Click chemistry inspired one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles and their Src kinase inhibitory activity

Article abstract of DOI:10.1016/j.bmcl.2010.10.121

Two classes of 1,4-disubstituted 1,2,3-triazoles were synthesized using one-pot reaction of α-tosyloxy ketones/α-halo ketones, sodium azide, and terminal alkynes in the presence of aq PEG (1:1, v/v) using the click chemistry approach and evaluated for Src

Full text of DOI:10.1016/j.bmcl.2010.10.121

Bioorganic & Medicinal Chemistry Letters 21 (2011) 449–452
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Click chemistry inspired one-pot synthesis of 1,4-disubstituted
1,2,3-triazoles and their Src kinase inhibitory activity
Dalip Kumar a, , V. Buchi Reddy a, Anil Kumar a, Deendayal Mandal b, Rakesh Tiwari b, Keykavous Parang b,
⇑
⇑
a Chemistry Group, Birla Institute of Technology and Science, Pilani 333031, Rajasthan, India
b Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, 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:
Two classes of 1,4-disubstituted 1,2,3-triazoles were synthesized using one-pot reaction of
ketones/a-halo ketones, sodium azide, and terminal alkynes in the presence of aq PEG (1:1, v/v) using
the click chemistry approach and evaluated for Src kinase inhibitory activity. Structure–activity relation-
ship analysis demonstrated that insertion of C6H5– and 4-CH3C6H4– at position 4 for both classes and less
bulkier aromatic group at position 1 in class 1 contribute critically to the modest Src inhibition activity
a
-tosyloxy
Received 13 April 2010
Revised 6 October 2010
Accepted 25 October 2010
Available online 30 October 2010
(IC50 = 32–43 lM) of 1,4-disubstituted 1,2,3-triazoles.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Click chemistry
Triazoles
Src kinase
Protein tyrosine kinase
Structure–activity relationship
Protein tyrosine kinases (PTKs) catalyze the phosphorylation of
phenolic group of tyrosine residue in many substrate proteins by
the transfer of c-phosphate moiety of ATP. PTKs play a crucial role
hydrophobic binding pocket near the ATP binding site of Src family
kinases for the aryl moiety of the pyrazolopyrimidine template. We
have previously shown that the hydrophobic interaction of the
phenyl group with hydrophobic pocket is essential for the binding
of 3-phenylpyrazolopyrimidines (Fig. 1) to the ATP binding site.15
The pyrazolopyrimidine core resembles the purine core of ATP it-
self and bind in the nucleotide binding site in the position normally
occupied by the adenine base. Any substituent attached to N1 of
pyrazole occupies a mostly hydrophobic cavity in PP1. Most of this
hydrophobic cavity remains unfilled. This cavity, in part, formed
in the signal transduction pathways. The non-receptor tyrosine
kinases of the Src family, Src, Yes, Lck, Fyn, Lyn, Fgr, Hck, Blk, and
Yrk, share a great deal of structural homology and are present in
the cytoplasm.1 Src tyrosine kinase plays a prominent role in regu-
lating cell growth and differentiation. Src has been implicated in
development of variety of cancers. Src mutations and/or overexpres-
sion has been correlated with tumor growth, metastasis, and
angiogenesis.2
from side chains of helix aC and helix aD.
Various structural motifs have been reported to target Src kinase3
such as quinolinecarbonitriles,4 ATP-phosphopeptide conjugates,5
pyrazolopyrimidines,6 purines,7 imidazo[1,5-a]pyrazines,8 benzo-
triazines,9 pyrimidoquinolines,10 pyridopyrimidinones,11 and quin-
azolines.12 Imatinib, a well known marketed PTK inhibitor, is used to
treat a number of malignancies like chronic myelogenous leukemia
(CML) and gastrointestinal stromal tumors (GISTs). Dasatinib is
another marketed kinase inhibitor that inhibits Src family tyrosine
kinases and BCR/ABL and is approved to use after Imatinib treat-
ment. A 3-quinolinecarbonitrile-based Src kinase inhibitor, Bosuti-
nib, is undergoing rigorous trials for cancer treatment.13
Herein, we describe synthesis and evaluation of 1,4-disubsti-
tuted 1,2,3-triazoles (Fig. 1) as a novel template for Src kinase inhi-
bition. The 1,2,3-triazoles are important heterocycles that are
X
R2
N
R2
N
NH2
N
N
N
N
N
N
N
N
O
X-ray studies of phenylpyrazolopyrimidine inhibitors in Hck
O
R1
R1 and R2 = alkyl, cycloalkyl, or aryl
R1
kinase-PP1 and Lck kinase-PP214 complexes have revealed a deep
PP1 X = Me
PP2 X = Cl
⇑
Corresponding authors. Tel.: +911596 245073 279; fax: +91 1596 244183 (D.K.).
E-mail addresses: dalipk@bits-pilani.ac.in (D. Kumar), kparang@uri.edu (K.
Figure 1. Chemical structures of 3-phenylpyrazolopyrimidines and 1,4-disubsti-
Parang).
tuted 1,2,3-triazoles.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.121

450
D. Kumar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 449–452
Table 1
reported to possess several biological properties including
anti-HIV,16 antiallergic,17 antifungal,18 and antimicrobial,19 activi-
ties. The 1,2,3-triazole based compounds have been previously
reported to inhibit p38 MAP kinase and PfPK7 protein kinase.20
We hypothesized that substitution at N1 and position 4 of
1,2,3-triazoles with hydrophobic residues may occupy and interact
with the hydrophobic binding pocket of Src ATP binding site simi-
lar to that of 3-phenylpyrazolo-pyrimidines. The hydrophobic
interactions of the hydrophobic groups with several amino acids
in the hydrophobic pockets may contribute to the enhancement
of potency. Furthermore, the attachment of hydrophobic group to
1,2,3-triazoles may generate novel geometric features that might
contribute to binding of such compounds to Src kinase.
Preparation of 1,2,3-triazoles (3a–z and 4a–m) has been widely
explored using click chemistry approach due to its complete spec-
ificity, efficiency, simple reaction workup procedure, and quantita-
tive reaction yield of the products.21 Furthermore, multicomponent
reactions have been contributing considerably for the drug discov-
ery by putting forth multiple arrays of compounds with diverse
substitution patterns expeditiously.22 The synthetic strategy of
these reactions can yield complex molecules with several new
bonds and points of diversity in one pot thus alleviating the labor
involved over a series of reaction workups.23
The Src kinase inhibitory activities of 1,2,3-triazoles 3a–z (class 1)
N
O
N
N
R2
R1
a
Compd
R1
R2
IC50 (lM)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
C6H5
C6H5
C6H5
C6H5
C6H5
>100.0
41.6
4-CH3C6H4
4-F-3-CH3C6H3
2-Pyridyl
C6H5
81.0
NAb
Styryl
C6H5
>100.0
NA
49.8
82.3
>100.0
72.8
139.0
108.7
NA
NA
>150.0
NA
NA
NA
>100.0
89.5
>150.0
32.5
>150.0
>150.0
>100
>150.0
0.3
n-Butyl
4-CH3C6H4
4-CH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
Coumarin-3-yl
Coumarin-3-yl
2-Thienyl
CH3
4-CH3C6H4
4-F-3-CH3C6H3
C6H5
3-CH3C6H4
C6H5
4-CH3C6H4
4-FC6H4
4-OCH3C6H4
3-Thienyl
4-CH3C6H4
4-FC6H4
n-Butyl
1-Cl-butan-4-yl
C6H5
4-CH3C6H4
C6H5
C6H5
4-CH3C6H4
C6H5
The facile and eco-friendly synthesis of these derivatives involves
a one-pot reaction of
a-tosyloxy ketones/a-halo ketones, sodium
azide, and terminal alkynes in the presence of aq PEG 400 (1:1, v/
v) at room temperature under ‘Click’ conditions24 (Scheme 1). The
convenient preparation of 1,2,3-triazoles involves initial nucleo-
CH3
3y
3z
OCH3
N(C2H5)
—
C6H5
philic substitution reaction of
a-tosyloxy ketones/a-halo ketones
Staurosporine
PP2
—
—
with sodium azide to generate in situ
a-azido ketones which is fol-
—
2.8
lowed by Cu (I) catalyzed regioselective cycloaddition reaction with
alkynes. The protocol is broadly applicable for the preparation of
a
The concentration of the compound that inhibited enzyme activity by 50%.
Less than 10% enzyme inhibitory activity was observed up to the concentration
b
1,2,3-triazoles as demonstrated by the use of various
tones/ -halo ketones (aliphatic, aromatic and cyclic) and alkynes
(alkyl and aryl). Both the -tosyloxy ketones and -halo ketones
reacted with almost the same efficiency. It was observed that the
-tosyloxy ketones required marginally shorter reaction time when
compared to -halo ketones. Moreover, -tosyloxy ketones are ideal
substitutes for the lachrymatory -halo ketones. The mild reaction
a-tosyloxy ke-
of 75 lM.
a
a
a
Table 2
a
The Src kinase inhibitory activity of compounds 4a–m (class 2)
a
a
a
N
O
N
N
R2
conditions and simple workup allowed us to rapidly prepare various
substituted 1,2,3-triazoles in good yields (60–90%). After comple-
tion of the reaction, the contents were simply diluted with water,
filtered, and dried to obtain 1,2,3-triazole which was finally recrys-
tallized from ethyl acetate/hexane. The IR spectra of all the
compounds exhibited a strong band at about 1685 cmÀ1. In 1H
NMR a characteristic singlet was observed for triazolyl C5–H at about
d 7.90 ppm. All the synthesized compounds were characterized by
IR, 1H NMR, and mass spectroscopy.
R1
a
Compd
R1
R2
IC50 (lM)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Cyclopentan-1-on-2-yl
Cyclopentan-1-on-2-yl
Cyclopentan-1-on-2-yl
Cyclopentan-1-on-2-yl
Cyclopentan-1-on-2-yl
Cyclopentan-1-on-3-yl
Cyclohexan-1-on-2-yl
Cyclohexan-1-on-2-yl
Cyclohexan-1-on-2-yl
Cyclohexan-1-on-2-yl
Cyclohexan-1-on-2-yl
Cyclohexan-1-on-3-yl
Cycloheptan-1-on-2-yl
C6H5
105.5
62.1
NAb
NA
NA
NA
43.2
33.9
NA
NA
NA
4-CH3C6H4
3-Thienyl
4-OCH3C6H4
4-FC6H4
C6H5
Two classes of compounds with R1-CO(CH)-substitution at posi-
tion 1 were synthesized using this procedure. The first class of
compounds (3a–z) (Table 1) includes 1,2,3-triazoles where R1 is a
hydrophobic residue, such as phenyl, substituted phenyl, coumari-
nyl, 2-thienyl, or other nonaromatic substituents (i.e., CH3, OCH3,
C6H5
4-CH3C6H4
3-Thienyl
4-FC6H4
4-OCH3C6H4
C6H5
4j
4k
4l
N(C2H5)). In class
2 a
compounds (4a–m) (Table 2), R1 is
NA
66.1
cyclopentanone-2-yl, cyclohexanone-2-yl, or cycloheptanone-2-
4m
4-CH3C6H4
a
The concentration of the compound that inhibited enzyme activity by 50%.
Less than 10% enzyme inhibitory activity was observed up to the concentration
b
NaN3
of 75 lM.
O
N
O
N
N
R2
R2
(2)
X
R1
R1
CuSO4.5H2O (5 mol%)
Na Ascorbate (10 mol%)
aq. PEG-H2O (1:1, v/v)
yl. The substitution at position 4 (R2) is phenyl, substituted phenyl,
short alkyl, or a heteroaromatic (i.e., 2-pyridyl, 3-thienyl). The
diversity of hydrophobic substitutions at R1 and R2 positions al-
lowed the structure–activity relationship analysis of 1,4-disubsti-
tuted 1,2,3-triazoles.
3
1
X = Br, OTs
Scheme 1. Synthesis of 1,4-disubstituted 1,2,3-triazoles.

D. Kumar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 449–452
451
An array of 39 diversely substituted 1,2,3-triazoles (20 novel
compounds) was evaluated against Src kinase. The results of Src ki-
nase inhibitory activity of compounds in classes 1 and 2 are shown
in Tables 1 and 2, respectively.
Molecular modeling was utilized to examine how the structures
would fit within the ATP binding site of the enzyme (Fig. 2). The
modeling studies indicated that tolyl groups in 3b and 4h occupy
the hydrophobic binding pocket similar to tolyl group of PP1 with
slightly different orientations (Fig. 2). The substitution at N1 posi-
tion of triazole occupied mostly the hydrophobic cavity of Src ATP
binding site similar to that of t-butyl group of PP1. The compounds
demonstrated only modest inhibitory potency possibly because of
mostly hydrophobic interactions. The 4-amino group of PP1 and
PP2 is hydrogen bonded to the side chain of Thr338 as well as
the carbonyl of Glu339 that contributes significantly to their po-
tency as Src kinase inhibitors.
In summary, compounds 3b, 3g, 3v, 4g, and 4h exhibited modest
Src kinase inhibitory activity among the synthesized 1,2,3-triazoles
with IC50 values in the range of 32–43 lM. Comparison of moder-
ately active compounds indicate that the insertion of C6H5– and
4-CH3C6H4– at R2 position in both groupswith appropriate less bulk-
ier group at R1 position in class 1 is well tolerated for the modest Src
inhibition activity of 1,2,3-triazoles. The structure–activity relation-
ship data provide insights for further optimization of this scaffold
and/or use in fragment-based discovery of Src kinase inhibitors.
In general, the compounds in class 1 with R1 as nonaromatic al-
kyl groups (Me, N-ethyl, OMe, 3w–z) exhibited weak Src kinase
inhibition with IC50 values more than 100
tory activity at highest concentration tested (375
l
M or minimal inhibi-
M). Further-
l
more, compounds with large aromatic groups such as styryl (3e),
3-coumarinyl (e.g., 3t, 3u) or aromatic groups with a bulky substi-
tution (4-ClC6H4, 4-BrC6H4) in 3k–q showed weak Src inhibitory
potency. Attempts to improve the activity by introducing an ali-
phatic substituent at R2 (3r, 3s) also resulted in poor inhibition,
suggesting that the size of aromatic moiety at R1 position is critical,
and a bulky moiety at this position must be avoided. In contrast,
the introduction of less bulkier unsubstituted phenyl and thienyl
groups at position 1 in compounds 3b (IC50 = 41.6
l
M) and 3v
(IC50 = 32.5
activities.
lM) in class 1 significantly improved the Src inhibitory
The presence of an electron-donating methyl group in R1 and R2
phenyl ring in 3g (IC50 = 49.8 lM) did not result in improved inhi-
bition when compared with 3b. The introduction of phenyl (3a),
4-F-3-CH3C6H3 (3c), 2-pyridyl (3d), and n-butyl (3f) as R2 group
drastically decreased the Src inhibitory activity versus 3b. Intro-
duction of electronegative fluorine also did not improve the activ-
ity (3h, 3m, and 3q). These data indicate that the nature of R2
group contributes significantly to the overall activity.
In order to explore the effect of nonaromatic cyclic functional
groups at R1 position in Src inhibitory activity, a series of analogs
4a–m having different cyclic ketones and bearing nonaromatic
groups at R1 position were prepared and evaluated (Table 2).
Compounds 4g and 4h with N1 2-cyclohexanone and C4 phenyl/to-
lyl groups exhibited modest Src kinase inhibition with IC50 values
Acknowledgments
We thank University Grants Commission (SAP, DRS), Birla Insti-
tute of Technology & Science, Pilani, India National Science Foun-
dation, Grant # CHE 0748555, and the American Cancer Society
Grant # RSG-07-290-01-CDD for the financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.10.121.
of 43.2 and 33.9 lM, respectively. Introduction of 4-fluorophenyl,
4-methoxyphenyl and 3-thienyl substituents at C4 position of
1,2,3-triazole also led to the compounds (4c, 4d, 4e, 4i, 4j, and
4k) with poor activity. Other compounds in class 2 showed dimin-
ished activity versus 4g and 4h, confirming the importance of R2
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