The investigation and bioorthogonal anticancer activity enhancement of a triphenylphosphine-labile prodrug of seleno-combretastatin-4

Article abstract of DOI:10.1039/d0cc05498d

Here, a triphenylphosphine (TPP)-labile prodrug of seleno-combretastatin-4 (CSeD) was designed and synthesized. A detailed investigation revealed that CSeD, which was shown to be very safe in circulating blood, could react with TPP to release CA-4 and a selenodiazole derivative, with accompanying powerful anticancer and antiangiogenesis effects, as well as radiosensitization properties.

Full text of DOI:10.1039/d0cc05498d

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DOI: 10.1039/D0CC05498D.
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DOI: 10.1039/D0CC05498D
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Investigation and Bioorthogonal Anticancer Activity Enhancement
of Triphenylphosphine-labile Prodrug of Seleno-Combretastatin-4
Liyuan Hou‡, Wei Huang‡, Jiaqi Cheng, Xuanru Deng, Haoqiang Lai, Zhen Chen, Zepang Zhan,
Pengju Feng*, Yiqun Li*, Fang Yang*, Tianfeng Chen
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Here, the triphenylphosphine (TPP)-labile prodrug of seleno- out on derivatization CA-4 to obtain better drug candidates, its
Combretastatin-4 (CSeD) has been designed and synthesized. A low blood compatibility and obvious toxic side effects for
detail investigation was revealed that CSeD which showed higher normal tissues still limit its use in clinical research and cancer
safety in the blood circulation could react with TPP to release CA-4 treatment. Hence, the proper modification of CA-4 is still highly
and selenodiazole derivative, accompanying powerful anticancer, anticipated in order to optimize its clinical behaviour. Selenium
antiangiogenesis effects and radiosentization property.
(Se), as a necessary trace element for human, plays an
important role in many life activities. Organic Se compounds
usually possess high bioavailability, strong anticancer activity
and high biological safety.13 In addition, the selenodiazole
compounds were proved universal anticancer activity and
radiosensitization effect, suggesting high bioavailability, high
biological safety and strong medical significance. 13 In view of
unique properties Se compouds, we designed a combined
prodrug of CA-4 and azide selenodiazole via esterfication and
which could react with TPP to release
Triarylphosphine (TPP) initiated Staudinger ligation reaction
was firstly developed in 2003,1 which ignited scientist’s long-
lasting and explosive interest on bioorthogonal chemistry.2
Several coupling strategies have been well developed over
these ten years which allow the covalent linkage of isotope
labels, fluorescent probes or affinity tags to different
biomolecules.3-4 Apart from these bioorthogonal ligation
reactions, the bond-cleavage type of bioorthogonal reactions
were also received tremendous attention5 and a series of
biocompatible reduction, deprotection reactions with various
bio-application have emerged after well documented photo-
decaging reactions.6 To extend the application of bioorthogonal
cleavage reactions, numerous elegant strategies were
developed to use bioorthogonal tools as a trigger for drug
release. The key focus is on the development of biocompatible
small molecules or reagents as trigger elements. Besides
intensively studied metal catalysts, such as Pd, Ru, Cu(I), etc.,7-9
TPP, both primary and oxidative state of which are nontoxic
proved in many known Staudinger ligation reaction, should be
a biocompatible key to unlock certain derivatized prodrugs for
drug releasing at a controllable manner.10-11 While the
strategies involving TPP as trigger to release drugs with
enhanced bioactivities via Staudinger reaction are seldom
reported.
Mechanism of TPP initiated anticancer activity of CSeD
O
a
O
N
N2 , H2O
OH
O
N
O
N3
O
Se
N
Se
HN
N
O
O
O
O
O
O
TPP
TPO
Anticancer drug
X-Ray sensitivity
Staudinger reaction
TPP
b
c
TPO
0 h
O
O
P
N
O
O
N3
Se 1 h
N
H
O
O
O
H
2 h
After initiation 4h
3 h
4 h
TPP
P
Before initiation
Spectrum from FPJ.wiff (sample 9)
8.5e4
-
3, Experiment 1, +TOF MS (50
-
1000) from 0.162 to 0.210 min
317.1388
d
8.0e4
7.5e4
7.0e4
6.5e4
6.0e4
5.5e4
5.0e4
4.5e4
4.0e4
3.5e4
3.0e4
2.5e4
2.0e4
1.5e4
1.0e4
5.0e3
0.0e0
OH
O
O
O
O
CA-4
[M+H]+
calcd for
317.1389
found
O
N
Combretastatin A-4 (CA-4), a natural tubulin polymerization
inhibitor, can effectively inhibit the aggregation of tubulin, so as
to prevent cancer cells from mitosis, block them in G2/M phase,
and finally induce apoptosis, exhibiting good prospect of clinical
application.12 Although a large number of studies have carried
Se
N
HN
315.9988
SeD derivative
[M+H]+
calcd for
315.9989
found
317.1388
315.9988
Department of Chemistry, Jinan University, Guangzhou 510632, China.
E-mail: pfeng@jnu.edu.cn; tlyq@jnu.edu.cn.
315.7
315.8
315.9
316.0
316.1
316.2
316.3
316.4
316.5
316.6
316.7
316.8
316.9
317.0
317.1
317.2
317.3
317.4
317.5
Mass/Charge, Da
† Electronic Supplementary Information (ESI) available: Experimental details,
supplementary figures, tables, characterization and spectroscopy data. See DOI:
10.1039/x0xx00000x.
Fig. 1 TPP initiated CSeD monitored by 1H NMR 31P NMR and HMRS. (a) The
mechanism of CSeD responding to TPP in the cells. (b) A comparison of reactants’
‡These authors contributed equally to this work.
1 | J. Name., 2012, 00, 1-3
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31P NMR spectrum between before begin and after 4 h. (c) The 1H NMR monitoring
of characteristic H peaks during 4 h. (d) The HMRS has found the mass of CA-4 and
SeD derivative.
effect of various compounds on Caski and HUVEC cells with or without TPP
initiating. (d) CI values demonstrating the synergistic effect of VTiPePw aAnrtdiclCeSOenDlinine
DOI: 10.1039/D0CC05498D
various cells.
CA-4 and SeD derivative at certain location, accompanying
enhanced anticancer activity and synergy efficiency for cancer
treatment (Fig. 1a). With the idea in mind, we firstly synthesized
azide seleno diazole (SeD), which was reacted with CA-4 via
esterification to gain compound CSeD. All new compounds were
well characterized by NMR and HMRS, as shown in Fig. S11-S26
(see supporting information for detail procedure). To prove
CSeD could release CA-4 and SeD derivative by Staudinger
reaction, a series transformation were recorded. As presented
in Fig. 1b, a 31P NMR shows that triphenylphosphine oxide was
formed during the mixing of CSeD and TPP in DMSO-d6 for 4 h.
As shown in Fig. 1c, a gradual diminishment of the peak of
proton next to azide in CSeD was observed during the 4 h as TPP
was constantly added to a solution of CSeD. In addition, the
HRMS of PBS solution of TPP and CSeD shows the Mass of CA-4
normal cells (Fig. S2 and Table S1). As shown in Table S1, TPP
have no obvious cytotoxicity toward various types of cancer and
normal cells, demonstrating TPP with excellent biological safety
can be used as inducer to initiate the reaction with CSeD. Then,
in order to find out the time required for TPP to be absorbed by
cells, we detected the intracellular uptake of TPP in Caski and
HUVEC cells by inductively coupled plasma-mass spectrometry
(ICP-MS). The uptake of TPP in Caski and HUVEC cells enhanced
in time-dependent manner, while its uptake efficiencies at 4 h
were as high as 76.32% and 74.33%, respectively (Fig. S3).
Hence, according to our design in the study, SeD/CSeD was
added to cells after TPP pre-incubation for 4 h in the following
biological experiments. Astonishingly, after the conjugation
between SeD and CA-4, an obvious improvement in the
antiproliferative effect against various cancer cells of CSeD was
observed. Taking the Caski cell for example, the IC50 value of
CSeD against Caski cells was 2.69-fold higher than that of CA-4,
demonstrating that the conjugation of SeD increases CA-4’s
anticancer efficacy. Subsequently, to demonstrate our design,
cells were pre-incubated with TPP for 4 h and then co-treated
with SeD/CSeD to enable SeD/CSeD react with TPP accumulated
in cancer cells. As shown in Fig. 2b-c, SeD/CSeD in combination
with TPP (TPP-SeD/TPP-CSeD) further suppressed cell
proliferation. More strikingly, the IC50 value of TPP-CSeD against
Caski cells was 13.39-fold higher than that of CA-4. The
combination indexes (CI) was used to analysis the relationship
of TPP and CSeD, the value of which was lower than 1.0 (Fig.
2d), indicating that TPP can be used as a key to react with CSeD
and release CA-4 and SeD, achieving synergistic anticancer
effect.
+
(calcd for C18H21O5 ([M+H])+, 317.1389, found, 317.1388) and
SeD derivative (calcd for C14H10N3OSe+ ([M+H])+, 315.9989,
found, 315.9988), as presented in Fig.1d, S27-28. These results
indicated that TPP could serve as a trigger to react with CSeD
and achieve bioorthogonal cleavage reactions in the
physiological environment.
It’s well known that hemocompatibility is an essential
requirement for the intravenous use of chemotherapeutic
drugs in the clinical situation. Therefore, hemolysis rate of red
blood cells (RBCs) treated with different compounds and their
morphology were measured and captured. As shown in Fig. 2a
and Fig. S1a-b, hemolysis rate of RBCs treated with CA-4 was
notably higher than those of TPP, SeD and CSeD alone.
However, co-incubation with TPP and CSeD rapidly enhanced
the hemolysis rate and destructed the morphology of RBCs. The
results exhibited that free TPP and CSeD showed higher safety
in the blood circulation compared with CA-4, but after the
combination of TPP and CSeD, it could cause serious damage to
the RBCs. Clearly, the Se modified CA-4 demonstrated a positive
effect on its physical and chemical properties. Then, MTT assay
was performed to assess the antiproliferative effect of
compounds against cancer and
Moreover, clonogenic assay demonstrated that treatment
with TPP-CSeD compounds effectively inhibit the colony
formation of Caski and HUVEC cells (Fig. S4a-b). Inhibition effect
of TPP-CSeD on Caski tumor spheroids cultured in vitro
exhibited
a
dose-dependent manner, further proving
antiproliferative effect of TPP-CSeD (Fig. S5a-b).
The tumor cells always release a large amount of vascular
growth factors (VEGF) to stimulate the directional growth of
vascular endothelial cells, resulting in the growth of micro-
vessels around and inside the tumor.15 Previous studies proved
that as a common vascular disrupting agent, CA-4 destructs the
morphology of endothelial cells by prohibiting tubulin from
polymerizing to microtubules and cytoskeletons, finally
a
b
5
4
3
2
1
0
100
80
60
6 h
10 h
10 μM
1 h
2 h
4 h
Caski
40
20
10
8
6
4
2
0
4
D
P
D
e
CSe CSe
D
D
4
P
D
TPP
D
D
D
-
TPP
D
e
S
-
e
S
-
TP
S
-
Se
CA-
TP
Se
TPP
16
4
-
CA-
CSe CSe
c
d
achieving the purpose of destroying tumour blood vessels.
CA-
500
TPP
0.6
0.4
0.2
0.0
CI>1, antagonism
CI=1, addictive effect
CI<1, synergism
Therefore, we performed the cell migration, transwell and tube
formation assays to evaluate the suppression effect of these
compounds on angiogenesis activities. As indicated in Fig. 3,
VEGF stimulates the migration and invasion of HUVEC cells and
promotes its tube formation. However, these effects were
markedly inhibited by the treatment of TPP-CSeD at non-toxic
concentration (1.25 μM). For instance, the migration and
invasion of HUVEC cells trigged by VEGF enhanced from 100 %
(control group) to 140% and 151%, whereas the treatment of
TPP-CSeD significantly decreased the migration and invasion
400
300
200
100
HUVEC
10
8
6
4
2
0
i
a
1
7
/E
Wi3
8
C
E6
k
4
P
D
D
D
D
F-7
M23
HUVE
e
S
-
Hel
TP
Se
TPP
Cas
CA-
MC
CSe CSe
TPP
-
Fig. 2 Anticancer efficiency of different compounds. (a) Effects of different
compounds with concentrations of 10 μM on hemolysis of RBCs. (b)(c) Cytotoxic
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC05498D
a
b
d
c
0 h
24 h
48 h
Control
Control+VEGF
TPP+VEGF
CA-4+VEGF
250
200
150
100
50
24 h
Control
48 h
Control
+VEGF
0
l
l
4
-
A
S
T
P
C
D
P
D
C
T
D
D
e
o
o
SeD+VEGF
TPP+SeD
+VEGF
CSeD+VEGF
TPP+VEGF
TPP+CSeD
+VEGF
r
r
t
n
e
P
e
S
-
e
S
C
-
P
t
T
S
n
o
o
C
C
P
TPP
+VEGF
P
VEGF
200
150
100
50
CA-4
+VEGF
100 μm
✱✱✱
e
✱✱✱
Control
Control+VEGF
CA-4+VEGF
SeD
+VEGF
0
l
l
4
C
P
D
P
D
D
D
e
S
o
o
r
t
-
A
r
t
P
e
e
e
T
S
S
S
n
n
C
+
C
o
o
+
C
C
P
P
T
P
T
TPP
- SeD
+VEGF
f
VEGF
150
100
50
✱✱✱
TPP+SeD
+VEGF
CSeD+VEGF
TPP+CSeD
+VEGF
SeD+VEGF
CSeD
+VEGF
✱✱✱
TPP
- CSeD
+VEGF
0
l
l
4
C
P
D
D
D
D
e
S
o
o
r
t
-
A
r
t
P
e
e
e
T
S
T
S
S
n
n
C
500 μm
+
C
o
o
P
+
C
C
P
P
P
1000 μm
T
VEGF
Fig. 3 The comparison of different compounds suppress VEGF-induced HUVEC cell migration, invasion and angiogenesis. Representative images of inhibition of VEGF-
induced HUVEC migration (a), invasion (c) and tube formation (e) by different compounds. Quantitative analysis of migrated cells (b), invasive numbers (d) and tube
length (f). Significant of difference between groups is indicated at*P < 0.05, **P < 0.01, ***P < 0.001.
rates to 62% and 8.8%, which was much lower than that SeD and S7a), which means TPP-CSeD can also enhance the Caski
(186% and 66%) and CA-4 (67% and 47.4%), demonstrating TPP- cell’s apoptotic Sub-G1 fraction. Moreover, as shown in Fig. S8,
CSeD enhances inhibition effect for cancer cells migration (Fig. CA-4 treatment caused obvious G2/M phase arrest in Caski and
3a-b) and invasion (Fig. 3c-d). Similarly, as illustrated in Fig. 3e- HUVEC cells, which was consistent with previous studies.17
f, the reduction in tube length in TPP-CSeD group was much
greater than that of induced by CSeD or CA-4, indicating a better
antiangiogenic activity. Therefore, the efficacy of TPP-CSeD for
inhibition of VEGF-induced cancer cell migration, invasion and
angiogenesis was further improved versus CA-4 compound.
In addition, TPP-CSeD not only enhances the antiproliferative
effect of CSeD, but also provides a possibility to strength the
radiotherapeutic effect of X-Ray. Seleno compounds could
effectively enhance the radiosensitization of tumor cells for X-
ray, resulting in strong anticancer ability according to previous
studies.14 Therefore, the radiosensitization effects of CA-
4/SeD/CSeD/TPP-SeD/TPP-CSeD was investigated by irradiating
different doses of X-Ray. As shown in Table S2 and Figure S6a-
b, with the increase of the X-Ray intensity from 0-8 Gy, the IC50
values of these compounds obviously decreased. Furthermore,
isobologram analysis was used to assess the interaction
between X-Ray and compounds, as shown in Fig. S6c-f, the data
point of in co-treatment group is below the additional effect,
revealing that Seleno compounds could synergistically
enhanced the radiotherapeutic effect in Caski and HUVEC cells.
Overall, TPP-CSeD is not only an efficacy strategy to improve the
antitumor effect of CA-4, but also provide a possibility to
strength its radiotherapeutic effect of X-Ray.
a
b
Control
S
G2/M
Sub-1
G0/G1
Caski
400
X-Ray (4Gy)
X-Ray+TPP-CSeD (1.25 μM)
X-Ray+TPP-CSeD (2.5 μM)
X-Ray+TPP-CSeD (5 μM)
100
50
300
200
100
0
0
y
SeD
TPP
CA-4
CSeD
X-Ray
TPP-CSeD
Control
Caspase 9
Caspase 8
Caspase 3
TPP-SeD
TPP-CXSe-DR+Xa-yRa
9.46%
TPP-CSeD
TPP-CSeD-X-Ray
40.51%
c
Control
7.69%
25.50%
7.01%
13.57%
30.06%
32.57%
FITC
d
Control
X-Ray
TPP+CSeD
TPP+CSeD
-X-Ray
10 μm
Fig. 4 Action mechanisms of cell apoptosis induced by compounds and X-ray
radiotherapy. (a) Cell cycle distribution of Caski cells induced by different
treatments for 24 h. (b) Combined treatments of X-Ray and compounds activated
caspase3/8/9 activity in Caski cells. (c) Flow cytometry analysis of apoptosis in
Caski and HUVEC cells caused by compounds and X-Ray. (d) Effects of TPP-CSeD
and X-Ray on mitochondrial dysfunction in Caski cells.
The death mechanism of Caski and HUVEC cells caused by
TPP-CSeD in combination with X-Ray was also explored. After
combined with X-Ray irradiation, the population of apoptotic
Sub-G1 fraction in Caski cells was further increased (Figure 4a
Furthermore, according to the results of Annexin V-FITC
apoptosis detection kit, TPP-CSeD combined with X-Ray
irradiation effectively enhanced the population of early and late
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J. Name., 2013, 00, 1-3 | 3
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apoptosis cells in a dose-dependent manner, which was much
greater than those of TPP-CSeD or X-Ray alone (Fig. S9). These
results revealed that under X-Ray irradiation, TPP-CSeD trigged
cancer cells death mainly through inducting apoptosis and a
small amount of G2/M phase cell arrest. It’s well known that
mitochondrial dysfunction acts as critical role in inducing
apoptotic.18 Hence, we used mitochondrial probe to
dynamically observe the morphological changes of
mitochondria in real time. As shown in Fig. 4d and Fig. S7d, the
mitochondria in the control group extended to the whole
cytoplasm in a filamentous manner. But in the Caski and HUVEC
cells treated with TPP-CSeD and X-Ray, obvious mitochondrial
fragmentation and rupture were observed. These results
commonly suggested that the combination of TPP-CSeD and X-
Ray irradiation plays an important role in inducing
mitochondrial dysfunction and triggering cell apoptosis. Many
studies reported that caspases, as a family of proteases, plays
an important role in initiating and executing apoptosis.19
Therefore, we next examined the caspase activities including
caspase-3/8/9 trigged by different concentrations of TPP-CSeD
and X-Ray in combination. A dose-dependent manner increase
in caspase 3/8/9 activities were observed after the treatment
(Fig. 4b and S7b). Western blot analysis further showed that
treatment of Caski cells with TPP-CSeD and X-Ray also caused
dose-dependent increase in activation of caspase-3, caspase-8
and caspase-9 (Fig. S10). Taken together, apoptosis mediated
by TPP-CSeD and X-Ray is mainly dependent on caspase
pathway, mainly through death receptor-mediated and
mitochondrial-mediated pathways.
In summary, TPP-labile CSeD prodrug was successfully
designed and synthesized by using -OH group from CA-4 and -
COOH group from azide SeD via esterification process. TPP
could serve as a trigger to react with CSeD for releasing SeD and
CA-4 via Staudinger reaction, thus achieving bioorthogonal
cleavage reactions. Compound CSeD showed higher safety in
the blood circulation compared with CA-4 and the anticancer
efficiency of TPP-CSeD was also highly superior to that of CA-4.
Moreover, TPP-CSeD displayed excellent radiosentization
properties and enhanced the inhibition effect for cancer cells
migration, invasion and angiogenesis. The mechanism of cell
death suggested TPP-CSeD with X-Ray illumination induced
mitochondrial dysfunction and activated of caspase activities,
thus triggering cell apoptosis. Taken together, this study
provides a new approach for the rational design of late-stage
activation multiple chemotherapeutic prodrugs that showed
bioorthogonal bioactivity enhancement for simultaneous
anticancer and antiangiogenesis therapy.
Conflicts of interest
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The authors declare that there are no confliDctOsI:o1f0i.n10te3r9e/Dst0.CC05498D
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This work was supported by Natural Science Foundation of
China (21602078, 21877049), the Pearl River talent program of
Guangdong Province (Youth top-notch talent, 2017GC010302),
Guangdong Basic and Applied Basic Research Foundation
(2019A1515011743), National Program for Support of Top-
notch Young Professionals (W02070191), the Fundamental
Research Funds for the Central Universities.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC05498D