Discovery and SAR studies of novel 2-anilinopyrimidine-based selective inhibitors against triple-negative breast cancer cell line MDA-MB-468

Article abstract of DOI:10.1016/j.bmcl.2018.11.010

Triple-negative breast cancers (TNBCs) are characterized as an invasive and intractable subtype of breast cancers. Overexpression of epidermal growth factor receptor (EGFR) has been considered to be an important target for TNBC therapy, but efficacies of

Full text of DOI:10.1016/j.bmcl.2018.11.010

Accepted Manuscript
Discovery and SAR studies of novel 2-anilinopyrimidine-based selective in-
hibitors against triple-negative breast cancer cell line MDA-MB-468
Jeyun Jo, Sou Hyun Kim, Heegyu Kim, Myeonggyo Jeong, Jae-Hwan Kwak,
Young Taek Han, Jee-Yeong Jeong, Young-Suk Jung, Hwayoung Yun
PII:
S0960-894X(18)30864-3
https://doi.org/10.1016/j.bmcl.2018.11.010
BMCL 26121
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 August 2018
30 October 2018
6 November 2018
Please cite this article as: Jo, J., Hyun Kim, S., Kim, H., Jeong, M., Kwak, J-H., Taek Han, Y., Jeong, J-Y., Jung,
Y-S., Yun, H., Discovery and SAR studies of novel 2-anilinopyrimidine-based selective inhibitors against triple-
negative breast cancer cell line MDA-MB-468, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://
doi.org/10.1016/j.bmcl.2018.11.010
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Graphical Abstract
Discovery and SAR studies of novel 2-
anilinopyrimidine-based selective inhibitors
against triple-negative breast cancer cell line
MDA-MB-468
Leave this area blank for abstract info.
Jeyun Joa,†, Sou Hyun Kima,†, Heegyu Kima, Myeonggyo Jeonga, Jae-Hwan Kwakb, Young Taek Hanc, Jee-
Yeong Jeongd, Young-Suk Junga, and Hwayoung Yuna,
R2
O
Me
21 (R = piperidine)
GI50 (MDA-MB-468) = 6.4 M
GI50 (MCF-7) = 28.1 M
N
R
R1
N
Ring Modification
O
N
N
N
N
N
O
O
N
38 (R = diethylamine)
GI50 (MDA-MB-468) = 6.9 M
GI50 (MCF-7) > 30 M
N
N
H
N
N
H
2-anilinopyrimidine analogs
H
1 (hit compound)
29 compounds

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Discovery and SAR studies of novel 2-anilinopyrimidine-based selective
inhibitors against triple-negative breast cancer cell line MDA-MB-468
Jeyun Joa,†, Sou Hyun Kima,†, Heegyu Kima, Myeonggyo Jeonga, Jae-Hwan Kwakb, Young Taek Hanc, Jee-
Yeong Jeongd, Young-Suk Junga, and Hwayoung Yuna,
aCollege of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
bCollege of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea
cCollege of Pharmacy, Dankook University, Cheonan 31116, Republic of Korea
dDepartment of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Triple-negative breast cancers (TNBCs) are characterized as an invasive and intractable subtype
of breast cancers. Overexpression of epidermal growth factor receptor (EGFR) has been
considered to be an important target for TNBC therapy, but efficacies of EGFR inhibitors in
clinical trials are elusive. In this study, novel series of 2-anilinopyrimidines were synthesized in
an effort to identify selective inhibitors against an EGFR-overexpressing TNBC cell line.
Biological evaluation demonstrated that compounds 21 and 38, with a 4-methylpiperidine group
and a high ClogP value, exhibited good potency and selectivity for the TNBC cell line. This study
has provided evidence to support further development of 2-anilinopyrimidine-based TNBC
selective inhibitors and investigation of the targets of compounds 21 and 38.
Keywords:
Triple-negative breast cancer
2-Anilinopyrimidine
Growth inhibition
Lipophilicity
2009 Elsevier Ltd. All rights reserved.
Selectivity index
———
 Corresponding author. Tel.: +82-51-510-2816; fax: +82-51-513-6754; e-mail: youngjung@pusan.ac.kr (Y.-S. Jung)
 Corresponding author. Tel.: +82-51-510-2810; fax: +82-51-513-6754; e-mail: hyun@pusan.ac.kr (H. Yun)
† These authors contributed equally to this work.

OH
O
Cl
Triple-negative breast cancers (TNBCs) are defined as
aggressive mammary tumors that are characterized by the lack of
estrogen receptor (ER), progesterone receptor (PR), and human
epidermal growth factor receptor 2 (HER2).1-4 Based on the gene
expression (GE) profiles, TNBCs can be subdivided into six
a
c
O2N
R
7
: R = NO2
: R = NH2
6
b
4
X
Cl
subtypes: basal-like
1
(BL1), basal-like
2
(BL2),
N
X = O, S, CH2
immunomodulatory (IM), mesenchymal (M), mesenchymal stem-
like (MSL), and luminal androgen receptor (LAR).3-5 TNBCs
account for approximately 15%–20% of all diagnosed breast
cancer cases and basal-like type breast cancer constitute
approximately 50%–75% of all TNBC tumors.4-8 Cytotoxic
chemotherapy remains the standard treatment for TNBC, but
contributes to the improvement of only approximately 20% of
patients with TNBC.1-7 In addition, no approved targeted therapy
has been made available for TNBCs.
R1
N
d
R1
N
O
N
O
N
N
H
N
H
Me
N
O
N
S
8 30
-
N
N
N
5a
Me
5b
Cl
5c
5d
R1
=
Numerous molecular-profiling studies have revealed the
potential therapeutic targets of TNBCs, which belong to
proliferative and survival-dependent pathways.8-10 In particular,
the overexpression of epidermal growth factor receptor (EGFR) in
TNBC is well known in comparison with other breast cancer
subtypes and has shown to be a negative prognostic factor.8-13
Furthermore, many EGFR inhibitors have been clinically
investigated against TNBC. However, triple-negative and basal-
like breast cancers frequently display abnormalities in PTEN (the
gene encoding the phosphatase and tensin homolog), which
counteracts the antitumor activity of anti-EGFR therapies.14,15
Currently, there is no effective single anti-EGFR agent for the
treatment of TNBC.8-13
N
N
N
N
5e
5f
5g
5h
X
X
Me
X
O
N
S
N
N
N
N
N
N
N
N
O
O
O
N
N
N
N
H
N
N
N
H
H
8
9
10
11
12
13
14
15
16
X = O
X = S
X = CH2
X = O
X = S
X = CH2
X = O
X = S
X = CH2
R'
N
N
X
X
X
In the context of finding novel EGFR-overexpressing TNBC
selective inhibitors, an in-house chemical library was screened in
MCF-7 and MDA-MB-468 cell lines using a dose dependent MTT
assay. MCF-7 is a representative luminal-type breast cancer cell
line, whereas MDA-MB-468 is a unique EGFR-overexpressing
TNBC cell line.16 In particular, MDA-MB-468 exhibits resistance
to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib,
because the lack of PTEN permits a high threshold of Akt activity,
independent of receptor tyrosine kinase input.15,17 Moreover, the
cell line has a p53 mutation that can drive cell survival and
proliferation through diverse pathways.18-20 For these reasons, the
discovery of potent inhibitors against MDA-MB-468 is
challenging and only a limited number of studies have been
conducted.21-25 After cell-based screening of the chemical library,
we have identified hit compound 1 (Figure 1A). Interestingly,
compound 1 selectively inhibited the proliferation of MDA-MB-
468 cells (GI50 = 18.3 μM) compared with that of the MCF-7 cells
(GI50 > 30.0 μM), and had relatively good lead-like properties
(MW ≤ 460, rings ≤ 4, hydrogen-bond donors ≤ 5, hydrogen-bond
acceptors ≤ 9, and -4 ≤ LogP ≤ 4.2).26 In addition, the structure of
compound 1 contains a 2-anilinopyrimidine backbone, which has
widely been investigated in the field of medicinal chemistry.27-31
Thus, we designed and synthesized a library of novel 2-
anilinopyrimidine derivatives through the modification of the
piperidine and morpholine rings of 1 and attempted to establish a
brief structure-activity relationship (SAR).
N
N
N
N
N
N
N
O
O
O
N
N
N
N
H
N
H
N
H
1
25
26
27
28
29
30
R' = H; X = O
R' = H; X = S
X = O
X = S
X = CH2
X = O
X = S
X = CH2
17
18
19
20
21
22
23
24
R' = H; X = CH2
R' = Me; X = O
R' = Me; X = S
R' = Me; X = CH2
R' = Cl; X = O
R' = Cl; X = S
R' = Cl; X = CH2
Scheme 2. Synthesis of analogs 1, 8-30. Reagent and conditions: (a) 3-chloro-
1-propanol, DIAD, PPh3, THF, 0 °C, 99%; (b) SnCl2·H2O, EtOH, 70 °C, 51%;
(c) 3a-3h, 1N HCl in AcOH, MW, 1-butanol, 15-60%; (d) morpholine or
thiomorpholine or piperidine, K2CO3, KI, DMF, 100 °C, 14-86%.
Our synthetic strategy for the 2-anilinopyrimidine analogs is
outlined in Figure 1B. The overall strategy focused on the
modification of both the A and B parts within the final 2-
anilinopyrimidines. The efficient synthesis incorporated two
simple derivatization processes: the SNAr reaction of the
commercially available 2 with various amines, and the SN2
reaction of the advanced intermediate 5 with various amines.

A.
O
B
R2
N
A
Ring Modification
R1
N
N
N
O
O
N
N
N
N
H
H
1
2-anilinopyrimidine analogs
GI50 (MCF-7) > 30 M
GI50 (MDA-MB-468) = 18.3 M
Cl
2nd
derivatization
B.
Cl
4
O
1st
R1
R1
Cl
derivatization
H2N
O
N
N
N
N
N
N
Cl
N
Cl
H
Figure 2. Correlation between the lipophilicity parameter ClogP and
2
3
5
cytotoxic activity at 10 µM in MDA-MB-468 cells
Figure 1. (A) Design of novel 2-anilinopyrimidines; (B) Derivatization
OH
a
c
O
N
The synthesis of novel 2-anilinopyrimidine derivatives
O2N
commenced
with
the
preparation
of
2-chloro-4-
R
aminopyrimidines
substitution of 2 and various cyclic and acyclic amines smoothly
afforded the desired aminopyrimidines 3a–3e, 3g, and 3h,
3
(Scheme 1). Nucleophilic aromatic
31
: R = NO2
: R = NH2
6
b
32
Me
N
O
N
S
without
the
use
of
a
base.
However,
4-
1
1
1
33
36
34
35
38
R
=
=
R
=
=
R =
chloropiperidinopyrimidine 3f was obtained in the presence of
n-BuLi.
N
N
N
R1
N
Me
With the 4-substituted 2-chloropyrimidines 3 available, we
executed the synthesis of the final analogs (Scheme 2).
Mitsunobu reaction of 6 with DIAD and PPh3, followed by nitro
reduction of the resultant chloropropoxybenzene 7 largely
provided the chloropropoxyaniline 4. Unfortunately, our initial
attempts to combine aniline 4 and the 2-chloropyrimidines 3a-
3h under conventional conditions were unsuccessful. However,
these reluctant couplings achieved under microwave-assisted
conditions. The desired 2-anilinopyrimidines 5a-5h were
O
N
1
1
1
37
R
R
R =
N
N
H
N
N
Scheme 3. Synthesis of analogs 33-38. Reagent and conditions: (a) 3-
diethylamino-1-propanol, DIAD, PPh3, THF, 0 °C, 95%; (b) SnCl2·H2O, EtOH,
70 °C, 79%; (c) 3a-3e or 3g, 1N HCl in AcOH, MW, 1-butanol, 8-33%.
Having established a synthetic procedure, we undertook the
Table 1. Cytotoxic activities of 2-anilinopyrmidines against the MCF-7 and MDA-MB-468 cell lines.
readily obtained, although the yields of some reactions were
unsatisfactory. Finally, simple SN2 reactions of 5a-5h with
morpholine, thiomorpholine, and piperidine provided the 2-
anilinopyrimidine analogs 8-30.
synthesis of the acyclic analogs 33-38, as shown in Scheme 3.
Mitsunobu reaction of 6 with 3-diethylamino-1-propanol in the
presence of DIAD and the subsequent reduction of the resulting
nitrobenzene 31 afforded the diethylaminopropoxyaniline 32.
Finally, the microwave-assisted SNAr reaction of 32 with 3a-3e or
3g under acidic condition successfully provided the desired 2-
anilinopyrimidine analogs 33-38.
R1
Cl
a or b
N
N
N
Cl
N
Cl
With the synthesized compounds in hand, we evaluated their
antiproliferative activities on luminal type breast cancer cells
MCF-7 and TNBC cells MDA-MB-468 through a dose dependent
2
3
Me
N
O
N
S
N
MTT
(3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assay (Table 1). The results demonstrated that newly
synthesized analogs were generally less cytotoxic to MCF-7 cells
than gefitinib, when compounds were treated at 10 µM
concentration. Interestingly, we observed that antiproliferative
effects of 2-anilinopyrimidines in MDA-MB-468 cells relied upon
specific molecular features. First, an investigation into the effect
of substituents in the A part was conducted. 4-Methylpiperidine
analogs 19, 20, 21 and 38 exhibited pronounced cytotoxic activity
in TNBC cells. In particular, the presence of a methyl group in the
4-position of piperidine, as seen in 19, resulted in substantially
increased antiproliferative activity in TNBC cells and decreased
toxicity in MCF-7 cells as compared to hit compound 1. This result
showed that a methyl group in the 4-position of piperidine had an
essential role in the selective cytotoxicity on MDA-MB-468 cells.
However, the substitution of relatively hydrophilic groups, such as
morpholine (8-10), thiomorpholine (11-13) or N-methylpiperazine
N
N
N
N
N
R
Cl
N
Cl
N
Cl
3a
3b
3c
N
N
N
N
N
N
N
N
N
Cl
Cl
Cl
3d
3e
3f
3g
3h
R = H
R = Me
R = Cl
Scheme 1. Preparation of 2-chloro-4-aminopyrimidines 3a-3h. Reagent and
conditions: (a) morpholine, thiomorpholine, 1-methylpiperazine, piperidine, 4-
methylpiperidine, pyrrolidine or diethylamine, EtOH, rt, 17-70%; (b) 4-
chloropiperidine, n-BuLi, THF, 0 °C, 41%.
a Values are the mean ± standard deviation of three experiments.
b ClogP values were calculated from ChemDraw Professional 15.1.

the A part, exhibited great potent activity with 16.9% of MDA-
MB-468 cells survival even at 10 µM.
Table 2. Growth inhibitory effects and selectivity index (SI) of selected
compounds.
The preliminary SAR study guided us to evaluate the
relationship between the lipophilicity parameter ClogP and the
cytotoxic activity in MDA-MB-468 cells. As displayed in Table 1,
the synthesized analogs have wide range of ClogP values from
2.89 to 6.01. Generally, analogs with low ClogP values exhibit low
activities. However, the most potent compounds, 21 and 38, have
highest ClogP values with 6.01 and 5.87, respectively. This result
showed that the activity of the compounds was strongly dependent
on lipophilicity, as depicted in Figure 2. As increased lipophilicity
of compounds leads to improved membrane permeability,32,33 the
activity of the analogs might be closely associated with the cell
permeability. The SAR study did not reveal any relationship
between the activity in MCF-7 cells and lipophilicity or specific
structural features. Thus, these results led us to suggest that the
target of novel 2-anilinopyrimidines was located intracellularly or
intranuclearly in MDA-MB-468 cells specifically.
Comp.
GI50 (µM)a
MDA-MB-468
MDA-MB-468 SI b
MCF-7
>30
18
9.2
>3.3
>1.8
4.4
19
>30
16.3
6.4
21
28.1
>30
24
11.5
7.6
>2.6
3.6
29
27.3
18.3
>30
30
11.4
6.9
1.6
38
>4.3
>1.2
gefitinib
>30
25.5
a GI50 values are the mean of three experiments and correspond to the
concentration of compound that causes a 50% decrease in net cell growth.
b SI = GI50 for MCF-7 cells/GI50 for MDA-MB-468 cells.
The aim of our work was not only to discover potent analogs
against the TNBC cell line, but also to develop selective inhibitors.
The selectivity of potent analogs for TNBC cells was evaluated by
dividing the GI50 for MCF-7 cells by the GI50 values for MDA-
MB-468 cells (Table 2). As expected, all selected compounds
displayed higher potency than gefitinib against MDA-MB-468
cells. Compound 30 exhibited the lowest selectivity, with an SI of
1.6, whereas the selectivity of compound 18 was more 2-fold
greater (SI > 3.3) than 30. It is assumed that the presence of cyclic
amine in the A part was of great importance for the selectivity.
Especially, the most potent compounds, 21 (GI50 = 6.4 µM) and 38
(GI50 = 6.9 µM), showed highly selective activity against TNBC
cell line, as indicated by selectivity index (SI > 4.3). This finding
supports that the introduction of 4-methylpiperidine in A part led
to 2-anilinopyrimidines with promising activity and selectivity for
the target TNBC cell line.
(14-16) in the A part did not lead to potent inhibition against the
TNBC cells. The analogs 22-24, bearing 4-chloropiperidine in the
same part, were moderately cytotoxic to TNBC cells while the
pyrrolidine or acyclic amine substituted analogs 25-30 were less
active than 1. From these results, we suggest that the insertion of
less polar substituent into the A part led to 2-anilinopyrimidines
with promising activity for TNBC cells.
Next, we turned our attention to the effects of substituents in
the B part. The results shown in Table 1 demonstrate that the 2-
anilinopyrimidines bearing morpholine or thiomorpholine were
generally not potent inhibitors of the MDA-MB-468 cell line, with
the exception of 29. However, the piperidine substituted analogs
18, 21, 24 and 30 were more cytotoxic to TNBC cells than 1. This
result suggested that the piperidine group in the B part was
preferred to other substituents for anti-TNBC activity. The
introduction of acyclic amine into the B part (33-37) resulted in
In summary, a series of novel 2-anilinopyrimidine-based
derivatives were synthesized and evaluated for their in vitro
Comp.
Cell viability at 10 µM (% of untreated control)a
ClogPb
Comp.
Cell viability at 10 µM (% of untreated control)a
ClogPb
MCF-7
MDA-MB-468
55.2 ± 1.3
84.5 ± 1.4
57.4 ± 0.5
86.8 ± 1.9
73.4 ± 0.7
65.0 ± 2.2
78.1 ± 4.4
80.7 ± 1.0
56.5 ± 2.7
71.7 ± 2.7
71.8 ± 3.9
45.1 ± 0.6
51.3 ± 1.9
61.3 ± 1.2
21.3 ± 2.4
61.6 ± 3.7
MCF-7
MDA-MB-468
62.7 ± 1.8
52.1 ± 2.5
77.1 ± 2.6
78.3 ± 0.3
58.1 ± 0.9
69.7 ± 2.5
36.0 ± 2.3
53.1 ± 3.2
79.4 ± 3.6
88.0 ± 4.7
64.6 ± 1.3
69.7 ± 3.2
62.0 ± 5.1
16.9 ± 1.2
60.3 ± 1.6
1
61.8 ± 1.0
83.2 ± 3.7
67.9 ± 2.8
95.7 ± 4.0
86.1 ± 2.2
77.8 ± 4.3
60.0 ± 1.4
89.6 ± 2.9
79.8 ± 2.3
76.9 ± 5.0
72.9 ± 1.3
86.7 ± 2.4
71.8 ± 0.9
79.5 ± 1.9
73.7 ± 4.0
93.3 ± 4.1
4.27
2.89
3.63
3.96
3.72
4.46
4.79
3.45
4.18
4.67
5.01
5.34
4.79
5.53
6.01
4.41
23
87.7 ± 1.4
87.1 ± 2.9
89.0 ± 3.8
84.7 ± 3.7
66.1 ± 1.3
94.9 ± 3.3
91.9 ± 2.5
69.7 ± 2.4
66.5 ± 1.5
86.4 ± 4.5
67.0 ± 3.4
78.5 ± 1.8
95.4 ± 3.4
93.2 ± 5.0
70.3 ± 1.5
5.14
5.62
3.71
4.45
4.78
4.66
5.39
5.87
3.97
4.81
4.42
4.80
5.36
5.87
5.45
8
24
9
25
10
11
12
13
14
15
16
17
18
19
20
21
22
26
27
28
29
30
33
34
35
36
37
38
gefitinib
moderate toxicity to TNBC cells. However, for the acyclic amine
analog 38, in which a 4-methylpiperidine group is substituted in
growth inhibition activities in luminal type breast cancer cell line
MCF-7 and basal-like TNBC cell line MDA-MB-468. In these
newly synthesized compounds, a strong correlation was observed

23. Weldon, D. J.; Saulsbury, M. D.; Goh, J.; Rowland, L.; Campbell,
P.; Robinson, L.; Miller, C.; Christian, J.; Amis, L.; Taylor, N.;
Dill, C.; Davis Jr, W.; Evans, S. L.; Brantley, E. Bioorg. Med.
Chem. Lett. 2014, 24, 3381.
24. Kim, Y. J.; Pyo, J. S.; Jung, Y.-S.; Kwak, J.-H. Bioorg. Med.
Chem. Lett. 2017, 27, 607.
25. Yamashita, N.; Kondo, M.; Zhao, S.; Li, W.; Koike, K.; Nemoto,
K.; Kanno, Y. Bioorg. Med. Chem. Lett. 2017, 27, 2608.
26. Hann, M. H.; Oprea T. I. Curr. Opin. Chem. Biol. 2004, 8, 255.
27. Cocuzza, A. J.; Hobbs, F. W.; Arnold, C. R.; Chidester, D. R.;
Yarem, J. A.; Culp, S.; Fitzgerald, L.; Gilligan, P. J. Bioorg. Med.
Chem. Lett. 1999, 9, 1057.
between the lipophilicity parameter ClogP and the
antiproliferative activity against the TNBC cell line. The SAR
studies and selectivity analysis suggested that the 4-
methylpiperidine group in A part turned out crucial for the
selective cytotoxicity on MDA-MB-468 cells. Two compounds 21
and 38 showed the most promising potency and the highest SI
values for the TNBC cell line. From these observations,
investigation of novel lead scaffolds and identification of target of
MDA-MB-468 selective inhibitors are underway.
28. Ali, A.; Aster, S. D.; Graham, D. W.; Patel, G. F.; Taylor, G. E.;
Tolman, R. L.; Painter, R. E.; Silver, L. L.; Young, K.; Ellsworth,
K.; Geissler, W.; Harris, G. S. Bioorg. Med. Chem. Lett. 2001, 11,
2185.
29. Romu, A. A.; Lei, Z.; Zhou, B.; Chen, Z.-S.; Korlipara, V. Bioorg.
Med. Chem. Lett. 2017, 27, 4832.
30. Determann, R.; Dreher, J.; Baumann, K.; Peru, L.; Jones, P. G.;
Totzke, F.; Schächtele, C.; Kubbutat, M. H. G.; Kunick C. Eur. J.
Med. Chem. 2012, 53, 254.
Acknowledgments
This research was supported by the Bio & Medical Technology
Development Program of the National Research Foundation (NRF)
funded by the Ministry of Science, ICT & Future Planning,
Republic of Korea (NRF-2016M3A9A5916225) and the Korean
government (MSIT) (NRF-2017M3A9G7072568).
31. Han, Y. T.; Kim, K.; Son, D.; An, H.; Kim, H.; Lee, J.; Park, H.-J.
Lee, J.; Suh, Y.-G. Bioorg. Med. Chem. 2015, 23, 579.
32. Sarmento, B.; Andrade, F.; da Silva, S. B.; Rodrigues, F.; das
Neves, J.; Ferreira, D. Expert Opin. Drug Metabol. Toxicol. 2012,
8, 607.
A. Supplementary data
33. Dasari, R.; Banuls, L. M. Y.; Masi, M.; Pelly, S. C.; Mathieu, V.;
Green, I. R.; van Otterlo, W. A. L.; Evidente, A.; Kiss, R.;
Kornienko, A. Bioorg. Med. Chem. Lett. 2014, 24, 923.
References
1.
Foulkes, W. D.; Smith, I. E.; Reis-Filho, J. S. N Engl J Med. 2010,
363, 1938.
∙ A series of novel 2-anilinopyrimidines were
synthesized and evaluated for anti-cancer activities.
∙ A strong correlation of the lipophilicity parameter
ClogP with antiproliferative activity against TNBC
cell line was observed.
∙ Compounds 21 and 38 possessing a 4-
methylpiperidine group exhibited good potency and
selectivity for TNBC cell line.
2.
3.
Hudis, C. A.; Gianni, L. The Oncologist. 2011, 16, 1.
Bianchini, G.; Balko, J. M.; Mayer, I. A.; Sanders, M. E.; Gianni,
L. Nat. Rev. Clin. Oncol. 2016, 13, 674.
Kalimutho, M.; Parsons, K.; Mittal, D.; López, J. A.; Srihari, S.;
Khanna, K. K. Trends Pharmacol Sci. 2015, 36, 822.
Lehmann, B. D.; Bauer, J. A.; Chen, X.; Sanders, M. E.;
Chakravarthy, A. B.; Shyr, Y.; Pietenpol, J. A. J Clin Invest. 2011,
121, 2750.
Perou, C. M. The Oncologist. 2010, 15, 39.
Polyak, K. J Clin Invest. 2011, 121, 3786.
Bauer, K. R.; Brown, M.; Cress, R. D.; Parise, C. A.; Caggiano, V.
Cancer. 2007, 109, 1721.
4.
5.
6.
7.
8.
9.
Crown, J.; O’Shaughnessy, J.; Gullo, G. Annals Oncol. 2012, 23,
vi56.
R2
O
10. Mayer, I. A.; Abramson, V. G.; Lehmann, B. D.; Pietenpol, J. A.
Clin Cancer Res. 2014, 20, 782.
11. Fosu-Mensah, N.; Peris, M. S.; Weeks, H. P.; Cai, J.; Westwell, A.
Future Med. Chem. 2015, 7, 2019.
12. Ueno, N. T.; Zhang, D. J. Cancer. 2011, 2, 324.
13. Tomao, F.; Papa, A.; Zaccarelli, E.; Rossi, L.; Caruso, D.;
Minozzi, M.; Vici, P.; Frati, L.; Tomao, S. Onco Targets Ther.
2015, 8, 177.
N
R1
N
Ring Modification
O
N
N
N
O
N
N
H
N
H
2-anilinopyrimidine analogs
29 compounds
1 (hit compound)
14. Marty, B.; Maire, V.; Gravier, E.; Rigaill, G.; Vincent-Salomon,
A.; Kappler, M.; Lebigot, I.; Djelti, F.; Tourdès, A.; Gestraud, P.;
Hupé, P.; Barillot, E.; Cruzalegui, F.; Tucker, G. C.; Stern, M.-H.;
Thiery, J.-P.; Hickman, J. A.; Dubois, T. Breast Cancer Res. 2008,
10, R101.
15. Bianco, R.; Shin, I.; Ritter, C. A.; Yakes, F. M.; Basso, A.; Rosen,
N.; Tsurutani, J.; Dennis, P. A.; Mills, G. B.; Arteaga, C. L.
Oncogene. 2003, 22, 2812.
16. Holliday, D. L.; Speirs, V. Breast Cancer Res. 2011, 13, 215.
17. Yamasaki, F.; Zhang, D.; Bartholomeusz, C.; Sudo, T.;
Hortobagyi, G. N.; Kurisu, K.; Ueno, N. T. Mol Cancer Ther.
2007, 6, 2168.
18. Lim, L.Y.; Vidnovic, N.; Ellisen, L. W.; Leong, C.-O. Br. J.
Cancer. 2009, 101, 1606.
19. Wang, W.; Cheng, B.; Miao, L.; Mei, Y.; Wu, M. Cell Death Dis.
2013, 4, e574.
20. Tan, B. S.; Tiong, K. H.; Choo, H. L.; Chung, F. F.-L.; Hii, L.-W.;
Tan, S. H.; Yap, I. K. S.; Pani, S.; Khor, N. T. W.; Wong, S. F.;
Rosli, R.; Cheong, S.-K.; Leong, C.-O. Cell Death Dis. 2015, 6,
e1826.
21. Mandal, S.; Bérubé, G.; Asselin, É.; Richardson, V. J.; Church, J.
G.; Bridson, J.; Pham, T. N. Q.; Pramanik, S. K.; Mandal, S. K.
Bioorg. Med. Chem. Lett. 2007, 17, 2139.
22. Lion, C. J.; Matthews, C. S.; Stevens, M. F. G.; Westwell, A. D. J.
Med. Chem. 2005, 48, 1292.