Synthesis of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates and evaluation of their Src kinase inhibitory and anticancer activities

Article abstract of DOI:10.1016/j.bmcl.2011.01.047

A series of two classes of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates were synthesized using click chemistry approach. All compounds were evaluated for inhibition of Src kinase and human ovarian adenocarcinoma (SK-Ov-3), breast carcinoma (MDA-MB

Full text of DOI:10.1016/j.bmcl.2011.01.047

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1342–1346
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates and
evaluation of their Src kinase inhibitory and anticancer activities
Anil Kumar a,b, , Israr Ahmad a, Bhupender S. Chhikara b, Rakesh Tiwari b, Deendayal Mandal b,
⇑
Keykavous Parang b,
⇑
a Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India
b Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of two classes of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates were synthesized using
click chemistry approach. All compounds were evaluated for inhibition of Src kinase and human ovarian
adenocarcinoma (SK-Ov-3), breast carcinoma (MDA-MB-361), and colon adenocarcinoma (HT-29). Hexyl
triazolyl-substituted 3-phenylpyrazolopyrimidine exhibited inhibition of Src kinase with an IC50 value of
Received 24 December 2010
Revised 10 January 2011
Accepted 12 January 2011
Available online 15 January 2011
5.6
l
M. 4-Methoxyphenyl triazolyl-substituted 3-phenylpyrazolopyrimidine inhibited the cell prolifera-
M.
tion of HT-29 and SK-Ov-3 by 73% and 58%, respectively, at a concentration of 50
l
Keywords:
Anticancer activity
Click reaction
Ó 2011 Elsevier Ltd. All rights reserved.
Phenylpyrazolopyrimidine
Src kinase
1,2,3-Triazole
Tyrosine kinase
Phosphorylation of many protein substrates occurs in the pres-
ence of protein tyrosine kinases (PTKs) that catalyze the transfer of
leukemia (CML) and gastrointestinal stromal tumors (GISTs).18
However, various imatinib-resistant mutations are generated
spontaneously on Abl over long-term course of treatment.19 Dasat-
inib (BMS-354825) is a pyrimidinylthiazole-based ATP-competi-
tive dual SRC/ABL inhibitor20 approved to use in patients with
CML after imatinib treatment. Bosutinib (SKI-606), a 3-quinoline-
carbonitrile-based Src kinase inhibitor, is known to suppress
migration and invasion of human breast cancer cells.21
c-phosphate group from ATP to specific tyrosine residues. PTKs
have critical roles in the signal transduction pathways. Src family
kinases (SFKs) are a family of nine different PTKs, including c-Src,
c-Yes, Fyn, Lck, Lyn, Hck, Frk, Blk, and c-Fgr of which Src is the pro-
totype.1 SFKs have important roles in the regulation of a wide vari-
ety of normal cellular signal transduction pathways, such as cell
division, growth factor signaling, differentiation, survival, adhe-
sion, migration, and invasion.2 Src tyrosine kinase expression is fre-
quently elevated in a number of epithelial tumors including colon,
breast, prostate, lung, ovary, and pancreas compared with the adja-
cent normal tissues. Src kinase is a key modulator of cancer cell
invasion and metastasis.3–6
Crystallographic studies of an ATP mimic, AMP–PNP, bound to
c-Src (PDB 2SRC)22 and complexes of 3-phenylpyrazolopyrimidine
X
In recent years development of Src kinase inhibitors for the
treatment of cancer is a subject of major interest.7 A number of
inhibitors of protein kinases8 such as quinazolines,9 quinolinecar-
bonitriles,10 pyrazolopyrimidines,11 imidazo[1,5-a]pyrazines,12
benzotriazines,13 ATP–phosphopeptide conjugates,14 pyrimido-
quinolines,15 and pyridopyrimidinones16, have been investigated
for the treatment of cancer, chronic inflammatory diseases, and
other indications.17 Imatinib is a 2-phenylaminopyrimidine nonse-
lective PTK inhibitor of ABL, c-Kit, and PDGFR approved for the
treatment of a number of malignancies like chronic myelogenous
NH2
N
NH2
N
NH2
N
3
N
N
N
N
N
2
N
1
N
N
N
N
N
N
N
PP1 X = Me
PP2 X = Cl
N
O
R
N
R
R = alkyl, aryl, or heteroaryl
⇑
Corresponding authors.
E-mail address: kparang@uri.edu (K. Parang).
Figure 1. Chemical structures of 3-phenylpyrazolopyrimidines and 1,4-disubsti-
tuted 1,2,3-triazoles.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.047

A. Kumar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1342–1346
1343
H3CO
CN
CN
O
HO
CN
CN
Cl
CN
CN
NaH
THF
Me2SO4
NaHCO3
+
4
2
3
1
NH2
RNHNH2
NC
H2N
(5a-b)
N
HCONH2
N
N
N
NEt3
N
N
R
7a-b
R
6a-b
a R = H
b R = CH2CH2OH
Scheme 1. Synthesis of N1-substituted PhPP scaffolds.
derivatives (PP1 and PP2) (Fig. 1) as ATP-binding site inhibitors
with Hck (PDB 1QCF)23 and Lck (PDB 1QPE)24 have revealed that
the pyrazolopyrimidine core of PP1 and PP2 mimic the adenine
base of ATP in binding to the nucleotide binding site. We have pre-
viously shown that 3-phenyl group contributes significantly to Src
kinase inhibitory activity through a hydrophobic interaction with a
large hydrophobic pocket in the ATP-binding site.25a Another cav-
1,2,3-triazoles containing hydrophobic residues can occupy and/
or interact with amino acids of this cavity and contribute to the
enhancement of Src kinase inhibitory potency. Herein, we describe
synthesis and evaluation of Src kinase inhibitory activity of two
classes of 3-phenylpyrazolopyrimidine (PhPP)-1,2,3-traizole con-
jugates (Fig. 1), in which the pyrazolo ring of PhPP is attached
through an ethylene or a methylene linker to positions 1 and 4
of the triazole, respectively. All the compounds were synthesized
under click reaction conditions.
Synthesis of PhPP scaffolds (7a–b) was achieved according to
the previously reported procedure with slight modification as
shown in Scheme 1.25,26 2-Benzoylmalononitrile (3) was synthe-
sized from the reaction of benzoyl chloride (1) with malononitrile
(2) in the presence of sodium hydride in THF. Methylation of 3 with
ity is formed from side chains of helix aC and helix aD. This cavity
is normally occupied by carbohydrate moiety followed by triphos-
phate group of ATP and remains mostly unfilled by tert-butyl of 3-
phenylpyrazolopyrimidines (PP1 and PP2).
In continuation of our efforts to design or identify new Src
kinase inhibitors,14,25 we investigated whether that variation of
N1 substitution in 3-phenylpyrazolopyrimidines with different
NH2
N
NH2
N
NH2
MsCl
N
NaN3,DMF
N
N
N
N
N
Pyridine
N
N
N
N
OH
7b
OMs
8
N3
9
NH2
R = H, CH3(CH2)2CH2-, CH3(CH2)4CH2- ,
CH3(CH2)5CH2-, CH3(CH2)8CH2-, C6H5CH2-,
4-CH3OC6H4-, 4-FC6H4-, 4-CH3COC6H4-,
-CH2CH2CH2Cl
R
N
N
10a-i
N
N
CuSO4
Sodium Ascorbate
CH3CN/DMSO
N
N
11a-i
N
R
Scheme 2. Synthesis of PhPP-1,2,3-triazole conjugates 11a–i.
NH2
N
O
NH2
N3
13a-k
CuSO4
NH2
N
Br
R
N
N
N
N
N
N
N
H
N
N
K2CO3
N
Sodium Ascorbate
CH3CN/DMSO
N
14a-j
N
N
O
12
7a
R = 4-Cl-C6H4-, C6H5-, 4-CH3C6H5-, -CH2CH2CH2OH, CH3CH2O-,
C6H5NH-, FC6H5NH-, ClC6H5NH-, 1-naphthyl-CH2CH2, 2-thiophenyl-
R
Scheme 3. Synthesis of PhPP-1,2,3-triazole conjugates 14a–j.

1344
A. Kumar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1342–1346
Table 1
The Src kinase inhibitory activities of compounds 11a–i (class 1)
NH2
N
N
N
N
N
N
N
R
Log Pc (calcd)
a
Compds
R
IC50
(lM)
9
—
6.2
—
11a
11b
11c
11d
11e
11f
11g
11h
CH3(CH2)2CH2–
CH3(CH2)4CH2–
CH3(CH2)5CH2–
CH3(CH2)8CH2–
C6H5CH2–
4-CH3OC6H4–
4-FC6H4–
4-CH3COC6H4–
–CH2CH2CH2Cl
—
>75
5.6
2.83
3.89
4.41
5.47
2.81
3.06
3.25
2.60
2.01
—
>75
>75
NAb
17.4
29.6
>75
NA
Figure 2. Comparison of structural complexes of Src kinase with different PhPP
derivatives. 11b (green), PP1 (blue), and (b) 14f (red) based on molecular modeling.
The compounds and side chains of amino acids are rendered in stick styles.
Compounds are in the lowest energy conformers predicted. The figure is drawn
using the Accelrys visualization system.
11i
Staurosporine
PP2
0.3
2.8
—
3.57
a
dimethyl sulfate in the presence of sodium bicarbonate in dioxane
afforded 2-(methoxyphenylmethylene)malononitrile (4), which
was cyclized by treatment with hydrazine hydrochloride or 2-
hydroxyethyl hydrazine in the presence of triethylamine to afford
5-amino-3-phenyl-1H-pyrazole-4-carbonitrile (6a) or 5-amino-1-
(2-hydroxyethyl)-3-phenyl-1H-pyrazole-4-carbonitrile (6b), res-
pectively. Reaction of (6a–b) with formamide at 180 °C for 24 h
afforded the corresponding PhPP scaffolds 7a and 7b in 72% and
76% yields, respectively.
The concentration that inhibited enzyme activity by 50%.
b
Less than 10% enzyme inhibitory activity was observed up to the concentration
M.
Calculated partition coefficient using ChemBioDraw Ultra 12.0.
of 250
l
c
Table 2
The Src kinase inhibitory activities of compounds 14a–j (class 2)
NH2
Compounds 7b and 7a were used for the synthesis of azido- and
alkyne-substituted building blocks 9 and 12, respectively, needed
for click reactions. Synthesis of compound 9 was carried out by
mesylation of 7b followed by nucleophilic substitution with sodium
azide in DMF (Scheme 2). Compound 12 was prepared by the
reaction of 7a with propargyl bromide in the presence of potassium
carbonate in acetone at room temperature (Scheme 3). Only the
N1-endocyclic amino group of PhPP derivatives was reacted with
propargyl bromide. Unprotected N4-exocyclic amine was not reac-
tive under these reaction conditions as shown previously.27
Two classes of PhPP-1,2,3-triazole conjugates (11a–i and 14a–j)
were prepared by the click chemistry approach using regioselec-
tive addition of 9 with different alkynes (10a–i) (Scheme 2) and
12 with different azides (13a–k) (Scheme 3) catalyzed by in situ
generated copper(I) salt at room temperature. The reactions pro-
ceeded in high yields (76–88%) and in a regioselective manner.
All the compounds were purified using column chromatography
and characterized by 1H NMR, 13C NMR, and HRMS spectroscopy.
The IR spectra of the compounds (14a–j) exhibited a strong band
at about 1685 cmÀ1 confirming the presence of a carbonyl group.
In 1H NMR spectra of 11a–i and 14a–j a characteristic singlet
was observed for triazolyl C5-H at about d 7.90 ppm.
N
N
N
N
N
N
N
O
R
a
Compds
R
IC50
(lM)
Log Pc (calcd)
14a
14b
14c
4-Cl-C6H4–
C6H5–
4-CH3C6H5–
>75
>75
>75
2.89
2.11
2.60
14d
>75
1.88
S
14e
14f
14g
23.1
16.4
>75
1.82
2.22
2.79
NH
F
NH
Cl
NH
CH2CH2
An array of 20 diversely substituted PhPP-1,2,3-triazole conju-
gates were evaluated against Src kinase. The results of Src kinase
inhibitory activity of compounds in classes 1 (11a–i) and 2 (14a–j)
are shown in Tables 1 and 2, respectively.
All compounds in class 1 showed less inhibitory activities when
compared with that of PP2. A number of compounds 11b, 11f, and
14h
NAb
3.83
14i
14j
–CH2CH2CH2OH
CH3CH2O–
9.1
12.7
0.3
0.32
1.35
Staurosporine
PP2
—
—
2.8
11g showed modest inhibitory activity (IC50 = 5.6–29.6 lM) (Table
a
1). These data suggest that the presence of 1,2,3-triazole-substi-
tuted with bulky groups and attached through an ethylene to PhPP
scaffold is less tolerated, possibly because the cavity cannot
accommodate large groups. Furthermore, the substitutions may
The concentration that inhibited enzyme activity by 50%.
b
Less than 10% enzyme inhibitory activity was observed up to the concentration
M.
Calculated partition coefficient using ChemBioDraw Ultra 12.0.
of 250
l
c

A. Kumar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1342–1346
1345
140
120
100
80
HT-29
MDA-MB-361
SK-Ov-3
60
40
20
0
Figure 3. Inhibition of HT-29, MDA-MB-361, and SK-Ov-3 cell proliferation by compounds 11a–i and 14a–j (50
lM) after 72 h incubation. The results are shown as the
percentage of the control DMSO that has no compound (set at 100%). All the experiments were performed in triplicate.
not be oriented appropriately in the cavity or may have unfavor-
able interactions.
Compounds in class 2 exhibited more diverse inhibitory activi-
ties (Table 2). Compounds 14e, 14f, 14i, and 14j demonstrated
modest Src inhibitory activities with IC50 values between 9.1 and
is not always perfect possibly because of the diversity in solubility
(see calculated Log P values in Tables 1 and 2) and cellular uptake
of these compounds in these cell lines as 11b a modest Src kinase
inhibitor was not a potent inhibitor of cell proliferation.
In summary, compounds 11b and 14i exhibited modest inhibi-
23.1
lM. 1,2,3-Triazole-substituted with naphthyl (14h), tolyl
tory potency (IC50 = 5.6–9.1 lM) against Src kinase. Structure–
(14c), and 4-chlorophenyl (14a and 14g) showed significantly
weak inhibitory potency, suggesting incorporation of bulky groups
are less tolerated in the cavity. The presence of 1,2,3-triazole
between PhPP scaffold and the substitution through a carbonyl
group provides less flexibility for the substituted moieties at N1
position to be accommodated into cavity.
activity relationship studies suggested that the incorporation of
bulky groups at N1 position of PhPP is less tolerated. 4-Methoxy-
phenyl triazolyl-substituted 3-phenylpyrazolo-pyrimidine (11f)
inhibited the cell proliferation of HT-29 by 73% at a concentration
of 50 lM. The data provide insights for further optimization of
these compounds as Src kinase inhibitors and/or anticancer agents.
Molecular modeling and minimization was used to explore how
the structures would fit within the ATP-binding site of the enzyme
(Fig. 2). The modeling studies indicated that phenyl groups in 11b
and 14f occupy the hydrophobic binding pocket similar to tolyl
group of PP1 with slightly different orientations (Fig. 2). In case
of 11b, the flexible hexyl group is oriented towards the hydropho-
bic pocket possibly because of favorable hydrophobic interactions.
On the other hand, the fluorophenyl group in 14f is positioned to-
wards the large cavity where the triphosphate group of ATP usually
binds similar to that of t-butyl group of PP1, possibly because the
amide moiety in 14f does not allow flexibility seen in 11b.
Acknowledgments
We acknowledge Department of Science and Technology, New
Delhi Project # SR-FTP-CS-34-2007, the American Cancer Society
Grant # RSG-07-290-01-CDD, and National Science Foundation,
Grant Number CHE 0748555 for the financial support.
Supplementary data
Supplementary data (experimental procedures and character-
ization of compounds) associated with this article can be found,
in the online version, at doi:10.1016/j.bmcl.2011.01.047.
The effect of the inhibitors at the concentration of 50 lM on the
cell proliferation of cancer cells that overexpress c-Src was also
evaluated against human ovarian adenocarcinoma cells (SK-
Ov-3), breast carcinoma (MDA-MB-361), and colon adenocarci-
noma (HT-29) cell lines (Fig. 3). All three cell lines express highly
activated Src.28,29 Compounds 11f and 11i inhibited the cell prolif-
eration of colon cancer cells (HT-29) by 73% and 57%, respectively,
(Fig. 3) whereas compounds 11f and 14h inhibited the growth of
ovarian cancer cells (SK-Ov-3) by approximately 58% and 48%,
respectively (Fig. 3). Compounds 11g and 14e were able to inhibit
the cell proliferation of breast cancer cells (MDA-MB-361) by 49%
and 51%, respectively (Fig. 3).
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