Syntheses and biological evaluation of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib

Article abstract of DOI:10.1016/j.bmcl.2016.01.068

Three novel series of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib were prepared and evaluated in vitro for their cytostatic effects against a human chronic myeloid leukemia (K562), acute myeloid leukemia (HL60), and human leukemia stem-like cell line (KG1a). The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analog. Benzene and piperazine rings were necessary groups in these compounds for maintaining inhibitory activities against the K562 and HL60 cell lines. Introducing a trifluoromethyl group significantly enhanced the potency of the compounds against these two cell lines. Surprisingly, some compounds showed significant inhibitory activities against KG1a cells without inhibiting common leukemia cell lines (K562 and HL60). These findings suggest that these compounds are able to inhibit leukemia stem-like cells.

Full text of DOI:10.1016/j.bmcl.2016.01.068

Accepted Manuscript
Syntheses and Biological Evaluation of 1,2,3-triazole and 1,3,4-oxadiazole De-
rivatives of Imatinib
Yong-Tao Li, Jing-Han Wang, Cheng-Wen Pan, Fan-Fei Meng, Xiao-Qian Chu,
Ya-hui Ding, Wen-Zheng Qu, Hui-ying Li, Cheng Yang, Quan Zhang, Cui-Gai
Bai, Yue Chen
PII:
S0960-894X(16)30068-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.01.068
BMCL 23533
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 June 2015
21 January 2016
23 January 2016
Please cite this article as: Li, Y-T., Wang, J-H., Pan, C-W., Meng, F-F., Chu, X-Q., Ding, Y-h., Qu, W-Z., Li, H-
y., Yang, C., Zhang, Q., Bai, C-G., Chen, Y., Syntheses and Biological Evaluation of 1,2,3-triazole and 1,3,4-
oxadiazole Derivatives of Imatinib, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/
10.1016/j.bmcl.2016.01.068
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Syntheses and Biological Evaluation of 1,2,3-triazole and
1,3,4-oxadiazole Derivatives of Imatinib
Yong-Tao Lia,b,+, Jing-Han Wanga,b,+, Cheng-Wen Pana,b, Fan-Fei Menga,b, Xiao-Qian Chub, Ya-hui
Dinga, Wen-Zheng Qua,b, Hui-ying Lib, Cheng Yanga,b, Quan Zhanga , Cui-Gai Baib,*, Yue Chena,*
aThe State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin), and Tianjin Key Laboratory
of Molecular Drug Research, Nankai University, Tianjin 300071, P. R. of China
bHigh-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of
BioMedicine, Tianjin 300457, P. R. of China
+These authors contributed equally to this work.
*Corresponding Author: Tel.: + 86 22 23508090; Fax: + 86 22 23508090; E-mail:
baicuigai@tjab.org (CG.B); yuechen@nankai.edu.cn (Y.C.)

Abstract: Three novel series of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of
imatinib were prepared and evaluated in vitro for their cytostatic effects against a
human chronic myeloid leukemia (K562), acute myeloid leukemia (HL60), and
human leukemia stem-like cell line (KG1a). The structure-activity relationship was
analyzed by determining the inhibitory rate of each imatinib analog. Benzene and
piperazine rings were necessary groups in these compounds for maintaining inhibitory
activities against the K562 and HL60 cell lines. Introducing a trifluoromethyl group
significantly enhanced the potency of the compounds against these two cell lines.
Surprisingly, some compounds showed significant inhibitory activities against KG1a
cells without inhibiting common leukemia cell lines (K562 and HL60). These findings
suggest that these compounds are able to inhibit leukemia stem-like cells.
Keywords: Chronic myelogenous leukemia; K562; KG-1a; Imatinib; Synthesis

Chronic myelogenous leukemia (CML) is a hematological disorder that is
associated with a characteristic translocation between chromosomes 9 and 22. This
translocation forms a gene encoding the Bcr-Abl fusion protein with constitutively
activate kinase activity, which is necessary for cell transformation1-3. Bcr-Abl kinase
plays an important role in cell signal transformation and activates several downstream
survival pathways, including NF-κB and STAT5/Bcl-xL, eventually leading to
uncontrolled cell proliferation and reduced apoptosis. Because Bcr-Abl kinase is not
expressed in normal cells, it is an ideal target to treat CML4-6.
Imatinib (Gleevec, STI571), an effective Bcr-Abl tyrosine-kinase (TK) inhibitor, is
now the first-line treatment for most cases of CML. The inhibitor competitively binds
the ATP-binding site of Bcr-Abl. This binding prevents a conformational switch to the
active form and reduces the activity of Bcr-Abl7,8. Imatinib is a successful model for
targeting a dominant oncogene with a small molecule9. Despite achieving great
success in the treatment of chronic CML, imatinib has been associated with acquired
resistance that ultimately leads to relapse. Postulated reasons for this resistance
include overexpression of the Bcr-Abl protein, point mutations in the Abl kinase
domain, amplification of the BCR-ABL gene, overexpression of P-glycoprotein, and
yet-unknown resistance mechanisms10-12
.
Cancer stem cells remain in a quiescent state and, as a result, are resistant to
conventional cancer therapies. These cells can provide a sanctuary for the
development of mutations in BCR-ABL, resulting in drug resistance13. One important
cause of resistance in CML is thought to be the existence of quiescent leukemia stem

cells (LSCs) that are highly tumorigenic and resistant to conventional chemo and
radiation therapies. Thus, new therapeutics targeting LSCs are urgently needed14.
Human promyeloblastic leukemia KG1a cells are characterized by the CD34+
biomarker. As they exhibit many characteristics similar to LSCs15, KG1a cells maybe
a suitable cellular model for LSC research. Some synthesized imatinib analogs16-18
have demonstrated improved bioactivity against certain cell lines, such as K562 and
KU812, but it is unknown whether they have activity against KG1a cells.
Bioisosterism is a widely accepted concept in medicinal chemistry and has been
used to elicit changes in a lead structure to obtain various goals, such as enhancement
of the chemical stability or pharmacokinetic properties while maintaining or even
improving biological activity19-21. The 4-(pyridin-3-yl)-N-(o-tolyl)pyrimidin-2-amine
scaffolds in imatinib play a crucial role in blocking the ATP-binding site22.
Bioisosteres of the amide bond include a 1,2,3-triazole ring and 1,3,4-oxadiazole.
Similarities between the two moieties can be seen in the dipolar character, size, and
H-bond acceptor capacity23. 1,2,3-Triazole also acts as a linker and can be easily
constructed under mild conditions at any stage of target molecule preparation24.
1,3,4-Oxadiazole is a five-member ring that is seen in the structure of drugs, such as
zibotentan25 and raltegravir26. Regioisomeric forms of this ring are frequently
occurring motifs in drug-like molecules and often are used as bioisosteres for ester
and amide functionalities, offering increased aqueous solubility27, decreased hERG
inhibition, and improved metabolic stability.
Many natural products have the ability to inhibit cancer stem cells28. For example,

recent investigations revealed that the combination of imatinib with sulforaphane29 or
curcumin30,31 could enhance the inhibitory activity of imatinib against leukemia cells.
Analysis of the structure-activity relationship of these combined molecules suggested
that isothiocyanate and the conjugate structure of curcumin are the groups of
sulforaphane and curcumin, respectively, needed to maintain the inhibitory activity.
Irreversible TK inhibitors can enhance potent and selective inhibition, and may
overcome tumor resistance32. These inhibitors target specific cysteine residues but
only a few kinases specific location with cysteine33,34
In this study, we replaced the
4-(pyridin-3-yl)-N-(o-tolyl)pyrimidin-2-amine scaffold in imatinib with
.
amide
bond
of
the
a
1,2,3-triazole ring or 1,3,4-oxadiazole ring to form imatinib analogs. We added
isothiocyanate, curcumin or acrylamide to the “tail” of the analogs, with the goal of
enhancing the inhibitory activity of the drugs against leukemia cells. We report the
synthesis and biological evaluation of the resulting compounds.
Scheme 1 outlines the routes used to synthesize compounds 8a–8j. Briefly,
compound 3 was synthesized from benzoic acid derivative 2 by acylation with starting
material 1.Benzaldehyde derivative 4 was synthesized by a reduction reaction from
intermediate 3 with LiAlH4 in anhydrous THF. Alkyne intermediate 5 was obtained by
Seyferth-Gilbert homologation35. Reaction of compound 5 with various azides7a–7j,
prepared by diazotization and coupling reactions with amines 6a–6j in the presence of
Cu2O nanoparticles, afforded the corresponding products 8a–8j36.

Scheme 1. Reagents and conditions: (a)NMM, EDCI, HOBT, rt, 6h, 60%; (b) LiAlH4,THF, 0 °C,
3h, 80%; (c) dimethyl(1-diazo-2-oxopropyl)phosphonate, K2CO3, MeOH, rt, 6h, 80%; (d) NaNO2,
HCl, NaN3, H2O, 3h, 0 °C; (e) Cu2O nanoparticles, CH3CN, rt.
Synthetic routes for compounds 15a–15h are outlined in Scheme 2. The method
was similar to that of Scheme 1. Weinreb amides 10a–10h were obtained from
carboxylic acid derivatives 9a–9h by acylation with N,O-dimethylhydroxyamide
hydrochloride. Aldehyde derivatives 11a–11h were synthesized by the reduction of
intermediates 10a–10h with LiAlH4 in anhydrous THF. Alkyne intermediates
11a–11h were obtained by Seyferth-Gilbert homologation. The azide derivative was
obtained by diazotization and coupling reactions with amine 13 in water. Reaction of
12a–12h with azide 14 in the presence of Cu2O nanoparticles afforded the
corresponding products 15a–15h.

Scheme 2. Reagents and conditions: (a) 4-methylmorpholine, HOBt, EDCI, CH2Cl2, rt, 6h, 72%;
(b) LiAlH4, THF, 0 °C, 3h, 78%; (c) dimethyl(1-diazo-2-oxopropyl)-phosphonate, K2CO3,
MeOH, r.t, 5.5h, 82%; (d) NaNO2, HCl, NaN3, H2O, 3h, 0 °C. (e) Cu2O-NPs, EtOH-H2O, r.t.
Scheme 3 outlines the synthetic routes of compounds 21a–21g and 22a-22d
Compound 17 was obtained by coupling with compound 16 and was treated with
hydrazine hydrate to provide compound 18, which underwent a condensation reaction
with 19a–19g to supply the hydrazide derivatives 20a–20g. Compounds 21a–21g
were synthesized under cyclization conditions of Ph3PO/Tf2O or TsCl/K2CO3.
Compounds21h and 21i were reacted with TBAF to provide compounds 22a and 22b.
Compound 21j was treated with TFA to obtain amino compound 22c. Compound 22a
was treated with DEAD, PPh3 and phthalimide. Hydrazine hydrate was added to
afford compound 22d.

Scheme 3. Synthesis of 1,3,4-oxadiazole analogue of imatinib (a) MeOH, H2SO4. (b) N2H4`H2O,
ethanol. (c) EDCI, HOBt, NMM. (d) triphenylphosphine oxide, Tf2O. (e) TsCl, K2CO3, RT. (f)
TBAF, THF. (g) TFA, CH2Cl2. (h) DEAD, PPh3, phthalimide. (i) N2H4`H2O
For synthesis of the curcumin derivative of the 1,3,4-oxadiazole analog of imatinib,
the Mitsunobu reaction was utilized to link curcumin with compound 23a.(in Scheme

4)
Scheme 4. Synthesis of curcumin derivation of 1,3,4-oxoadiazole analogue of imatinib
(a)DEAD, PPh3, curcumin
To introduce the isothiocyanate group into the 1,3,4-oxadiazole analog of imatinib,
amino groups of compounds 22c and 22d were treated with CS2 and DCC, and were
transferred to the isothiocyanate group to provide compounds 23b and 23c,
respectively. Coupling of 22c and acrylic acid with EDCI afforded compound 24.( in
Scheme 5 and Scheme 6)
Scheme 5. The introduction of isothiocyanate group on 1,3,4-oxadiazole analogue of imatinib.
(a) CS2, DCC.

Scheme 6. The introduction of irreversible group analogue of imatinib. (a) acrylicacid, EDCI,
HOBt, NMM, CH2Cl2, r.t., 12h.
We assessed the cellular activities of the compounds against the cancer cell line
K562 by the MTT-based assay, using imatinib as a positive control37, and the
inhibitory abilities of three series of imatinib analogs against three different leukemia
cell lines (Table 1 , Figure 1 and Figure 2).
Inhibitory abilities of imatinib analogs against the K562 and HL60 cell lines were
reduced when the amide group was replaced with the 1,2,3-triazole or
1,3,4-oxadiazole moiety, as in compounds 8a, 15a, and 21a (IC50 = 4.69, 0.75, and 4.9
μM for K562 cells, respectively; IC50 = 6.74 μM, >30 μM, and 0.57 μM for HL60
cells, respectively). The 1,2,3-triazole compound 15a demonstrated higher potency
than the 1,3,4-oxadiazole compound 21a. Passarella and colleagues previously
reported that compound 15a had an IC50 against K562 cancer cells of 0.89 μΜ38.
Inhibitory abilities against K562 and HL60 cells were enhanced when a
trifluoromethyl group was introduced into the benzene ring, as in compounds 8b, 15b,
and 21b (IC50 = 0.03, 0.04, and 0.51 μΜ for K562 cells, respectively; IC50 = 0.02,
0.02, and 0.05 μΜ for HL60 cells, respectively). One possible reason for this finding
might be the favorable lipid solubility of the trifluoromethyl group, which could lead

to increased permeability of the cancer cell membrane.
Removing or substituting the piperazinering with another heterocyclic ring
(compounds 8c–8j, 15c–15e, 21c–21e,21g) resulted in lower inhibitory activities
against K562 and HL60 cells. This finding suggests that the piperazine ring is very
important to the receptor binding of the analogs. Furthermore, inhibitor potency
against K562 and HL60 cells was significantly reduced when the benzene ring was
replaced with aliphatic groups (compounds15f–15h, 21f). This finding indicates that
the benzene ring is a necessary moiety to maintain the high activity of these analogs.
Introducing hydroxyl ethyl into the terminal of piperazine, as was the case for
compounds 22a and 22b, did not cause significant changes of activity. However,
when the trifluoromethyl group exists, the introduction of hydroxyl ethyl could make
inhibitory activity decease significantly, such as compound 21b and compound 22b.
Introducing the hydroxyl group with an amino group in the terminal of piperazine
(compound 22c) had a minimal effect on the activity.
Next, we evaluated the antiproliferative ability of these compounds against
LSC-like KG1a cells. Replacing amide with the 1,2,3-triazole or 1,3,4-oxadiazole
moiety (compounds 8a–8i, 15b–15c, 15f–15g, 21a–21b, 22a–22c) enhanced the
inhibitory activity against KG1a cells. Compounds with a benzene ring or saturated
nitrogen heterocyclic ring moiety (compounds 8a–8h, 15b, 21a–21b, 22a–22c)
demonstrated higher potency than other compounds, with the potencies of compounds
8g, 21b, and 22c being over 30 times greater than the potency of imatinib (IC50 = 0.44,
0.58, and 0.48 μΜ vs. 16.7 μΜ for KG1a). Compounds 21b and 22c, which both have

a trifluoromethyl phenyl and piperazine group, show high inhibitory activities against
all tested cancer cell lines (K562, HL60, and KG1a).
Table 1. Structure and inhibitory activity of 8, 15 and 21 against K562, HL60 and KG-1a cells in
vitro
IC50(μΜ) a
Compound
Imatinib
8a
R
K562
0.38
HL60
0.03
KG-1a
16.7
4.70
0.03
6.74
0.02
6.16
1.04
8b
3.29
3.89
0.74
1.57
1.75
5.42
8c
8d
22.6
23.4
5.86
6.96
>30
1.49
1.32
5.28
0.44
8e
8f
8g
9.99
17.5
2.43
8h

>30
>30
13.6
>30
2.93
8i
8j
N.A.
0.79
0.04
2.65
N.A.
0.02
1.6
N.A.
1.27
9.93
15a
15b
15c
>30
11.2
15.3
10.7
11.2
>30
21.2
25.5
9.1
>30
30
15d
15e
15f
12.7
6.54
N.A.
15g
15h
N.A.
21a
21b
21c
4.90
0.51
>30
0.57
0.05
>30
1.78
0.58
>30
>30
>30
>30
29.7
>30
>30
>15
>30
>30
>30
18.0
>30
21d
21e
21f
21g

4.85
1.81
0.3
0.81
0.39
0.02
4.53
0.98
0.48
22a
22b
22c
avalues are averages of three independent experiments
Figure 1. Inhibitory activity of Imatinib and different analogues toward leukemia cell lines (K562,
HL60 and KG1a). A collection of three leukemia cell lines were incubated for 72 h with the
indicated compounds, and rate of survival was measured by MTT viability assay.

Figure 2. Schematic illustrated structure activity relationship of analogue of imatinib.
We assessed the inhibitory activities of compounds containing a sulforaphane,
curcumin, or acrylic amide moiety (Tables 2). The curcumin derivative of imatinib
(compound 23a) was basically inactive against leukemia cell lines (IC50 > 30 μΜ).
However, the introduction of an isothiocyanate or acryl amide group (compound 23b
or 23c) had no significant effect on the activity (e.g., compare the IC50 values of
compound 22c vs.23b).
Table 2.Inhibition of compound 22, 23a,23b and 24 with K562, KG-1a and HL60 cell
lines
IC50(μΜ)
Compound
K562
>30
0.5
HL60
>30
KG-1a
>30
23a
23b
23c
24
0.07
0.29
2.66
0.94
0.92
0.6
0.37
N.A.

The inhibitory activities of compounds 8a, 8b, 15a, 15b, 21a and 21b against
Bcr-Abl kinase in the K562 cell line were analyzed (Fig. 3). The result showed that
the positive control (imatinib) decreased the Abl protein level by 82.8%. Compounds
15a and 15b significantly decreased the Abl protein level by 77.5% and 80.0%,
respectively. Compounds 21a and 21b slightly decreased the Abl protein level by
30.2% and 34.1%, respectively. However, compounds 8a and 8b had no inhibitory
activity against Abl kinase. Therefore, compound 8a and 8b probably has other targets
in the growth inhibition of the K562 cancer cell line. These results indicated that the
Bcr-Abl inhibitory ability could be influenced by nitrogen atom position.
Figure 3. Effects of Imatinib, compounds 8a, 8b, 15a, 15b, 21a and 21b on ABL expression. Cell
lysates from K562 treated or untreated with the compounds at their IC50 after 3 days were
subjected to Western blot analysis with antibody against ABL. β-actin was used as loading
control.
Besides, the toxicity of compounds 8a, 8b, 15a, 15b, 21a and 21b were assayed
through detecting the inhibitory effect on 293T cell line (Table. 3). Compounds 8a, 8b,
15b, 21a and 21b demonstrated higher potency than Iimatinib against 293T cell, (CC50

=4.15, 2.66, 8.18, 7.63, 2.17μΜ vs 20.53μΜ). Compound 15a exhibited comparable
activity to imatinib against 293T cell, (CC50 = 14.84 μΜ vs 20.53 μΜ).
Table 3. Effect of compounds 8a, 8b, 15a, 15b, 21a and 21b on 293T cell
compound
Imatinib
8a
CC50(μM)a
20.53
4.15
8b
2.66
15a
14.87
8.18
15b
21a
7.63
21b
2.17
We have efficiently prepared 32 imatinib derivatives with replacement of the
amide bond, including two series of 1,2,3-triazole analogs (8a–8j, 15a–15h) and one
series of 1,3,4-oxadiazole analogs. Compounds were evaluated in vitro for their
growth inhibitory activity against K562, HL60, and KG1a cells. According to the
analysis of structure-activity relationship, inhibitory activities against K562 and HL60
cells were enhanced when a trifluoromethyl group was introduced into the benzene
ring (compound 8b vs 8a). These compounds had piperazine ring show a higher
inhibitory activities against K562 and HL60 cells and better solubility than the
compounds with other heterocyclic rings. Furthermore, the potency of compounds
against K562 and HL60 cells was significantly reduced when the benzene ring was
replaced with aliphatic groups (15f–15h vs.15b). According to the comparisons of
inhibitory activities against Abl kinase and the K562 cancer cell line between imatinib
and compound 8b, compound 8b might have other targets. Comparing to imatinib,

many compounds (e.g., 8b–8i, 15b, 21a–b, 22a–c) demonstrated superior inhibitory
activities against the stem-like KG1a cells. Interestingly, KG1a cells were more
sensitive to compound 8g than the common leukemia cell line K562 (IC50 = 0.44 and
5.86 μΜ against KG1a and K562 respectively). The mechanism of inhibition of
stem-like cells is worthy of further investigation.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (NSFC) (No.
21072106 to Y.C.), Program for New Century Excellent Talents in University to Y.C., Hundred
Young Academic Leaders Program of Nankai University to Y.C.,and National Biomedical Special
Project of International Innovation Park (14ZCZDSY00050).
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