Design, synthesis and biological evaluation of acylhydrazone derivatives as PI3K inhibitors

Article abstract of DOI:10.1016/j.cclet.2014.10.016

Since the PI3K signaling pathway is the most commonly activated in human cancers, inhibition of PI3K is a promising approach to cancer therapy. In this study, a series of 2-methyl-5-nitrobenzeneacylhydrazones were designed and synthesized. All the new der

Full text of DOI:10.1016/j.cclet.2014.10.016

G Model
CCLET 3122 1–3
Chinese Chemical Letters xxx (2014) xxx–xxx
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Design, synthesis and biological evaluation of acylhydrazone
derivatives as PI3K inhibitors
a
b
c
b
b,
5
6
Q1 Guo-Rui Gao , Jia-Li Liu , De-Sheng Mei , Jian Ding , Ling-Hua Meng *,
a,c,
Wen-Hu Duan **
a
7
8
9
1
School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
b
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, China
c
0
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Since the PI3K signaling pathway is the most commonly activated in human cancers, inhibition of PI3K is
a promising approach to cancer therapy. In this study, a series of 2-methyl-5-nitrobenzeneacylhy-
Received 11 July 2014
Received in revised form 16 September 2014
Accepted 14 October 2014
Available online xxx
drazones were designed and synthesized. All the new derivatives were tested by p110a enzymatic and
Rh30 cellular assays. Further enzyme selectivity profiling proved that 6e and 7 were potential selective
PI3K inhibitors.
ß 2014 Ling-Hua Meng and Wen-Hu Duan. Published by Elsevier B.V. on behalf of Chinese Chemical
Keywords:
PI3K
Society. All rights reserved.
Inhibitor
Aclhydrazone
1
1
1
2
1. Introduction
have entered into preclinical or clinical stage [13], such as 29
compound 1 (PIK-75) [7] and 2 (PKI-587) [14]. Compound 1 30
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Phosphatidylinositol-3-kinases (PI3Ks) [1] play an important
role in signal transduction as a key regulator of cell cycle
proliferation, growth, survival and protein synthesis [2], and they
catalyze phosphorylation of 3-hydroxyl position of phosphatidy-
linositides (PIs) [3–5]. Based on their primary structure and
mechanism of action [6], PI3Ks are divided into three major classes
(PIK-75) was reported to be a sub-nanomolar p110
more than100-fold selectivity over p110 and p110
showed activity in human cancer xenograft model.
The work we reported here investigated the structure-activity 34
relationship (SAR) of compound 1 (PIK-75) by exploring major 35
changes on the bicyclic core structure and the side chains. We 36
intended to determine whether the position of substituents or the 37
number of the nitrogen atom on the ring was crucial, and to test the 38
influence of the variants in side chain. In this regard, a series of 39
acylhydrazone analogs were synthesized and tested in enzymatic 40
a inhibitor with 31
b
g
, and it also 32
33
[7]: class I, II, and III [8]. Class I is further split into class Ia: p110
p110 , and p110 , which are activated by tyrosine kinase
receptors; and class Ib: p110 , which is activated by G protein-
coupled receptor [9]. The PIK3CA gene that encodes p110 is also
frequently mutated in many cancers. Thus class Ia PI3Ks, and
a,
b
d
g
a
and cellular levels.
41
particularly p110
[10].
a, are potential therapeutic targets for cancers
Wortmannin [11] and LY-294002 [12] have been extensively
studied, but both of them lack selectivity over the class I PI3K
isoforms (Fig. 1). In recent years, many small molecular inhibitors
2. Experimental
42
The synthesis of compounds 6a–m, 7, and 9a–b was shown in 43
Scheme 1. Aldehydes 4a–g were prepared from 3a–g by cyclization 44
with bromomalonaldehyde. Compounds 6a–m and 9a–b were 45
synthesized by condensation of the aldehydes with substituted 46
benzohydrazide followed by alkylation. Compound 7 was obtained 47
from 6e by replacement of oxygen with sulfur using Lawesson’s 48
reagent. The synthesis of compound 12 was shown in Scheme 2. The 49
*
Corresponding author.
** Corresponding author at: School of Pharmacy, East China University of Science
Q2
&
Technology, Shanghai 200237, China.
E-mail addresses: lhmeng@simm.ac.cn (L.-H. Meng), whduan@simm.ac.cn
1
(W.-H. Duan).
structure of the newanalogs was characterized by H NMR and MS. 50
http://dx.doi.org/10.1016/j.cclet.2014.10.016
001-8417/ß 2014 Ling-Hua Meng and Wen-Hu Duan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
1
Please cite this article in press as: G.-R. Gao, et al., Design, synthesis and biological evaluation of acylhydrazone derivatives as PI3K
inhibitors, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.10.016

G Model
CCLET 3122 1–3
2
G.-R. Gao et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Fig. 1. Some reported PI3K inhibitors.
5
5
1
2
In addition, the structure of the analogs (represented by compound
6e) was also confirmed by single crystal X-ray diffraction.
activity with an IC50 of 11 nmol/L (Table 2). The results indicated
that the position of substituents and the number of nitrogen atoms
on the bicyclic core structure were crucial to maintain both
enzymatic and cellular activities for this series of compounds.
Next, various groups at the C6 position of the imidazo
59
60
61
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65
66
67
68
5
3
3. Results and discussion
54
55
56
57
58
We firstly investigated the influence of the position of
substituents and number of nitrogen atoms on the ring in the
compounds on their activity. Compounds 6a and 12 showed
[1,2-a]pyridine moiety were screened (Table 1). Compound 6b,
without any substituent at C6 position, showed poor activity.
Introduction of a methyl group as electron donor led to reduced
potency. The less bulky chloro-substituted derivative (6d) and the
poor activity against p110
a (IC50 > 10 mmol/L) and Rh30
(IC50 > 10 mmol/L) (Table 1). Compound 6e displayed good
2
derivatives with strong electron-withdrawing groups NO and CN
Scheme 1. Synthesis of compounds 6a–m, 7, and 9a–b. Reagents and conditions: (a) bromomalonaldehyde, EtOH, reflux, 12 h; (b) benzohydrazide, HOAc (cat.), MeOH, 60 8C,
3
h; (c) NaH, R-X, THF-DMF, rt, 1 h; (d) Lawesson’s reagent, dioxane, reflux, 12 h.
Scheme 2. Synthesis of compound 12. Reagents and conditions: (a) benzohydrazide, HOAc (cat.), MeOH, 60 8C, 3 h; (b) NaH, MeI, THF, rt, 1 h.
Please cite this article in press as: G.-R. Gao, et al., Design, synthesis and biological evaluation of acylhydrazone derivatives as PI3K
inhibitors, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.10.016

G Model
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G.-R. Gao et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
Table 1
Biological activity of compounds 6a–m, 7, 9a–b and 12.
Compd.
IC50
(
m
mol/L)
Compd.
IC50
(
mmol/L)
p110
a
Rh30
p110
a
Rh30
5.01
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
>10
>10
>10
>10
>10
6j
0.114
0.098
6k
6l
3.02
>10
>10
1.59
9.12
>10
>10
0.014
0.029
0.011
3.26
2.04
6m
7
>10
0.034
>10
0.261
>10
9a
3.742
0.049
8.61
4.11
g
h
i
4.2
9b
12
3.93
5.30
>10
>10
PIK-75
0.015
0.15
Table 2
Kinase-selectivity profiling of compound 7.
a
Compd.
Inhibition rate for tyrosine kinases (%)
Flt-1
KDR
c-Kit
PDGFR-
a
PDGFR-
b
RET
EGFR
ErbB2
EGFR/T790M/
L858R
ErbB4
Src
5.1
Abl
EPH-A2
54.4
RON
22.3
FGFR1
53.1
7
34.9
86.7
37.2
90.4
32.8
87.3
20.3
80.9
41.0
87.4
49.5
87.6
11.7
86.9
50.4
86.1
49.3
83.4
24.2
83.1
36.6
Su11248
BIBW2992
a
The inhibitory activity of compounds against 15 tyrosine kinases were measured with ELISA at a concentration of 10
m
mol/L.
6
7
7
7
7
7
7
7
7
7
7
8
8
8
8
8
8
8
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
(6f and 6g) were less potent than 6e. We envisioned that the
bromine atom played a critical role in compound binding with PI3K
due to the reason that compound with a bromine substitution may
fit well in the active site of PI3K.
National Programs for High Technology Research and Development 100
(No. 2012AA020302) and the Shanghai Science and Technology 101
Commission (Nos. 11431921100 and 12DZ1930802) for their 102
financial support.
103
With an optimized bromo substitution on bicyclic ring, various
R groups were screened. Compounds 6h and 6i with longer carbon
1
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104
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results indicated that the length and the size of the substituents
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8
8
4. Conclusion
89
90
91
92
93
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In summary, a series of acylhydrazone derivatives were
synthesized, and they were identified as potential PI3K inhibitors
with no apparent inhibition on a panel of other kinases. Therefore,
our results indicated that this class of compounds could be served
as lead compound for development of more selective anticancer
medication.
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Q3
We thank the National Natural Science Foundation (Nos.
81273365 and 81321092), National Science & Technology Major
Project ‘‘Key New Drug Creation and Manufacturing Program’’(Nos.
2012ZX09103101-024 and 2014ZX09304002-008-001), Chinese
(2010) 2636–2645.
141
Please cite this article in press as: G.-R. Gao, et al., Design, synthesis and biological evaluation of acylhydrazone derivatives as PI3K
inhibitors, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.10.016