Design, synthesis and pharmacokinetic evaluation of a novel series of triazole-based Src kinase inhibitors with anti-proliferative activity

Article abstract of DOI:10.2174/157018011793663930

Src has been recognized as an important therapeutic target for the treatment of cancer. A novel series of triazole-based Src inhibitors were synthesized and evaluated for their anti-proliferative activities in vitro against human lung cancer A549 cells wi

Full text of DOI:10.2174/157018011793663930

Letters in Drug Design & Discovery, 2011, 8, 9-13
9
Design, Synthesis and Pharmacokinetic Evaluation of a Novel Series of
Triazole-Based Src Kinase Inhibitors with Anti-proliferative Activity
Shaojun Chen1, Chuansheng Guo2, Shiting Shi2, Yanyan Shi2, Du Fang*,1 and Houxing Fan*,2
1Hunan University of Chinese Medicine, Changsha 410208, China
2Shanghai Sun-sail Pharmaceutical Science & Technology Co., Ltd., Shanghai 201203, China
Received April 09, 2010: Revised August 23, 2010: Accepted October 12, 2010
Abstract: Src has been recognized as an important therapeutic target for the treatment of cancer. A novel series of tria-
zole-based Src inhibitors were synthesized and evaluated for their anti-proliferative activities in vitro against human lung
cancer A549 cells with Bosutinib as reference compound, most of the compounds showed more potent activity than Bosu-
tinib. Compounds 6 and 8 were further subjected to pharmacokinetic performance assessment, both the compounds dis-
played low plasma concentrations and short half-time.
Keywords: Anti-proliferative activity, Biological activity, SKI-606, Src Kinase, Synthesis, Triazoly group.
INTRODUCTION
series quinazoline vascular ebdothelial growth factor recep-
tor tyrosine kinase (VEGFRr TK) inhibitors reported by As-
tra-Zeneca [11], the triazolyl group provided superior blood
levels compared to a morpholine group. In order to find new
Src kinase inhibitors with improved anticancer activity, we
combined the structural properties of SKI-606 and triazoly
group into one molecule. In this paper, we report our efforts
towards the synthesis and anti-proliferative activity of a
novel series of analogues of SKI-616 with introduction of
Src, a nonreceptor tyrosine kinase, is involved in the
transduction and regulation of signaling pathways involved
in normal cellular growth, proliferation, angiogenesis, adhe-
sion, motility, and survival [1]. During tumorigenesis, these
normal processes become aberrantly activated, leading to
excessive growth, metastasis, and tissue invasion [2]. So Src
has been recognized as an important therapeutic target in the
cancer, even in other diseases including osteoporosis, stroke,
Cl
Cl
Cl
O
O
O
Cl
NH
O
HN
N
O
HN
O
S
N
O
O
CN
N
N
N
N
N
N
O
N
H
N
N
N
N
Saracatinib
Dasatinib
OH
Bosutinib
Fig. (1). Structures of known Src inhibitors.
and myocardial infarction [3-7]. and various classes of small
molecule Src inhibitors have been synthesized including
Dasatinib (BMS354825; Bristol Meyers Squibb Oncology)
[8], Saracatinib (formerly AZD0530, AstraZeneca) [9], and
Bosutinib (SKI-606; Wyeth Research) [10], which have
reached Phase 1 or 2 clinical trials (Fig. 1).
substituted triazolyl groups. Furthermore, pharmacokinetic
properties of the selected compounds 6 and 8 were also dis-
closed herein.
CHEMISTRY
As shown in Scheme 1, condensation of 2,4-dichloro-5-
methoxyaniline with cyanoacetic acid in the presence of 1,3-
diisopropylcarbodiimide gave the acetamide derivative 1
Bosutinib (SKI-606), a Src kinase inhibitor with a 3-
quinolinecarbonitrile core, is currently in Phase 2 clinical
trials for the treatment of solid tumors. It is well known that
triazoly group is a common substructure seen in some mar-
keted drugs, which are examplified by Anastrozole and Le-
trozole (both used to treat breast cancer). In addition, in a
[12]. Treatment of compound
1
with 3-iodo-4-
methoxyaniline in the presence of triethylorthoformate and
iso-propanol as solvent provided 2, which upon subsequent
phosphorusoxychloride-mediated ring closure reaction in
acetonitrile and methanol resulted in formation of the desired
7-iodo-3-quinolinecarbonitrile 3. Compound 3 readily un-
derwent standard Sonogashira coupling reaction employing
TMS-Acetylene (TMS = trimethylsilyl) led to the formation
*Address correspondence to this author at the Department of Medicinal
Chemistry, Shanghai Sun-sail Pharmaceutical Science & Technology Co.,
Ltd., No. 1690 Cailun Road, Shanghai, 201203, People’s Republic of China;
Tel: +86-(0)21-50278490-8061; Fax: +86-(0)21-50278483;
E-mails: 1125fd@sina.com, hxfan@sun-sail.cn
1570-1808/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

10 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 1
Chen et al.
OMe
Cl
Cl
MeO
I
Cl
Cl
Cl
O
O
a
b
c
NC
N
H
OMe
N
N
H
OMe
NH2
H
CN
Cl
1
2
Cl
Cl
Cl
Cl
Cl
Cl
HN
N
OMe
MeO
CN
HN
OMe
HN
OMe
d
e
MeO
CN
MeO
CN
N
I
N
Si
5
3
4
Cl
Cl
HN
OMe
f
MeO
CN
N
R
N
N
N
6-17
Scheme 1. Reagents and conditions: (a) cyanoacetic acid, 1,3-diisopropylcarbodiimide, THF, reflux, 1 h; (b) triethylorthoformate, i-PrOH,
reflux, 20 h; (c) POCl3, CH3OH-CH3CN, reflux, overnight; (d) Trimethyl silyl acetylene, diisopropylanmine, CuI, Pd(PPh3)2Cl2, THF, reflux,
4 h; (e) TBAF, THF, r.t, 15 min; (f) RN3, CuSO4.5H2O, Sodium Ascorbate, DMF, 60 oC, 3 h.
of TMS-protected alkyne 4 in 90% yield. The desired build-
ing block 5 was obtained in 80% yield by deprotection of 4
with TBAF in THF at room temperature. Finally, compound
Pharmacokinetics
Compounds 6 and 8 were subjected to pharmacokinetic
properties study in healthy male Swiss mice (18-20 g weight,
15 mice in each group). The test compounds were adminis-
tered orally at the dose of 20 mg/kg. Series specimens (300
μL) were collected via retrobulbar vein and quantitation was
performed by LC-MS, pharmacokinetic parameters were
calculated from the mean plasma concentration by non-
compartmental analysis.
5
underwent cycloaddition with azide catalyzed by
CuSO4.5H2O and sodium ascorbate to give the target com-
pounds 6-17 in good yield and regioselectivity [13]. Struc-
1
tures of the desired compounds were confirmed by HNMR
and Ms (ESI) or HRMS (ESI) (Table 1).
BIOLOGY
Anti-Proliferative Activities
RESULTS AND DISCUSSION
The anti-proliferative activities of the target compounds
were examined using human lung cancer A549 cell (GIBCO,
Grand Island, NY, USA)with Bosutinib as reference com-
pound [9, 14]. Cells in 96-well plates were treated in tripli-
cate with equivalent concentration with Bosutinib of com-
The result of in vitro inhibition ratio of compounds 6-17
against human lung cancer A549 cells in 10 μM concentra-
tion is summarized in Table 2. It clearly showed that all
compounds expect compound 7 displayed more potent anti-
proliferative activity than the positive control SKI-606. Es-
pecially, compound 16 showed the best activity with inhibi-
tion ratio of 91.1% compared to that 78.5% of SKI-606. In
order to investigate the eꢀect of the length of the chain on
anti-proliferative activity, compounds 10 and 17 were pre-
pared, both of the compounds exhibited potent activity at the
same level. In generally, piperidine derivatives (compounds
12-16) showed more potent activity than that of azetidine
derivatives (compounds 6-9), but there is not significant dif-
ference between them.
o
pounds at 37 C for 72 h in 5% CO2 atmosphere. The cell
viability was assessed by measuring the conversion of 3-
(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) to a colered product. Briefly, cells were incubated
with MTT (5 mg/mL, 20 μL/well). After 4 h, the colored
product in the cells was dissoloved in DMSO and was meas-
ured at 570 nm using a multiskan spectrum (Thermo Elec-
tron Co., Vantaa, Finland). The inhibition rate on cell prolif-
eration was calculated for each well as (A570 control cells –
A570 treated cells) / A570 control cells ꢀ 100%. The aver-
age IC50 values were determined by Logit method from at
least three independent tests.
The IC50 values of the selected compounds against hu-
man lung cancer A549 cells are also listed in Table 2, most

Design, Synthesis and Pharmacokinetic Evaluation
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 1 11
Table 1. Physical and Spectral Properties of Target Compounds 6-17
Compd
6
Ms (ESI) or HRMS (ESI) m/z
m.p.(˚C)
1H NMR (400 MHz, DMSO-d6): ꢀ (ppm)
Yield(%)a
238-240
21
HRMS (ESI) calcd for
9.87 (s, 1H), 8.67-8.70 (m, 3H), 8.02 (s, 1H), 7.78 (s, 1H), 7.40
(s, 1H), 4.10 (s, 3H), 3.87 (s, 3H), 3.67 (d, J = 6.4 Hz, 4H), 1.00
(s, 9H).
C27H28N7O2Cl2 [M + H+]:
552.1682, found: 552.1675.
7
8
566. 5 [M+H]+
112-11ꢀ
28
21
9.86 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.00 (s,
1H), 7.76 (s, 1H), 7.39 (s, 1H), 5.26-5.30 (m, 1H), 4.08 (s, 3H),
3.86 (s, 3H), 3.74 (s, 2H), 3.45 (s, 2H), 2.19-2.23 (m, 1H), 1.22-
1.37 (m, 4H), 0.81 (t, J = 14.4 Hz, 6H).
238-240
HRMS (ESI) calcd for
9.92 (s, 1H), 8.72 (s, 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.00 (s,
1H), 7.81 (s, 1H), 7.36 (s, 1H), 5.27-5.31 (m, 1H), 4.09 (s, 3H),
3.50 (s, 3H), 3.74 (t, J = 7.6 Hz, 2H), 3.47 (t, J = 6.8 Hz, 2H),
2.86-2.89 (m, 1H), 1.63-1.65 (m, 2H), 1.57-1.60 (m, 4H), 1.43-
1.49 (m, 2H).
C28H28N7O2Cl2 [M + H+]:
564.1682, found: 564.1689.
9
578.6 [M+H]+
223-225
12
9.86 (s, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.02 (s,
1H), 7.78 (s, 1H), 7.40 (s, 1H), 5.29-5.33 (m, 1H), 4.07 (s, 3H),
3.87 (s, 3H), 3.77 ( t , J = 6.6 Hz, 2H), 3.50 ( t , J = 3.3 Hz, 2H),
2.19-2.21 (m, 1H), 1.69 (d, J = 1.2 Hz, 4H), 1.51-1.56 (m, 1H),
1.18-1.25 (m, 3H), 0.99-1.07 (m, 2H).
10
11
538.5 [M+H]+
552.25 [M+H]+
197-199
25
13
9.89 (s, 1H), 8.66-8.69 (m, 2H), 8.47 (s, 1H), 8.02 (s, 1H), 7.76
(s, 1H), 7.41 (s, 1H), 4.59-4.61 (m, 2H), 4.09 (s, 3H), 3.87 (s,
3H), 3.15-3.21 (m, 2H), 2.55-2.58 (m, 4H), 1.36-1.69 (m, 4H).
126-12ꢀ
9.93 (s, 1H), 8.64-8.66 (m, 2H), 8.47 (d, J = 6.0 Hz, 1H), 8.05
(s, 1H), 7.76 (s, 1H), 7.40 (s, 1H), 4.58 (t, J = 6.0 Hz, 2H), 4.09
(s, 3H), 3.86 (s, 3H), 3.20 (dd, J1 = 4.8 Hz, J2 = 7.5 Hz, 2H),
2.83 (t, J = 7.5 Hz, 2H), 2.42-2.48 (m, 6H), 2.22 (s, 3 H).
12
13
14
566.3 [M+H]+
580.5 [M+H]+
565.47 [M+H]+
163-165
156-158
220-222
14
21
39
9.91 (s, 1H), 8.66-8.69 (m, 2H), 8.46 (s, 1H), 8.01 (s, 1H), 7.76
(s, 1H), 7.39 (s, 1H), 4.60-4.63 (m, 1H), 4.09 (s, 3H), 3.89 (s,
3H), 3.00-3.04 (m, 2H), 2.86-2.90 (m, 1H), 2.40-2.45 (m, 2H),
2.11-2.17 (m, 4H), 1.05 (d, J = 6.6 Hz, 6H).
9.88 (s, 1H), 8.67 (s, 1H), 8.64 (s, 1H), 8.45 (s, 1H), 8.00 (s,
1H), 7.73 (d, J = 5.3 Hz, 1H), 7.38 (s, 1H), 4.59-4.62 (m, 1H),
4.09 (s, 3H), 3.86 (s, 3H), 3.29 (t, J = 0.6 Hz, 2H), 2.35-2.42
(m, 2H), 2.18 (s, 4H), 1.12 (s, 9H).
9.83 (s, 1H), 8.68 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 7.98 (s,
1H), 7.76 (s, 1H), 7.39 (s, 1H), 4.60-4.64 (m, 1H), 4.09 (s, 3H),
3.86 (s, 3H), 3.06 (d, J = 8.0 Hz, 2H), 2.35-2.41 (m, 2 H), 2.02-
2.08 (m, 4H), 1.66-1.69 (m, 1H), 0.43-0.47 (m, 2H), 0.31-0.34
(m, 2H).
15
16
17
592.5 [M+H]+
606.6 [M+H]+
552.45 [M+H]+
256-257
186-188
141-143
28
39
42
9.86 (s, 1H), 8.69 (s, 1H), 8.60 (s, 1H), 8.44 (s, 1H), 7.99 (s,
1H), 7.75 (s, 1H), 7.37 (s, 1H), 4.56-4.60 (m, 1H), 4.09 (s, 3H),
3.86 (s, 3H), 3.04-3.12 (m, 2H), 2.50-2.57 (m, 1H), 2.11-2.14
(m, 6H), 1.81-1.87 (m, 2H), 1.60-1.65 (m, 2H), 1.51-1.56 (m,
2H), 1.36-1.41 (m, 2H).
9.94 (s, 1H), 8.67 (s, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 8.06 (s,
1H), 7.78 (s, 1H), 7.41 (s, 1H), 4.88-4.92 (m, 1H), 4.22 (s, 3H),
3.87 (s, 3H), 3.39-3.55 (m, 2H), 3.17-3.29 (m, 3H), 2.46-2.50
(m, 4H), 2.08 (s, 2H), 1.82-1.85 (m, 2H), 1.61-1.64 (m, 1H),
1.42-1.45 (m, 2H), 1.24-1.34 (m, 2H), 1.14 (t, J = 8.0 Hz, 1H).
9.89 (s, 1H), 8.62-8.64 (m, 2H), 8.43 (d, J = 6.6 Hz, 1H), 8.01
(s, 1H), 7.73 (d, J = 4.4 Hz, 1H), 7.34 (d, J = 4.4 Hz, 1H), 4.51
(t, J = 4.4 Hz, 2H), 4.09 (s, 3H), 3.84 (s, 3H), 3.48-3.57 (m,
2H), 2.40-2.45 (m, 4H), 2.02-2.12 (m, 2H), 1.66-1.75 (m, 4H).
athe yields are for last step.
of the compounds displayed more potent activity than SKI-
606 against human lung cancer A549 cells. It clearly showed
that piperidine derivatives was inferior to azetidine deriva-
tives, it is not consistent with the situation indicated by cell
inhibition ratio. Compound 6 exhibited the most potent anti-
proliferative activity with IC50 value of 0.42 μM compared to
that 2.12 μM of SKI-606, in addition, compound 8 also
showed potent activity with IC50 value of 0.48 μM.

12 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 1
Chen et al.
Table 2. In Vitro Anticancer Activity of Synthetic Compounds
Cl
Cl
HN
OMe
MeO
CN
N
R
N
N
N
R
Compounds
6
Inhibition ratio(%) a, b
IC50 (uM) b
N
89.8 ± 2.5
0.42 ± 0.18
7
8
9
N
53.3 ± 27.2
87.1 ± 3.1
86.2 ± 4.3
ND c
0.48 ± 0.22
ND
N
N
10
11
90.8 ± 1.6
87.4 ± 4.5
1.36 ± 0.54
ND
N
N
N
12
13
14
15
16
N
87.5 ± 4.6
88.2 ± 3.8
81.4 ± 6.3
88.3 ± 3.3
91.1 ± 0.5
ND
1.65 ± 0.83
ND
N
N
N
1.81 ± 0.69
2.48 ± 0.57
N
17
89.8 ± 0.7
ND
N
Bosutinib (SKI-606)
78.5 ± 17.7
2.12 ± 0.58
aagainst human lung cancer A549 cell, in concentration of 10 μM, bvalues are means of three experiments, cnot determined.
Compounds 6 and 8, two of the most potent compounds,
were further subjected to pharmacokinetic properties study.
As shown in Table 3, both of the compounds exhibited low
plasma concentrations and AUC. Compounds 6 and 8 exhib-
ited the maximum plasma concentrations of 133 and 150
ng/mL, and the AUC0-t is 548 ng.h/mL and 450 ng.h/mL
respectively. In a word, the pharmacokinetics result was not
good enough to support the further study. We can decide

Design, Synthesis and Pharmacokinetic Evaluation
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 1 13
Table 3. Pharmacokinetics Properties of Compounds 6 and 8 in Mice
Compounds
Dose (mg/kg)
Tmax (h)
Cmax (ng/mL)
AUC0-ꢁ(ng.h/mL)
MRT (h)
t1/2 (h)
6
8
20
20
1.00
0.50
133
150
548
450
3.95
4.46
2.06
3.62
blockade stabilizes a Flk/cadgerin complex, reducing edema and
tissue injury following myocardial infarction. J. Clin. Invest., 2004,
113, 885-894.
whether the compounds go to the next step based the phar-
macokinetics paramaters. In an orally dose of 20 mg/kg in
mice, if the compound displayed Cmax > 500 ng/mL, AUC0-t
> 3000 ng.h/mL and t1/2 > 2.0 h, we will do a further re-
search. The poor pharmacokinetic performance may be due
to their poor cell permeability that results from the relatively
large molecular size.
[8]
Lombardo, L. J.; Lee, F. Y.; Chen, P.; Norris, D.; Barrish, J. C.;
Behnia, K.; Castaneda, S.; Cornelius, L. A.; Das, J.; Doweyko, A.
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CONCLUSION
In summary, a series of novel Triazole-based Src kinase
inhibitors were synthesized and evaluated for their anti-
proliferative activities against human lung cancer A549 cells.
Most of the compounds showed potent in vitro anticancer
activities, among them compounds 6 and 8 were further sub-
jected to pharmacokinetic performance study, unfortunately,
the result was not desirable. Further optimization of this new
series analogues to improve their PK profiles is ongoing in
our laboratory.
[9]
Hennequin, L.F.; Allen, J.; Breed, J.; Curwen, J.; Fennell, M.;
Green, T.P.; Lambert-van der Brempt, C.; Morgentin, R.; Norman,
R.A.; Olivier, A.; Otterbein, L.; Plꢀo, P.A.; Warin, N.; Costello, G.
N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-
yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine,
a
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Grod, J.; Lucas, J.; Weber, J. M.; Boschelli, F. Optimization of 4-
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