SAR optimization studies on a novel series of 2-anilinopyrimidines as selective inhibitors against triple-negative breast cancer cell line MDA-MB-468

Article abstract of DOI:10.1016/j.bmcl.2019.126752

Triple-negative breast cancers (TNBCs) account for approximately 15% of breast cancer cases and exhibit an aggressive clinical behavior. In this study, we designed and synthesized two series of 2-anilinopyrimidines based on the structure of our previously

Full text of DOI:10.1016/j.bmcl.2019.126752

Journal Pre-proofs
SAR optimization studies on a novel series of 2-anilinopyrimidines as selective
inhibitors against triple-negative breast cancer cell line MDA-MB-468
Jeyun Jo, Heegyu Kim, Ji Youn Oh, Soyeong Kim, Yeong Hye Park, Hyeonjin
Choi, Jee-Yeong Jeong, Young-Suk Jung, Hwayoung Yun
PII:
S0960-894X(19)30715-2
DOI:
https://doi.org/10.1016/j.bmcl.2019.126752
BMCL 126752
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 September 2019
9 October 2019
10 October 2019
Please cite this article as: Jo, J., Kim, H., Oh, J.Y., Kim, S., Park, Y.H., Choi, H., Jeong, J-Y., Jung, Y-S., Yun, H.,
SAR optimization studies on a novel series of 2-anilinopyrimidines as selective inhibitors against triple-negative
breast cancer cell line MDA-MB-468, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/
10.1016/j.bmcl.2019.126752
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will
undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing
this version to give early visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Elsevier Ltd. All rights reserved.

Graphical Abstract
SAR optimization studies on a novel series of
2-anilinopyrimidines as selective inhibitors
against triple-negative breast cancer cell line
MDA-MB-468
Leave this area blank for abstract info.
Jeyun Joa,†, Heegyu Kima,†, Ji Youn Oha,†, Soyeong Kima, Yeong Hye Parka, Hyeonjin Choia, Jee-Yeong
Jeongb, Young-Suk Junga, , Hwayoung Yuna,

Bioorganic & Medicinal Chemistry Letters
SAR optimization studies on a novel series of 2-anilinopyrimidines as selective
inhibitors against triple-negative breast cancer cell line MDA-MB-468
Jeyun Joa,†, Heegyu Kima,†, Ji Youn Oha,†, Soyeong Kima, Yeong Hye Parka, Hyeonjin Choia, Jee-Yeong
Jeongb, Young-Suk Junga, , Hwayoung Yuna,
aCollege of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
bDepartment 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) account for approximately 15% of breast cancer cases
and exhibit an aggressive clinical behavior. In this study, we designed and synthesized two series
of 2-anilinopyrimidines based on the structure of our previously reported compound 1 that act as
a selective inhibitor of the basal-like TNBC cell line MDA-MB-468. Through the fine-tuning of
1, cyclic and acyclic amines at 4-position of the pyrimidine core were turned out to be crucial for
the selectivity. An extensive analysis of structure-activity relationships of the analogs revealed
that aminoalkyl groups at the end of the propyl chain are amenable to modification. Among the
newly synthesized analogs, compound 38, bearing 4-chloropiperidine and cyclohexyl groups, was
found to be the most potent and selective, and was about three times more potent and selective
than 1 was against the TNBC cells.
Keywords:
Triple-negative breast cancer
2-Anilinopyrimidines
Selective inhibitor
Growth inhibition
Basal-like
2009 Elsevier Ltd. All rights reserved.
Triple-negative breast cancers (TNBCs), which represent a
highly aggressive subtype of mammary tumors, are defined by
lack of estrogen receptor (ER), progesterone receptor (PR), and
amplified human epidermal growth factor receptor 2 (HER2).1
Based on the gene expression (GE) profiles, breast cancers can be
subdivided into distinct groups, including luminal A, luminal B,
HER2-enriched, basal-like, and claudin-low.2-6 In particular, the
basal-like group typically shows a triple-negative phenotype and
approximately 80% of TNBCs are also basal-like breast cancers
(BLBCs).1,7 Basal-like TNBCs account for about 15% of all
diagnosed cases of mammary tumors and tend to exhibit a high
histological grade.8 Basal-like TNBCs are associated with poor
prognoses due to rapid metastatic recurrence and a lack of targeted
therapies.8 Currently, the only available systemic therapy for
basal-like TNBCs is cytotoxic chemotherapy, but only 20% of
patients respond to the treatment.8,9
poor overall survival rates.13-16 Some monoclonal antibodies and
small-molecules targeting EGFR have been clinically
investigated.17,18 However, preclinical and clinical trials of EGFR
inhibitors have demonstrated limited efficacy in TNBCs possibly
because of the activation of bypass signaling pathways, including
HER3, c-MET, and AXL.19-21 One of useful in vitro model systems
to identify novel inhibitors against TNBCs is the basal-like TNBC
cell line MDA-MB-468, which shows overexpression of EGFR
but resistance to EGFR tyrosine kinase inhibitors. This cell line
exhibits a high level of Akt activity due to the loss of PTEN
(phosphatase and tensin homolog) function, which accounts for
the anti-EGFR resistance.22 Moreover, the cell line shows other
recurrent basal-like molecular aberrations such as gene mutations
in TP53 (the gene encoding tumor protein 53) and constitutive
activation of the MEK/ERK pathway.23 Thus, MDA-MB-468 cells
provide a unique molecular status including triple-negative/basal-
like features. In this respect, finding potent and selective inhibitors
against MDA-MB-468 cells would be an effective approach to
develop novel targeted therapies for TNBCs, however, only a few
studies have been reported to date.24-29
Recent genomics and proteomics studies have revealed
molecularly distinct subtypes of TNBCs, which enabled the
identification of putative therapeutic targets for each subclass.10-12
In particular, several studies have shown that epidermal growth
factor receptor (EGFR), one of the positive markers of BLBCs, is
frequently overexpressed in TNBCs and highly associated with
We have recently demonstrated
a novel series of 2-
anilinopyrimidine-based selective inhibitors against TNBC cell
———
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.

line MDA-MB-468.29 Detailed structure-activity relationship
(SAR) analysis indicated that the lipophilicity parameter ClogP
was strongly correlated to the antiproliferative activity. In
particular, compound 1 containing a 4-methylpiperidine and a
piperidine groups exhibited the best potency and the highest
selectivity index (SI) values for the TNBC cell line (Figure 1). This
successful achievement prompted us to attempt further structural
modification of 1. Our fine-tuning strategy for newly designed 2-
anilinopyrimidine analogs mainly consists of a two-step process:
(1) introduction of aromaticity on the part A, and then (2)
substitution of the carbocycle or acyclic ether for the azacycle in
part B. Herein, we describe the continued optimization of our
TNBC selective inhibitor 1 and attempt to explore a brief
structure-activity relationship (SAR).
Our synthesis began with practical preparation of the 4-
substituted-2-chloropyrimidine 3 which could serve as a useful
building block (Scheme 1). Commercially available 2 was reacted
with pyrrole and indole in the presence of n-BuLi to afford the
fully conjugated fragments 3a and 3b, respectively. The remaining
2-chloropyrimidines 3c-3j were smoothly prepared from the
previously reported procedure by our group.29
Scheme 2. Synthesis of 2-anilinopyrimidines 7-12, 15, and 16. Reagents and
conditions: (a) 3-chloro-1-propanol, DIAD, PPh3, THF, 0 °C, 99%; (b)
SnCl2·H2O, EtOH, 70 °C, 51%; (c) 3a or 3b, 1 N HCl in AcOH, MW, 1-
butanol, 59-81%; (d) morpholine or thiomorpholine or piperidine, K2CO3, KI,
DMF, 100 °C, 30-64%; (e) 3-diethylamino-1-propanol, DIAD, PPh3, THF, 0
°C, 95%; (f) SnCl2·H2O, EtOH, 70 °C, 79%; (g) 3a or 3b, 1 N HCl in AcOH,
MW, 1-butanol, 27-29%.
With the building blocks 3 in hand, we first executed the
synthesis of the part A-modified analogs bearing a pyrrolyl or
indolyl group (Scheme 2). Our synthetic route initially focused on
construction of the common intermediates, 6a and 6b, which could
be diversified at the final stage (Scheme 2A). Aniline 5 was readily
synthesized from 4-nitrophenol (4) through a Mitsunobu reaction
with 3-chloro-1-propanol and a subsequent nitro reduction.29 The
common intermediates 6a and 6b were produced using
microwave-assisted nucleophilic aromatic substitution of aniline 5
with 3a and 3b, respectively. SN2-type derivatizations of 6a or 6b
with morpholine, thiomorpholine, or piperidine successfully
provided the final analogs 7-12. The synthetic journey toward
novel N,N-diethylamino analogs is described in Scheme 2B. A
Mitsunobu reaction of 4 with 3-diethylamino-1-propanol yielded
13, which was subjected to nitro reduction to furnish aniline 14.29
The acyclic analogs 15 and 16 were readily prepared through the
microwave-assisted SNAr reaction of 14 with the 4-substituted-2-
chloropyrimidines 3a and 3b, respectively.
At this stage, we conducted a dose-dependent MTT (3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay to
evaluate the antiproliferative activities of the synthesized
derivatives 7-12, 15, and 16 on luminal-type breast cancer cell line
MCF-7 and basal-like TNBC cell line MDA-MB-468. Table 1
shows cell viabilities at a concentration of 10 µM and the
concentrations required for 50% growth inhibition (GI50) for the
Table 1. Growth inhibitory effects and selectivity index (SI) values of
compounds 7-12, 15, and 16.
Comp.
Cell viability (%) at 10 µM (GI50 µM)a
MDA-
MB-
ClogPc
468 SIb
MCF-7
MDA-MB-468
1
73.1 ± 5.4 (28.6)
90.0 ± 6.1 (>30)
77.6 ± 3.3 (>30)
64.1 ± 2.6 (19.1)
22.7 ± 0.5 (6.2)
31.3 ± 0.6 (5.0)
20.6 ± 0.6 (2.4)
48.9 ± 2.7 (9.4)
19.3 ± 0.6 (2.2)
21.9 ± 2.9 (6.5)
90.2 ± 1.2 (>30)
86.9 ± 7.7 (>30)
87.7 ± 2.8 (22.0)
44.3 ± 1.6 (9.0)
43.5 ± 2.0 (8.8)
13.0 ± 1.2 (7.0)
69.1 ± 2.6 (16.8)
12.1 ± 0.6 (6.5)
4.4
6.01
4.13
4.87
5.20
5.51
6.25
6.58
5.21
6.60
7
N/A
N/A
0.87
0.69
0.57
0.34
0.56
0.34
8
9
10
11
12
15
16
Scheme 1. Preparation of 4-substituted-2-chloropyrimidine building blocks
3a-3j. Reagents and conditions: (a) pyrrole, indole or 4-chloropiperidine, n-
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.
BuLi, THF,
0
°C, 24-49%; (b) morpholine, thiomorpholine, 1-
b SI = GI50 for MCF-7 cells/GI50 for MDA-MB-468 cells.
methylpiperazine, piperidine, 4-methylpiperidine, pyrrolidine or diethylamine,
EtOH, 17-70%.
c ClogP values were calculated from ChemDraw Professional 15.1.

compounds. The results demonstrated that the indolyl analogs (10-
12 and 16) were more potent against the TNBC cell line than the
pyrrolyl analogs (7-9 and 15) were. The indolyl analogs possess a
higher ClogP value (5.51-6.60) than the value of pyrrolyl analogs
(4.13-5.21), which can explain an increased activities of the indole
derivatives against the TNBC cells. Among the compounds, 12
and 16 showed the highest potency with GI50 values of 7.0 and 6.5
µM, respectively against MDA-MB-468 cells, which is equipotent
to that of compound 1 (6.5 µM). Unexpectedly, some of the new
analogs displayed dramatically increased anti-proliferative
activities against the luminal-type cell line. In particular, 2-
anilinopyrimidines possessing a piperidine (12) or diethylamine
group (16) at part B exhibited a significantly higher potency (about
12 and 13-fold, GI50 = 2.4 and 2.2 µM, respectively) than that of 1
in MCF-7 cells. The result of our previous work showed that a
single change of piperidine to diethylamine on part B for
compound 1 maintained activity against and selectivity to the
TNBC cells.29 Similarly, compounds 12 and 16 also showed
equipotent activity and selectivity. Thus, this observation suggests
that the introduction of a heteroaromatic group into part A would
increase the cytotoxicity against the luminal-type breast cancer
cells rather than the TNBC cells.
Having accomplished the synthesis and biological evaluation of
the part A-modified derivatives, we then turned our attention to the
substitution of the azacyclic motif at the part B. The synthesis of
the part B-modified analogs commenced with the efficient
production of the common intermediates 19 and 20 as shown in
scheme 3. Utilizing 4 as a starting material, Mitsunobu reactions
with 3-methoxy-1-propanol or 3-cyclohexyl-1-propanol afforded
17 or 18, respectively, with good yields. Subsequently, simple
reduction of nitrobenzenes 17 and 18 gave the desired
intermediates 19 and 20, respectively. Finally, microwave-assisted
SNAr reactions of anilines 19 or 20 with the fragments 3a-3j
successfully rendered the target 2-anilinopyrimidine derivatives
21-40.
Scheme 3. Synthesis of 2-anilinopyrimidines 21-40. Reagents and conditions:
(a) 3-cyclohexyl-1-propanol or 3-methoxy-1-propanol, DIAD, PPh3, THF, 0
°C, 89-91%; (b) SnCl2·H2O, EtOH, 70 °C, 63-78%; (c) 3a-3j, 1 N HCl in
AcOH, MW, 1-butanol, 21-70%.
concentration. For the target TNBC cell line (MDA-MB-468), the
analogs generally displayed loss of activity but, nevertheless, some
compounds maintained reasonable cytotoxicity. In particular, the
4-methylpiperidinyl (27) and diethylamino (30) compounds
exhibited the highest potency with GI50 values of 11.8 and 13.6
µM, respectively. Although these analogs showed decreased anti-
proliferative activity against the target cells, we identified
important SARs. Specifically, acyclic ether compounds with a GI50
value lower than 30 µM against TNBC cells possess a
heteroaromatic (21 and 22), piperidinyl (26), 4-methylpiperidinyl
(27), 4-chloropiperidinyl (28), and diethylamino group (30) on
part A. These compounds have higher ClogP values (3.98-5.36)
than those with GI50 value over 30 µM (23-25 and 29, ClogP value
range of 2.74-3.57). This observation corresponded to the previous
With an efficient synthesis of the part B-modified analogs 21-
40 accomplished, we evaluated their cytotoxicity at graded
concentrations against the panel of cancer cell lines using an MTT
assay (Table 2). First, we investigated the effect of the acyclic
ether in part B. The results showed that analogs 21-30 were
generally less toxic to the luminal-type breast cancer cells than
compound 1 was, when the cells were treated at 10 µM
Table 2. Growth inhibitory effects and selectivity index (SI) values of compounds 21-40.
Comp.
Cell viability (%) at 10 µM (GI50 µM)a MDA-MB-
468 SIb
ClogPc
Comp.
Cell viability (%) at 10 µM (GI50 µM)a MDA-MB-
468 SIb
ClogPc
MCF-7
MDA-MB-468
MCF-7
MDA-MB-468
1
72.1 ± 4.0 (27.6) 22.6 ± 1.9 (6.5)
73.4 ± 4.7 (>30) 55.1 ± 0.9 (15.2)
82.4 ± 3.3 (>30) 53.8 ± 1.6 (16.6)
71.0 ± 4.4 (>30) 65.5 ± 3.7 (>30)
96.3 ± 7.1 (>30) 66.3 ± 3.6 (>30)
85.7 ± 3.9 (>30) 61.3 ± 2.6 (>30)
83.5 ± 3.7 (>30) 56.1 ± 4.2 (20.7)
76.3 ± 4.8 (26.7) 52.6 ± 4.1 (11.8)
90.7 ± 3.1 (>30) 57.1 ± 1.7 (21.6)
91.2 ± 2.6 (>30) 62.6 ± 2.9 (>30)
88.0 ± 1.0 (>30) 58.3 ± 3.0 (13.6)
4.2
6.01
3.98
5.36
2.74
3.57
3.18
4.12
4.64
4.25
3.56
4.51
31
32
33
34
35
36
37
38
39
40
85.5 ± 7.4 (26.9)
89.6 ± 6.1 (>30)
82.6 ± 1.6 (>30)
87.6 ± 2.9 (>30)
47.4 ± 3.6 (9.4)
67.6 ± 2.0 (>30)
49.9 ± 3.1 (10.0)
77.9 ± 1.2 (>30)
45.3 ± 1.0 (7.0)
24.5 ± 1.1 (5.9)
72.3 ± 1.5 (24.6) 1.1
79.8 ± 7.5 (23.5) >1.3
63.3 ± 7.5 (>30) N/A
60.9 ± 4.3 (16.6) >1.8
7.42
8.80
6.17
7.01
6.74
7.56
8.08
7.69
7.00
7.94
21
22
23
24
25
26
27
28
29
30
>2.0
>1.8
N/A
N/A
N/A
>1.4
2.3
29.6 ± 6.0 (5.6)
1.7
50.5 ± 2.8 (10.8) >2.8
30.1 ± 1.4 (5.1)
36.9 ± 3.2 (2.5)
29.3 ± 1.7 (2.6)
6.9 ± 0.9 (3.3)
2.0
>12
2.7
1.8
>1.4
N/A
>2.2
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.
c ClogP values were calculated from ChemDraw Professional 15.1.

3. Prat, A.; Parker, J. S.; Karginova, O.; Fan, C.; Livasy, C.;
Herschkowitz, J. I. Breast Cancer Res. 2010, 12, R68.
4. Eroles, P.; Bosch, A.; Pérez-Fidalgo, J. A.; Lluch, A. Cancer Treat.
Rev. 2012, 38, 698.
5. The Cancer Genome Atlas Network. Nature 2012, 490, 61.
6. Gayle, S. S.; Sahni, J. M.; Webb, B. M.; Weber-Bonk, K. L.;
Shively, M. S.; Spina, R.; Bar, E. E.; Summers, M. K.; Keri, R. A.
J. Biol. Chem. 2019, 294, 875.
7. Rakha, E. A.; Reis-Filho, J. S.; Ellis, I. O. J. Clin. Oncol. 2008, 26,
2568.
8. Reis-Filho, J. S.; Tutt, A. N. J. Histopathology 2008, 52, 108.
9. Polyak, K. J. Clin. Invest. 2011, 121, 3786.
10. 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.
11. Kalimutho, M.; Parsons, K.; Mittal, D.; López, J. A.; Srihari, S.;
Khanna, K. K. Trends Pharmacol. Sci. 2015, 36, 822.
12. Bianchini, G.; Balko, J. M.; Mayer, I. A.; Sanders, M. E.; Gianni,
L. Nat. Rev. Clin. Oncol. 2016, 13, 674.
13. Cheang, M. C. U.; Voduc, D.; Bajdik, C.; Leung, S.; McKinney, S.;
Chia, S. K.; Perou, C. M.; Nielsen, T. O. Clin. Cancer Res. 2008,
14, 1368.
14. Corkery, B.; Crown, J.; Clynes, M.; O’Donovan, N. Ann. Oncol.
2009, 20, 862.
15. Glynn, S. A.; Boersma, B. J.; Dorsey, T. H.; Yi, M.; Yfantis, H. G.;
Ridnour, L. A.; Martin, D. N.; Switzer, C. H.; Hudson, R. S.; Wink,
D. A.; Lee, D. H.; Stephens, R. M.; Ambs, S. J. Clin. Invest. 2010,
120, 3843.
16. Ueno, N. T.; Zhang, D. J. Cancer 2011, 2, 324.
17. Tomao, F.; Papa, A.; Zaccarelli, E.; Rossi, L.; Caruso, D.; Minozzi,
M.; Vici, P.; Frati, L.; Tomao, S. OncoTargets Ther. 2015, 8, 177.
18. Crown, J.; O’Shaughnessy, J.; Gullo, G. Ann. Oncol. 2012, 23, vi56.
19. Sergina, N. V.; Rausch, M.; Wang, D.; Blair, J.; Hann, B.; Shokat,
K. M.; Moasser, M. M. Nature 2007, 445, 437.
20. Meyer, A. S.; Miller, M. A.; Gertler, F. B.; Lauffenburger, D. A.
Sci. Signaling 2013, 6, ra66.
21. Sohn, J.; Liu, S.; Parinyanitikul, N.; Lee, J.; Hortobagyi, G. N.;
Mills, G. B.; Ueno, N. T.; Gonzalez-Angulo, A. M. J. Cancer 2014,
5, 745.
22. 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.
23. Oliveras-Ferraros, C.; Vazquez-Martin, A.; López-Bonet, E.;
Martín-Castillo, B.; Del Barco, S.; Brunet, J.; Menendez, J. A. Int.
J. Oncol. 2008, 33, 1165.
24. Lion, C. J.; Matthews, C. S.; Stevens, M. F. G.; Westwell, A. D. J.
Med. Chem. 2005, 48, 1292.
25. 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.
suggestion that the activity of the 2-anilinopyrimidine analogs is
strongly dependent on lipophilicity.29
Subsequently, we turned our attention to the analysis of the
anti-TNBC activities for cyclohexyl analogs 31-40. The results in
Table 2 show that all compounds had a GI50 value below 30 µM
against the TNBC cell line, except for 33. In particular, analogs 35
and 37-40 recorded single-digit GI50 values (2.5-5.6 µM) on the
MDA-MB-468 cells, which all indicated an improved potency
compared to that of the compound 1 (GI50 = 6.5 µM). Especially,
compound 38, which possesses a 4-chloropiperidinyl group on
part A and cyclohexyl group on part B, showed the highest activity
with a GI50 of 2.5 µM. Furthermore, the SI of the compound (>12),
which was approximately three times higher than that of the 1 (SI
= 4.2), was also the highest in the series. Meanwhile, substitution
of the acyclic amine on part A, as seen in analog 40, resulted in a
compound with the highest toxicity against the TNBC cells at a
concentration of 10 µM and an approximately 2-fold increase in
potency (GI50 = 3.3 µM) over that of 1. However, the selectivity
on the TNBC cells was moderate. This result is similar to the
finding observed with compounds possessing a diethylamino
group on part A in our previous study.29 Interestingly, the indolyl
compound 32 showed low TNBC inhibitory activity with a GI50
value of 23.5 µM. This result is contrary to the observations that
part A-indolyl compounds (10-12 and 16) were generally highly
potent. This implies that increasing the lipophilicity above a
certain level has a negative effect on the desired activity. In
addition, the overall effect of the part B methoxy group (21-30)
and cyclohexyl group (31-40) compounds suggest hydrophobic
interactions between the part B substituent of 2-anilinopyrimidines
and their potential target.
In summary, we expanded our 2-anilinopyrimidine-based
selective inhibitors of the TNBC cell line using two derivatization
strategies. The first strategy was designed to introduce aromaticity
on the part A. The part A-aromatized series maintained their
activities against the TNBC cells, while their potency on the
luminal type breast cancer cells increased dramatically. The
second strategy was focused on the modification of the piperidine
at part B. Substitution of the cyclohexyl group on part B improved
the activity against the TNBC cell line. In particular, the
cyclohexyl compound 38, possessing a 4-chloropiperidinyl group
on the part A, showed the highest activity and selectivity against
the TNBC cells. The results from the optimization study will guide
us in further refining the structure of 2-anilinopyrimidines and
identify the target of the MDA-MB-468 selective inhibitors.
26. 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.
27. Kim, Y. J.; Pyo, J. S.; Jung, Y.-S.; Kwak, J.-H. Bioorg. Med. Chem.
Lett. 2017, 27, 607.
Acknowledgments
28. Yamashita, N.; Kondo, M.; Zhao, S.; Li, W.; Koike, K.; Nemoto,
K.; Kanno, Y. Bioorg. Med. Chem. Lett. 2017, 27, 2608.
29. Jo, J.; Kim, S. H.; Kim, H.; Jeong, M.; Kwak, J.-H.; Han, Y. T.;
Jeong, J.-Y.; Jung, Y.-S.; Yun, H. Bioorg. Med. Chem. Lett. 2019,
29, 62.
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education (NRF-
2018R1D1A1B07045101) and the Bio & Medical Technology
Development Program of the National Research Foundation (NRF)
funded by the Korean government (MSIT) (NRF-
2017M3A9G7072568).
A. Supplementary data
References
1. Foulkes, W. D.; Smith, I. E.; Reis-Filho, J. S. N. Engl. J. Med. 2010,
363, 1938.
2. Prat, A.; Perou, C. M. Mol. Oncol. 2011, 5, 5.