Design, synthesis, and biological evaluation of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia

Article abstract of DOI:10.1016/j.bmcl.2019.126630

FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N′-dimeth

Full text of DOI:10.1016/j.bmcl.2019.126630

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and biological evaluation of 4-((6,7-dimethoxyquinoline-
4-yl)oxy)aniline derivatives as FLT3 inhibitors for the treatment of acute
myeloid leukemia
Qiaoling Xu, Baozhu Dai, Zhiwei Li, Le Xu, Di Yang, Ping Gong, Yunlei Hou⁎, Yajing Liu⁎
Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang
110016, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We
synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide
moiety and 2,2,2-trifluoro-N,N′-dimethylacetamide moiety as the linker. The cell proliferation assay in vitro
against HL-60 and MV4-11 cell lines demonstrated that most series I compounds containing semicarbazide
moiety had more potent than Cabozantinib. Furthermore, the enzyme assay showed that compound 12c and 12g
were potent FLT3 inhibitors with IC50 values of 312 nM and 384 nM, respectively. Following that, molecular
docking analysis was also performed to determine possible binding mode between FLT3 and the target com-
pound.
Acute myeloid leukemia
FLT3
Structure-activity relationships
Inhibitors
Acute myeloid leukemia (AML) is a hematopoietic system clonal
malignant tumor resulting from the hyperproliferation and abnormal
differentiation of immature hematopoietic cells.1 Many research find-
ings indicated that the aberrant activation of cell signaling pathways
mediated was closely related to the occurrence and development of
AML.2–4
inhibitors that have advanced to clinical trials (Fig. 1). As for Cabo-
zantinib, initially was used to treat medullary thyroid cancer and
second-line treatment for renal cell carcinoma, which also showed
promising inhibitory activity against FLT3 with IC50 values of
11.30 nM.13a By analyzing the docking model, Cabozantinib could form
some conjugation with a variety of amino acid residues through qui-
nolone13b,13c and benzene ring fragment (Fig. 2). For example, the
linker section found to form two hydrogen bonds with Asp 829 and Lys
644, respectively. In the meantime, the 6,7-dimethoxyquinoline nuclei
was found to form one hydrogen bond with the Cys 694. These results
portend that this segment played a crucial role in the combination of
the receptor and ligand. Moreover, recent studies that mainly modified
the structure of Cabozantinib exhibited better activities against FLT3
exemplified by Foretinib14, I15, and II16,17 (Fig. 3). All these evidence
prompted us to design new potential drugs with different structural
fragments based on the retention of its active structure 4-((6,7-di-
methoxyquinoline-4-yl)oxy)aniline scaffold.
FMS-like tyrosine kinase 3 (FLT3), was a member of type III receptor
tyrosine kinase family that mainly expressed in early bone marrow and
lymphocytes. Physiologically, ligand stimulated FLT3 phosphorylation
induced the homodimerization of the receptor that ultimately can
promote the activation of downstream signaling pathways (the PI3K/
Akt, MAPK/ERK and STAT pathways).5–7 Therefore, it had confirmed as
an essential role in the process of cell proliferation, differentiation and
apoptosis. Approximately 30% of adult AML cases existed FLT3 muta-
tions,8 including the predominant mutation internal tandem duplica-
tions (ITD) in the juxtamembrane domain of FLT3 (20%–25%) and
point mutations within the tyrosine kinase domain (TKD) (5%–10%).9
Both of them result in continuous activation of the FTL3 receptor,
thereby leading a loss of the autoinhibitory function on FLT3.8,10
Therefore, it was an urgent need to develop FLT3 inhibitors with po-
tential activities to FLT3 mutations in AML.
Some kinds of compounds were incidentally found to have selective
activity against FLT3 while developing C-Met inhibitors based on 4-
phenoxy-6,7-disubstituted quinoline scaffold as reported in our pre-
vious work, including the compound III.18,19 The molecular docking
study of the compound III revealed that the semicarbazide fragment
played a key role in the interaction with FLT3 kinase due to its binding
mode and the presence of hydrogen bonds (Asp 829 and Glu 661)
In recent years, much effort had been invested in the development
of small-molecule FLT3 inhibitors targeting its kinase domain. Among
them, Sorafenib,11 Linifanib12 and Cabozantinib were the multitargets
⁎ Corresponding authors.
E-mail addresses: houyunlei901202@163.com (Y. Hou), lyjpharm@126.com (Y. Liu).
https://doi.org/10.1016/j.bmcl.2019.126630
Received 21 July 2019; Received in revised form 3 August 2019; Accepted 19 August 2019
0960-894X/©2019PublishedbyElsevierLtd.
Pleasecitethisarticleas:QiaolingXu,etal.,Bioorganic&MedicinalChemistryLetters,https://doi.org/10.1016/j.bmcl.2019.126630

Q. Xu, et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Fig. 1. Structures of some FLT3 inhibitors.
Fig. 2. The mode of Cabozantinib bound to FLT3 (PDB code: 4RT7). (A) The overview of Cabozantinib docked into FLT3. (B) Interactions of docked Cabozantinib
with FLT3 residues. The amino acid residues were displayed by red sticks and compound was displayed by purple sticks. Green dotted lines represent H-bonds.
Fig. 3. Structures of FLT3 inhibitors modified on Cabozantinib.
Fig. 4. (A) The model of compound III bound to FLT3 (PDB code: 4RT7). The amino acid residues were displayed by sticks and compound III was displayed by pink
sticks. Green dotted lines represent H-bonds. (B) Interactions of docked compound III with FLT3 residues.
(Fig. 4). Besides, the phenyl-1,2,3-triazole skeleton had been widely
used in EGFR inhibitors, ERR inhibitors and FLT3 inhibitors due to its
diverse biological activities, including anti-tumor, antibacterial and
estrogen receptor inhibitor activity, which play critical roles in the
regulation of tumor genesis.20–23 Given these observations, we used
semicarbazide as the linker between 4-((6,7-dimethoxyquinoline-4-yl)
oxy)aniline scaffold and 1,2,3-triazole to generate target compounds
12a-12l as novel promising drugs (Series I, Fig. 5).
absorption.27,28 Meanwhile, a 2,2,2-trifluoro-N,N′-dimethylacetamide
is present in certain drugs. These characteristics promoted us to attempt
to replace the linker by this segment to get another series compounds
14a-14j (Series II, Fig. 6).
All of the target compounds were afforded from the key inter-
mediate 6, which was obtained by a convenient six-step procedure
based on our previous research about Foretinib.17,29 (Scheme 1). A six-
step synthesis to generate compound 6 included: (i) nitration of 3,4-
dimethoxyacetophenone to yield 1; (ii) 1 was then condensed with
DMF-DMA to afford 2; (iii) reduction and cyclization the latter at the
presence of iron powder to produce bicyclic compound 3; (iv) 3 was
converted to chloro-substituted intermediate 4 using POCl3; (v) a nu-
cleophilic substitution of the chlorine of 4 with 4-nitrophenol to gen-
erate 5; (vi) coupled with Fe powder to yield 6.
Recently, fluoro substituents are widely used in the drug design,
which exhibit a broad spectrum of biological activities, including me-
tabolic stability, lipophilicity, solubility, bioavailability and enhance-
ment of the interaction between drugs and targets.24–26 Moreover, in-
troduction a trifluoromethyl group into some small-molecule drugs
might improve their lipophilicity, promote transport and
2

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Fig. 5. The design strategy for series I compounds 12a-12l.
Fig. 6. The design strategy for series II compounds 14a-14j.
The target compounds 12a-12l were prepared by condensation of 8 (Scheme 4).
and 11a-11l under N,N-dimethylformamide solution (Scheme 2). The
synthesis of 8 was accessible through two steps: the first involved
acylation of 6 with phenyl carbonochloridate in the presence of ap-
propriate pyridine, and then reacted with hydrazine to afford 8. The
route that enabled the synthesis of 11a-11l is outlined in Scheme 3.
Substituted anilines were treated with sodium nitrite at 0 °C to get
azides. Subsequently, the cycloaddition of propynyl alcohol under
copper catalysis by Huisgen [3 + 2] reaction was readily achieved,
which was then oxidized with chromium trioxide to afford 11a-11l.
The reaction of anilines with various substitute groups convert to
compounds 13a-13j has already been reported in the literature.30 All of
the quinoline derivatives 14a-14j containing 2,2,2-trifluoro-N-pheny-
lacetimidamide structure were afforded following electrophilic sub-
stitution reactions between intermediate 6 and the corresponding 2,2,2-
trifluoro-N-phenylacetimido chlorides 13a-13j in basic conditions
The chemical structures of the target compounds were confirmed by
mass spectrometry and NMR. In order to determine the relative con-
figuration of series I compounds, the NOESY experiment of compound
12c was carried out and an evident NOE signal was observed between
the proton H1 (8.13 ppm) and the proton H2 (10.96 ppm) (Fig. 7).
Therefore, we proved that the double bond of compounds 12a-12l is
the E configuration.
The growth inhibitory activities of target compounds against the
human promyelocytic leukemia cell (PML) line HL-60 (FLT3-WT) and
the human AML cell line MV4-11 (FLT3-ITD) were evaluated by CCK-8
method.31–34 Meanwhile, Cabozantinib was served as the positive
control. The results were depicted as IC50 values in the micromolar
range with an average of three separate determinations.
The cytotoxicity values in vitro assay of series I compounds against
HL-60 were screened in Table 1. Notably, the twelve compounds
Scheme 1. The synthetic route of key intermediate 6. Reagents and conditions: (i) 98% HNO3, CH2Cl2, −10 °C, 2 h; (ii) DMF-DMA, toluene, 110 °C, 11 h; (iii) Fe
powder, AcOH, 80 °C, 2 h; (iv) POCl3, CH3CN, 85 °C, 2 h; (v) 4-nitrophenol, DIPEA, PhCl, 140 °C, 14 h; (vi) Fe powder, HCl, 90% EtOH, reflux, 1 h.
3

Q. Xu, et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Scheme 2. General scheme for the synthesis of series I compounds. Reagents and conditions: (i) phenyl carbonochloridate, pyridine, DCM, 0 °C, 2 h; (ii) NH2-
NH2·H2O, toluene, 70 °C, 3 h; (iii) AcOH, DMF, r.t., 24 h.
Scheme 3. The synthetic route of compounds 11a-
11 l. Reagents and conditions: (i) NaNO2, 10% HCl,
H2O, 0 °C, 1 h; NaN3, H2O, 25 °C, 2 h; (ii) propargyl
alcohol, CuI, DIPEA, EtOH, 25 °C, 24 h; (iii) CrO3,
AcOH-H2O, 100 °C, 1 h.
(EDGs) have little effect on the antiproliferative activity in MV4-11 cell.
Interestingly, it can be deduced from results that the position and the
type of substituents actually contribute significantly to the inhibitory
activity. For example, 12e, 12d, 12c containing the methoxy at C-4, C-3
and C-2 position respectively displayed diverse antiproliferation activ-
ities, the IC50 values descended from 12e to 12c (16.26 μM, 13.85 μM,
8.29 μM, respectively). Among the compounds introduced F atom as
EWGs, 12g substituted at C-3 position of benzene ring showed better
activity with IC50 values of 5.80 μM. And 12h substituted at C-4 posi-
tion exhibited lowest activity with IC50 values of 21.24 μM. Meanwhile,
Scheme 4. General scheme for the synthesis of series II compounds. Reagents
halogen atoms including F, Cl, and Br at C-2 position of benzene ring
showed notably difference in inhibitory activity with IC50 values of
13.60 μM, 48.44 μM and not active, respectively.
and conditions: (i) TFA, Et3N, Ph3P, CCl4, reflux, 5 h; (ii) Et3N, DMF, 25 °C,3h.
Compounds 14a-14j containing 2,2,2-trifluoro-N,N′-dimethylaceta-
mide with optionally substituted phenyl ring were also subjected to cell
assay against HL-60. Overall, these compounds exhibited weak cyto-
toxic activity. Interestingly, the results showed that there was a positive
correlation between the potency of the compounds and electron-with-
drawing effect of substituents. In conclusion, all data derived from
Table 1, indicated that the semicarbazide and 1,2,3-triazole fragment
was recognized as a driving force in the antiproliferative activities.
Based on the cytotoxicity results showed in Table 1, five promising
compounds were determined inhibition values against FLT3 in enzy-
matic activities. The results were summarized as IC50 values at nano-
molar concentration by Mobility shift assay in vitro (Table 2).
introduced a triazole group holistically exhibited par excellence ac-
tivity, which were then further carried on bioactive determination
against MV4-11 cell and the results were also summarized in Table 1.
The compounds 12c-12h and 12i showed better activities than Cabo-
zantinib. In particular, compound 12g inhibited the growth of HL-60
cell tremendously better with the IC50 values of 8.91 μM, which was
2.52-fold higher than that of Cabozantinib (22.46 μM).
The antiproliferative effects of compounds against HL-60 and MV4-
11 are similar. Five of the tested compounds exhibited moderate to
higher cytotoxicity against the MV4-11 cell line. Remarkably, 12c and
12g showed superior activities with IC50 values of 8.29 and 5.80 μM,
respectively. Preliminary structure-activity relationships (SARs) were
inferred from the data Table 1. The compounds whether substituted
with electron drawing groups (EWGs) or the electron donating groups
Encouragingly, 12g and 12c both showed higher enzymatic in-
hibitory activities than the other three compounds. The two synthesized
Fig. 7. 2D NOESY spectrum of representative compound 12c.
4

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Table 1
Cytotoxicity activities of target compounds in vitro.
R1
IC50 (μM)
HL-60
SDb
Compd.
R2
IC50a(μM)
HL-60
SDb
a
Compd.
MV4-11
12a
H
41.33
25.69
14.16
18.84
19.28
16.37
8.91
2.02
38.72
19.31
8.29
1.03
0.92
0.24
0.84
1.13
0.75
0.42
2.35
2.06
0.93
14a
14b
14c
14d
14e
14f
14g
14h
14i
H
44.60
46.17
36.20
＞50
3.03
12b
3-CH3
2-OCH3
3-OCH3
4-OCH3
2-F
0.43
0.22
1.04
0.53
1.06
4-CH3
4-OCH3
3-CF3
4-OCF3
3-Cl
2.17
1.02
12c
12d
13.85
16.26
13.60
5.80
12e
32.69
> 50
> 50
> 50
48.89
> 50
0.93
12f
12g
3-F
0.66
3,4-(Cl)2
4-Cl-3-CF3
4-F
12h
4-F
21.67
> 50
21.12
> 50
> 50
22.46
2.13
1.05
21.45
48.44
13.37
> 50
49.15
15.16
12i
2-Cl
3.06
12j
3-Cl
14j
4-NO2
12k
2-Br
12l
3-CF3
2.65
1.06
Cabozantinibc
1.64
a
b
c
Values are the means of at least three independent experiments.
SD: standard deviation.
Used as a positive control.
downloaded from the Protein Data Bank (http://www.rcsb.org/pdb/
).35 In the binding model (Fig. 8), 12c was found to form three hy-
drogen bonds via nitrogen atom, the NH and the oxygen atom of
semicarbazide segment linker with Asp 829 and Glu 661, respectively.
In the meantime, the 6,7-dimethoxyquinoline nuclei was found to form
one hydrogen bond with the Cys 694. The π-π stacked interaction be-
tween 1,2,3-triazole with His 809 and π-Sigma interaction between
terminal benzene ring with Leu 802 was also present.
Table 2
Kinase inhibitory activities of selected compounds.
Compd.
R1
FLT3a
IC50 (nM)
12c
2-OCH3
3-OCH3
2-F
312
12d
> 1000
> 1000
384
12f
12g
3-F
Besides, some physicochemical properties of most active com-
pounds and Cabozantinib were predicted using a free web tool to
evaluate pharmacokinetics, drug likeness and medicinal chemistry
friendliness for their adaptability with Lipinski’s rule of five (http://
www.swissadme.ch/index.php). Compounds conforming at least three
of the five criteria are considered to adhere to Lipinski Rule.36,37 As
shown in Table 3, compounds 12c and 12g accorded well with Lipinski
Rule. Data derived from Table 3 suggested that 12c and 12g could
considered as promising compounds for the further research of potent
FLT3 inhibitors.
12j
3-Cl
> 1000
418
Cabozantinibb
a
b
Values are the means of at least three independent experiments.
Used as a positive control.
compounds inhibited the tyrosine kinase activity of FLT3 with
IC50 = 384 and 312 nM, respectively, which are slightly superior than
that of Cabozantinib (IC50 = 418 nM). All these data can provide to
further research in modifying the structure of the most promising
compound 12c to rummage more potent FLT3 inhibitors for AML
treatment.
In summary, two series of 4-((6,7-dimethoxyquinolin-4-yl)oxy)ani-
line scaffold compounds were designed and synthesized, which were
initially evaluated inhibitory activities against HL-60 cell. On the
The co-crystal structure of Quizartinib with FLT3 was selected as the
docking model (PDB code: 4RT7). The protein coordinates were
Fig. 8. (A) The model of compound 12c bound to FLT3 (PDB code: 4RT7). The amino acid residues were displayed by sticks and compound 12c was displayed by
blue sticks. Green dotted lines represent H-bonds. (B) Interactions of docked 12c with FLT3 residues.
5

Q. Xu, et al.
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Table 3
Physicochemical properties of most active compounds.
Compd.
MW
H-bond acceptors
H-bond donors
< 5
Log P o/w
< 5
Violation Lipinski
Rule of 5
aPSA
(Å2)
Rotatable bonds
≤10
bBBB
(g/mol)
< 500
< 10
≤140
12c
539.54
539.54
527.51
527.51
543.96
501.51
9
9
9
9
8
7
2
2
2
2
2
2
3.51
3.61
3.83
3.90
4.12
4.40
2
2
2
2
2
1
134.01
134.01
124.78
124.78
124.78
98.78
11
11
10
10
10
10
NO
NO
NO
NO
NO
NO
12d
12f
12g
12j
Cabozantinib
a
b
PSA – Polar surface area.
BBB – blood–brain barrier.
whole, the twelve series I compounds containing 1,2,3-triazole frag-
ment exhibited high potency against HL-60 compared with series II,
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most of series
I compounds also showed better activities than
Cabozantinib. All series I compounds were subjected to inhibitory ac-
tivity assay against the MV4-11 cell line. Five of these compounds
emerged as more effectively inhibitors with excellent values of
5.80–13.85 μM were further selected for determination of enzymatic
activities against FLT3. Overall, these compounds exhibited that series I
compounds were superior to series II compounds on cytotoxic activity.
Among these compounds, the activities of two compounds 12g, 12c
(IC50 = 384, 312 nM, respectively) surpassed that of the reference
compound Cabozantinib (418 nM). According to the above data, com-
pounds introduced the semicarbazide to 4-((6,7-dimethoxyquinolin-4-
yl)oxy)aniline scaffold were confirmed to be beneficial to the im-
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Our work was supported by Program for Innovative Research Team
of the Ministry of Education Program for Liaoning Innovative Research
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