Design, synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor

Article abstract of DOI:10.1016/j.bmcl.2019.126666

A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC₅₀ value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC₅₀ values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.

Full text of DOI:10.1016/j.bmcl.2019.126666

Journal Pre-proofs
Design, Synthesis, and Biological Evaluation of 4-Phenoxyquinoline Deriva-
tives as Potent c-Met Kinase Inhibitor
Yifeng Yang, Yingxiu Li, Yunlei Hou, Mingze Qin, Ping Gong, Ju Liu, Yanfang
Zhao
PII:
S0960-894X(19)30616-X
https://doi.org/10.1016/j.bmcl.2019.126666
BMCL 126666
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
7 August 2019
27 August 2019
2 September 2019
Please cite this article as: Yang, Y., Li, Y., Hou, Y., Qin, M., Gong, P., Liu, J., Zhao, Y., Design, Synthesis, and
Biological Evaluation of 4-Phenoxyquinoline Derivatives as Potent c-Met Kinase Inhibitor, Bioorganic & Medicinal
Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.126666
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Design, Synthesis, and Biological Evaluation of 4-Phenoxyquinoline Derivatives as Potent
c-Met Kinase Inhibitor
Yifeng Yang a, Yingxiu Li a, Yunlei Hou a, Mingze Qin a, Ping Gong a, Ju Liu b,*, Yanfang Zhao a,*
a Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103
Wenhua Road, Shenhe District, Shenyang 110016, P.R. China
bCollege of Pharmacy of Liaoning University, Key Laboratory of New Drug Research and Development of Liaoning Province, 66
Chongshan Road, Huanggu District, Shenyang 110036, P.R. China.
Abstract
A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were
synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460,
HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities
than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity
against c-Met kinase. The most promising compound 1s (with c-Met IC50 value of 1.42 nM) showed remarkable
cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC50 values of 0.39 μM, 0.18 μM,
0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the
replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.
The c-Met (Mesenchymal-epithelial transition factor) tyrosine kinase is a key member of receptor tyrosine
kinases (RTKs) family 1-3, which can affect the occurrence, development, invasion and metastasis of tumor cells.
4
The c-Met is a high-affinity receptor for hepatocyte growth factor (HGF) . Whereas, abnormal activation of
HGF/c-Met signaling pathway is associated with cell processes such as tumor formation, migration and apoptosis.
Furthermore, tumor angiogenesis, tumor invasion and metastasis and drug resistance are also closely related to this
signaling pathway. Therefore, the HGF/c-Met signaling pathway has been emerging as an attractive target for
cancer therapies 5.
At present, most of the small molecule c-Met kinase inhibitors have been found to be competitive inhibitors of
ATP, which inhibited c-Met kinase by blocking the phosphorylation of tyrosine. Small molecule c-Met kinase
inhibitors were mainly divided into Type I and Type II, according to the way of combination. Recent research6
shows that Type II inhibitors 7,8, which have a wide variety of structural types and can be modified with more sites,
target multiple links of the c-Met signaling pathway. Over the last decade, a large number of c-Met inhibitors
containing 6,7-disubstituted-4-phenoxyquinolines have been reported as class II c-Met inhibitors, such as Kirin
Brewery 9, Cabozantinib 10, Foretinib 11, AMG458 12, and AM7 13 (Figure 1)
* Corresponding authors.
E-mail addresses: liuju1216@126.com (Ju Liu), yanfangzhao@syphu.edu.cn (Y. Zhao).

H
H
N
N
F
A moiety
H
H
N
N
A moiety
O
O
O
F
O
O
C moiety
B moiety
O
N
F
O
O
C moiety
B moiety
O
O
N
N
O
2 Carbozatinib
3 Foretinib
Replacement
Replacement
H
H
N
N
F
A moiety
S
O
O
4
5
C moiety
B moiety
O
O
6
7
3
2
N
8
1
Cyclization
Cyclization
1
Kirin Brewery
HO
N
N
F
A moiety
F
N
N
H
O
N
B moiety
O
A moiety
C moiety
O
O
O
N
O
N
C moiety B moiety
N
O
N
O
O
5 AM7
4 AMG458
Fig. 1 Classical TypeⅡ c-Met inhibitors
These structures of 4-phenoxyquinolines as c-Met kinase inhibitors mainly consist of three parts: A
(4-phenoxyquinoline core moiety), B (aryl hydrophobic moiety), and C (linker moiety). The modification of
4-phenoxyquinoline reported in the literature mainly included the following aspects: (1) Introduction of a
hydrophilic group at the 7 position in moiety A; (2) Replacement the phenyl ring with various substituents (moiety
B); (3) Transformation of moiety C.
In our previous work, the C fragment was modified to obtain three series of compounds, containing
15-17
1,2,4-triazolone fragment, imidazole fragment and quinoxalinone fragment respectively
(Figure 2).
Particularly, compounds bearing quinoxalinone fragment had been confirmed to exhibit comparable or superior
anticancer activity to foretinib. Our latest study had focused on the effects of B ring substituents, which can affect
the electrical properties of part B. In the above research, it was very fortunate for us to obtain the most potent
compound 9, which showed 3-fold more potent activity against A549 and HT29 cell lines than foretinib.
Meanwhile, its activity against H460, MKN-45 and U87MG cell lines is comparable to foretinib. However,
according to the molecular simulation docking experiments of compound 9, using the co-crystal protein of
foretinib and c-Met (PDB ID code: 3LQ8) as a docking model (Figure 3), we found that B ring does not fit into the
binding site completely due to the rigidity of the B ring. Therefore, we hoped to change the flexibility of the B
ring by adding a flexible carbon chain between the B ring and the C ring for better occupying the cavity. On this
basis, we further explored the influence of carbon chain between the B and C parts, so compounds 1a-1p had been
synthesized in order to prove our point of view. On the other hand, we are also interested to investigate the effect
of the aromatic ring π electron of B on antitumor activity by replacing the aromatic ring with the non-planar
aliphatic ring (compounds 1q-1x).

O
N
R3
N
N
N
H
H
H
N
F
N
F
N
N
F
N
N
R2
R2
R2
O
O
O
O
O
O
O
O
O
O
O
O
O
R1
N
R1
N
R1
N
8( 3-oxo-3,4-dihydroquinoxaline)
7( imidazolone)
6(1,2,4-triazolone)
Fig. 2 Our team previous work
N
N
O
N
N
H
N
N
N
F
N
O
O
F
O
Replacement
R
O
O
R
N
N
N
change the flexibility of B moiety (1a-1p)
compound 9
replace the aromatic ring with the aliphatic ring(1q-1x)
N
H
N
F
N
R2
O
O
O
O
O
R1
N
target compounds
Fig. 3 Design strategy and general structure of the target compounds.
A
B
Fig. 4 (A) Binding poses of compound 9 with c-Met ; (B) 2D interactions of the docking model of 9 to c-Met
The key intermediates 6,7-disubstituted-4-phenoxyquinolines L1-L4 were synthesized by a convenient
eight-step route starting from 1-(4-hydroxy-3-methoxyphenyl)ethanone, which was described in detail in our
previous study18 (Scheme 1). Commercially available 1-(4-hydroxy-3-methoxyphenyl)ethanone reacted with

1-chloro-3-bromopropane under basic condition to obtain intermediate M1, which was then nitrified by fuming
nitric acid at -20℃ for 6 h to give intermediate M2. Then, condensation of M2 with dimethyl formamide dimethyl
acetal (DMF-DMA) in refluxing toluene provided a yellow solid M3, which was reduced and cyclized by glacial
acetic acid and iron powder to afford hydroxyquinoline M4 with a high yield and purity. The condensation reaction
of M4 with excessive secondary amines (piperidine, 4-methyl piperidine, N-methylpiperazine and morpholine) in
acetonitrile at reflux provided intermediates M5, which were converted to 4-chloroquinoline M6 by refluxing in
the mixed solvent of phosphorus oxychloride and acetonitrile in sequence. Next, the etherification reaction of M6
with 2-fluoro-4-nitrophenol afforded purified M7, which were reduced using iron powder and catalytic amounts of
ammonium chloride in ethanol to obtain amides L1-L4.
O
O
O
O
O
O
O
O
O
O
O
i
ii
N
iii
HO
Cl
Cl
NO2
Cl
NO2
M3
Cl
M2
OH
M1
OH
O
O
O
O
O
O
vi
iv
v
vii
R1
N
Cl
N
R1
N
M5
M6
M4
F
NH2
F
NO2
viii
R1=
L1:
N
O
O
L2: R1=
L3: R1=
N
N
O
O
O
R1
O
N
R1
N
N
O
M7
L1-L4
R1=
L4:
N
Scheme 1. Synthesis of intermediate L1-L4. Reagents and conditions: (i) Br(CH2)3Cl, acetone, 0 C, 30min, r.t., 12 h; (ii) 98%
HNO3, CH2Cl2, -20 C, 4 h; (iii) DMF-DMA, toluene, 110 C, 10 h; (iv) Fe powder, AcOH, rt, 30 min, 80 C, 2 h; (v) secondary
amines, CH3CN, 85 C, 10 h; (vi) POCl3, 85 C, 6 h; (vii) 2-fluoro-4-nitrophenol, PhCl, 140 C, 30 h; (viii) Fe powder, NH4Cl (sat.),
EtOH/H2O, reflux, 5 h.
The synthetic route of the target compounds is shown in Scheme 2. The condensation of commercially
available 1-fluoro-2-nitrobenzene with different substituted amines in the presence of sodium hydride in
N,N-dimethylformamide afforded intermediates B1. Reduction of the nitro group of B1 with iron powder provided
compounds
B2.
The
cyclization
of
B2
with
diethyl
ketomalonate
afforded
3-oxo-3,4-dihydro-quinoxaline-2-carboxylic acid esters B3, which were converted to acids B4 using lithium
hydroxide monohydrate in THF/H2O at room temperature for 2 h. B4 were refluxed in toluene and SOCl2 for 5 h to
afford acyl chlorides, which were condensed with intermediates L1-L4 in the presence of sodium carbonate in
DCM at room temperature overnight to afford the target compounds 1a-1x.

O
O
O
O
N
N
NO2
NH2
b
c
a
OEt
d
OH
R2
NH2
N
R2
N
R2
NH
R2
NH
R2
B1
B2
B3
B4
N
H
N
F
N
R2
O
O
O
O
O
N
Cl
L1-L4
f
e
O
N
R2
R1
O
N
1a-1x
B
1q~1t: R2=
1a~1d: R2=
1i~1l: R2=
OCH3
F
1g:
R2=
1m~1p: R2=
1u~1x: R2=
Scheme 2. The synthetic route of target compounds 1a-1x. Reagents and conditions: (a) amines, NaH, DMF, r.t., 16 h; (b) Fe powder,
AcOH, CH3COOEt/H2O, reflux, 6 h; (c) diethyl ketomalonate, toluene, reflux, 12 h; (d) LiOH, THF/ H2O, r.t., 1.5 h, then 6 N HCl; (e)
toluene, SOCl2, reflux, 5 h; (f) Na2CO3, CH2Cl2, 25 C, 3 h.
In this paper, all the synthesized compounds (1a-1d, 1g, 1i-1x) were screened for their cytotoxic activity by the
MTT-based assay using foretinib as a positive control. They were tested against five c-Met overexpressed human
cancer cell lines, namely human colon cancer cell line (HT-29), human lung cancer cell lines(H460), human lung
adenocarcinoma cell line (A549), human gastric cancer cell line (MKN-45) and human glioblastoma cell line
(U87MG). The results were expressed as IC50 values and summarized in Table 1. The IC50 values were the
average of at least three independent experiments.

Table 1 Structures and cytotoxicity of compounds 1a-1x
N
H
N
F
N
R2
O
O
O
O
R1
O
N
IC50 (μM)±SDa
HT-29 MKN-45
Compds.
1a
R1
R2
A549
H460
U87MG
F
Piperidinyl
1.29±0.05 0.87±0.03 0.72±0.02
0.48±0.03 0.62±0.02 0.38±0.05
2.02±0.08 0.93±0.03 2.38±0.06
2.77±0.03 2.24±0.04 1.83±0.03
5.33±0.06 6.70±0.04 1.12±0.03
1.01±0.04 0.45±0.02 0.94±0.04
0.55±0.05 0.51±0.03 1.22±0.06
6.23±0.09 2.33±0.06 4.94±0.07
1.67±0.04 3.30±0.04 0.79±0.01
2.36±0.06 2.11±0.05 0.87±0.03
1.92±0.02 1.07±0.02 1.41±0.03
0.91±0.02 1.59±0.04 0.35±0.01
1.04±0.03 0.45±0.03 0.96±0.04
0.81±0.03 0.27±0.02 0.27±0.01
1.07±0.04 0.25±0.02 0.61±0.02
0.39±0.03 0.18±0.03 0.38±0.02
0.32±0.03 0.23±0.02 0.23±0.03
0.22±0.01 2.12±0.07
0.25±0.01 1.96±0.06
0.26±0.01 0.65±0.04
0.23±0.01 1.73±0.04
2.79±0.04 4.28±0.07
0.48±0.02 1.60±0.06
0.41±0.02 2.27±0.07
0.23±0.04 12.8±0.10
F
1b
1c
4-methylpiperidinyl
Morpholinyl
F
F
1d
1g
N-methylpiperazinyl
Morpholinyl
1i
Piperidinyl
H3CO
H3CO
H3CO
H3CO
1j
4-methylpiperidinyl
Morpholinyl
1k
1l
N-methylpiperazinyl
Piperidinyl
4.17±0.04
>10
1m
1n
1o
0.18±0.01 3.62±0.03
0.65±0.03 2.74±0.03
0.78±0.04 1.35±0.07
0.31±0.02 1.26±0.04
0.27±0.03 0.76±0.02
0.25±0.02 1.67±0.06
0.18±0.02 0.81±0.04
0.23±0.02 0.56±0.04
4-methylpiperidinyl
Morpholinyl
1p
1q
1r
N-methylpiperazinyl
Piperidinyl
4-methylpiperidinyl
Morpholinyl
1s
1t
N-methylpiperazinyl

Refer to Table 1 (continued).
1u
1v
1w
1x
Piperidinyl
4.36±0.10 3.08±0.07 4.19±0.06
5.79±0.03 2.15±0.04 4.43±0.06
2.48±0.04 1.67±0.05 4.03±0.03
4.37±0.04 2.11±0.07 2.49±0.02
1.17±0.05 5.21±0.08
3.66±0.05 5.39±0.06
3.50±0.04 2.99±0.02
4-methylpiperidinyl
Morpholinyl
N-methylpiperazinyl
3.72±0.05 1.59±0.05
0.15±0.01 1.49±0.08
9
0.49±0.04 0.93±0.06 0.50±0.03
1.49±0.04 1.14±0.03 1.76±0.02
Foretinib
0.2±0.02
2.17±0.03
Bold values show the IC50 values of target compounds lower than the values of the positive control;
Blue values show the five cell lines IC50 values of target compounds all lower than positive control;
IC50a: concentration of the compound (μM) producing 50% cell growth inhibition after 72 h of drug exposure, as determined by the
MTT assay. Each experiment was carried out in triplicate.
As illustrated in Table 1, most of targeted compounds showed great activity against five cancer cell lines in
comparison with foretinib in vitro. In our design, two different schemes have been carried out, such as prolonging
the carbon chain between the B and C parts and replacing the aromatic ring with the aliphatic ring. In the study of
prolonging the carbon chain, compounds 1a, 1b, and 1i bearing 4-fluorobenzyl or 4-methoxyphenethyl was
obtained and their activity against the five cell lines were significantly better than the positive control foretinib. In
addition, in the exploration of the replacement of the aromatic ring by the aliphatic ring, compounds 1q and 1r
with cyclohexyl group exhibited similar activity levels in vitro. Notably, compounds 1s and 1t showed
approximately 5-fold more potent against A549, H460 and HT-29 cell lines than foretinib, which showed much
more potent than compound 9 as we mentioned above.
Based on these activity results in vitro, the SAR revealed that the series of compounds obtained by extending
the carbon chain between the B moiety and the C moiety exhibits comparable or superior activity to the positive
control foretinib, but do not improve compared to compound 9. It’s frustrating that the removal of the 4-position
substituent led to a significant decrease in activity. As shown in table 1, compound 1g showed a 2- to 10-fold
activity loss compared to compound 1c, in which R1 substituent is morpholinyl. Therefore, we only synthesize one
for this type of compounds. It could be known that the substituent on the B ring is very important. The potency
will suffer a heavy loss when the substituent is absent. When there were two carbon atoms between the B ring and
the C moiety, an obviously decrease on anticancer potency can be observed, which seemly indicated that the
narrow space of the cavity occupied by the B ring does not allow further extension of the carbon chain.
Additionally, in the study of the replacement of the aromatic ring by an aliphatic ring, when the incorporation of
cyclohexyl group, a significant enhancement was observed in cell activity, which indicated that the π-electron of
the aromatic ring is not necessary. Instead, the cyclohexyl group can exert a stronger hydrophobic interaction with
the protein cavity, thereby increasing the biological activity of the compound. However, when R2 is cyclopentyl
group, the activity was drastically reduced compared to cyclohexyl, which indicated that shrinking the fat ring will
cause a negative effect on activity.
On the basis of cellular assay results, three most potent compounds (1b, 1s, 1t) were selected for c-Met
enzymatic activity assay using homogeneous time-resolved fluorescence (HTRF). The results were outlined in
table 2. All the three compounds showed excellent c-Met enzymatic potency with IC50 values ranging from 1.42
to 2.56 nM while the IC50 values of positive control was 1.63 nM. Apparently, the data of enzymatic potency was

consistent with the cell cytotoxic activity, which elucidated that c-Met inhibition may lead to their antitumor effect.
Moreover, 1s exhibited the most potent activity with an IC50 values of 1.42 nM , which was preferable to foretinib.
Table 2. c-Met kinase activity of compounds 1b, 1s, 1t and Foretinib in vitro.
Compounds
IC50 on c-Met (nM)a
1b
1s
2.56
1.42
2.34
1.63
1t
Foretinibb
a The values are an average of two separate determinations.
b Used as a positive control.
To further elucidate the binding mode of the target compounds, the docking analysis of compound 1s was
performed. Similarly, the co-crystal protein of foretinib with c-Met (PDB ID code: 3LQ8) were used as a docking
mode. The docking simulation was conducted using Glide XP (Schrödinger 2014), since Glide uses a hierarchical
series of filters to search for possible locations of the ligand in the active-site region of the receptor. Then the
image files were generated using Accelrys DS visualizer 4.0 system. As shown in Figure 4, all these interactions
with Met1160, Asp1222 and Lys1110 that played an important role in stabilizing the conformation of
ligand-protein complex were retained. In addition ,the cyclohexyl group formed three hydrophobic interactions
with His1202, Phe1134 and Val1139, which suggested that terminal cyclohexyl group could inspire a new
optimization idea of c-Met inhibitor.
Fig. 5 (A) Binding poses of compound 1s with c-Met ; (B) 2D interactions of the docking model of 1s to c-Met
In summary, a series of 4-phenoxyquinoline derivatives 3-oxo-3,4-dihydro-quinoxaline moiety as novel c-Met
receptor tyrosine kinase inhibitors were designed and synthesized. Most of the tested compounds exhibited more
potent inhibitory activities than the positive control foretinib. Compounds 1b, 1s and 1t were proved to be the best
compounds of the series, showing anti-proliferative activity in the low microgram range on the five human cancer
cell lines (A549, H460, HT-29, MKN-45 and U87MG), and remarkable potency on c-Met kinase(IC50 values of
2.56 nM, 1.42 nM and 2.34 nM ). Additionally, compound 1s exhibited the most potent activity with an IC50
values of 1.42 nM, which was preferable to foretinib. Further exploration of the structure-activity relationship has
been carried out by the docking simulation analysis of compound 1s with c-Met. It can be observed that
cyclohexyl group formed three hydrophobic interactions with His1202, Phe1134 and Val1139, which suggested
that terminal cyclohexyl group might produce new structural optimization inspiration of c-Met inhibitor. Further
optimization of the terminal structure to enhance inhibitory activity against c-Met is in progress.

Acknowledgments
This work was supported by grant (No. 81573295) from the National Natural Science Foundation of China
and LiaoNing Revitalization Talents Program (XLYC1808037).
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