.t
n.t
n.t
0.365
3.970
0.170
0.941
1.180
0.116
0.818
0.820
0.263
—
—
—
—
—
0.911
—
—
1.33
n.t
n.t
—
—
—
n.t
n.t
n.t
n.t
2.96
9.39
8.66
3.63
5.36
8.78
3.98
8.77
3.25
—
—
—
—
—
—
—
—
—
n.t
n.t
—
—
—
n.t
n.t
n.t
n.t
1.91
5.41
1.39
1.24
2.45
4.45
5.69
0.532
0.435
—
—
—
—
—
—
—
—
n.t
n.t
—
—
—
n.t
n.t
n.t
n.t
2.73
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
3.71
0.859
0.589
1.72
3.47
2.48
3.04
2.61
2.25
4.72
7.08
n.t
n.t
0.529
0.134
0.101
0.065
0.196
0.302
0.138
2.10
1.68
2.00
—
n.t
n.t
n.t
—
—
n.t
n.t
n.t
n.t
6.62
2.20
2.97
2.67
2.67
3.61
4.71
—
—
n.t
—
—
n.t
n.t
n.t
n.t
1.49
1.28
3.13
5.74
7.17
n.t
n.t
6.48
—
n.t
n.t
n.t
n.t
7.19
7.15
n.t
n.t
n.t
0.396
0.472
0.452
1.94
0.406
0.611
9.73
—
n.t
n.t
n.t
n.t
n.t
n.t
n.t
n.t
n.t
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
1.77
1.68
0.650
2.57
2.36
1.76
4.20
3.59
2.18
7.25
5.18
4.52
9.96
7.68
6.12
n.t
n.t
—
—
—
—
0.558
—
—
—
—
—
n.t
n.t
—
—
—
—
—
—
—
—
—
—
—
n.t
n.t
—
1.85
0.469
0.724
3.45
3.55
1.56
—
—
3.04
—
—
—
—
—
n.t
n.t
—
0.102
0.177
0.714
0.201
0.251
3.32
7.51
—
5.73
4.04
—
—
Melanoma
LOX IMVI
M14
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
0.74
1.70
2.13
3.03
1.93
2.16
1.89
—
n.t
0.216
0.136
0.555
1.640
0.072
0.252
0.147
—
—
—
—
0.711
—
—
n.t
—
—
n.t
—
—
2.16
6.74
9.93
—
1.90
3.22
2.54
6.24
—
—
—
—
n.t
—
—
n.t
—
—
0.897
0.679
0.830
8.21
0.371
0.677
0.370
—
n.t
—
—
n.t
—
—
3.65
4.61
7.82
3.90
4.47
3.84
7.80
9.94
n.t
7.85
9.23
7.78
3.87
8.19
—
2.40
—
—
—
—
—
3.14
—
Ovarian cancer
IGROV 1
2.10
2.15
2.33
2.43
0.782
2.71
4.44
4.02
4.74
4.70
4.72
7.33
9.39
7.53
9.65
9.07
n.t
0.078
0.088
—
0.831
0.353
0.512
9.73
—
—
—
4.05
—
—
—
—
—
n.t
n.t
2.60
2.25
9.44
—
3.14
—
9.74
6.05
—
—
—
—
—
—
—
n.t
n.t
0.395
0.360
—
4.34
6.06
2.02
3.48
—
—
—
—
—
—
—
—
n.t
n.t
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
n.t
—
—
Renal cancer
786-0
A498
1.62
1.29
1.74
2.09
1.02
1.86
1.94
2.06
3.12
2.81
3.45
4.03
3.11
3.58
3.99
3.81
5.99
6.09
6.84
7.78
9.51
6.89
8.21
7.05
0.393
0.050
0.318
0.129
0.234
0.468
0.590
0.536
—
0.32
—
—
—
—
—
—
—
—
—
—
—
—
—
—
6.71
2.55
2.31
4.33
1.50
5.51
4.01
3.96
—
—
—
—
—
—
—
—
—
0.582
0.267
0.548
1.21
1.66
1.68
—
1.55
—
—
—
—
—
—
—
—
—
6.92
9.26
—
—
—
ACHN
CAKI-1
RXF 393
SN12C
TK-10
—
9.42
8.57
9.20
8.64
—
—
2.08
1.45
UO-31
Prostate cancer
PC-3
DU-145
1.47
1.18
3.22
3.20
7.02
8.66
0.289
0.522
4.00
—
—
—
2.46
2.88
—
—
—
—
0.392
1.60
9.58
—
—
—

H. N. Hafez, Abdel-Rahman B. A. El-Gazzar / Bioorg. Med. Chem. Lett. 19 (2009) 4143–4147
4147
Table 2 (continued)
Panel/cell line
Type of test
10a
10d
11a
11d
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
LC50
Breast cancer
MCF7
NCI/ADR-RES
MDA-MB-231/ATCC
HS578T
MDA-MB-435
BT-549
T-47D
1.53
1.41
1.22
1.30
2.41
1.91
3.12
4.78
4.02
3.29
3.40
6.46
4.63
8.94
n.t
n.t
8.86
8.87
n.t
0.580
0.150
0.325
0.305
0.032
1.130
—
—
n.t
n.t
—
7.73
4.31
2.53
4.11
3.50
—
—
—
—
—
—
—
—
n.t
n.t
—
0.318
0.998
1.17
1.33
0.326
1.80
—
n.t
n.t
—
0.698
4.22
—
0.52
—
6.48
5.61
8.21
3.60
—
—
—
—
n.t
n.t
nt
n.t
n.t
nt
n.t
n.t
n.
n.t
nt
—
—
4.80
—
n.t., means not tested; (—) values >10 ꢁ 10ꢀ5 M.
18. El-Gazzar, A. B. A.; Hafez, H. N.; Abu-Hashem, A. A.; Aly, A. S. Phosphorus Sulfur
Silicon Relat. Elem. 2009, 184, 379.
19. Franklin, A. D. J. Org. Chem. 2006, 71, 8993.
20. El-Gazzar, A. B. A.; Abu-Zied, Kh. M.; Khir El-Din, N. Heteroatom. Chem. 2007,
18, 34.
21. El-Gazzar, A. B. A.; Hafez, H. N.; Nawwar, G. W. Eur. J. Med. Chem. 2009, 44,
1427.
22. El-Gazzar, A. B. A.; El-Enany, M. M.; Mohmoud, M. N. Bioorg. Med. Chem. 2008,
16, 3261.
23. El-Gazzar, A. B. A.; Youssef, M. M.; Youssef, A. M. S.; Abu-Hashem, A. A.; Badria,
F. A. Eur. J. Med. Chem. 2009, 44, 609.
24. Pogorelova, I. P.; Orlov, V. D.; Isak, A. D. Russ. J. Appl. Chem. 2006, 79, 631.
25. (a) Makarov, V. A.; Sedov, A. L.; Nemeryuk, M. P. Khim.-Farm. Zh. 1993,
4, 26; (b) Mashkovskii, M.D. Lekarstvennye Sredstva (Drugs), Kharkov:
Torsing, 1997.
26. (a) Khromov-Borisov, M. V.; Karpinskaya, R. O. Zh. Obshch. Khim. 1957, 27,
2577; (b) Khromov-Borisov, M. V.; Karpinskaya, R. O. Zh. Obshch. Khim.
1964, 34, 2212; (c) Elderfield, R. E.; Prusad, R. N. J. Org. Chem. 1961, 26,
9863.
morpholine linked to arylthiazolidine on 6-position favorably affects
the activity. The introduction in the same position of an
4-chlorphenylthiazol-idine or 4-tolylthiazolidine group (compound
10b,c and 11b,c) and also, thiazolidine ring without substitution
(compounds 9a–d) or 3-methyltriazolo[4,3-a]pyrimidine (com-
pounds 6a–c, 7) and 6-arylmethylenesulfonoamide (compound 8a–
d) are detrimental. Among 6-arylthiazolidine derivatives thienyl or
4-methoxyphenyl groups on arylidene moiety were effective in
inducingstrongantitumoralactivity.Thebestactivityisshownbythi-
enyl group in presence of 4-methylpiparazine or morpholine deriva-
tives, whereas the presence of 4-chlorophenyl or 4-methylphenyl
group produces variable effects.
Acknowledgment
27. Grever, M. R.; Schepartz, S. A.; Chabner, B. A. Semin. Oncol. 1992, 19, 622.
28. Boyd, M. R.; Paull, K. D. Drug Dev. Res. 1995, 34, 91.
29. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; Mc Mahon, J.; Vistica, D.;
Warren, J. T.; Bokesh, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82,
1107.
We thank the antitumor Evaluation Branch of the National Can-
cer Institute (Cairo, Egypt) for performing biological evaluations.
Supplementary data
30. Boyd, M. R. Princ. Pract. Oncol. 1989, 3, 1.
31. General: Melting points were measured with Electrothermal IA 9100 apparatus
(Shimadzu, Japan). The 1H NMR spectra were recorded on JEOL ECA500 MHz.
Chemical shifts relative to TMS as internal standard are given as d values in
ppm and recorded in (DMSO-d6). IR spectra were recorded as KBr pellets on a
Nexus FT/IR spectrometer. Mass spectra were recorded on GCMS-QP 1000 EX
Shimadzu. Elemental analyses were performed in the Microanalytical Unit at
Cairo University (Egypt) and were found within 0.4% of the theoretical values
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.05.126.
References and notes
(see Table
3 as Supplementary data). The antitumor screening of the
1. Powers, D. L.; Sowell Sr, J. W.; Freeman, J. J.; Kosh, J. W. J .Pharm. Sci. 2006, 69,
473.
2. (a) Pemmsin, M.; Lnu-Due, C.; Hoguet, F.; Gaultier, C.; Narcisse, J. Eur. J. Chem.
1988, 23, 534; (b) El-Gazzar, A. B. A.; El-Enany, M. M.; Mahmoud, M. N. Bioorg.
Med. Chem. 2008, 16, 3261.
3. Kimura, T.; Teraoka, S.; Kuze, J.; Watanabe, K.; Kondo, S.; HO, I.; Yamamoto, I.
Nucleic Acids Symp. Ser. 1993, 29, 51.
4. Bernier, J. L.; Henichart, J. P.; Warin, V.; Baert, F. J .Pharm. Sci. 2006, 69, 1343.
5. Smith, P. A. S.; Kan, R. O. J. Org. Chem. 1964, 29, 2261.
6. Gavrilov, M. Y.; Mardanova, I. G.; Kolla, V. E.; Konshin, M. E. Pharm. Chem. J.
1988, 22, 554.
7. Dinan, F. J.; Bardos, T. J. J. Med. Chem. 1980, 23, 569.
8. Tanaka, H.; Baba, M.; Hayakawa, H.; Sakamaki, T.; Miyasaka, T.; Ubasawa, M.;
Takashima, H.; Sekiya, K.; Nitta, I.; Shigeta, S.; Walker, R. T.; Balzarini, J.; De
Clereq, E. J. Med. Chem. 1991, 34, 349.
9. Darias, V.; Abdallah, S. S.; Tello, M. L.; Delgada, L. D.; Vega, S. Arch. Pharm. 1994,
327, 779.
investigated compounds was carried out by the pharmacology Unit, National
Cancer Institute (NCI), Cancer Biology Department, Cairo University, Egypt).
Primary anticancer assay: The compounds were tested by NCI in an in vitro
three-cell line, one dose primary anticancer assay as a primary cancer screen.
The three-cell line panel consists of the MCF7 (breast), NCI-H460 (lung), and
SF-268 (CNS). Each cell line is inoculated and preincubated on a microtiter
plate. Test agents are then added at single 10-4 M concentration and the
culture is incubated for 48 h. End-point determinations are made with alamar
blue.32 Results for each test agent are reported as the percent of growth of the
treated cells when compared to untreated control cells. Compounds, which
reduce to growth of any one of cell lines to approximately 32% or less, are
passed on for evaluation in the full panel of 60 cell lines over a 5-log dose
range.
Determination of GI50, TGI and LC50 values: A total of 60 human tumor cell lines,
derived from nine cancer types (leukemia, lung, colon, brain, melanoma,
ovarian, renal, prostate, and breast), formed the basis of this test. The tumor
cells were cultured in RPMI1640 medium supplemented with 5% fetal calf
10. Hendry, J. A.; Homer, R. F. J. Chem. Soc. 1952, 328.
serum and 2 mM L-glutamine. The tumor cells are inoculated over a series of
11. Cordeu, L.; Cubedo, E.; Bandres, E.; Rebollo, A.; Saenz, X.; Chozes, H. M.;
Dominquez, V.; Echeverria, M.; Mendivil, B.; Sanmartin, C.; Palop, J. A.; Font,
M.; Garcia-Foncillas, J. Bioorg. Med. Chem. 2007, 15, 1659.
12. Navarro, J. A. R.; Salas, J. M.; Romero, M. A.; Vilaplana, R.; Faure, R. J. Med. Chem.
1998, 41, 332.
standard 96-well microtiter plates in 100 mL of medium.27,28 Density of
inoculums depends on the type of tumor cell and on its growth
characteristics.33 These cells are then preincubated on the microtiter plate
for 24 h before adding the compounds. They were tested in DMSO solution at
five different concentrations (10ꢀ4, 10ꢀ5, 10ꢀ6, 10ꢀ7, and 10ꢀ8 M). After an
13. Hafez, H. N.; El-Gazzar, A. B. A. Bioorg. Med. Chem. Lett. 2008, 18, 5222.
14. Sherif, M. S.; Youssef, M. M.; Mobarak, K. M.; Abdel-Fattah, A. M. Tetrahedron
1993, 49, 9561.
15. Wu, Z.; Hartnett, J. C.; Neilson, L. A.; Robinson, R. G.; Fu, S.; Barnett, S. F.; Defeo-
Jones, D.; Jones, R. E.; Kral, A. M.; Huber, H. E.; Hartman, G. D.; Bilodeau, M. T.
Bioorg. Med. Chem. Lett. 2008, 18, 1274.
incubation of the chemical agent for 48 h with the tumor cell lines, a
sulforhodamine B (SRB) protein assay was used to estimate cell viability or
growth. The cytotoxic effects are evaluated, and the assay results and dose-
response parameters were calculated as previously described.30
32. Gray, G. D.; Wickstrom, E. Biotechniques 1996, 21, 780.
33. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, P.; Paull, K.; Vistica, D.; Hose,
C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M.; Campbell, H.;
Mayo, J.; Boyd, M. R. J. Natl. Cancer Inst. 1991, 83, 757.
16. Hafez, H. N.; Abbas, H. A. S.; El-Gazzar, A. B. A. Acta Pharm. 2008, 58, 359.
17. El-Gazzar, A. B. A.; Hossein, H. A. R.; Hafez, H. N. Acta Pharm. 2007, 57, 395.