Design and synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.05.017

A novel series of benzoxazole analogs was designed and synthesized, and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited a promising activity with respect to the inhibition of Aurora B kinase. A structure-activity relationship study indicated that linker length, regiochemistry, and halogen substitution play important roles in kinase inhibitory potency. The binding modes between representative compounds and Aurora kinases were interpreted through a molecular docking study to explain the inhibitory activity and selectivity for Aurora A and B kinases. Compounds 13l and 13q also show an antiproliferative effect on the human tumor cell lines in a dose-dependent manner. The most potent 13q demonstrated good efficacy in the prostate cancer PC-3 tumor xenograft model.

Full text of DOI:10.1016/j.bmcl.2016.05.017

Accepted Manuscript
Design and synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors
Ying An, Eun Lee, Yeongji Yu, Jieun Yun, Myeong Youl Lee, Jong Soon Kang,
Woo-Young Kim, Raok Jeon
PII:
S0960-894X(16)30502-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.05.017
BMCL 23876
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 January 2016
1 May 2016
4 May 2016
Please cite this article as: An, Y., Lee, E., Yu, Y., Yun, J., Lee, M.Y., Kang, J.S., Kim, W-Y., Jeon, R., Design and
synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors, Bioorganic & Medicinal Chemistry Letters
(2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.05.017
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Bioorganic & Medicinal Chemistry Letters
Design and synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors
Ying Ana, 1, Eun Leea, 1, Yeongji Yua, Jieun Yun b, Myeong Youl Lee b, Jong Soon Kang b, Woo-Young Kim
*
a, and Raok Jeon a,
a Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul, 04310, Korea
b Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, chungcheongbuk-do, 28116, Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel series of benzoxazole analogs was designed and synthesized, and their inhibitory
activities against Aurora kinases were evaluated. Some of the tested compounds exhibited a
promising activity with respect to the inhibition of Aurora B kinase. A structure-activity
relationship study indicated that linker length, regiochemistry, and halogen substitution play
important roles in kinase inhibitory potency. The binding modes between representative
compounds and Aurora kinases were interpreted through a molecular docking study to explain
the inhibitory activity and selectivity for Aurora A and B kinases. Compounds 13l and 13q also
show an antiproliferative effect on the human tumor cell lines in a dose-dependent manner. The
most potent 13q demonstrated good efficacy in the prostate cancer PC-3 tumor xenograft model.
Available online
Keywords:
Aurora B kinase
Antiproliferation
Benzoxazole analogs
2016 Elsevier Ltd. All rights reserved.
———
1 Indicates equal contribution.
*
Corresponding author. Tel.: +82-2-710 9571; fax: +82-2-715-9571; e-mail: rjeon@sookmyung.ac.kr

Auroras, serine-threonine kinases, have emerged as key
regulators in the control of the cell cycle and mitosis.
Mammalian genomes contain three genes encoding Aurora
kinases, denoted Aurora A, B, and C. Each Aurora kinase shows
a different subcellular location. Aurora A localizes to the
centrosome and spindle poles, and is mainly related to
centrosome function and spindle assembly.1 Aurora A may also
be involved in cytokinesis, in accordance with its localization at
the central spindle and midbody in the anaphase and telophase of
mitosis.2 Aurora B is a member of the chromosome passenger
complex,3 and localizes to centromeres during early mitosis,
transfers to the midzone of the mitotic spindle and contractile
ring during anaphase, and stays in the midbody during
cytokinesis.4,5 Aurora C is specifically expressed in the testis and
plays many roles in meiosis. Aurora C has been reported to be a
chromosomal passenger protein with maximal expression in the
G2/M phase of the cell cycle, and can complement the functions
of Aurora B. Aurora kinases are strongly associated with human
cancer.6 Accumulating evidence indicates that Aurora kinases are
significantly overexpressed in a wide range of human cancer cell
lines. Deregulation of Aurora kinase activity causes mitotic
abnormalities, leading to genomic instability and ultimately
tumorigenesis.7,8 Considering their importance in mitosis and
association with tumorigenesis, aurora kinases have been
proposed as promising targets for cancer therapy.7,8 A growing
number of aurora kinase inhibitors are being developed, and
many of these are in clinical trials. Recently, the pan-aurora
kinase inhibitor Danusertib (PHA-739358)9 and the selective
Aurora B inhibitor Barasertib (AZD1152)10 have been in clinical
trials for the treatment of leukemia, myeloma, and other solid
tumors (Fig. 1).11,12
kinases. Firstly, an Asp residue (Asp218 in Aurora B) interacting
with the gamma phosphate is reoriented in the inactive
conformation by the DFG motif taking the “out” position. The
second important change is observed at a Glu residue (Glu125 in
Aurora B), which is responsible for the construction of a salt
bridge with β3 Lys (Lys106 in Aurora B), in the αC-helix.15,16
These conformational changes generate an additional allosteric
site that opens favorable interactions for selectivity.17 In the
present article, we report the discovery and identification of a
novel series of 2-aminobenzoxazole analogs as type II kinase
inhibitors. The representative structure of the targeted molecules
is depicted in Figure 2. Similar to many other type II kinase
inhibitors, our aminobenzoxazole analogs consist of three parts; a
hinge binder, a solvent accessible group, and DFG and allosteric
site-interacting groups.13 Here, we examined their activities with
respect to the inhibition of aurora kinases, cell growth, and tumor
growth using an ADP-GloTM kinase assay, a cell-based assay, and
PC-3 tumor xenograft model, respectively. We found that
compound 13q potentially inhibited Aurora kinase B activity and
suppressed cell proliferation in the human cancer cell lines in
vitro and the growth of PC-3 xenograft tumors in vivo. These
observations suggest that compound 13q is worthy of further
study directed towards the identification of more potent and
selective Aurora B kinase inhibitors as anticancer agents.
Figure 2. Representative structure of 2-aminobenzoxazole
The synthetic route for the aminobenzoxazole scaffold with a
solvent accessible moiety is described in Scheme 1. Nitration of
methoxyphenol and subsequent hydrogenation of the resulting
nitro compound afforded compound 2. Aminobenzoxazole 3 was
formed by the reaction of compound 2 with BrCN in EtOH. The
solvent accessible hydrophilic moiety, the morpholinylethyl
group, was attached to the OH or NH2 group of the
aminobenzoxazle scaffold to yield compounds 6 and 7.
O
F
Cl
O
NH
CO2H
N
N
HN
O
N
N
S
N
H3CO
N
N
H
Danusertib (PHA-739358)
MK-5108
Pan-Aurora kinase inhibitor
Aurora A IC50 13 nM
Aurora B IC50 79 nM
Aurora C IC50 61 nM
NO2
NH2
Aurora A inhibitor (Phase I)
Aurora A IC50 0.064 nM
a
b
H3CO
H3CO
H3CO
OH
OH
OH
1a : 5-OMe
1b : 4-OMe
2a : 5-OMe
2b : 4-OMe
m or p-Methoxyphenol
O
HO
P
N
O
N
N
O
N
O
c
d
HO
O
H3CO
NH2
HO
NH2
N
HN
3a : 6-OMe
3b : 5-OMe
4a : 6-OH
4b : 5-OH
Barasertib (AZD1152)
NH
NH
N
Aurora B inhibitor
Aurora B IC50 0.37 nM
O
e
f
F
N
N
H
O
NH2
R
N
N
N
O
O
O
O
Figure 1. The structures of Aurora kinase inhibitors.
5a : R = 6-OMe
5b : R = 5-OMe
7a : 6-alkoxy
7b : 5-alkoxy
Typical kinase inhibitors are classified by their binding mode
(type I - IV). Type I kinase inhibitors work on the active form of
enzymes in a competitive manner with ATP. In contrast, type II
inhibitors interact with the inactive conformation of enzymes.13
In the case of type III kinase inhibitors, they bind in an allosteric
pocket nearby active site, without any interaction with the ATP-
binding pocket. Type IV kinase inhibitors placed to an allosteric
site far from the ATP-binding pocket.14 There are two remarkable
differences between the active and inactive conformations of the
d
6a : R = 6-OH
6b : R = 5-OH
Scheme 1. Synthesis of the 2-aminobenzoxazole scaffold. Reagents and
conditions: a) HNO3, AcOH, 0 C, 30 min, 33%; b) H2, Pd/C, MeOH, rt, 4 h,
75%; c) BrCN, EtOH, reflux, 2 h, 70%; d) 48% HBr, AcOH, reflux, 30 h,
75%; e) 4-(2-chloroethyl)morpholine HCl, Cs2CO3, DMF, 120 C, 3 h, 33%; f)
4-(2-chloroethyl)morpholine HCl, Cs2CO3, DMF, 80 C, 6 h, 40%.

We prepared two types of benzoxazole analogs. Two
substituted groups of the aminobenzoxazole core were attached
in an inverse fashion. In a series of type A analogs, the solvent
accessible moiety, the morpholinyl alkoxy group, was attached to
the benzene ring of benzoxazole, and additional H-bond
donor/acceptor and hydrophobic moieties were attached to the
nitrogen of aminobenzoxazole. Type B analogs were shaped in
reverse (Fig. 2). Preparation of the hydrophobic moiety was
started with aminobenzyl alcohol, which was treated with
benzoyl chloride or substituted with phenyl isocyanate to form
amide 8 or urea compound 10, respectively. N-substituted
aminobenzyl alcohol 8 and 10 were transformed to bromide 12
by treatment with PBr3 or oxidized to respective aldehydes 9 and
11 by treatment with MnO2 (Scheme 2).
Scheme 4. Synthesis of type B compounds. Reagents and conditions: a)
compound 12a-d, Cs2CO3, DMF or MeCN, rt, 2-5 h, 10-40%.
Enzymatic activity of the prepared compounds against Aurora
A and B kinases was determined using the ADP-Glo assay
(Promega, USA), which quantifies the ADP generation
consumed from ATP during a kinase reaction. The inhibitory
activity was represented as the relative percentage inhibition of
the positive control staurosporine. Following assessment of all
the prepared compounds for Aurora A and B enzymatic activity,
selected compounds with sufficient activity against Aurora B
were examined for their antiproliferative activity against the
various human cancer cell lines. The results of the enzymatic
assay are summarized in Tables 1 and 2. At the beginning of the
study, we introduced an amide or urea group directly to the
benzoxazole scaffold as depicted in 13a, which was rarely active.
Docking studies indicated that the lengthening of the molecule
may be useful for activity. Introduction of a benzyl group as a
linker between benzoxazole and the H-bond donor/acceptor
moiety, amide or urea group, enhanced the activity depending on
the position of substituents, as shown in Table 1.
O
O
8a : ortho
8b : meta
8c : para
9a : ortho
9b : meta
9c : para
a
c
N
H
N
H
HO
H
O
NH2
HO
H
N
H
H
N
H
N
c
N
HO
H
X
X
b
O
O
O
11a : meta, X = H
10g : para, X = 4-F
11g : para, X = 4-F
11h : para, X = 4-Cl
11i : para, X = 4-Br
11j : para, X = 4-OMe
11k : para, X = 4-Me
10a : meta, X = H
10h : para, X = 4-Cl
10i : para, X = 4-Br
10j : para, X = 4-OMe
10k : para, X = 4-Me
10l : para, X = 2, 4-diCl
10m : para, X = 3, 4-diCl
10b : meta, X = 3-Cl
10c : meta, X = 4-Cl
10d : para, X = H
10e : para, X = 3-F
10f : para, X = 3-Cl
11b : meta, X = 3-Cl
11c : meta, X = 4-Cl
11d : para, X = H
Table 1
Aurora kinase inhibitory activities of aminobenzoxazole
11e : para, X = 3-F
11f : para, X = 3-Cl 11l : para, X = 2, 4-diCl
11m : para, X = 3, 4-diCl
analogs
N
O
N
d
N
X
H
O
O
12a : meta, X = H
H
H
X
% inhibitiona
12b : para, X = 4-Cl
12c : para, X = 4-Br
12d : para, X = 3, 4-diCl
N
N
Cpd.
Br
X
Position
Substituent
AURA
AURB
NAc
1
O
o
m
p
m
p
NHCOPh
NHCOPh
NHCOPh
NDb
ND
ND
ND
15
13b
13c
13d
13e
13h
Scheme 2. Synthesis of hydrophobic substituents. Reagents and
conditions: a) benzoyl chloride, NaOAc, THF, rt, 2 h, 80%; b) substituted
phenyl isocyanate, THF, rt, 30 min, 80-90%; c) MnO2, DMF, 70-80 C, 2-4 h,
60-90%; d) PBr3, THF, 0 C, 30 min, 90%.
21
30
NHCONHPh
NHCONHPh
40
a Relative percent inhibitory activity against staurosporine at 10 μM.
Determined IC50 value of staurosporine was 1.5 nM according to provided
procedure of ADP-Glo assay kit by Promega. Compounds were treated at 10
μM. b ND = Not Determined. c NA = Not Active.
Type A compounds were prepared as depicted in Scheme 3.
Addition of compounds 7 to isocyanate afforded urea 13a, and
reductive amination with aldehydes 9 or 11 gave N-benzyl
substituted compounds 13b-s. Type B compounds 14 were also
prepared by O-alkylation of compounds 6 with various alkyl
halides 12 (Scheme 4).
The attachment position of the H-bond donor/acceptor moiety
(X) to the benzyl linker affected the activity. Better activity was
seen when group X was substituted at the para position
(compound 13d) as compared with the ortho isomer 13b and the
meta isomer 13c. A urea substituent group was more favorable
than an amide as demonstrated when comparing 13c vs 13e and
13d vs 13h. Therefore, a further structure-activity relationship
study was carried out with phenylurea analogs. As observed in
Table 2, the para-substituted urea analogs (13h, 13j, and 13l)
revealed a higher activity than the meta-substituted analogs (13e-
g). We investigated the effect of a halogen substituent (X) on the
terminal benzene ring. Introduction of a halogen atom generally
increased activity. In the case of chlorine substitutions, the
activities were in the order of; 2,4- or 3,4-diCl > 4-Cl > 3-Cl. The
hydrophilic morpholine substituent was attached at the C6 or C5
position of the benzoxazole scaffold. 6-Alkoxy analogs were
more potent than 5-alkoxy analogs when comparing 13l and 13m
with 13r and 13s, respectively. With respect to type B analogs,
most of the compounds revealed promising activities. However,
the structure-activity relationships were more obscure than those
of type A analogs. Compound 14b showed the highest relative
inhibitory activity but a lower IC50 value. The majority of the
tested compounds showed selectivity for Aurora B kinase over
Aurora A kinase. Considering the relative inhibitory activities,
five representative compounds were chosen and their IC50 values
were evaluated (Table 2). Dichloro-substituted compounds 13p
and 13q were the most potent, with IC50 values of 0.7 and 0.6
μM, respectively.
O
N
a
b
b
O
N
H
N
13a
N
N
H
O
O
N
O
O
N
O
O
O
NH2
13b : ortho
13c : meta
13d : para
N
N
H
N
O
O
5
H
7a-b
O
N
O
m
p
X
O
N
N
N
N
H
6
H
H
O
13e : 6, meta, X = H
13j : 6, para, X = 3-Cl
13k : 6, para, X = 4-F
13l : 6, para, X = 4-Cl
13m : 6, para, X = 4-Br
13n : 6, para, X = 4-OMe
13o : 6, para, X = 4-Me
13p : 6, para, X = 2,4-diCl
13q : 6, para, X = 3,4-diCl
13r : 5, para, X = 4-Cl
13s : 5, para, X = 4-Br
13f : 6, meta, X = 3-Cl
13g : 6, meta, X = 4-Cl
13h : 6, para, X = H
13i : 6, para, X = 3-F
Scheme 3. Synthesis of type A compounds. Reagents and conditions: a)
benzyl isocyanate, NaH (60%), DMF, 80 C, 2 h, 20%; b) compound 9a-c or
11a-m, Ti(iPrO)4, THF, reflux, 3 h then NaBH3CN, 40-50 C, 4 h - overnight,
10-30%.
H m
N
5
H
N
O
N
O
H
N
H
N
HO
a
O
N
N
X
N
p
O
6
O
O
6a-b
14a-g
14a : 6, meta, X = H
14e : 5, para, X = 4-Cl
14f : 5, para, X = 4-Br
14g : 5, para, X = 3,4-diCl
14b : 6, para, X = 4-Cl
14c : 6, para, X = 4-Br
14d : 6, para, X = 3,4-diCl

Table 2
Aurora kinase inhibitory activities of benzoxazole compounds containing a phenylurea group
Type A
Type B
R
R
O
O
5
6
5
O
O
N
O
m
m
N
O
N
X
X
N
N
H
O
O
N
N
N
N
N
H
6
p H
H
H
H p
R
% inhibitiona
Alkoxy
position
Cpd.
Type
AURB IC50 (μM)
Position
X
H
3-Cl
4-Cl
H
3-F
3-Cl
4-F
4-Cl
4-Br
4-OMe
4-Me
2,4-diCl
3,4-diCl
4-Cl
4-Br
H
4-Cl
4-Br
3,4-diCl
4-Cl
4-Br
3,4-diCl
AURA
NDb
ND
8
AURB
30
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
6
6
6
6
6
6
6
6
6
6
6
6
6
5
5
6
6
6
6
5
5
5
m
m
m
p
p
p
p
p
p
p
p
p
p
p
p
m
p
p
p
p
p
p
ND
ND
ND
ND
ND
ND
ND
10.2
ND
ND
ND
0.7
13e
13f
13g
13h
13i
13j
13k
13l
13m
13n
13o
13p
13q
13r
13s
14a
14b
14c
14d
14e
14f
NAc
45
15
7
40
63
58
34
66
69
76
65
86
88
42
35
80
94
55
70
13
NA
5
NA
10
NA
8
24
8
6
0.6
ND
ND
ND
50.4
ND
49.4
ND
ND
ND
1
NA
NA
2
4
3
5
37
74
74
14g
a Relative percent inhibitory activity against staurosporine at 10 μM. Determined IC50 value of staurosporine was 1.5 nM according to provided procedure of
ADP-Glo assay kit by Promega. Compounds were treated at 10 μM. b ND = Not Determined. c NA = Not Active.
Figure 3. The predicted docking results of compound 13q with Aurora A and Aurora B kinase. (A) Overlay structure of human Aurora A-TPX2 complex colored
blue (PDB ID: 3E5A) and human Aurora B-INCENP complex colored yellow (PDB ID: 4AF3), with compound 13q colored magenta. (B) Docked conformation
of compound 13q in the active site of Aurora B kinase colored yellow.
Compound 13q was docked into the active site of Aurora B
kinase using Tripos sybyl-X ver. 2.1.1. The crystal structure of
human Aurora B kinase cocrystalized with its potent inhibitor
VX-680 was used for the docking analysis (PDB ID: 4AF3).16
The most likely binding conformations were selected based on
the docking score and the binding mode. In addition, the crystal
structure of human Aurora A kinase (PDB ID: 3E5A)18 was
aligned with Aurora B to provide a possible explanation for the
selectivity of our compounds for Aurora B over Aurora A kinase
(Fig. 3A). The binding mode of compound 13q was similar to
that of the reference compound VX-680 in the active site of
Aurora B kinase. The nitrogen atom of the benzoxazole ring and
the amino group of the aminobenzoxazole moiety interacted with
Tyr156 and Glu155 at the hinge backbone, which is considered
to be a key interaction in the maintenance of the activity against
kinases. The terminal aromatic ring substituted with a halogen
atom reached up to near the DFG motif. Additionally, the
carbonyl group of the urea linker formed a H-bond interaction
with Lys106 at the β3 strand. As colored in blue and yellow in
Figure 3, respectively, Aurora A and B kinases have high
sequence homology, however there is a critical difference at
residue Glu161 in Aurora B (Thr217 in Aurora A), which can

give different electrostatic and spatial states in the active site.19,20
In the active site of Aurora B, the oxygen atom of the
alkoxybenzoxazole moiety could make an additional H-bond
with Glu161 through a water molecule (Fig. 3B). This water-
mediated H-bond interaction could be the cause of selectivity.20
Figure 4. Antitumor activity of compound 13q on prostate cancer PC-3
xenograft model. (A) Growth curve of the prostate cancer PC-3 xenograft in
nude mice treated with compound 13q (50 mg/kg) or vehicle (10%
dimethylacetamide and 10% Tween 80 in water) once a day p.o. for 16 days.
The tumor volumes in each group were measured every two or three days. (B)
The weight of xenograft tumors from different groups that harvested on day
16 after the first administration of 13q or vehicle. (C) Body weight change of
mice during treatment with compound 13q or vehicle. Student’s t-test was
used to determine the statistical significance: *** p < 0.001.
Table 3
Growth inhibitory effect of compound 13l and 13q
GI50 (μM)
A novel series of aminobenzoxazole analogs were designed
and synthesized as Aurora B kinase inhibitors and their structure
activity relationship was investigated. Some of the tested
compounds revealed promising inhibitory activities against
Aurora B kinase. Among these compounds, dichloro-substituted
compound 13q was the most potent. A molecular docking study
suggested the putative binding mode of the most potent
compound 13q, implying the cause of the Aurora B selectivity.
Compound 13q showed antitumor activity against the human
adenocarcinoma cell lines and PC-3 tumor xenograft model in
vivo. This work provides an attractive lead for further structure
optimization in the discovery of more selective and potent
Aurora B kinase inhibitors.
MDA-
MB-231
Cpd.
ACHN
PC-3 NUGC- HCT-
NCI-
H23
3
15
2.2
2.6
7.6
6.2
4.8
5.5
4.8
4.0
3.4
13l
5.0
8.4
3.0
13q
Cell proliferation assay was performed on various
adenocarcinoma cell lines with the potent compounds 13l and
13q. GI50 values of compounds 13l and 13q ranged from 2.2 to
8.4 μM (Table 3). In vivo antitumor activity of compound 13q
was evaluated against prostate cancer PC-3 xenograft tumors in
nude mice (Fig. 4). Compound 13q was subsequently dosed
orally at 50 mg/kg for 16 days (qdx16). In vivo efficacy was
assessed as reduction of tumor growth in 13q-treated versus
vehicle-treated mice. In contrast to the vehicle-treated mice,
tumor growth suppression was observed in all mice that treated
13q without significant loss of body weight or visible toxicity.
Taken together, we provide 13q as a potential lead compound for
the development of wide range of Aurora B kinase inhibitor with
better activity and safety profile.
Acknowledgments
We dedicate this article to Professor Young-Ger Suh on the
occasion of his retirement. This research was supported by the
National Research Foundation of Korea (NRF) grant funded by
the Korea government (MSIP) (No. 2011-0030074 and
2014R1A2A1A11052761).
A. Growth curve
900
Vehicle
13q (50 mg/kg)
Supplementary data
600
***
Supplementary data associated with this article can be found, in
the online version, at.
300
0
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20
13q (50 mg/kg)
0
0
4
8
12
16
Days

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Graphical Abstract
Design and synthesis of novel
benzoxazole analogs as Aurora B
kinase inhibitors
Leave this area blank for abstract info.
Ying An a, 1, Eun Lee a, 1, Yeongji Yu a, Ji Eun Yun b, Myeong Youl Lee b, Jong Soon Kang b, Woo-
Young Kim a, and Raok Jeon a, *
a
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University,
Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul, 04310, Korea
b Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang,
chungcheongbuk-do, 28116, Korea