Two novel platinum(II) complexes with sorafenib and regorafenib: Synthesis, structural characterization, and evaluation of in vitro antitumor activity

Article abstract of DOI:10.1016/j.inoche.2019.03.031

Two new Pt(II) complexes with sorafenib (SRFN) and regorafenib (RGFN), having the general formulae [Pt(SRFN)(DMSO)Cl₂] (SRFN-Pt) and [Pt(RGFN)(DMSO)Cl₂] (RGFN-Pt), were prepared and characterized by ESI-MS, IR, UV–Vis spectroscopy, elemental analyses, and ¹H and ¹³C NMR, respectively. The anticancer activities of SRFN-Pt and RGFN-Pt were evaluated by MTT assay with NCI-H460 (human non-small cell lung cancer NCI-H460 cell line), SK-OV-3 (ovarian cancer cell line), SK-OV-3/DDP (cisplatin-resistant SK-OV-3 cell line), T-24 (human bladder cancer cell line), HeLa (cervical cancer cell line), A549/DDP (cisplatin-resistant A549/DDP non-small cell lung cancer cell line) cancer cells and in the normal HL-7702 cells. The results suggested that SRFN-Pt and RGFN-Pt were more effective against the A549/DDP tumor cells (IC₅₀ = 1.18 ± 0.15 μM and 0.13 ± 0.03 μM) than SRFN (45.03 ± 0.79 μM), RGFN (40.11 ± 2.15 μM), and cisplatin (97.63 ± 1.06 μM), respectively, and RGFN-Pt was more effective than SRFN-Pt. In addition, SRFN-Pt and RGFN-Pt induced G2/M and S phase arrest. Cytotoxic mechanism studies revealed that SRFN-Pt and RGFN-Pt triggered mitochondria-mediated apoptotic cell death at low concentration. RGFN-Pt exhibited obvious priority on the in vitro antitumor activity than SRFN-Pt, which should be undoubtedly correlated with the key roles of the fluoro substituted groups in the RGFN ligand of RGFN-Pt. The in vitro anti-tumor activity studies suggested that RGFN-Pt pointed to a new direction in developing Pt(II) drugs as anti-cancer agent.

Full text of DOI:10.1016/j.inoche.2019.03.031

InorganicChemistryCommunications104(2019)27–30
Contents lists available at ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Short communication
Two novel platinum(II) complexes with sorafenib and regorafenib:
Synthesis, structural characterization, and evaluation of in vitro antitumor
activity
⁎
⁎
Qi-Pin Qina,1, Zhen-Feng Wanga,1, Ming-Xiong Tana, , Shu-Long Wanga, Bi-Qun Zoub,
,
⁎
⁎
Dong-Mei Luoa, Jiao-Lan Qind, , Shu-Hua Zhangc,
a 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
b Department of Chemistry, Guilin Normal College, 9 Feihu Road, Gulin 541001, China
c Guangxi Key Laboratory of Electrochemical and Magnetochemical Functional Materials, College of Chemistry and Bioengineering, Guilin University of Technology, Guilin
541004, China
d Guangxi Colleges and Universities Key Laboratory of Regional Ecological Environment Analysis and Pollution Control of West Guangxi, College of Chemistry and
Environmental Engineering, Baise University, Baise, Guangxi 533000, China
G R A P H I C A L A B S T R A C T
SRFN-Pt and RGFN-Pt triggered mitochondria-mediated apoptotic at low concentration.
A R T I C L E I N F O
A B S T R A C T
Keywords:
Two new Pt(II) complexes with sorafenib (SRFN) and regorafenib (RGFN), having the general formulae [Pt
(SRFN)(DMSO)Cl2] (SRFN-Pt) and [Pt(RGFN)(DMSO)Cl2] (RGFN-Pt), were prepared and characterized by ESI-
MS, IR, UV–Vis spectroscopy, elemental analyses, and 1H and 13C NMR, respectively. The anticancer activities of
SRFN-Pt and RGFN-Pt were evaluated by MTT assay with NCI-H460 (human non-small cell lung cancer NCI-
H460 cell line), SK-OV-3 (ovarian cancer cell line), SK-OV-3/DDP (cisplatin-resistant SK-OV-3 cell line), T-24
(human bladder cancer cell line), HeLa (cervical cancer cell line), A549/DDP (cisplatin-resistant A549/DDP non-
small cell lung cancer cell line) cancer cells and in the normal HL-7702 cells. The results suggested that SRFN-Pt
Regorafenib
Platinum(II) complex
Cell apoptosis
Mitochondria
and RGFN-Pt were more effective against the A549/DDP tumor cells (IC50 = 1.18
0.15 μM and
0.13
0.03 μM) than SRFN (45.03
0.79 μM), RGFN (40.11
2.15 μM), and cisplatin (97.63 1.06 μM),
respectively, and RGFN-Pt was more effective than SRFN-Pt. In addition, SRFN-Pt and RGFN-Pt induced G2/M
and S phase arrest. Cytotoxic mechanism studies revealed that SRFN-Pt and RGFN-Pt triggered mitochondria-
mediated apoptotic cell death at low concentration. RGFN-Pt exhibited obvious priority on the in vitro anti-
tumor activity than SRFN-Pt, which should be undoubtedly correlated with the key roles of the fluoro
⁎ Corresponding authors.
E-mail addresses: mxtan2018@126.com (M.-X. Tan), zoubiqun@163.com (B.-Q. Zou), qinjiaolan508@163.com (J.-L. Qin), zsh720108@163.com (S.-H. Zhang).
1 These authors contributed equally to this work.
https://doi.org/10.1016/j.inoche.2019.03.031
Received 15 February 2019; Received in revised form 22 March 2019; Accepted 26 March 2019
Availableonline28March2019
1387-7003/©2019ElsevierB.V.Allrightsreserved.

Q.-P. Qin, et al.
InorganicChemistryCommunications104(2019)27–30
substituted groups in the RGFN ligand of RGFN-Pt. The in vitro anti-tumor activity studies suggested that RGFN-
Pt pointed to a new direction in developing Pt(II) drugs as anti-cancer agent.
To date, cisplatin (cDDP) and its derivatives still play a major role in
complexes and the free sorafenib (SRFN) and regorafenib (RGFN) li-
gands were evaluated by MTT assay in NCI-H460 (human non-small cell
lung cancer NCI-H460 cell line), SK-OV-3 (ovarian cancer cell line), SK-
OV-3/DDP (cisplatin-resistant SK-OV-3 cell line), T-24 (human bladder
cancer cell line), HeLa (cervical cancer cell line), A549/DDP (cisplatin-
resistant A549/DDP non-small-cell lung cancer cell line) cancer cells
and the normal HL-7702 cells [49], using cisplatin and cis-Pt
(DMSO)2Cl2 as a positive control [50,51]. The free sorafenib (SRFN)
and regorafenib (RGFN) ligands were more cytotoxic to NCI-H460, SK-
OV-3, SK-OV-3/DDP, T-24, and HeLa cancer cell lines than the SRFN-
Pt, cisplatin, RGFN-Pt, and cis-Pt(DMSO)2Cl2 complexes (Tables 1 and
S1), indicating that the two platinum(II) complexes were not potent for
these tumor cells [52–58]. Nevertheless, the two platinum(II) com-
plexes were more cytotoxic than the ligands toward the A549/DDP
tumor treatment [1–18]. Although drug resistance and cell toxicity
have restricted their use [14–20]. Thus, the search for novel series of Pt
(II/IV) compounds is of constant research interest [16,17,21–44]. For
example, the Pt-c(RGDfK) conjugate as a Pt(IV) pro-drug increased the
number of cancer cells that could be targeted. [1] Besides, a novel
noncovalent polynuclear Pt complex, [{Pt(NH3)3}2-μ-{trans-Pt
(NH3)2(NH2(CH2)6NH2)2}]6+ (TriplatinNC-A), could work as a DNA
condensing agent to bind regulatory proteins and initiate the onset of
tumor cell apoptosis [44]. In addition, sixteen anticancer Pt(II) com-
plexes, [PtCl(hq)(S-dmso)](1a–8a, hq = quinolinol derivatives) and
[PtCl(hq)(pta)] (1b–8b, pta = 1,3,5‑triaza‑7‑phosphaadamantane),
could induce much stronger oxidative stress response in zebrafish than
cisplatin [22]. They inhibited the growth of breast cancer (MDA-MB-
231 cells) xenografts in mice via apoptosis induction and proteasome
inhibition [38].
tumor cells, giving low IC50 values (1.18
0.13
0.15 μM for SRFN-Pt and
0.03 μM for RGFN-Pt) that corresponded to 47.90 and 501.38
In addition, Sorafenib (SRFN) and regorafenib (RGFN) play im-
portant roles in the clinical treatment of gastrointestinal stromal tumor
(GIST) and metastatic colorectal cancer (mCRC) [45,46]. To date, there
have been no reports about the Pt(II) complexes with sorafenib (SRFN)
and regorafenib (RGFN). In this work, we synthesized two new Pt(II)
complexes with sorafenib (SRFN) and regorafenib (RGFN), denoted as
[Pt(SRFN)(DMSO)Cl2] (SRFN-Pt) and [Pt(RGFN)(DMSO)Cl2] (RGFN-
Pt). In addition, we explored the in vitro antitumor activity of SRFN-Pt
and RGFN-Pt and evaluated their action mechanisms in human tumor
cells.
times the cytotoxicity of the free SRFN and RGFN ligands and 103.86
and 1220.38 times the cytotoxicity of cisplatin, respectively. We were
pleased to find that SRFN-Pt and RGFN-Pt were less cytotoxic against
the normal live HL-7702 cells than the SRFN and RGFN ligands or
cisplatin.
We then examined the effects of SRFN-Pt (1.18 μM) and RGFN-Pt
(0.13 μM) on the progression of cell apoptosis and on the cell cycle
phase arrest in A549/DDP cancer cells. The A549/DDP cancer cells
were incubated with complexes for 24 h and stained with propidium
iodide (PI) and/or annexin V fluorescein isothiocyanate (FITC), and
then analyzed by flow cytometry to determine the DNA content
[59,60]. Fig. S9 shows that SRFN-Pt (1.18 μM) and RGFN-Pt (0.13 μM)
caused cell cycle arrest at the G2/M and S phase in the A549/DDP
cancer cells, which indicated the apoptosis of A549/DDP cells [59,60].
The A549/DDP cells treated with RGFN-Pt (0.13 μM) showed stronger
apoptosis (ca. 67.4%) than those treated with SRFN-Pt (1.18 μM, ca.
48.6%) and cisplatin (97.63 μM, ca. 24.3%) (Figs. 1 and S10). The re-
sults indicated that the SRFN-Pt (1.18 μM) and RGFN-Pt (0.13 μM)
inhibited the proliferation of the A549/DDP cancer cells by inducing
apoptosis.
Scheme 1 illustrates the synthesis of the sorafenib (SRFN) and re-
gorafenib (RGFN) ligands, which were prepared according to reported
procedures [46]. The synthesis of [Pt(SRFN)(DMSO)Cl2] (SRFN-Pt) and
[Pt(RGFN)(DMSO)Cl2] (RGFN-Pt) was accomplished by mixing the
respective ligand with cis-Pt(DMSO)2Cl2 in acetone (5.0 mL) and
CH3OH (10.0 mL) at 65 °C for 24 h. Both SRFN-Pt and RGFN-Pt were
characterized by ESI-MS, elemental analysis, IR, and 1H and 13C NMR
(Figs. S1–S8). In addition to the corresponding SRFN or RGFN ligands,
the Pt(II) complexes SRFN-Pt and RGFN-Pt were coordinated by two Cl
ligands and one DMSO molecule coordinated via the S atom, respec-
tively. Furthermore, the stability of SRFN-Pt and RGFN-Pt
(2.5 × 10−5 M) in Tris-HCl buffer (10 mM, pH = 7.35) was analyzed by
ESI-MS analysis [47,48]. At 0 h, the Pt(II) complexes showed base peaks
at m/z = 884.6 (SRFN-Pt, [M − H + DMSO]−) and 902.1 (RGFN-Pt,
[M − H + DMSO]−), respectively, which remained unchanged in the
original species after incubation for 48 h (Figs. S3 and S6). Hence,
SRFN-Pt and RGFN-Pt were stable in Tris-HCl buffer solution at the
concentration of 2.5 × 10−5 M.
Cellular uptake, flow cytometry, and Western blot assays were
carried out for the A549/DDP cancer cells treated with SRFN-Pt
(1.18 μM) and RGFN-Pt (0.13 μM) to further study the anticancer ac-
tivities of the complexes [61–71]. Tables S2 and S3 shows that, as ex-
pected, the cellular uptake and distribution of RGFN-Pt in the mi-
tochondria were higher than those of SRFN-Pt. Next, the mitochondrial
Ca2+ fluctuation, mitochondria membrane potential (MMP), caspase-3/
9 activation, and ROS generation in the A549/DDP cells were examined
by appropriate assays. Figs. S10–S15 show that the A549/DDP cells
The in vitro anticancer activities of SRFN-Pt and RGFN-Pt
Scheme 1. Synthesis of Pt(II) complexes SRFN-Pt and RGFN-Pt. Reagents: (a) CH2Cl2, reflux, 6.0 h; (b) DMF, 90 °C, 3.0 h; (c) cis-Pt(DMSO)2Cl2, 5.0 mL acetone and
10.0 mL CH3OH, 65 °C, 24 h.
28

Q.-P. Qin, et al.
InorganicChemistryCommunications104(2019)27–30
Table 1
a
IC50 values (μM) of SRFN, RGFN, cis-Pt(DMSO)2Cl2, SRFN-Pt, RGFN-Pt, and cisplatin against seven selected human cell lines.
Compound
NCI-H460
SK-OV-3
SK-OV-3/DDP
T-24
HeLa
A549/DDP
HL-7702
SRFN
6.95
13.43
2.10
0.45
4.65
20.79
1.18
1.09
0.74
0.24
1.33
30.12
39.37
25.06
28.12
1.56
0.66
0.76
0.19
3.48
21.08
1.02
1.18
0.58
0.46
1.49
7.38
49.20
0.84
0.22
1.75
0.35
1.11
45.03
1.18
0.79
37.02
75.03
37.46
85.06
1.48
0.31
1.11
2.01
SRFN-Pt
RGFN
0.36
0.96
0.36
0.15
2.15
0.03
40.11
0.13
RGFN-Pt
cis-PtCl2(DMSO)2
Cisplatinb
10.81
14.75
19.11
35.66
> 150
> 150
> 150
> 150
> 150
> 150
> 150
12.11
1.06
14.23
0.49
80.15
0.93
15.44
1.36
13.07
1.93
97.63
1.06
18.12
0.54
a
b
IC50 values are presented as the mean
SD (standard error of the mean) from five independent experiments.
Cisplatin (1.0 mM) was dissolved in NaCl solution (0.154 M) [52–58].
Fig. 1. Cell apoptosis (A–C) of A549/DDP cancer cells treated with SRFN-Pt (1.18 μM) and RGFN-Pt (0.13 μM).
Fig. 2. (A) Western blot assay of apoptosis proteins in the A549/DDP cancer cells treated with SRFN-Pt (1.18 μM) and RGFN-Pt (0.13 μM); (B) relative expression of
each band, determined by dividing the density of each band by the density of the actin band; mean and SD were calculated from three independent measurements.
treated with SRFN-Pt (1.18 μM), cisplatin (97.63 μM) and RGFN-Pt
(0.13 μM), more evidently the cells treated with RGFN-Pt, induced the
activation of caspase-3/9, increased the mitochondrial Ca2+ level,
triggered ROS generation, and disrupted the MMP. Western blot ana-
lyses showed that after the cells were treated with SRFN-Pt (1.18 μM)
and RGFN-Pt (0.13 μM), the expression of apaf-1, cytochrome c (cyt c),
and bax increased but the expression of bcl-2 decreased (Fig. 2). These
findings demonstrated that SRFN-Pt (1.18 μM) and RGFN-Pt (0.13 μM)
probably induced the mitochondrial death pathway (Figs. 2, S9 and
S10).
potential for further development into safe and effective anticancer
agents.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Nos. 21867017, 21861014 and 21761033), the
Natural Science Foundation of Guangxi (No. 2018GXNSFBA138021,
2018GXNSFBA281188 and 2016GXNSFBA380237), the China
University Students Innovative Project (201810606008), the PhD
Research Startup Program of Yulin Normal University (No. G2017009),
the Innovative Team & Outstanding Talent Program of Colleges and
Universities in Guangxi (2014-49 and 2017-38) as well as the scientific
research project of Guilin Normal College (KYA201804).
In conclusion, [Pt(RGFN)(DMSO)Cl2] (RGFN-Pt) and [Pt(SRFN)
(DMSO)Cl2] (SRFN-Pt) showed significantly enhanced cytotoxicities
than cisplatin against the A549/DDP cancer cells. They effectively in-
duced cell apoptosis by activating the corresponding apoptotic path-
ways and by inducing G2/M and S phase arrest according to in vitro
cytotoxicity, flow cytometry, cellular uptake, and Western blot assays.
The IC50 value of RGFN-Pt was lower (0.13 μM) than that of SRFN-Pt
(1.18 μM). A fluoro substituent might promote its effect on the cell
intake, which had also been proven in our study by examining the
platinum(II) intake and distribution of SRFN-Pt and RGFN-Pt using the
ICP-MS method. This may be the most rational explanation for the
better anticancer effect/activity of RGFN-Pt compared to SRFN-Pt till
now based on the present results. Therefore, RGFN-Pt may have the
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.inoche.2019.03.031. These data include synthesis,
materials and methods of SRFN-Pt and RGFN-Pt described in this ar-
ticle.
29

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InorganicChemistryCommunications104(2019)27–30
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