Synthesis of mitochondria-targeted coumarin-3-carboxamide fluorescent derivatives: Inhibiting mitochondrial TrxR2 and cell proliferation on breast cancer cells

Article abstract of DOI:10.1016/j.bmcl.2020.127750

Targeting specific mitochondrial alterations to kill cancer cells without affecting their normal counterparts emerges as a feasible strategy. Coumarin derivatives have demonstrated the potential anti-breast cancer activities. By coupling coumarin-3-carbox

Full text of DOI:10.1016/j.bmcl.2020.127750

Bioorg. Med. Chem. Lett. 33 (2021) 127750
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of mitochondria-targeted coumarin-3-carboxamide fluorescent
derivatives: Inhibiting mitochondrial TrxR2 and cell proliferation on breast
cancer cells
Yuanyuan Li, Qun Tang, Yu Xie, Dian He, Kun Yang, Lifang Zheng*
School of Pharmacy, Lanzhou University, Lanzhou 730000, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Targeting specific mitochondrial alterations to kill cancer cells without affecting their normal counterparts
emerges as a feasible strategy. Coumarin derivatives have demonstrated the potential anti-breast cancer activ-
ities. By coupling coumarin-3-carboxamide derivatives with mitochondria carrier triphenylphosphonium,
mitocoumarins 15a-c were produced and tested as the anti-breast cancer fluorescence agents. Among them, 15b
as the amide-based drug potently suppressed the cell growth in MCF-7, MDA-231, SK-BR-3 breast cancer cells
Breast cancer
Mitochondria
Mitochondrial thioredoxin reductase
Coumarin-3-carboxamide
Oxidative stress
with the IC50 values from 3.0 to 4.1
μ
M, including the lower cytotoxicity to normal MCF-10A cells with the IC50
value around 45.30 ± 2.45
μ
M. In mechanistic study for 15b in MDA-MB-231 cells, it could localize in mito-
chondria to elicit ROS burst and collapse Δψm. Besides, it could deplete GSH by an irreversible alkylation process
and moderately inhibit mitochondrial thioredoxin reductase TrxR2, thus leading to aggravate cellular oxidative
stress. This study reported 15b might be useful for the further development into a mitochondria-targeted anti-
triple negative breast cancer drug.
Breast cancer (BC) is the most common malignancy which remains a
leading killer among women in the world. It is predicted that by 2021,
there will be 2.2 million breast cancer cases among women aged 35–49
in China.1 In breast cancer, mitochondrial alterations have been detec-
ted, including increased oxidative stress, aberrant apoptotic machinery,
increased membrane potential and deleted or mutated mtDNA.2 Tar-
geting these mitochondrial alterations could promote tumor cell death,
and decrease drug resistance, possible side effects as well.3 Due to the
higher Δψm of tumor cells, the triphenylphosphonium cation (TPP) has
been discovered as a successful carrier to deliver the drugs to tumor cell
mitochondria, leaving the rest of cells unaffected. TPP cation has the
delocalized positive charge and hydrophobic surface area, facilitating a
fast-mitochondrial matrix uptake independent of the hydrophobicity of
cargo molecules.4,5 For example, Mito-Tam (1),6a Mito-Chlor (2)6b and
Mito-Vitamin E (3)6c have been devised, which are far more efficient in
killing BC cells than parental compounds and can bypass multidrug
resistance (Fig. 1A). Encouragingly, Mito-Tam has passed pre-clinical
testing and proceeds to phase I clinical trial for Her2high breast cancer.6a
Additionally, overexpression of mitochondrial thioredoxin reductase
(TrxR2) is detected in tumors, including BC,7 which associates with poor
prognosis and therapeutic resistance of cancer.8 Inhibition of TrxR2 can
increase cellular oxidative stress and activate apoptosis pathway.9 The
tumor cells are in a higher oxidative stress environment. If a drug could
further aggravate oxidative stress and overwhelm the antioxidant de-
fense system, the tumor cells would more easily be killed. Hence, the
inhibitors of thioredoxin reductase have been extensively studied. So
far, mitocurcumin (4)10a and BODIPY-TPA (5)10b have been reported to
inhibit TrxR2 activity (Fig. 1A).
Natural and synthetic coumarin derivatives are widely used in a
number of fields, especially in medicine.11,12 Specific to anti-breast
cancer activity, coumarin derivatives show sulfatase and aromatase
inhibitory activities, including acting as selective estrogen receptor
Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor-2; TPP, triphenylphosphonium; BSO, L-
Buthionine-sulfoximine; DCFH-DA, 2′,7′-dichlorofluorescin diacetate; FBS, fetal bovine serum; CsA, cyclosporin A; ROS, reactive oxygen species; MTDR, mito-Tracker
deep red; TMRE, tetramethylrhodamine ethyl ester; TrxR, thioredoxin reductase; TrxR2, mitochondrial thioredoxin reductase; NMM, N-methylmaleimide; BC, breast
cancer; TNBC, triple-negative breast cancer; CCCP, carbonyl cyanide m-chlorophenylhydrazone; TBAB, tetrabutylammonium bromide; HOBT, hydroxybenzotriazole;
TFA, trifluoroacetic acid; DMAP, 4-dimethylaminopyridine; EDCI, 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide.
* Corresponding author.
E-mail address: zhenglf@lzu.edu.cn (L. Zheng).
https://doi.org/10.1016/j.bmcl.2020.127750
Received 27 October 2020; Received in revised form 27 November 2020; Accepted 9 December 2020
Available online 21 December 2020
0960-894X/© 2020 Elsevier Ltd. All rights reserved.

Y. Li et al.
Bioorganic & Medicinal Chemistry Letters 33 (2021) 127750
The mitochondria-targeted anti-BC drugs (1-3) and TrxR2 inhibitors (4-5)
A
H3CO
OCH3
H
N
PPh3
O
N
Cl
O
N
N
PPh3
8
Cl
Mito-Chlor (2)
Ref: [6b]
Mito-Tam (1)
S
Ref: [6a]
O
O
H3CO
O
OCH3
O
HO
N
N
F
O
B
F
Ph3P
PPh3
9
PPh3
O
O
BODIPY-TPA (5)
Mitocurcumin (4)
Mito-Vitamin E (3)
Ref: [10a]
Ref: [10b]
Ref: [6c]
B
The design of Mitocoumarin (15a-c)
O
O
PPh3
N
H
N
N
O
O
O
15a
N
H
O
N
O
O
PPh3
N
15d
H
O
fluorescent carrier targeting mitochondria
Ref: [16]
15b
Ph3P
O
PPh3
O
O
O
Mito-methyl coumarin displaying
antitumor activity (6)
N
O
O
Ref: [17]
15c
Fig. 1. The overview of introduction.
modulators and down regulator.13,14 Besides, Xu et al. reported that
TPP-coumarin conjugate (6) was effective in inhibiting proliferation and
inducing apoptosis in HeLa cells.15 In recent years, the coumarin-3-
carboxamide 15d has been applied as a blue fluorescent vector to
deliver drugs specifically to mitochondria in cancer cells together with
imaging mitochondria.16 Therefore, we were motivated to study
whether the installment of TPP onto 15d might produce the novel
compound with an optical imaging and cytotoxic activity simulta-
neously. Therefore, the mitochondria-targeted coumarin derivatives
(15a-c) were designed and synthesized (Fig. 1B). Next, the physico-
chemical properties, cytotoxicity toward breast cancer cells (MCF-7,
MDA-231, SK-BR-3) were evaluated. The cytotoxic mechanism of the
most potent compound 15b in MDA-MB-231 cells was investigated.
The synthesis of target compounds 15a-c is depicted in Scheme 1,
which are reported herein for the first time and fully characterized by
1H, 13C NMR, and ESI-HRMS (please see the supporting information).
Briefly, after the two steps of bromination, compound 9 was obtained
from 3-methoxyaniline (7), which was treated with BBr3 to give 10 by
demethylation.17 Subsequently, the alkylated aminophenol 10 was for-
mylated with POCl3 in DMF to give the corresponding aldehyde 11a
through Vilsmeier Haack conditions. Upon the Knoevenagel condensa-
tion, aldehyde 11a was treated with Meldrum’s acid to give the
coumarin-3-carboxylic acid (12a).16 After coupling 12a with amino-
butanol and then bromination of the alcoholic function of 13a, 14a was
obtained.18 Finally, the reaction of 14a with PPh3 in toluene under
reflux for 3 days yielded the title compounds 15a.19 Besides, compound
15b-d was synthesized using the similar procedures (Scheme 1). Next,
the optical properties and solubility were determined and the results are
in Table S1 (please see the supporting information). The compounds
15a-d displayed the inherent fluorescence with λex around 420 nm, and
λem around 475 nm (Fig.1A).
We used MTT assay to determine cytotoxicity of 15a-d on three
breast cancer cell lines (MCF-7, MDA-MB-231, SK-BR-3) and one normal
breast cell line MCF-10A after 48 h of treatment. It was also determined
by Sulforhodamine B method, giving the consistent results as MTT
method. Butyltriphenylphosphonium bromide (Butyl-TPP) and 15d
were used as the reference compounds. Drug tamoxifen was a positive
control. The results are listed in Table 1. The ranges of IC50 are from 2.73
to 4.90 μM of 15a, from 3.03 to 3.46 μM of 15b, from 27.84 to 30.86 μM
of 15c, so the order of cytotoxicity is 15a 15b ≫ 15c. The reference
compound 15d and Butyl-TPP did not show cytotoxicity. Compared
with tamoxifen, 15a and 15b are more potent. It has discovered that
cationic compounds can be 100–1000-fold or more concentrated in the
mitochondrial matrix, when compared to the extracellular medium.4
Based on this principle, we could easily understand why 15b increased
over 30-fold cytotoxicity, compared to the reference compound 15d
(Table 1). Next, the cytotoxicity toward normal cells MCF-10A, the IC50
of 15b was 3-fold higher than that of 15a, showing 15b was less toxic.
Finally, the cytotoxicity of 15a-d against other cancer cell lines were
also tested (please see the supporting information, Table S2). The results
of this screening suggested that 15a and 15b might have a broad spec-
trum of outstanding anticancer activities. The structure-cytotoxicity
relationship for 15a-d was obtained: (i) installment of TPP carrier
dramatically increased the cytotoxicity over 30-fold, confirming that the
delivery of drugs to mitochondria was effective and mitochondria was
an ideal cellular target for drug distribution; (ii) the changing amide to
ester at C-3 significantly weakened cytotoxicity, showing amide was an
optimum linker.
The uptake of 15b and 15c by MDA-MB-231 cells was measured by
flow cytometry.
2

Y. Li et al.
Bioorganic & Medicinal Chemistry Letters 33 (2021) 127750
Scheme 1. Reagents and conditions: i)
CH3CH2Br, K2CO3, NaI, TBAB, CH3CN,
N
OH
N
OCH3
reflux,
8 h, 51.2%; ii) benzyl bromide,
i
ii
iii
K2CO3, DMF, rt, 14 h, 39%; iii) BBr3,
N
OCH3
H2N
OCH3
0 1 h, 42%; iv)
◦C-rt,
H
dichloromethane,
10
8
9
POCl3, DMF, 0 ◦C for 30 min, 60 ◦C for 4 h,
56.9%; v) piperidine, acetic acid, Meldrum’s
acid, ethanol, rt for 30 min, reflux for 3 h,
69.3%; vi) 4-amino-1-butanol or 1-aminobu-
tane, EDCI, HOBt, dichloromethane, 0 ◦C-rt,
1 h, 55–61.2%; vii) PPh3, CBr4, acetonitrile,
rt, 2 h, 65–74.2%; viii) PPh3, toluene, reflux,
72 h, 61–68%; ix) Br(CH2)4Br, Et3N, acetone,
reflux, 6 h, 61.6%.
7
O
O
OH
OH
N
O
vi
H
iv
v
N
OH
N
O
O
N
O
O
13a
11a
12a
O
O
O
PPh3
Br
N
H
N
vii
H
viii
N
O
N
O
O
14a
15a
O
O
O
OH
v
N
O
O
N
O
O
O
12b
11b
O
O
N
PPh
3
3
H
N
H
Br
3
N
OH
vii
3
H
N
O
viii
vi
N
O
O
O
N
O
O
15b
14b
13b
O
O
PPh
3
O
Br
3
3
viii
ix
vi
N
O
O
N
N
O
O
15c
14c
O
N
H
O
O
15d
The stabilities of 15b and 15c in methanol–water (v/v = 1:1) after three
days were measured by HPLC-MS. Chromatogram result showed that
15b was stable in methanol–water solution, while15c produced the
degradation reaction, giving three new peaks in the chromatogram
(Fig. S1, please see the supporting information). The possible molecular
fragments were obtained by analyzing the mass spectrometry data
(Table S3, please see the supporting information). Collectively, the
intrinsic instability of 15c impaired cytotoxicity and decreased cellular
effective concentration.
Table 1
The cytotoxicity of 15a-d against breast cancer cells.
Compd.
IC50
MCF-7b
(
μ
M)a
MDA-MB-231b
SK-BR-3b
MCF-10Ab
15a
4.90 ± 0.34
3.26 ± 0.65
27.84 ± 0.58
>100
3.73 ± 0.21
3.03 ± 0.12
29.39 ± 0.23
>100
2.73 ± 0.11
3.46 ± 0.09
15.06 ± 0.52
45.30 ± 2.45
83.66 ± 1.57
>100
15b
15c
30.86 ± 0.94
>100
15d
Butyl-TPP
57.39 ± 0.63
15.21 ± 0.33
>100
>100
>100
Until now, it has been a great challenge in clinical treatment for
triple-negative breast cancer (TNBC), which is the most aggressive
cancers with a high recurrence rate and rapidly acquired drug resistance
among various breast cancer subtypes.20 Therefore, we selected TNBC
cells MDA-MB-231 for the following study. Because of higher cytotox-
icity and stability of 15b, we then used laser confocal imaging to explore
the subcellular distribution of 15b. As shown in Fig. 3, blue fluorescence
of 15b and red fluorescence of mitochondrial specific red probe MTDR
are highly overlapping with the colocalization coefficient value of 0.87,
confirming 15b permeates into mitochondria and localizes in and
around mitochondria. Next, we used protonophore CCCP (carbonyl cy-
anide m-chlorophenylhydrazone) to verify whether 15b entering the
mitochondria was Δψm-dependent. The protonophore CCCP allows for
the dissipation of the proton gradient across the mitochondrial inner
Tamoxifen
35.80 ± 0.15
28.32 ± 31
>50
a
Values represent mean ± SD from at least three independent experiments by
MTT assay for 48 h.
Their native blue fluorescence was used to detect data signal. After 2
h of treatment, 15b and 15c entered MDA-MB-231 cells in a
concentration-dependent manner, as evidenced by the increased fluo-
rescence intensity (Fig. 2A). Besides, incubating with 15b and 15c at 8
μ
M for different duration, the cellular uptake level of 15b or 15c
increased just within 1.5 h and then decreased over time, giving the
highest level at 0.5 h (Fig. 2B). Taken together, the amount of cellular
uptake of 15b was much higher than that of 15c.
Next, in order to explore why cytotoxicity and cellular uptake level of
15b were much higher than those of 15c, we determined the stability.
membrane, providing a pharmacological method to eliminate Δψm
.
21 At
3

Y. Li et al.
Bioorganic & Medicinal Chemistry Letters 33 (2021) 127750
Fig. 2. The relative uptake levels of 15b and 15c in MDA-MB-231 cells were determined by flow cytometry. (A) the dose-dependent uptake. (B) the time-dependent
uptake. Geometric means of fluorescence intensity values were calculated. Results are presented as means ± SD, n = 3.
Fig. 3. The visualization of 15b in mitochondria of MDA-MB-231 cells by laser confocal microscopy. The cells were incubated with 1
μ
M of 15b for 30 min, and then
stained with 100 nm of MTDR (an exclusive red dye for mitochondria) for another 30 min. Besides, the cells were pre-incubated with 20
μ
M of CCCP for 30 min, and
then treated with 15b and MTDR. The blue images are from 15b, the red images from dye. The mean fluorescence intensity was evaluated by the image J software.
22
the same voltage on the laser confocal, the images of CCCP pre-treated
group showed weaker blue and red fluorescence, showing the mito-
chondria uptake of 15b might be reduced to half its amount according to
the relative fluorescence intensity (Fig. 3). The results established that
15b entered mitochondria in a Δψm -dependent manner.
proportion to Δψm
.
The percentages of stained cells decreased dose-
dependently, showing the dissipation of Δψm (Fig. 4A). The amount of
ROS was augumented by 15b in a dose-dependent manner (Fig. 4B), as
evidenced by the increasement in fluorescent intensity of DCFH-DA
probe. Next, we tested whether mitochondrial permeability transition
pore (mPTP) was involved in 15b-induced cell death. Cyclosporin A
(CsA) which is an inhibitor for the formation of mitochondrial perme-
ability transition pore (mPTP) pronounced attenuated cell death at low
and medium concentrations, indicating mPTP at least partly involved in
The Δψm changes in intact cells can imply for mitochondrial func-
tionality during diseases and cell death. Hence, the dissipation of Δψm
by 15b was detected by the fluorescent probe tetramethylrhodamine
methyl ester (TMRE) which accumulated in the mitochondrial matrix in
4

Y. Li et al.
Bioorganic & Medicinal Chemistry Letters 33 (2021) 127750
Fig. 4. The effects of 15b on Δψm, ROS level and apoptosis percents in MDA-MB-231 cells. (A) Upon incubation with 15b for 24 h and then with TMRE probe (100
nM) for 30 min, the Δψm was determined by flow cytometry. (B) Upon incubation for 6 h , then cellular ROS level was probed by DCFH-DA using flow cytometry.
Geometric means of fluorescence intensity values were calculated. (C) The cells were pre-incubated with CsA (2 and 4 μM) for 2 h, then exposed to 15b for 48 h,
followed by MTT assay. (D) Upon incubation for 48 h, then apoptosis were detected by Annexin V/PI double-staining assay. Results are presented as means ± SD, n =
3, ***P < 0.001.
Fig. 5. The chemical interaction of 15b and GSH and the effects of GSH on 15b-indcued cell death and Δψm collapsion. (A) UV–vis absorption spectrum changes for
15b (10 μM) in the presence of GSH (100 μ μM). (B)
M) in PBS buffer (pH7.4) at 37 ◦C. After the reaction reaches equilibrium, adding N-methylmaleimide (NMM, 100
The MDA-MB-231 cells were pre-incubated with BSO (50
μM) for 24 h, then exposed to 15b for another 24 h, then MTT method was performed. (C) Determination of
Δ
ψm using flow cytometry. Results are presented as means ± SD, n = 3, ***P < 0.001.
5

Y. Li et al.
Bioorganic & Medicinal Chemistry Letters 33 (2021) 127750
Fig. 6. The effects of 15b on TrxR activity and protein expression in MDA-MB-231 cells. (A) Upon incubation with 15b (10
μ
M) for 4 h, total cell and mitochondrial
M) for 48 h, then
extracts were assessed for TrxR activity by Micro Oxidized Thioredoxin Reductase (TrxR) assay Kit. (B) Upon incubation with 15b (2, 4, 8
μ
expression of TrxR2 were determined using Western blot. (C) The level of target protein was calculated by gray scanning. (D) Docking of 15b in the binding site of
TrxR2 in 3D style. For above configuration yellow sticks represent the ligand (15b), and red dashed lines represent the hydrogen bonds, black dashed lines represent
Pi-interaction. Values are expressed as the means ± SD; n = 3, * p ＜ 0.05.
the mechanism of cell death23 (Fig. 4C). Finally, the percentages of
apoptotic cells were measured using Annexin V-FITC/PI double staining.
The proportion of late apoptotic/necrotic cells increased in response to
concentration (Fig. 4D). Consequently, the resluts indicated that 15b
impaired mitochondrial function and might induce mitochondria-
mediated cell death.
Hence, we explored the effects of 15b on TrxR. Firstly, treatment of
MDA-MB-231 cells with 15b for 4 h decreased TrxR activity in whole
cell and mitochondrial extracts (Fig. 6A). Next, the results of western
blots showed that 15b dose-dependently reduced the expression level of
TrxR2 (Fig. 6B&C). Thirdly, molecular docking showed that the ligand
15b had the binding free energy of ꢀ 49.76 kcal/mol to TrxR2. Ligand
15b formed the hydrogen bond interactions with Ser24. And the ben-
zene ring formed the Pi-interactions with Arg166 and Gly59 which were
conducive to the stable binding of proteins toward small molecules
(Fig. 6D). Consequently, the results demonstrated that 15b could act as a
TrxR2 inhibitor and bind with TrxR2 well.
Promoting cellular oxidative stress in cancer cells could intensify
mitochondrial dysfunction and trigger cell death. Glutathione (GSH) is a
key molecular in defending against oxidative stress and removing ROS
in vivo.24 Thus, we investiated whether 15b could deplete GSH amount.
The interaction between 15b and GSH was observed using the UV–vi-
sible absorption spectrum. After addition of GSH, the absorption peak of
15b at 420 nm slightly deceresed, indicating the presence of interaction
between GSH and 15b (Fig. 5A). Next, we added N-methylmaleimide
(NMM) to scavenge all the added GSH but observed that the absorbance
still maintained decreasing at 420 nm, proving that the the reaction
between 15b and GSH is fully irreversible (Fig. 5A). Further, the effects
of GSH on 15b-induced cell viability and Δψm collapsion were evaluated
by manipulation of cellular GSH level. MDA-MB-231 cells were pre-
treated with buthionine sulfoximine (BSO) to lower the level of GSH.25
After cells were pretreated with BSO for 24 h, the inhibitory effects of
15b on cell viability were augumented nearly 50% at each concentration
(Fig. 5B). The depolarization of Δψm was also incereased nerarly 13% at
each concentration (Fig. 5C). Thus, GSH played a protective role against
15b-induced cell death and mitochondrial dysfunction and a 15b-GSH
conjugate might be produced.
In the present study, we reported on the anti-breast cancer effect and
possible mechanism of coumarin-3-carboxamide analogues containing
the mitochondria-targeting carrier TPP at C-3 through amide-butyl or
eater-butyl chain. Interestingly, 15b has been found to be a potent
anticancer agent against TNBC. 15b acted by enrichment in mitochon-
dria, alkylation of GSH and inhibition on TrxR2, which could lead to the
higher accumulation of ROS and thereby improve oxidative stress in
cells. Simultaneously, 15b also damaged mitochondria function, even-
tually triggering cell death. Overall, our wok showed that delivering
drugs to mitochondria and targeting TrxR2 might be a feasible strategy
to develop anti-TNBC drugs.
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.
In addition to decrease cellular GSH level, inhibition of TrxR also can
increase ROS concentration and aggravate oxidative stress in vivo.24
6

Y. Li et al.
Bioorganic & Medicinal Chemistry Letters 33 (2021) 127750
Chem. 56 (2013) 9170-9179; (c) B. Yan, M. Stantic, R. Zobalova, et al., BMC Cancer.
15 (2015) 401.
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