Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents

Article abstract of DOI:10.1016/j.bmcl.2021.128253

Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brigatinib and similar to Ceritinib. Mechanism study revealed that the optimal compound 9e decreased the mitochondrial membrane potential and arrested NCI-H2228 cells in the G0/G1 phase, finally resulting in cellular apoptosis. It is interesting that 9e could effectively inhibit the migration of NCI-H2228 cells and may be a promising leading compound for chemotherapy of metastatic cancer.

Full text of DOI:10.1016/j.bmcl.2021.128253

Bioorg. Med. Chem. Lett. 48 (2021) 128253
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a
sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents
Feng Wua, Han Yaoa, Wei Lia, Niuniu Zhangc, Yangyang Fanb, Albert S.C. Chana,
,
,*
Xingshu Lia *, Baijiao Anb
a School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China
b School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong Province 264003, PR China
c School of Pharmaceutical Sciences, Guilin Medical University, Guilin 541199, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive
lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2,4-diaminopyrimidines bearing a
sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent
antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brig-
atinib and similar to Ceritinib. Mechanism study revealed that the optimal compound 9e decreased the mito-
chondrial membrane potential and arrested NCI-H2228 cells in the G0/G1 phase, finally resulting in cellular
apoptosis. It is interesting that 9e could effectively inhibit the migration of NCI-H2228 cells and may be a
promising leading compound for chemotherapy of metastatic cancer.
Anaplastic lymphoma kinase inhibitors
Antiproliferative activity
Mechanism
Sulfoxide
Anaplastic lymphoma kinase (ALK) is a key member of the insulin
receptor tyrosine kinase family.1 The deregulation of ALK has been
observed in various cancers, such as non-small cell lung cancer
(NSCLC),2 anaplastic large cell lymphoma (ALCL),3 diffuse large B-cell
lymphoma (DLBCL)4 and inflammatory myofibroblastic tumor (IMT).5
Being a validated target for cancer therapy, the development of ALK
inhibitors has received more and more attention. To date, six drugs
targeting ALK have been approved by the FDA including Crizotinib,6
Ceritinib,7,8 Alectinib,9 Brigatinib,10,11 Lorlatinib12,13 and Entrecti-
nib14,15 (Fig. 1). However, regardless of the initial clinical benefit
demonstrated in ALK inhibitors, the development of drug resistance still
remains a major problem.16,17,18 Therefore, it is still necessary to
develop new ALK inhibitors for combating the obstacle.
drug, its chiral isomer, esomeprazole, which provide better effect than
the former, was also approved by the FDA later.
Inspired by the success of drugs containing sulfoxide, and the widely
used 2,4-diaminopyrimidines moiety in anti-tumor drugs. A series of
novel ALK inhibitors were designed, synthesized and evaluated on the
basis of the molecular scaffold of Brigatinib and Ceritinib, the two suc-
cessful drugs approved by FDA, by replacing the dimethylphosphine
oxide moiety or sulfone moiety with sulfoxide and the other structural
modifications (Scheme 1).
The synthetic route for the designed compounds (9a-9c, 9f-9h, 9j-
9n) was shown in Scheme 2. Treating 1a-1c with appropriate iodides in
the presence of NaOH or t-BuOK gave 2a-2d,25 which were oxidized by
hydrogen peroxide to afford 3a-3d. Reaction of 3a-3d with 2,4,5-tri-
chloropyrimidine in the presence of NaH in DMF provided the in-
termediates 4a-4d, which undergone substitution with appropriate
aromatic amines 8a-8f to afford target compounds (9a-9c, 9f-9h, 9j-9n).
Meanwhile, the aromatic amines 8a-8f were prepared with compound 5,
which was alkylated with MeI to obtain 6,26 and then converted to 7a-7f
via the nucleophilic substitution with appropriate amines. Finally, the
nitro group of 7a-7f was reduced with hydrogen in the presence of
palladium on activated carbon to give 8a-8f.27
Sulfoxide moiety is an effective pharmacophore that is included in
the structure of many important drugs such as Armodafinil,19 Sulfo-
raphane,20 Sulindac,21 Modafinil,22 Omeprazole23 and its S-isomer
Esomeprazole24 (Fig 2). Different from the sulfone moiety, the sulfur
atom of sulfoxide is the chiral center and can produce two different
chiral isomers. In many cases, two chiral isomers have obvious differ-
ences in biological activity. The typical example is omeprazole and
esomeprazole, the proton pump inhibitors used in the treatment of
gastric ulcers. Although omeprazole (racemic) itself is a widely used
The synthetic route of the designed compounds 9d, 9e, 9i, 9o was
* Corresponding authors.
E-mail addresses: lixsh@mail.sysu.edu.cn (X. Li), Anbj3@bzmc.edu.cn (B. An).
https://doi.org/10.1016/j.bmcl.2021.128253
Received 5 April 2021; Received in revised form 28 June 2021; Accepted 5 July 2021
Available online 8 July 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

F. Wu et al.
Bioorganic & Medicinal Chemistry Letters 48 (2021) 128253
N
C
O
HN
O
S O
l
C
H
H
N
N
N
N
N
O
NH
N
F
N
l
C
O
l
C
H2N
N
NH
N
r zo t n
C i i i ib
ect n
er t n
C
i i ib
A
l
i ib
O
N
O
F
N
O
HN
HN
N
O
e
M
O
P
H
H
O
N
N
N
F
O
N
N
N
N
H2N
N
l
N
C
N
H
F
N
N
N
r
at n
B i i ib
ntrect n
E
i ib
g
rat n
o
L
i ib
Fig. 1. Representative ALK inhibitors.
O
S
O
O
NH2
H
S
O
N
S
C
H
OOC
S
F
u uora ane
S lf
u n ac
S li d
rmo a n
A d fi il
h
p
H
N
O
O
H
N
O
S
O
S
S
N
N
NH2
N
N
O
O
O
O
o a n
M d fi il
me razo e
l
O
some razo e
E
l
p
p
Fig. 2. Representative drugs containing sulfoxide moiety.
outlined in Scheme 3. First, 4a or 4b reacted with 4-fluoro-2-methoxy-5-
nitroaniline to give compounds 10a and 10b, which were convert to
11a-11c by the reaction with various amines. Then, reduction of 11a-
11c with tin (II) chloride dehydrate provided 9o, 12b and 12c, which
reacted with acrylic chloride in the presence of NaHCO3 to yield the
target compounds 9d, 9e, 9i.
diisopropylethylamine in isopropanol to provide intermediate 13.
Coupling of 13 with 8c at 80 ◦C in the presence of trifluoroacetic acid
provided the compound 9p.
To evaluate the antiproliferative activities of the newly synthesized
2,4-diaminopyrimidines derivatives bearing a sulfoxide moiety, CCK8
assay was performed against two cancer cell lines including NCI-H2228
and BAF3-ALK with Ceritinib and Brigatinib as positive controls. The
results listed in Table 1 indicated that most of the synthesized
Compound 9p was prepared according to Scheme 4. Compound 2a
reacted with 2,4,5-trichloropyrimidine in the presence of N,N-
2

F. Wu et al.
Bioorganic & Medicinal Chemistry Letters 48 (2021) 128253
Scheme 1. Design of AlK inhibitors.
compounds exhibited excellent antiproliferative activity with IC50
values in sub-micromolar level. Among them, compound 9e, bearing a
propionamido group in C ring (Table 1), exhibited the best results with
the IC50 values ranging from 8 to 24 nM, which is better than that of
Brigatinib and similar to Ceritinib. Further structure–activity studies
showed that when the other moiety of the molecule remain unchanged,
a cyclic R3 group seems beneficial for anti-tumor activity than that of
chain group. For example, 9b and 9c, a homopiperazine or piperazinyl
connected to the C ring, provided 51.5 and 35.2 nM of the IC50
comparing the 69.3 nM of compound 9a, which bears a chain R3 group.
When there is a halogen atom such as fluorine or chlorine on the A ring
(Table 1), the activity generally decreases (48.1 to 1435 nM of the IC50
values of compounds 9f-9h, 9k-9n via the 35.2 nM of 9a). Comparing
the isopropyl group in the sulfoxide moiety (9j, 82.9 nM of the IC50 for
H2228 cancer lines), ethyl is more beneficial to the anticancer activity
(9c, 35.2 nM of the IC50). In general, that the sulfoxide moiety is con-
nected to the ethyl group, the A ring does not contain a halogen com-
pound, and the R3 group on the C ring is piperazinyl and a propionamido
group in its neighbor may be the best scaffold.
western blot assay was performed to detect the changes of related pro-
teins (the cell cycle activators CDK4 and Cyclin D1). The results in
Fig. 3B exhibited that the levels of CDK4 and Cyclin D1 were down
regulated in a certain extent, especially the level of Cyclin D1 which was
significantly decreased after the treatment of compound 9e.
The results of the cell cycle analysis hypothesized that compound 9e
induced the apoptosis of cancer cells. To evaluate the effect of apoptosis
progression, flow cytometry assay was performed using propidium io-
dide (PI) and fluorescent immunolabeling of the protein annexin-V (V-
FITC). Brigatinib, with high selectivity and potency to ALK, was chosen
as a positive drug. After NCI-H2228 cells were treated for 24 h with 9e at
indicated concentrations, the cells were harvested, stained with Annexin
V-FITC and PI, and analyzed by flow cytometry (Fig. 4A). The early and
late apoptosis cells at the concentrations of 5, 25 and 50 nМ or DMSO
(0.01%) were founded to be 6.58%, 23.53%, 23.44% and 4.30%,
respectively. When the incubation time was extended to 48 h (Fig. 4A),
the early and late apoptosis cells increased to 22.3%, 57.0%, 85.4% and
1.81%, respectively. These results indicated that 9e induced cell
apoptosis in a concentration- and time-dependent manner. To study the
morphological alterations of cancer cells caused by compound 9e, NCI-
H2228 cells were exposed to different concentrations of 9e (5, 25 and 50
nМ) for 48 h, stained with Hoechst 33342, and then photographed with
an Olympus inverted fluorescence microscope. As shown in Fig. 4C, the
cell membrane of NCI-H2228 cells is intact and the nucleus is uniform in
size in the control group. After the treatment of 9e under different
concentrations (5, 25 and 50 nМ), the nucleus of the NCI-H2228 cells
gradually pyknosis into a uniform dense mass and then breaks into
fragments of varying size.
Due to its best antiproliferative activity against cancer cell lines, in
the following study, 9e was selected as the optimal compound for
further study on cellular mechanism. The flow cytometry analysis was
performed to study its effect on the cell cycle using human NCI-H2228
cancer cells. Treatment of the tumor cells with 20 nM of 9e for 0, 12,
24 and 48 h, we found compound 9e induced cell cycle arrest at the G0/
G1 phase in a time-dependent manner, with a concomitant change in
G2/M or S phase cells. At beginning, the percentage of cells in G0/G1
phase of the cell cycle was 67.7%. When the time was increased from 12,
24 to 48 h, the percentage of cells at the G0/G1 phase increased to
71.23%, 82.13%, and 86.49%, respectively (Fig. 3A). Meanwhile,
A prelusion of cell apoptosis is the mitochondrial membrane depo-
larization, which usually leads to the decrease of mitochondrial
3

F. Wu et al.
Bioorganic & Medicinal Chemistry Letters 48 (2021) 128253
Scheme 2. Reagents and conditions: (a) appropriate iodides, t-BuOK or NaOH, C2H5OH or CH3OH, rt; (b) H2O2, AcOH, 0 ◦C to rt; (c) 2,4,5-trichloropyrimidine, NaH,
DMF, 0 ◦C to rt; (d) CH3I, K2CO3, DMF, 60 ◦C; (e) appropriate amines, K2CO3, DMF, 110 ◦C; (f) Pd/C, H2, MeOH, rt. (g) 4a-4d, TFA, i-PrOH, 80 ◦C;
4

F. Wu et al.
Bioorganic & Medicinal Chemistry Letters 48 (2021) 128253
Scheme 3. Reagents and conditions: (a) 4-fluoro-2-methoxy-5-nitroaniline, 37% hydrochloride, 2-butanol, 80 ◦C; (b) appropriate amines, DIEA, dioxane, 100 ◦C; (c)
tin (II) chloride dehydrate, HCl (aq) , DCM, MeOH, 50 ◦C; (d) acryloyl chloride, saturated NaHCO3 (aq) , THF, 0 ◦C.
5

F. Wu et al.
Bioorganic & Medicinal Chemistry Letters 48 (2021) 128253
S
S
H
N
H
S
a
N
N
b
NH
N
NH2
N
l
C
O
l
C
N
N
N
l
C
9
p
13
a
2
Scheme 4. Reagents and conditions: (a) 2,4,5-trichloropyrimidine, DIEA, i-PrOH, 80 ◦C; (b) 8c, TFA, i-PrOH, 80 ◦C.
Table 1
Evaluation of antiproliferative activity of the synthesized compounds
Comp.
R1
R2
R3
Cell type (IC50 /nM) a
NCI-H2228
BAF3-ALK
9a
9b
H
H
Et
Et
69.3 ± 0.05
26.3 ± 0.09
51.5 ± 0.07
23.5 ± 0.08
9c
9d
H
H
Et
/
35.2 ± 0.03
55.4 ± 0.11
13.1 ± 0.06
35.4 ± 0.02
9e
9f
F
F
/
24.4 ± 0.10
64.5 ± 0.01
8.11 ± 0.01
26.7 ± 0.02
Et
9g
F
Et
84.3 ± 0.11
34.7 ± 0.11
9h
9i
F
F
Et
/
104.1 ± 0.03
48.1 ± 0.02
48.9 ± 0.03
47.2 ± 0.04
9j
H
Cl
F
iPr
Et
Et
Et
82.9 ± 0.13
134.1 ± 0.14
337 ± 0.58
704 ± 0.77
32.3 ± 0.08
128.1 ± 0.11
79.4 ± 0.23
85.7 ± 0.72
9k
9l
9m
F
9n
F
Et
1435 ± 1.89
82 ± 0.57
9o
/
/
/
/
/
/
2632 ± 2.77
981 ± 1.38
22.1 ± 0.08
31.2 ± 0.02
75 ± 0.45
78 ± 0.33
7.11 ± 0.02
8.49 ± 0.01
9p
Ceritinib
Brigatinib
a
The anti-proliferative activities of the compounds were assessed by the CCK8 assay. IC50 values are indicated as the mean ± SD (standard error) of three inde-
pendent experiments.
membrane potential. The decreased mitochondrial membrane potential
(MMP, ΔΨm) is thought to be a signal of apoptosis. To explore whether
compound 9e could reduce mitochondrial membrane potential in cancer
cells, NCI-H2228 cells were treated with 9e at different concentrations
(5, 25, and 50 nM) or DMSO (0.01%) for 24 h, followed by incubation
with the fluorescence probe JC-1 for 30 min, and then analyzed by
fluorescence microscopy. As the concentration of 9e increased, a shift
from aggregates (red fluorescence) toward the form of monomers (green
fluorescence) occurred, which indicated that 9e can induce MMP
collapse, and eventually trigger apoptotic cell death (Fig. 5A).
Tumor cell migration is one of the most important factors leading to
the death of tumor patients. To evaluate the ability of 9e to inhibit the
tumor cell migration, NCI-H2228 cells were suspended in 1640 medium
containing 9e for 12 h or 24 h, and then photographed under a phase
contrast microscope. As showed in the Fig. 5B, NCI-H2228 cells incu-
bated with 9e (25 nM) for 12 h exhibited obvious inhibition of tumor
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F. Wu et al.
Bioorganic & Medicinal Chemistry Letters 48 (2021) 128253
Fig. 3. The cell cycle distribution of NCI-H2228 cells treated with 9e (20 nM) for the indicated time (0, 12, 24 or 48 h) was measured by flow cytometry with PI
staining. (A) The expression levels of G0/G1 phase-related proteins in the NCI-H2228 cells treated with 9e (20 nM) for 0–48 h. (B) NCI-H2228 cells were treated for 0,
12, 24 or 48 h with 9e (20 nM), cell cycle regulatory protein were analyzed by western blotting. (C) Quantitative analysis of the percentage of cells in each cell cycle
phase was analyzed by EXPO32 ADC analysis software. The experiments were performed three times, and the results of representative experiments are shown.
7

F. Wu et al.
Bioorganic & Medicinal Chemistry Letters 48 (2021) 128253
Fig. 4. Apoptosis of NCI-H2228 cells with or without 9e treatment at the indicated concentrations. (A) Treated with 9e (5, 25 and 50 nM) or Brigatininb (25 nM) for
24 h, or 48 h, x-axis is Annexin-V-FITC-fluorescence vs y-axis is PI-fluorescence. (B) The percentages of cells in each stage of apoptosis were quantitated by EXPO32
ADC analysis software. (C) NCI-H2228 cells were treated with 9e (5, 25 and 50 nM) for 48 h and then stained with Hoechst 33,342 and photographed with an
Olympus inverted fluorescence microscope. The experiments were performed three times, and the results of representative experiments are shown.
cell migration. The wound closure in the migration assay was signifi-
cantly suppressed when the time was extended to 24 h. In contrast, the
tumor cells spanned the wound closure and nearly covered the whole
area in the control. These results suggested that compound 9e effectively
inhibited the migration of NCI-H2228 cells and might be a promising
candidate for chemotherapy of metastatic cancer.
migration of NCI-H2228 cells as tumor-cell spreading is one of the major
causes of death in tumor patients. Overall, these results demonstrated
the promising value of 9e as a potential anticancer leading compound.
Further progression concerning the chiral properties of these sulfoxide
analogs, including the asymmetric preparation and anti-tumor activity
assays, will be reported in due course.
In this study, we have developed a series of 2,4-diaminopyrimidines
derivatives bearing a sulfoxide moiety as novel potent ALK inhibitors.
The optimal compound, 9e exhibited nearly the same potent anti-
proliferative activity as Ceritinib and better than Brigatinib which
approved by FDA in 2017. The mechanism study indicated that com-
pound 9e induced cell cycle arrest at the G0/G1 phase, down regulated
the related proteins CDK4 and Cyclin D1, thereby inducing cell
apoptosis. It is noteworthy that compound 9e effectively inhibited the
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
8

F. Wu et al.
Bioorganic & Medicinal Chemistry Letters 48 (2021) 128253
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.128253.
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We thank the Science and Technology Base and Special Fund for
Talents of Guangxi (GuikeAD20297031) for financial support of this
study.
9