A potent aminonaphthalimide platinum(IV) complex with effective antitumor activities in vitro and in vivo displaying dual DNA damage effects on tumor cells

Article abstract of DOI:10.1016/j.bmcl.2019.126670

A new aminonaphthalimide platinum(IV) complex was developed by incorporating aminonaphthalimide, a DNA intercalator, into the platinum(IV) system. This complex displayed potent antitumor activities against all tested tumor cell lines in vitro and showed great potential in overcoming drug resistance of cisplatin. Moreover, it remarkably inhibited the growth of CT26 xenografts in BALB/c mice without severe side effects in vivo. Then, the compound exhibited a dual DNA damage antitumor mechanism that it could interact with DNA in tetravalent form via the naphthalimide group to cause DNA lesion, and the further liberation of platinum(II) complex after reduction would induce remarkable secondary damage to DNA. Meanwhile, it caused cell apoptosis through an intrinsic apoptosis pathway by up-regulating the expression of caspase 3 and caspase 9.

Full text of DOI:10.1016/j.bmcl.2019.126670

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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A potent aminonaphthalimide platinum(IV) complex with effective
antitumor activities in vitro and in vivo displaying dual DNA damage effects
on tumor cells
⁎
Qingpeng Wanga, , Yan Chena, Guoshuai Lia,b, Yanna Zhaoa, Zhifang Liua, Ruiyan Zhanga,
⁎
⁎
Min Liua, , Dacheng Lia,c, , Jun Hana
a Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, PR China
b State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, PR China
c Shandong Provincial Key Laboratory of Chemical Energy Storage and Novel Cell Technology, Liaocheng University, Liaocheng 252059, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A new aminonaphthalimide platinum(IV) complex was developed by incorporating aminonaphthalimide, a DNA
intercalator, into the platinum(IV) system. This complex displayed potent antitumor activities against all tested
tumor cell lines in vitro and showed great potential in overcoming drug resistance of cisplatin. Moreover, it
remarkably inhibited the growth of CT26 xenografts in BALB/c mice without severe side effects in vivo. Then, the
compound exhibited a dual DNA damage antitumor mechanism that it could interact with DNA in tetravalent
form via the naphthalimide group to cause DNA lesion, and the further liberation of platinum(II) complex after
reduction would induce remarkable secondary damage to DNA. Meanwhile, it caused cell apoptosis through an
intrinsic apoptosis pathway by up-regulating the expression of caspase 3 and caspase 9.
Antitumor
Platinum
Prodrug
DNA damage
Naphthalimide
Platinum drugs have been widely used in the chemotherapy of
various types of cancers.1,2 Among which, cisplatin, carboplatin and
oxaliplatin display major roles in clinic. Platinum drugs cause apoptosis
of cancer cells mainly through DNA damage. However, they are prone
to inducing serious drug resistances and side effects, due to drug efflux,
self-repair to DNA damage, and increased tolerance to DNA lesion.3,4
During the past decades, abundant efforts have been devoted to en-
hancing activities of platinum drugs and minimizing unwanted toxic
effects, and great achievements have been made in platinum drug de-
velopment.5–7
exhibited potent antitumor activities with much potential in over-
coming cisplatin resistance.19,20 The naphthalimide platinum(IV)
compounds represent an effective antitumor scaffold possessing dual
DNA damage mechanism. However, some drawbacks of complex III,
such as weak water solubility, badly affected its potential application as
antitumor drug. Thus, it was of great interest for us to design new
complexes with enhanced solubility and bioactivities based on such
naphthalimide platinum(IV) scaffold.
Herein, in continuation of our ongoing enthusiasm for the devel-
opment of new antitumor agents,21–24 a mono aminonaphthalimide
pended platinum(IV) complex ANOxp as shown in Fig. 2 was designed,
synthesized and evaluated as antitumor agent. The mono ligand mod-
ified platinum(IV) system was regarded to possess higher solubility in
water than the dual substituted one, and would further exert much
influence on the antitumor activities. Furthermore, oxaliplatin as the
third generation of platinum(II) drug was selected as the core of pla-
tinum(IV) with the aim of gaining target compound to overcome re-
sistance of cisplatin25 Moreover, it has been proven in our previous
work that, aminonaphthalimide was a promising ligand in improving
bioactivities of platinum(IV) compounds.19,20 Thereby, amino-
naphthalimide ligand was employed expecting that the amino-
naphthalimide and platinum fragments would display synergetic DNA
Platinum(IV) complexes as versatile prodrugs of platinum(II) drugs
displayed much potential in overcoming limitations of platinum(II)
drugs.8–13 The easily modification of the axial ligands of platinum(IV)
complexes affords an effective and convenient way to construct new
complexes with desired properties. The incorporation of functional
moieties with potent DNA targeting properties remarkably increased
the antitumor activities of the platinum(IV) complexes.14–16 Complexes
I and II (Fig. 1) with DNA alkylating agent chlorambucil and nucleotide
excision repair inhibitor (NERi) reduced the self-repair to DNA damage
of tumor cells, and enhanced their sensitivity to Pt-DNA lesions.17,18
Moreover, in our previous work, the naphthalimide platinum(IV) hy-
brid III with dual promising DNA intercalated ligands naphthalimide
⁎ Corresponding authors at: Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, PR China (D. Li).
E-mail addresses: lywqp@126.com (Q. Wang), panpanliumin@163.com (M. Liu), lidacheng62@163.com (D. Li).
https://doi.org/10.1016/j.bmcl.2019.126670
Received 21 July 2019; Received in revised form 2 September 2019; Accepted 3 September 2019
0960-894X/©2019ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:QingpengWang,etal.,Bioorganic&MedicinalChemistryLetters,https://doi.org/10.1016/j.bmcl.2019.126670

Q. Wang, et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Table 2
Comparison of cytotoxicity profiles for ANOxp with complex III.
Compds
Water solubility (μM) ALog Pa SKOV-3 Hela A549 A549R
ANOxp/Cisb
ANOxp/Oxpb
III/Cisc
152.9
37.9
2.713
3.764
1.58
0.72
2.44
1.13
0.96 1.65
0.31 0.83
4.03 2.25
1.15 1.82
0.46
0.46
0.40
0.75
III/Oxpc
a
b
The values of ALog P were predicted by Discovery Studio.
ANOxp/Cis = IC50(ANOxp)/IC50(Cisplatin); ANOxp/Oxp = IC50(ANOxp)/
IC50(Oxaliplatin). ANOxp/Cis and ANOxp/Oxp were calculated based on data in
Table 1.
c
III/Cis = IC50(III)/IC50(Cisplatin), III/Oxp = IC50(III)/IC50(Oxaliplatin).
III/Cis and III/Oxp were calculated based on data in Ref. 19.
cytotoxicity against which was stronger than that of control drugs cis-
platin and oxaliplatin. Moreover, the antitumor activities of ANOxp are
remarkably more potent than its precursors O1 and A, as well as the
mixture A&O1. Thereby, the conjugation of oxoplatin with naphthali-
mide acid to form ANOxp displays significant positive effects on anti-
tumor activities.
Fig. 1. Platinum(IV) compounds with DNA targeting axial ligands.
Importantly, ANOxp exerts great potential in overcoming resistance
of cisplatin. ANOxp reduces the resistant factor (RF) toward A549R to
0.5 from 1.7 for cisplatin, which is even more effective than oxaliplatin
(RF = 0.8). However, ANOxp shows no obvious selectivity to tumor
cells, and it displays IC50 value of 6.4 μM toward normal cell 293 T,
which is comparable to that of cisplatin and oxaliplatin.
To compare the antitumor activities of ANOxp with complex III, the
ratio of their IC50 values to that of cisplatin and oxaliplatin were cal-
culated respectively and provided in Table 2. Moreover, water solubi-
lity for both compounds was tested and the lipid-water partition coef-
ficient ALog P was also calculated. As observed that ANOxp exhibits
more potent activities than complex III in vitro, and the enhanced ac-
tivities seem to relevant with the water solubility and lipid-water par-
tition properties. The more potent mono aminonaphthalimide pended
platinum(IV) ANOxp possesses a 4.0 times higher solubility than the
dual substituted complex III in water, meanwhile ANOxp also displays
satisfactory lipid-water distribution (2.713) in comparison with com-
plex III (3.764). Accordingly, the design of mono aminonaphthalimide
platinum(IV) complex ANOxp is proven a useful strategy in enhancing
antitumor activities of platinum(IV) compounds.
Fig. 2. Structures of aminonaphthalimide platinum(IV) ANOxp, oxoplatin O1
and aminonaphthalimide acid A.
damage to tumor cells. The antitumor activities in vitro and in vivo were
evaluated and the potential action mechanism was also investigated.
ANOxp was prepared by the condensation of aminonaphthalimide
acid A with oxoplatin O1 in yield of 24% (Fig. S1). The structure was
confirmed by 1HNMR, 13C NMR, IR, and HRMS. The correct HRMS data
of ANOxp indicates the combination of oxoplatin O1 with amino-
naphthalimide acid A. Five protons upon 5.9 ppm in 1H NMR are as-
cribed to the protons on naphthalimide moiety. Cyclohexyl group dis-
plays peaks in upfield below 2.5 ppm. The peaks in 13C NMR spectrum
are also appeared in the expected regions. For the IR spectrum, the
carboxyl groups of ANOxp give signals in the area of 1660–1730 cm−1
,
To further confirm the antitumor competence of ANOxp, its activ-
ities in vivo were evaluated with oxaliplatin as reference drug. The
BALB/c mouse bearing CT26 xenograft tumor was selected as model for
the reason that the immune system is important for the anticancer ac-
tivity of oxaliplatin and its derivatives.26,27 Oxaliplatin and ANOxp
were injected via intraperitoneal injection (i.p.) at days 6, 9, 12, 15 and
18 post-tumor inoculation with dosage of 5 mg Pt per kg, with saline as
negative reference. The results in Fig. 3 show that ANOxp could ef-
fectively inhibit the growth of tumor in contrast to the NaCl group
(Fig. 3A). Furthermore, the average tumor weight for ANOxp treated
group at the end of the treatment is 0.17 g with tumor growth inhibition
and the aromatic frame of aminonaphthalimide fragment shows peaks
between 1623 and 1450 cm−1. The purity of ANOxp is determined by
HPLC (98.85%).
The antitumor activities of ANOxp against five cancer cell lines
including human ovarian cancer (SKOV-3), human cervical cancer
(HeLa), human lung cancer (A549), cisplatin resistant cell A549R, and
murine colon cancer (CT26) were tested to evaluate its potential as
antitumor agent. Moreover, the human kidney cell 293 T was used to
detect its toxic properties. The results in Table 1 indicate that ANOxp
could effectively inhibit the proliferation of all tested tumor cell lines
with IC50 values below 22.3 μM. Especially for HeLa and A549R, its
Table 1
Cytotoxicity profiles of complex ANOxp and oxoplatin O1 toward four human carcinoma cell lines, one murine carcinoma cell line and one normal human cell line
expressed as IC50 (μM).
Compds
SKOV-3
Hela
A549
A549R
RFa
CT26
293 T
ANOxp
O1
3.8
0.4
2.3
0.6
0.7
22.3
28.0
82.5
36.4
13.5
26.8
1.2
2.5
13.7
3.3
2.1
3.8
10.3
43.8
> 100
38.8
22.6
22.2
0.8
8.3
0.5
1.6
NC
1.1
1.7
0.8
7.1
0.9
2.7
6.4
0.4
0.7
11.3
> 100
24.6
2.4
0.9
1.8
6.7
12.6
> 100
20.1
5.3
11.3
> 100
18.7
12.2
2.7
A
> 100
7.4
A&O1b
Cisplatin
Oxaliplatin
1.0
0.5
1.0
4.2
3.2
1.8
2.5
1.9
0.8
1.5
0.5
0.2
2.4
5.3
0.4
7.4
3.9
0.4
a
b
RF: Resistant factor. RF(A549) = IC50(A549R)/IC50(A549).
A&O1: 1 equivalent of acid A mixed with 1 equivalent of oxoplatin O1.
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Fig. 3. In vivo antitumor activities of ANOxp and oxaliplatin against CT26 xenograft tumors in BALB/c mice. (A) Tumor growth as a function of time. (B) The body
weight of the mice during the treatment. (C) The tumor weight in each group at the end of the experiment. (D) The images of the tumors at the end of the experiment.
(E) Final magnification (200×) of the H&E staining of slices from tumor. (E) Final magnification (200×) of the H&E staining of slices from normal tissues. Results are
representative of at least three independent experiments and shown as the mean
compared with control group.
S.D. *p < 0.05, **p < 0.01, ***p < 0.001, ns: no significant difference
(TGI) of 83% compared to the NaCl group (1.02 g), which is more ef-
fective than the oxaliplatin group (0.38 g, 62%) (Fig. 3C and D). Then,
the hematoxylin and eosin (H&E) staining slices from tumours in Fig. 3E
manifest that ANOxp induces significant histological change to tumor
tissues in contrast to the NaCl group, which is similar to that of ox-
aliplatin. The average tumor cell numbers in each microscopic field for
the ANOxp treated group are less than the NaCl group, which de-
monstrates the inhibitory effects of ANOxp on proliferation of tumor
cells. When consider the toxic effects of ANOxp, we find that ANOxp
causes no remarkable body weight loss of the mice during such ex-
periment progress (Fig. 3B). Moreover, no noticeable organ damages or
appreciable histological differences of H&E staining slices from normal
tissues including heart, lung, liver, spleen and kidney is found after
treatment with ANOxp. These facts disclose that ANOxp displays no
severe side effects on mice. Therefore, ANOxp could significantly in-
hibit the growth of CT-26 xenograft tumors in vivo, which are even
better than oxaliplatin, without causing remarkable side effects.
ANOxp was supposed to display a dual DNA damage mechanism by
the aminonaphthalimide and platinum groups. Its potential antitumor
mechanism was investigated by electrophoretic dsDNA plasmid assay,
fluorescence, UV–vis, CD and HPLC methods.
The electrophoretic dsDNA plasmid assay for DNA binding studies
of ANOxp in Fig. 4 reveals that plasmid pAUR101 keeps stable for at
least 4 h in PBS (bands a and b). Meanwhile, ANOxp effectively causes
untwisting of the covalently closed circular plasmid within 4 h (bands e
and f) which is similar to that of the platinum(II) reference drug ox-
aliplatin (bands c and d). These facts are probably owing to the inter-
calation of ANOxp with DNA plasmid via naphthalimide fragment. The
platinum(IV) core is considered to release platinum(II) complex after
reduction and realize the DNA damage function. Thus, the reduced
system of ANOxp (ANOxp&AsA) was prepared under treatment of as-
corbic acid (AsA) at 37 °C for 48 h to allow the platinum(IV) complex
fully converting to divalent form. Bands g and h show that the reduced
system ANOxp&AsA causes even much faster and more serious damage
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Fig. 7. UV–vis absorption spectra of NR-DNA system in the absence and pre-
Fig. 4. Electropherograms of dsDNA plasmid pAUR101 incubated with 50 μM
of oxaliplatin, platinum(IV) compound ANOxp or its reduced system ANOxp&
AsA for different incubation time (1 h or 4 h) at 37 °C.
sence of compound ANOxp (pH = 7.4, T = 298 K). c(NR) = 40.0 μM,
c
(DNA) = 43 μM. a-k: c(ANOxp) = 0.0–30.0 μM with increments of 3.0 μM; l:
spectrum of ANOxp (30 μM); m: spectrum of CT-DNA (43 μM).
Fig. 8. CD spectra of CT-DNA in the absence and presence of the platinum(IV)
compound ANOxp. a-b: c(DNA) = 80 μM, c(ANOxp) = 0, 20 μM.
Fig. 5. UV–vis absorption spectra of CT-DNA (43.0 μM) in the absence and
presence of compound ANOxp. a-i: c(ANOxp) = 0.0–24.0 μM with increments
of 3.0 μM. Inset: The comparison of absorbance at 260 nm between the DNA-
ANOxp system (DNA-ANOxp) and the sum values of free compound ANOxp
and free DNA (DNA + ANOxp).
Fig. 9. Fluorescence spectrum of CT-DNA (100 μM) in the absence and presence
of ANOxp (λex = 260 nm, T = 298 K). a-l: c(ANOxp) = 0.00, 0.57, 1.14, 1.71,
2.28, 3.99, 4.56, 5.13, 5.70, 6.27, 6.84, 7.41 μM; m: spectrum of ANOxp
(7.41 μM). Inset: Sterne-Volmer plots for F0/F vs [c] × 106 of CT-DNA and
ANOxp system.
Fig. 6. UV–vis absorption spectra of ANOxp (40.0 μM) in the absence and
presence of CT-DNA. a-i: c(CT-DNA) = 0.0–40.0 μM with increments of 4.0 μM.
Inset: The comparison of absorbance at 250 nm between the ANOxp-DNA
system (ANOxp-DNA) and the sum values of free compound ANOxp and free
DNA (ANOxp + DNA).
DNA in Fig. 6 provides similar results. A hypochromic effect for
ANOxp-DNA system was also revealed at 246 nm than ANOxp + DNA
(Inset of Fig. 6). The facts mentioned above evidence the interaction of
ANOxp with CT-DNA.
Neutral red (NR) was a planar phenazine dye which could interact
with DNA by intercalated function. It is observed in Fig. S2 that CT-
DNA could combine with NR to form a stable complex NR-DNA and
further cause a decrease of the absorption peak for NR at 450 nm. Then,
ANOxp was added to the NR-DNA system (Fig. 7). The absorption at
450 nm gradually increases with the concentration of ANOxp rising
from 0.0 μM to 24.0 μM, which is probably ascribed to the competitive
binding of ANOxp and NR with CT-DNA and further leading to the
release of NR from the NR-DNA complex.
to DNA than ANOxp and oxaliplatin, which are perhaps because of the
synergetic function of the released platinum(II) complex and the
naphthalimide moiety.
Then the UV–vis method was applied to detect the interaction of
ANOxp with calf thymus-DNA (CT-DNA). UV–vis absorption spectra of
CT-DNA in the absence and presence of ANOxp (Fig. 5) display that the
absorption of CT-DNA at 260 nm increases gradually with the addition
of ANOxp. Moreover, a hypochromic effect is observed that the ab-
sorption of DNA-ANOxp system is relatively weaker than the summa-
tion of ANOxp with DNA (DNA + ANOxp) (Inset of Fig. 5). Then,
UV–vis absorption spectra of ANOxp in the absence and presence of CT-
Further evidence for interaction of ANOxp with DNA was obtained
by CD assay (Fig. 8), which is a sensitive optical technique in
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Fig. 10. Cell apoptotic analysis of SKOV-
3
cells incubated with and without
compound ANOxp, cisplatin and ox-
aliplatin. SKOV-3 cells were incubated
with and without platinum complexes
for 24 h at 37 °C (blank: no compound;
cisplatin, oxaliplatin, ANOxp: 20 μM).
(a) Blank; (b) ANOxp; (c) Oxaliplatin;
(d) The stack column; (e) Fluorescence
microscopic images.
Fig. 11. Western blot analysis of cell apoptotic pathway induced by platinum complexes. SKOV-3 cells were incubated with and without compound ANOxp, cisplatin
and oxaliplatin for 24 h at 37 °C (blank: untreated group; oxaliplatin, ANOxp: 30 μM). (a) Blots; (b) Relative gray intensity analysis (Relative gray intensity = (gray
intensity of indicated protein)/(gray intensity of β-actin)).
monitoring the structural change of DNA. The two typical peaks of CT-
DNA (80.0 μM) at 245 nm and 275 nm change simultaneously with the
addition of ANOxp (20 μM). The decrease of the negative peak at
245 nm manifests the reduction of right-handed helicity, meanwhile the
increase of positive peak at 275 nm is attributed to the change of base
stacking. These facts reflect the combination of ANOxp with CT-DNA.
The fluorescence spectrum was then utilized to further verify the
interaction of ANOxp with DNA. The CT-DNA (100 μM) displays typical
fluorescence emission at 503 nm under excitation of 260 nm. ANOxp
quenches the emission of CT-DNA gradually with the concentration
rising to 7.41 μM (Fig. 9). The quenching trend is in accordance with
the Stern-Volmer equation. Then the Stern-Volmer constant KSV
in reducing condition. Then the released platinum(II) complex after
reduction would effectively combine with DNA, and cause serious da-
mage in tumor cells.
The apoptosis inducing properties were evaluated using annexin V-
FITC and propidium iodide (PI) double-staining method and the ex-
pression of apoptosis proteins caspase 3 and caspase 9 were monitored
by western blot assay. ANOxp effectively leads SKOV-3 cells undergo
apoptosis (29.11%) in contrast to the blank group (10.55%) (Fig. 10).
Furthermore, oxaliplatin (71.14%) seems more effective than ANOxp in
inducing apoptosis. This is probably because of that the activation of
platinum(IV) complex in tumor cells is accompanied with the reduction
to divalent form, which costs longer time than platinum(II) drugs.
Moreover, these results are reconfirmed by the following fluorescence
microscopic images (Fig. 10e). Additionally, the western blot results in
Fig. 11 display that the expression levels of pro-caspase 3 and pro-
caspase 9 as well as the cleaved-caspase 3 and cleaved-caspase 9 in-
crease conspicuously in ANOxp group in comparison with the blank
group. Notably, ANOxp up-regulates the expression of proteins pro-
caspase 3, pro-caspase 9 and cleaved-caspase 9 even more effectively
than reference drugs cisplatin and oxaliplatin. Accordingly, ANOxp
could induce cell apoptosis through an intrinsic apoptosis pathway.
In conclusion, a new aminonaphthalimide platinum(IV) complex
ANOxp was designed, prepared and evaluated for antitumor activities
in vitro and in vivo. The bioactivities in vitro reflects the effective ac-
tivities of ANOxp to all the tested tumor cell lines, which are com-
parable or even better than reference drugs cisplatin and oxaliplatin. It
exerts much potential in overcoming drug resistance of cisplatin. More
importantly, ANOxp could effectively inhibit the growth of CT26
(7.7 × 104 M−1) and quenching rate constant Kq (7.7 × 1012 M−1 S−1
)
were calculated based on the Stern-Volmer equation (the detail calcu-
lation procedure was applied in ESI). Notably, Kq is greater than the
maximum scatter collision quenching constant of the biomolecule
(2.0 × 1010 M−1 S−1) and this procedure is probably a static quenching
on account of ANOxp interacting with the CT-DNA.
The reduction potential of platinum(IV) complexes to the divalent
form, and the further DNA combination of the liberated platinum(II)
complexes play key roles in the activation of platinum(IV) compounds.
Herein, HPLC assay was employed to investigate the reduction and DNA
damage abilities of ANOxp. The results in Fig. S3 indicate that ANOxp
keeps stable for at least 8 h in PBS solution. It could easily undergo
reduction in the presence of reducing AsA accompanied with the release
of aminonaphthalimide acid. The formation of Platined-GMP peak
proves the DNA interaction properties of the liberated platinum(II)
complex. Summarily, platinum(IV) ANOxp easily undergoes reduction
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xenograft tumors in BALB/c mice without inducing severe side effects in
vivo. Furthermore, a dual DNA damage mechanism is evidenced by
multiple strategies that ANOxp could interact with DNA in tetravalent
form via the naphthalimide ligand and cause DNA lesion. Further re-
duction to platinum(II) complex would induce remarkable secondary
damage to DNA. Moreover, ANOxp effectively cause apoptosis of tumor
cells by up-regulating the expressions of caspase 3 and caspase 9. These
findings enable ANOxp to be a prominent compound for further in-
vestigation as new anticancer agents.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2019.126670.
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