Strong in vitro and vivo cytotoxicity of novel organoplatinum(II) complexes with quinoline-coumarin derivatives

Article abstract of DOI:10.1016/j.ejmech.2019.111751

A series of novel organoplatinum(II) complexes, [Pt^II(QC1)(H-QC1)Cl] (Pt1), [Pt^II(QC2)(H-QC2)Cl] (Pt2), [Pt^II(QC3)(H-QC3)Cl] (Pt3), [Pt^II(QC4)(H-QC4)Cl]?CH₃OH (Pt4), [Pt^II(QC5)(H-QC5)Cl] (Pt5), [Pt^II(H-QC6)(DMSO)Cl₂] (Pt6), [Pt^II(H-QC7)(DMSO)Cl₂]?H₂O (Pt7), [Pt^II(H-QC8)(DMSO)Cl₂] (Pt8), [Pt^II(H-QC9)(DMSO)Cl₂]?CH₃OH (Pt9), [Pt^II(H-QC10)(DMSO)Cl₂] (Pt10) and [Pt^II(H-QC11)(DMSO)Cl₂] (Pt11), bearing quinoline-coumarin derivatives (H-QC1?H-QC11) have been first designed. Complexes Pt1–Pt11 selectively displayed obvious cytotoxicities in comparison to cisplatin for A549/DDP (cisplatin-resistant human lung adenocarcinoma) cells and HeLa cervical carcinoma cells, with IC₅₀ values as low as 100 nM?10.33 μM. In addition, Pt4 and Pt5 display a green-colored luminescent properties, targeted mitochondrial membrane and, thereby induced mainly mitochondria-mediated cell apoptosis was in the following order: Pt4 > Pt5. The different anti-cancer activity of quinoline-coumarin complexes Pt4 (100 nM) and Pt5 (250 nM) were correlate with the presence of 3-(2′-quinolyl)-6-hydroxy-coumarin (H-QC4) ligand. The quinoline-coumarin complex Pt4 (2.0 mg/kg per 2 days) also displayed potent in vivo anti-tumor effect after 21 days-treated. In contrast, the H-QC4 ligand highly enhances the anti-tumor activity and selectivity of organoplatinum(II) complexes in comparison to other previously reported coumarin derivatives metal complexes.

Full text of DOI:10.1016/j.ejmech.2019.111751

European Journal of Medicinal Chemistry 184 (2019) 111751
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Strong in vitro and vivo cytotoxicity of novel organoplatinum(II)
complexes with quinoline-coumarin derivatives
Qi-Pin Qin a
Bi-Qun Zou
a
,
b
,
*
, Zhen-Feng Wang , Xiao-Ling Huang , Ming-Xiong Tan
a
a
a, **
,
b
,
c
,
d,
****
, Hong Liang b
, ***
Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong
Road, Yulin, 537000, PR China
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University,
b
1
5 Yucai Road, Guilin, 541004, PR China
Department of Chemistry, Guilin Normal College, 9 Feihu Road, Gulin, 541001, China
School of Pharmacy, Guilin Medical University, Guilin, 541004, China
c
d
a r t i c l e i n f o
a b s t r a c t
II
II
Article history:
Received 24 July 2019
Received in revised form
A series of novel organoplatinum(II) complexes, [Pt (QC1)(H-QC1)Cl] (Pt1), [Pt (QC2)(H-QC2)Cl] (Pt2),
II
II
II
II
[
Pt (QC3)(H-QC3)Cl] (Pt3), [Pt (QC4)(H-QC4)Cl],CH
3
OH (Pt4), [Pt (QC5)(H-QC5)Cl] (Pt5), [Pt (H-
(Pt7), [Pt (H-QC8)(DMSO)Cl
] (Pt10) and [Pt (H-QC11)(DMSO)Cl
II
II
II
QC6)(DMSO)Cl
QC9)(DMSO)Cl
2
]
(Pt6), [Pt (H-QC7)(DMSO)Cl
2
],H
2
O
2
]
(Pt8), [Pt (H-
] (Pt11),
29 September 2019
II
II
2
],CH
3
OH (Pt9), [Pt (H-QC10)(DMSO)Cl
2
2
Accepted 30 September 2019
Available online 2 October 2019
bearing quinoline-coumarin derivatives (H-QC1ꢀH-QC11) have been first designed. Complexes Pt1ePt11
selectively displayed obvious cytotoxicities in comparison to cisplatin for A549/DDP (cisplatin-resistant
human lung adenocarcinoma) cells and HeLa cervical carcinoma cells, with IC50 values as low as
mM. In addition, Pt4 and Pt5 display a green-colored luminescent properties, targeted
mitochondrial membrane and, thereby induced mainly mitochondria-mediated cell apoptosis was in the
Keywords:
100 nMꢀ10.33
quinoline-coumarin derivatives
Organoplatinum(II) complexes
Cell apoptosis
following order: Pt4 > Pt5. The different anti-cancer activity of quinoline-coumarin complexes Pt4
(100 nM) and Pt5 (250 nM) were correlate with the presence of 3-(2 -quinolyl)-6-hydroxy-coumarin (H-
0
Mitochondria dysfunction
QC4) ligand. The quinoline-coumarin complex Pt4 (2.0 mg/kg per 2 days) also displayed potent in vivo
anti-tumor effect after 21 days-treated. In contrast, the H-QC4 ligand highly enhances the anti-tumor
activity and selectivity of organoplatinum(II) complexes in comparison to other previously reported
coumarin derivatives metal complexes.
©
2019 Elsevier Masson SAS. All rights reserved.
1
. Introduction
therapy [8e20]. To overcome these shortcomings of cisplatin and
its antiproliferative derivatives, different methods have been
explored [21e24], including the study of organoplatinum(II) com-
plexes, such as iminophosphorane cyclometalated-Pt(II) complexes
Pt-based anti-tumor drugs, such as cisplatin and its ramification,
have become important complexes in many tumor types therapy
II
0
[
1e7]. Unfortunately, the highly side effects (high toxicity) and
[21], oxoisoaporphine Pt complexes [25], 3-(2 -benzimidazolyl)-7-
II
II
drug-tolerance of Pt-based drugs and, thereby limiting their clinical
methoxycoumarin Pt complex [26], rhomboidal Pt metallacycles
[
II
27], C,N-dimethylbenzylamine cycloplatinated Pt compounds
[
28], nucleobases and their derivatives organoplatinum(II) com-
II
plexes [29], 1,5-cyclooctadiene and alkynyl Pt complexes [30,31],
luminescent cyclometalated Pt complex [32], N,N-dimethyl-1-(2-
aryl)methanamine-
*
Corresponding authors. Guangxi Key Lab of Agricultural Resources Chemistry
and Biotechnology, College of Chemistry and Food Science, Yulin Normal University,
303 Jiaoyudong Road, Yulin, 537000, PR China
II
II
k
2
C
2
,N organometallic Pt complexes [33], and
1
curcumin organoplatinum(II) metallacycle [34], etc.
*
*
*
* Corresponding author.
** Corresponding authors.
*** Corresponding author. Department of Chemistry, Guilin Normal College, 9
Since coumarin and its metal complexes possesses anti-cancer,
anti-HIV, anti-Alzheimer effects, and most of them have been
extensively considered as an ideal anti-tumor agents and a telo-
Feihu Road, Gulin, 541001, China
E-mail addresses: qpqin2018@126.com (Q.-P. Qin), mxtan2018@126.com
€
merase inhibitor [35e46]. For example, Ozdemir reported that
(
M.-X. Tan), zoubiqun@163.com (B.-Q. Zou), hliang@mailbox.gxnu.edu.cn (H. Liang).
https://doi.org/10.1016/j.ejmech.2019.111751
223-5234/© 2019 Elsevier Masson SAS. All rights reserved.
0

2
Q.-P. Qin et al. / European Journal of Medicinal Chemistry 184 (2019) 111751
coumarin-thiazole PdII complex has the most anti-cancer activity
against LNCaP cells, with IC50 value was 10.05 g/mL [45]. Kostova
investigated the coumarins Ce(III) complex, which exhibited high
cytotoxic against HL-60 cells (12.5e50.0 M) by affecting pro-
complex Pt1ePt11 were characterized by various spectral
methods and single-crystal X-ray diffraction analyses (Figs. 1 and 2
and S1eS29). Moreover, Pt4 and Pt5 were stable in Tris-HCl buffer
solution at 48.0 h by HPLC analysis (Figs. S28 and S29).
m
m
grammed cell death [46]. Besides, a new coumarin derivative to
monitor Cu(II) in cultured cells [42]. Paul and Bodio suggested that
coumarin-phosphine Au complexes may induce cell death/
2.2. Crystal structures
III
apoptosis by interaction with related-protein(s) contained in lipid
Figs. 1 and 2 and S1eS5 represents that, in the Pt1ePt5, the
II
II
rafts [41]. In addition, Qin reported Pt and Ru complexes with 3-
II
square-planar geometry around the four-coordinated Pt center
atom and the selective coordination of H-QC1, H-QC2, H-QC3, H-
QC4 and H-QC5 via the C and N atoms. The CePt and NePt bond
distances are 1.963e2.013 Å and 2.005e2.054 Å, respectively
0
(
2 -benzimidazolyl) coumarins as a telomerase inhibitor and c-myc
G-quadruplex (G4) ligands [26,35,36]. On the basis of our first re-
0
ported 3-(2 -benzimidazolyl) coumarins Pt(II) and Ru(II) complexes
as potential anticancer agents [26,35,36], in order to exploit new
(
Table S1ꢀS15), which were in agreement with previously reported
II
Pt complexes with more extended planar coumarins derivatives
organoplatinum(II) complexes [31,47e54]. In addition, the Pt(II)
centers of Pt6ePt11 also adopt four coordinated square planar
geometry (Fig. S1ꢀS11 and Table S16ꢀS33).
ligands, herein, we first synthesized 11 new quinoline-coumarin
derivatives (H-QC1ꢀH-QC11) and their novel organoplatinum(II)
complexes Pt1ePt11. And the study of their anticancer (anti-
proliferative) effect against A549/DDP (cisplatin-resistant human
lung adenocarcinoma) cells or HeLa cancer cells in comparison to
cisplatin in vitro and vivo.
2
.3. Cytotoxicity
The cytotoxicity of quinoline-coumarin derivatives (H-QC1ꢀH-
QC11) and their Pt(II) complexes Pt1ePt11 against human A549
lung cells, drug resistance (cisplatin-resistant) of A549/DDP lung
cells, SK-OV-3 ovarian cells, cisplatin-resistance SK-OV-3 ovarian
cells (SK-OV-3/DDP), HeLa cervical carcinoma cells, non-small
NCIeH460 lung cells, as well as against HL-7702 nontumorous
cells were evaluated by MTT assay in vitro. Pt1ePt11 exhibited
significantly enhanced antineoplastic activity in comparision to cis-
2
. Results and discussion
2.1. Synthesis
0
The 11 new quinoline-coumarin derivatives, namly 3-(2 -pyr-
0
idyl)-8-methoxyl-coumarin (H-QC1), 3-(2 -pyridyl)-7-methoxyl-
coumarin (H-QC2), 3-(2 -pyridyl)-6-chloro-coumarin (H-QC3), 3-
0
2
Pt(DMSO) Cl
2
, and quinoline-coumarin derivatives (H-QC1ꢀH-
0
0
(
2 -quinolyl)-6-hydroxy-coumarin (H-QC4), 3-(2 -quinolyl)-6,8-
QC11) in general. In addition, the new quinoline-coumarin de-
rivatives complexes Pt1ePt11 display a highly promising antineo-
plastic activity. All the quinoline-coumarin derivatives complexes
Pt1ePt11 inhibit the growth of the cisplatin-resistant of A549/DDP
lung cells and HeLa cervical carcinoma cells at low nanomole
concentrations (or micromole concentrations), with IC50 values as
0
dichloro-coumarin
coumarin (H-QC6),
coumarin (H-QC7), 3-(2 -benzothiazolyl)-7-chloro-coumarin (H-
(H-QC5),
3-(2 -benzothiazolyl)-7-fluoro-
0
3-(2 -benzothiazolyl)-7-dimethylamino-
0
0
QC8), 3-(2 -benzothiazolyl)-5,6-butadienyl-coumarin (H-QC9), 3-
0
0
(
2 -benzothiazolyl)-7-diethylamino-coumarin (H-QC10), and 3-(2 -
quinolyl)-5,6-butadienyl-coumarin (H-QC11) were designed (seen
in Schemes 1e3), starting from 2-pyridylacetonitrile, benzothia-
zole-2-acetonitrile and 2-(quinolin-2-yl)acetonitrile, very similar
to the previously synthesis step of 3-(2 -benzimidazolyl) coumarins
derivatives [26,35e46]. In addition, the reaction of quinoline-
low as 100 nMꢀ10.33
m
M, and were more promising than cisplatin
(75.02 ± 1.18 M for A549/DDP or 12.09 ± 0.24
m
mM for HeLa) and
other previously reported coumarin derivatives metal complexes
[35e46]. The different antineoplastic activity for quinoline-
coumarin derivatives complexes Pt1ePt11 were in the following
order: Pt4 > Pt5 > Pt1 > Pt2 > Pt3 > Pt11 > Pt9 > Pt10 > Pt7 >
Pt6 > Pt8 > cisplatin. In all cases, the new quinoline-coumarin
derivatives complexes Pt1ePt11 show selectivity toward A549/
DDP lung cells and HeLa cervical carcinoma cells over the other
0
coumarin derivatives (H-QC1ꢀH-QC11) with cis-Pt(DMSO)
1.0 mmol) in a 2/1 M ratio in refluxing CH OH (10.0 mL) for 12 h
afforded reddish-brown complexes Pt1ePt11 in good yield
86.2%e94.0%). The chemical structures of quinoline-coumarin
2 2
Cl
(
3
(
ꢁ
Scheme 1. Synthetic routes for coumarin derivatives ligands (H-QC1, H-QC2, H-QC3) and their Pt(II) complexes Pt1ePt3. Reagents are the following: (a) EtOH, piperidine, 65 C,
ꢁ
2.5 h; (b) 2.5% HCl, H
2
O, 95 C, 6.0 h; (c) cis-Pt(DMSO)
2
Cl
2
, CH
3
OH, refluxing, 12 h.

Q.-P. Qin et al. / European Journal of Medicinal Chemistry 184 (2019) 111751
3
Scheme 2. Synthetic routes for quinoline-coumarin derivatives ligands (H-QC4, H-QC5) and their Pt(II) complexes Pt4 and Pt5. Reagents are the following: (a) EtOH, piperidine,
ꢁ ꢁ
2 2 2 3
5 C, 2.5 h; (b) 2.5% HCl, H O, 95 C, 6.0 h; (c) cis-Pt(DMSO) Cl , CH OH, refluxing, 12 h.
6
ꢁ
Scheme 3. Synthetic routes for coumarin derivatives ligands (H-QC6ꢀH-QC11) and their Pt(II) complexes Pt6ePt11. Reagents are the following: (a) EtOH, piperidine, 65 C, 2.5 h;
ꢁ
(
b) 2.5% HCl, H
2
O, 95 C, 6.0 h; (c) cis-Pt(DMSO)
2
Cl
2
, CH
3
OH, refluxing, 12.0 h.
cancer cells and nontumorous HL-7002 cell line (IC50 > 150
m
M).
(1.0% DMSO) showed low inhibitory rates against human cells,
suggesting that it has no effect on cell growth and was suitable for
control.
Because of the experimental group contained 1% DMSO solution,
thus the vehicle group solution (including 1.0% DMSO) as another
positive control. As shown in Table 1, the vehicle group solution

4
Q.-P. Qin et al. / European Journal of Medicinal Chemistry 184 (2019) 111751
apoptosis [47e68].
2.5. Mitochondria dysfunction
Besides this, the increase in the cytochrome c (cyt c), caspases-3,
apaf-1 and caspase-9 activity in quinoline-coumarin derivatives
complexes Pt4 (100 nM)- and Pt5 (250 nM)-treatmented cells, and
a quantity of bcl-2 was decreased (Fig. 4) was in the following or-
der: Pt4 (100 nM) > Pt5 (250 nM), indicating that quinoline-
coumarin derivatives complexes Pt4 (100 nM) and Pt5 (250 nM)
induce mitochondria-mediated apoptosis in A549/DDP cells.
2.6. Apoptosis induction in vitro and vivo
The apoptosis-causing properties of quinoline-coumarin de-
rivatives complexes Pt4 (100 nM) and Pt5 (250 nM) in A549/DDP
cells were checked by flow cytometry (FCM). Treating the cisplatin-
resistant of A549/DDP lung cells with quinoline-coumarin de-
rivatives complexes Pt4 (100 nM) and Pt5 (250 nM) for 24.0 h
(Fig. 5AeC), the amount of late (UR) and early (LR) apoptotic cells
were 18.70% and 69.64%, and 63.21% and 10.66%, respectively.
Considering the cytotoxicity in vitro, we assessed the anti-tumor
activity of quinoline-coumarin derivatives complexes Pt4 against
HeLa xenograft in vivo (Fig. 5CꢀD and Table S34ꢀS36). The vehicle
Fig. 1. Molecular structures of Pt4.
(
5% DMSO in saline, v/v), and quinoline-coumarin complex Pt4
(
2.0 mg/kg per 2 days) (n ¼ 6) were injected when the tumor vol-
3
ume grew to 200e400 mm . As shown in Fig. 5CꢀD and
Table S34ꢀS36, the effect of treated with quinoline-coumarin
complex Pt4 (37.2%) was higher than that of observed for
cisplatin (2.0 mg/kg per 2 days, 35.2%) [69e86]. The tumor volume
decreases by 42.7% after quinoline-coumarin complex Pt4 treat-
ment. There was no xenograft mouse death or obvious body weight
loss under these conditions (Fig. 5CꢀD and Table S34ꢀS36), indi-
cating that quinoline-coumarin complex Pt4 have no serious side
effects.
3. Conclusion
Novel organoplatinum(II) complexes Pt1ePt11 with quinoline-
Fig. 2. Molecular structures of Pt5.
coumarin derivatives (H-QC1ꢀH-QC11) were first described.
Pt1ePt11 were more selective for A549/DDP cells and HeLa cervical
carcinoma cells (IC50 ¼ 100 nMꢀ10.33
selected cells, and interestingly, they were considerably less cyto-
toxic to HL-7002 nontumorous cells (IC50 > 150 M). The presence
mM) in comparision to other
2.4. Cellular uptake
m
or absence of different 3-substituted groups in coumarin de-
rivatives in organoplatinum(II) complexes, and thereby leading to
differences in anti-tumor activity were in the following order:
Pt4 > Pt5 > Pt1 > Pt2 > Pt3 > Pt11 > Pt9 > Pt10 > Pt7 > Pt6 > Pt8 >
To confirm the location of two new organoplatinum(II) com-
plexes within the A549/DDP cells, colocalization (confocal mi-
croscopy) studies of quinoline-coumarin derivatives complexes
Pt4 (100 nM) and Pt5 (250 nM) with commercially available
Mito-Red (red), which a mitochondria membrane imaging agent.
Confocal microscopy assays suggested that quinoline-coumarin
derivatives complexes Pt4 (100 nM) and Pt5 (250 nM) exhibi-
0
cisplatin, whereas the 3-(2 -quinolyl)-6,8-dichloro-hydroxy-
coumarin (H-QC5) ligand appears to significantly enhance the
antineoplastic properties of the coumarin-modified organo-
platinum(II) complexes. In addition, Pt4 and Pt5 display a green-
colored luminescent properties, targeted mitochondrial and,
thereby induced mainly mitochondria-mediated cell apoptosis. The
quinoline-coumarin complex Pt4 also showed potent in vivo anti-
tumor effect after 21.0 days-treated. Therefore, the superior cyto-
toxicity and selectivity for coumarin organoplatinum(II) complexes
Pt1ePt11 in comparison to cisplatin were further developed as
some of Pt-based complexes.
ted 525e530 nm emission (
conditions upon excitation (
l
l
em) in A549/DDP cells by ambient
ex) at 490e495 nm (Fig. 3), which
maybe acted as a green-colored luminescent agents for cellular
applications. In addition, the results showed that the staining
effect of quinoline-coumarin derivatives complexes Pt4 (100 nM)
and Pt5 (250 nM) on mitochondria membrane was similar to
that of mito-red (Fig. 3). Then, further than that, quinoline-
coumarin derivatives complexes Pt4 (100 nM) and Pt5
(
250 nM) could be effectively taken up by A549/DDP cells and
4. Experimental methods
were mainly retained (or accumulated) within the mitochondria
membrane fraction, lossed of mitochondrial membrane potential
4.1. Synthesis of the quinoline-coumarin derivatives ligands
The 11 quinoline-coumarin derivatives (H-QC1ꢀH-QC11)
(
(
MMP) and targeted-mitochondria after 24.0 h of incubation
Fig. 3) and, thereby induced mitochondria damage and

Q.-P. Qin et al. / European Journal of Medicinal Chemistry 184 (2019) 111751
5
Table 1
Cytotoxicity (IC50±SD,
mM) of quinoline-coumarin derivatives (H-QC1ꢀH-QC11) and their Pt(II) complexes Pt1ePt11 following incubation for 24 h with select the cell lines.
compounds
A549
A549/DDP
SK-OV-3
HeLa
SK-OV-3/DDP
NCIeH460
HL-7702
H-QC1
H-QC2
H-QC3
Pt1
Pt2
Pt3
H-QC4
H-QC5
Pt4
Pt5
H-QC6
P6
>150
>150
>150
>100
>100
>100
>100
>100
35.22 ± 0.45
50.78 ± 1.33
>150
>100
>150
>100
>150
>100
>150
>100
>150
>100
>100
>100
>150
>150
13.99 ± 1.033
>150
>150
>150
0.54 ± 0.14
1.02 ± 0.35
1.94 ± 0.76
>100
>150
>150
>150
>100
>100
>100
>100
>100
75.25 ± 1.51
91.08 ± 1.01
>150
>100
>150
>100
>150
>100
>150
>100
>150
>100
>100
>100
>150
>150
15.33 ± 1.78
>150
>150
>150
1.05 ± 0.72
2.19 ± 1.02
3.58 ± 0.83
>100
>150
>150
>150
>100
>100
>100
>100
>100
58.41 ± 0.39
70.01 ± 0.94
>150
>100
>150
>100
>150
>100
>150
>100
>150
>100
>100
>100
>150
>150
81.25 ± 1.03
>150
>150
>150
>100
>100
>100
>100
>100
18.09 ± 0.54
34.51 ± 0.19
>150
>100
>150
>100
>150
>100
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
19.33 ± 0.24
>100
>100
0.10 ± 0.05
0.25 ± 0.11
>150
8.01 ± 1.88
>150
6.55 ± 0.19
>150
10.27 ± 1.23
>150
3.68 ± 0.84
>150
5.97 ± 1.06
>100
2.99 ± 0.41
>150
>150
0.15 ± 0.09
0.32 ± 0.14
>150
8.86 ± 0.56
>150
6.97 ± 1.11
>150
10.33 ± 0.73
>150
4.53 ± 1.09
>150
6.30 ± 1.58
>100
3.99 ± 0.15
>150
>150
H-QC7
Pt7
H-QC8
Pt8
H-QC9
Pt9
H-QC10
Pt10
H-QC11
Pt11
cis-PtCl
vehicle group (1.0% DMSO)
cisplatin
67.98 ± 1.99
>150
>100
>100
59.03 ± 0.83
>150
2
(DMSO)
2
>150
12.89 ± 1.29
75.02 ± 1.18
12.09 ± 0.24
Fig. 3. Confocal microscopy imaging of A549/DDP cells incubated with quinoline-coumarin derivatives complexes Pt4 (100 nM) and Pt5 (250 nM) for 24.0 h, and then processed for
Mito-Red (red, 500 nM) and the nuclei were stained with DAPI (blue). Quinoline-coumarin derivatives complexes Pt4 and Pt5:
interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
l
em ¼ 525e530 nm, ex ¼ at 490e495 nm. (For
l
ligands were designed (seen in Schemes 1ꢀ3), starting from 2-
(86.2%e94.0%).
pyridylacetonitrile, benzothiazole-2-acetonitrile and 2-(quinolin-
2
-yl)acetonitrile, very similar to the previously synthesis step of
4.1.1.1. Data for Pt1. Yield: 86.2%. Elemental analysis: calcd (%) for
coumarin derivatives [35e46].
C31H25ClN O Pt: C 49.51, H 3.35, N 3.72; found: C 49.49, H 3.38, N
2
6
3
.70. IR (KBr): 3429, 2939, 1727, 1713, 1696, 1601, 1577, 1475, 1348,
ꢀ1
4.1.1. Synthesis of Pt1ePt11
1276, 1096, 961, 793, 771, 554 cm . ESI-MS: m/z ¼ 462.5 for
þ
The reaction of H-QC1ꢀH-QC11 with cis-Pt(DMSO)
2
Cl
2
[QC1þPt] .
(
3
1.0 mmol) in a 2/1 M ratio in refluxing CH OH (10.0 mL) for 12.0 h
afforded reddish-brown complexes Pt1ePt11 in good yield
4.1.1.2. Data for Pt2. Yield: 94.0%. Elemental analysis: calcd (%) for

6
Q.-P. Qin et al. / European Journal of Medicinal Chemistry 184 (2019) 111751
Fig. 4. Western blot images (A) and analysis (B) of certain apoptosis proteins in A549/DDP cells for 24.0 h incubation with quinoline-coumarin derivatives complexes Pt4 (100 nM)
and Pt5 (250 nM).
Fig. 5. Quinoline-coumarin derivatives Pt complexes caused cancer cell apoptosis in vitro and vivo. (AeC) The quinoline-coumarin derivatives complexes Pt4 (100 nM) and Pt5
(
250 nM) induces apoptosis in A549/DDP cells for 24 h, and the cells stains by Annexin-V APC (Ex/Em ¼ 633 nm/660 nm) and 7AAD (red, Ex/Em ¼ 546 nm/647 nm) staining, and
checked by FCM. (C and D) The growth and photographs of HeLa tumor xenograft after treated with quinoline-coumarin complex Pt4 (2.0 mg/kg per 2 days) (n ¼ 6). (For inter-
pretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
C
31
H25ClN
2
O
6
Pt: C 49.51, H 3.35, N 3.72; found: C 49.50, H 3.37, N
(m, 2H).
2
.69. IR (KBr): 3433, 1725, 1698, 1604, 1477, 1461, 1369, 1277, 1218,
ꢀ1
1
127, 1027, 832, 788, 758, 524 cm . ESI-MS: m/z ¼ 518.3 for
4
C
3
.1.1.4. Data for Pt4. Yield: 87.6%. Elemental analysis: calcd (%) for
25ClN Pt: C 53.92, H 3.06, N 3.40; found: C 53.90, H 3.10, N
.38. IR (KBr): 3434, 3035, 3010, 2917, 1627, 1402, 1302, 1156, 1133,
ꢀ
1
[QC2þPt þ Cl þ H
2 6
OeH] . H NMR (500 MHz, DMSO‑d ) d 9.30 (d,
37
H
2 6
O
J ¼ 5.9 Hz, 1H), 8.87 (s, 2H), 8.69 (d, J ¼ 4.9 Hz, 2H), 8.27 (d,
J ¼ 8.0 Hz, 2H), 7.92e7.86 (m, 4H), 7.09 (d, J ¼ 2.4 Hz, 2H), 7.02 (dd,
J ¼ 8.6, 2.5 Hz, 2H), 3.90 (s, 6H).
ꢀ1
1
020, 982, 941, 736, 691, 431 cm . ESI-MS: m/z ¼ 522.2 for
ꢀ
1
[QC4þPt þ CleH] . H NMR (500 MHz, DMSO‑d
6
) d 8.84 (s, 2H),
8
.72 (s, 1H), 8.33 (d, J ¼ 8.7 Hz, 2H), 8.22 (d, J ¼ 8.5 Hz, 2H), 8.15 (d,
J ¼ 8.1 Hz, 2H), 7.97e7.92 (m, 2H), 7.76 (t, J ¼ 7.5 Hz, 2H), 7.39 (d,
J ¼ 8.8 Hz, 2H), 7.28 (d, J ¼ 2.8 Hz, 2H), 7.18 (dd, J ¼ 8.9, 2.9 Hz, 2H).
4
C
3
.1.1.3. Data for Pt3. Yield: 90.3%. Elemental analysis: calcd (%) for
Pt: C 45.78, H 2.52, N 3.68; found: C 45.76, H 2.55, N
.67. IR (KBr): 3450, 3086, 1732, 1705, 1598, 1565, 1482, 1351, 1233,
29 3 2 4
H19Cl N O
ꢀ
1
1
129, 1082, 990, 837, 792, 695, 575 cm . ESI-MS: m/z ¼ 542.7 for
4.1.1.5. Data for Pt5. Yield: 89.1%. Elemental analysis: calcd (%) for
ꢀ
1
[
QC3þPtþ2Cl] . H NMR (500 MHz, DMSO‑d
H), 8.86 (s, 1H), 8.71 (d, J ¼ 4.7 Hz, 1H), 8.29 (d, J ¼ 8.0 Hz, 1H),
.92 (dd, J ¼ 8.5, 6.6 Hz, 1H), 7.49 (dd, J ¼ 7.2, 1.9 Hz, 1H), 7.38e7.34
6
)
d
9.35 (d, J ¼ 6.1 Hz,
37
C H21Cl
5
N
2
O
4
Pt: C 47.79, H 2.28, N 3.01; found: C 47.75, H 2.30, N
1
7
2.26. IR (KBr): 3427, 3013, 1721, 1566, 1508, 1215, 1144, 1025, 960,
ꢀ
1
ꢀ
832, 752, 505, 436 cm . ESI-MS: m/z ¼ 606.1 for [QC5þPtþ2Cl] .

Q.-P. Qin et al. / European Journal of Medicinal Chemistry 184 (2019) 111751
7
1H NMR (500 MHz, DMSO‑d
.60 (dd, J ¼ 8.9, 4.3 Hz, 2H), 8.51 (d, J ¼ 8.6 Hz, 2H), 8.26 (d,
J ¼ 8.6 Hz, 2H), 8.16 (d, J ¼ 2.4 Hz, 2H), 8.11 (d, J ¼ 8.5 Hz, 2H), 7.69
dt, J ¼ 11.8, 7.0 Hz, 4H).
)
d
8.88 (s, 2H), 8.72 (d, J ¼ 2.5 Hz, 1H),
Appendix A. Supplementary data
6
8
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ejmech.2019.111751.
(
4.1.1.6. Data for Pt6. Yield: 86.9%. Elemental analysis: calcd (%) for
References
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6
18
H
14Cl
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PtS
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: C 33.71, H 2.20, N 2.18; found: C 33.69, H 2.25, N
9.28 (s, 1H), 8.19 (dd, J ¼ 9.5,
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14Cl
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