Synthesis, characterization, and antitumor activity of novel tumor-targeted platinum(IV) complexes

Article abstract of DOI:10.1002/aoc.5577

Four tumor-targeted platinum(IV) complexes with ammonia and cyclohexylamine as the carrier groups and biotin as the axial group were designed, synthesized, and characterized. In vitro evaluation of the antitumor activity of complexes C1–C4 against lung cancer cells (A549), liver cancer cells (SMMC-7721), breast cancer cells (MCF-7), and colon cancer cells (SW480) was carried out. Complex C3 had the best cellular activity. Compared with cisplatin, complex C3 showed good anticancer activity against A549 cell line,complex C3 (6.34±0.44) is 3 times more cytotoxic than cisplatin (19.40±0.71),and against MCF-7 cell line complex C3 (4.22±0.11) is 5.4 times more cytotoxic than cisplatin (22.96±0.58), and against SW480 cell line complex C3 (6.65±0.60) is 3.4 times more cytotoxic than cisplatin (23.15±0.22). (Table 1) Axial chloride increased the redox power of complex C3 to increase the intercellular accumulation and the introduction of mixed amine had the ability to overcome cisplatin resistance. Complex C3 works best on MCF-7, then SW480, A549, and SMMC-7721. Thus, complex C3 is targeted by the axial introduction of biotin.

Full text of DOI:10.1002/aoc.5577

Received: 15 October 2019
DOI: 10.1002/aoc.5577
Revised: 8 January 2020
Accepted: 20 January 2020
F U L L P A P E R
Synthesis, characterization, and antitumor activity of novel
tumor-targeted platinum(IV) complexes
Yunshuang Zhong1
| Chunyan Jia1 | Xinzhong Zhang1 | Xiali Liao1
|
Bo Yang1 | Yanwei Cong2 | Shaoping Pu2 | Chuanzhu Gao1
1Faculty of Life Science and Technology,
Four tumor-targeted platinum(IV) complexes with ammonia and cyclohexyl-
amine as the carrier groups and biotin as the axial group were designed, syn-
thesized, and characterized. In vitro evaluation of the antitumor activity of
complexes C1–C4 against lung cancer cells (A549), liver cancer cells (SMMC-
7721), breast cancer cells (MCF-7), and colon cancer cells (SW480) was carried
out. Complex C3 had the best cellular activity. Compared with cisplatin, com-
plex C3 showed good anticancer activity against A549 cell line,complex C3
(6.34 0.44) is 3 times more cytotoxic than cisplatin (19.40 0.71),and against
MCF-7 cell line complex C3 (4.22 0.11) is 5.4 times more cytotoxic than cis-
platin (22.96 0.58), and against SW480 cell line complex C3 (6.65 0.60) is 3.4
times more cytotoxic than cisplatin (23.15 0.22). (Table 1) Axial chloride
increased the redox power of complex C3 to increase the intercellular accumu-
lation and the introduction of mixed amine had the ability to overcome cis-
platin resistance. Complex C3 works best on MCF-7, then SW480, A549, and
SMMC-7721. Thus, complex C3 is targeted by the axial introduction of biotin.
Kunming University of Science and
Technology, Kunming, 650500, China
2Kunming Guiyan Pharmaceutical
Co. Ltd, Kunming, Yunnan, 650221,
China
Correspondence
ChuanZhu Gao, Faculty of Life Science
and Technology, Kunming University of
Science and Technology, Kunming
650500, China.
Email: gczasd@163.com
Funding information
National Natural Science Foundation of
China, Grant/Award Numbers: 21961017,
21642001, 21662021; Yunnan Applied
Basic Research Projects, Grant/Award
Number: 2018FA047, 2018FB018
K E Y W O R D S
oral, platinum(IV), tumor targeted
1 | INTRODUCTION
Oxaliplatin (Figure 1) is limited in dosage range due to
side effects such as neurotoxicity, hematology, gastroin-
Classical platinum(II) anticancer agents are chemothera-
peutic drugs that are widely used in the clinic against a
range of cancers.[1] However, as classical platinum(II)
antitumor drugs are used as a carrier group with symmet-
rical diamine or amino, they can be damaged in the gas-
trointestinal tract, and therefore cannot be taken orally,
only injected. They also cause severe side effects and
cross resistance.[2,3] The side effects and cross-resistance
are the main obstacles which limit the application and
effectiveness of these drugs. The side effects of cisplatin
(Figure 1), such as nephrotoxicity, neurotoxicity, ototox-
icity, and spitting, limit its efficacy. The main clinical
manifestation of carboplatin (Figure 1) limitations is that
bone marrow depression limits its dosage range.[4,5]
testinal toxicity, neutropenia, nausea, and vomiting.[6]
Therefore, the development of platinum-based complexes
with good anticancer activity, fewer side effects, and low
drug resistance is the focus of anticancer drug research.
In the search for platinum drugs with low toxicity
and favorable pharmacological profiles, platinum(IV)
complexes emerge as promising candidates for overcom-
ing the shortcomings of platinum(II) drugs.[7] The oral
properties of platinum(IV) drugs break the current situa-
tion that platinum(II) drugs can only be injected.[8,9]
Platinum(IV) complexes are stable and undamaged in the
gastrointestinal environment. They can be absorbed into
the blood system and then reduced to active platinum(II),
so they can be taken orally. Importantly, they contain
Appl Organometal Chem. 2020;e5577.
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© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5577

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ZHONG ET AL.
FIGURE 1 Structures of cisplatin,
carboplatin, and oxaliplatin
two axial ligands, which can be used to influence the
reduction kinetics, lipophilicity, cellular accumulation,
and activity of the platinum species.[10,11] It has been
reported that chloride increases the reduction power of
platinum(IV), leading to its preferential combination
with glutathione and reduction to platinum(II).[6,12,13]
The most prominent platinum(IV) drug is satraplatin,
which has been investigated in advanced phase III clini-
cal trials.[14] The asymmetric amino and cyclohexylamine
ligands of satraplatin have unique and excellent anti-
tumor activity. Due to the different structure–activity
relationship between the asymmetric carrier groups and
the symmetrical amine ligands of classical platinum
drugs, the mechanism of action of the two groups is dif-
ferent.[15] Satraplatin is reduced to divalent platinum by
intracellular antioxidants after entering the cell and acts
directly on DNA to form an adduct with it. The adduct
does not bind to high mobility group protein 1, identifies
DNA damage caused by cisplatin, and prevents DNA rep-
lication by inhibiting some DNA polymerase transfer,
making it possible to overcome cross-resistance.[16] In
addition, the satraplatin-induced adduct is not recognized
by DNA mismatch repair protein, solving the problem of
classical platinum drug resistance.
The non-selectivity distribution of platinum drugs in
normal and cancer cells can lead to severe systemic toxic-
ity, reducing the accumulation of drugs in tumor cells
and increasing drug resistance. In addition, platinum
drugs interact with plasma and tissue proteins, which
could lead to inactivation of platinum-based drugs. An
efficient way to solve these problems is to increase the
targeting of platinum drugs to cancer cells.[17] Biotin, also
known as vitamin H, is a necessary nutrient to maintain
human natural growth, development and normal
functional health.[18] Vitamin H is widely used in drug
delivery for tumor targeting because of its high demand
for the rapid growth of tumors, which leads to over-
expression of biotin-specific receptors on the surface of
cancer cells.[19] Biotin-induced platinum-toxic complexes
have high cytotoxicity to breast cancer cells, but low tox-
icity to breast epithelial cells. In the treatment of breast
cancer, the mono-biotinylated platinum(IV) complexes
FIGURE 2 Mechanism of action of
platinum(IV)

ZHONG ET AL.
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nitrate to form
a
hydrolysate and reacted with
K2C2O4ÁH2O to form oxalate, ammonia and cyclohexyl-
amine platinum (PT(II)L2) (Scheme 1).
When preparing the targeted platinum complexes, we
first prepared the biotin-NHS ester. Pt(II)L1 was oxidized
with H2O2 (30%) and N-chlorosuccinimide to form
platinum(IV) precursors, which further reacted with
biotin-NHS ester to form complexes C1 and C3. Pt(II)L2
was also oxidized with H2O2 (30%) and N-
chlorosuccinimide to form platinum(IV) precursors,
which further reacted with biotin-NHS ester to form
complexes C2 and C4 (Scheme 2).
FIGURE 3 Platinum(IV) complexes C1–C4, with ammonia
and cyclohexylamine as the carrier groups and biotin as the axial
group
Pt(II)L1, Pt(II)L2, and the targeted platinum(IV) com-
1
plexes were characterized by IR, H NMR, 13C NMR and
1
ESI-MS spectra. The H NMR, 13C NMR and HR-MS of
all products have provided as a supporting information.
In the IR spectra, amino group participation in binding
with Pt(IV) was confirmed by the examination of the
νNH2 and δNH2 frequencies, which were shifted to lower
frequencies compared with the free amino group due to
Pt(IV)–NH2 coordination. The binding of the axial
hydroxyl of Pt(IV) with the carboxylic acid of the biotin-
NHS ester was confirmed by the examination of Pt–O
absorptions shifting from near 959 cm−1 to bands near
934–869 cm−1. The complexes showed [M – H]−,
[M + H]+, [M + Na]+ or [M + K]+ corresponding to their
formula weights and relative fragment peaks in their ESI
are more targeted than the di-biotinylated com-
plexes.[20,21] Moreover, sodium-dependent multi-vitamin
transporters also promote biotin uptake, leading to over-
expression of cancer cell lines and the potential advan-
tages of chloride in increasing reduction power, which
significantly enhance the bioactivity of platinum
complexes (Figure 2).
We therefore synthesized novel tumor-targeted
platinum(IV) complexes C1–C4 (Figure 3), with ammonia
and cyclohexylamine as the carrier groups and biotin as
the axial group, with the advantages of satraplatin and
targeted drug therapy.
1
mass spectra. The H NMR spectral of all prepared com-
plexes in Figure
3
were consistent with their
corresponding protons in both chemical shift and num-
ber of protons.
2 | RESULTS AND DISCUSSION
The in vitro cytotoxicity of platinum complexes C1–
C4 against human lung cancer cells (A549), liver cancer
cells (SMMC-7721), breast cancer cells (MCF-7), and
colon cancer cells (SW480) was measured by 3-(4,5-
Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) assay. The maximum inhibitory concentrations
(IC50) of platinum complexes C1–C4 at 48 hr are shown
in Table 1. Cisplatin and satraplatin were selected as pos-
itive controls to compare the cytotoxic activity of the
targeting platinum(IV) complexes C1–C4, which took
biotin as the active target group of the tumor. It can be
seen from Table 1 that complexes C2 and C4 have weak
cytotoxicity to the four kinds of cancer cells, while com-
plex C1 only shows certain biological activity to specific
colon cancer cells (28.37 0.98). The antitumor activity
of C1 is close to that of cisplatin in the SW480 cell line.
Compared with cisplatin, complex C3 with chloride in
the axial direction showed good anticancer activity
against A549 cell line,complex C3 (6.34 0.44) is 3 times
more cytotoxic than cisplatin (19.40 0.71), and against
MCF-7 cell line complex C3 (4.22 0.11) is 5.4 times more
cytotoxic than cisplatin (22.96 0.58), and against SW480
We prepared the Iodine/Chloride (I/CI) intermediate by
reaction of potassium trichloroplatinate with KI and
cyclohexylamine in a water bath, followed by filtration
and drying. The I/Cl intermediate hydrolyzed with silver
nitrate to form a hydrolysate and reacted with KI to form
Dichloro, ammonia and cyclohexylamine platinum (Pt
(II)L1). The I/Cl intermediate also hydrolyzed with silver
SCHEME 1 Synthesis of I/Cl intermediate, Pt (II)L1, and Pt
(II)L2

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ZHONG ET AL.
SCHEME 2 Synthesis of complexes C1–C4
TABLE 1 In vitro cytotoxicity against four selected human tumor cell lines of complexes C1 to C4
IC50 (μM)a
Complex
C1
A549b
SMMC-7721c
MCF-7d
SW480e
>40
>40
>40
28.37 0.98
>40
C2
>40
>40
>40
C3
6.34 0.44
>40
19.45 0.50
>40
4.22 0.11
>40
6.65 0.60
>40
C4
Satraplatin
Cisplatin
12.01 0.30
19.40 0.71
16.00 0.34
14.91 0.36
3.81 0.23
22.96 0.58
7.15 0.31
23.15 0.22
aAll IC50 values (drug concentration giving 50% survival) calculated based on at least three separated experiments.
bHuman nonsmall-cell lung cancer cell.
cHuman liver cell.
dHuman breast carcinoma cell.
eHuman colon cancer cell.
cell line complex C3 (6.65 0.60) is 3.4 times more cyto-
toxic than cisplatin (23.15 0.22). (Table 1) Compared
with satraplatin, the antitumor activity of complex C3
against A549 and SW480 was also improved, while the
cytotoxic activity against SMMC-7721 and MCF-7 was
comparable. The cell activity of C3 is significantly better
than that of other complexes, which may reduce the
redox potential and increase the reduction power due to
the presence of chloride on the axis, increasing the accu-
mulation of C3 in cells and giving it better anticancer
activity than cisplatin and satraplatin in specific cell
lines. Of the four cancer cell lines, C3 works best on
MCF-7, then SW480, A549, and SMMC-7721. The active
tumor targeting function of biotin also plays a role, show-
ing the best cytotoxic activity against MCF-7, which is
consistent with the original intention of our design.

ZHONG ET AL.
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3 | CONCLUSIONS
60ꢀC. Data for [Pt(II)L1]: yield 51.23%, light yellow
solid. IR (ν, cm−1): v(NH) broad 3240, 3194 cm–1,
In summary, we designed and synthesized novel
platinum(IV) complexes with ammonia and cyclohexyl-
amine as carrier groups and targeted biotin as the axial
group, and evaluated their antitumor activity. Complexes
C2 and C4 showed weak antitumor activity against the
four cell lines. Complex C1 only showed antitumor activ-
ity against the SW480 cell line which is similar to cis-
platin. Lemma et al[22] concluded that reduction attack of
ascorbate on the chloride ligands that forms a bridged
transition state in which a concerted two-electron trans-
fer from ascorbate to platinum(IV) leads to the release of
two chlorides.[13] Choi et al concluded that the reduction
rates and reduction potentials increased in the following
order of axial ligand substitution: OH < Cl.[23] Moreover,
it was found by MTT assay that a faster reduction rate
exhibit higher cytotoxicity. Complex C3 showed good
antitumor activity against A549 and SW480 cell lines that
was better than satraplatin. Compared with cisplatin,
complex C3 showed good anticancer activity against
A549 cell line, complex C3(6.34 0.44) is 3 times more
cytotoxic than cisplatin(19.40 0.71),and against MCF-7
cell line complex C3(4.22 0.11) is 5.4 times more cyto-
toxic than cisplatin(22.96 0.58),and against SW480 cell
line complex C3(6.65 0.60) is 3.4 times more cytotoxic
than cisplatin(23.15 0.22). (Table 1) The cytotoxic order
of complex C3 among the four cell lines was MCF-7,
A549, SW480, and SMMC-7721. Complex C3 has particu-
larly prominent antitumor activity in MCF-7 compared
to other cell lines. Thus, biotin enacts complex C3 to tar-
get breast cancer cells.
vs(CH), vas(CH) 2922, 2859 cm−1, δ(NH) 1453 cm−1
v(C–C) 1299 cm−1, v(Pt–Cl) 783 cm−1, v(Pt–N) 534 cm−1
,
.
1H NMR (600 MHz, DMSO-d6) δ: 4.84–4.71 (m, 3H),
4.00 (s, 1H), 2.28–2.16 (m, 2H), 1.73–1.53 (m, 4H),
1.28–0.99 (m, 6H). high resolution mass spectrum (HR-
MS) (m/z): [C6H16Cl2N2Pt + Na]+ = 404.0222. 13C NMR
(151 MHz, DMSO) δ: 54.84, 54.51, 40.11, 39.99, 39.85,
39.72, 39.58, 39.44, 39.30, 39.16, 33.58, 33.49, 25.27,
25.01, 24.94, 24.65, 24.57.
4.2 | Synthesis of complex [Pt(II)L2]
I/Cl intermediate (10 mmol) was dissolved in about
300 ml of purified water, bathed at 50ꢀC, and stirred
evenly. AgNO3 (10 mmol) was dissolved in 30 ml of puri-
fied water. The separation funnel was slowly added into
I/Cl intermediate aqueous solution and the reaction was
kept in the dark for 3 hr. After the reaction was finished,
the AgI and AgCl precipitates were removed by filtration,
the pale yellow liquid was collected and water bathed at
50ꢀC with continuous stirring. K2C2O4ÁH2O (10 mmol)
was dissolved in purified water and slowly added to the
reaction system, and the reaction was kept in the dark for
3 hr. After the reaction, cool it in the refrigerator to below
10ꢀC.Then, G4 sand core funnel filtration, filter cake
purification water run-wash two to three times, ethanol
run-wash once or twice, and dried in an oven at 60ꢀC.
Data for [Pt(II)L2]: yield 65.18%, grey solid. IR (ν, cm−1):
v(NH) br 3267, 3116 cm−1, vs(CH), vas(CH) 2936,
2854 cm−1, δ(NH) 1448 cm−1, v(C–O) 1696, 1586 cm−1
v(C–C) 1248 cm−1, v(Pt–O) 807 cm−1, v(Pt–N) 633 cm−1
,
.
4 | MATERIALS AND METHODS
4.1 | Synthesis of complex [Pt(II)L1]
1H NMR (600 MHz, DMSO) δ: 5.12–5.13 (d, 2H), 4.28
(s, 3H), 2.20–2.17 (m, 2H), 1.69–1.65 (m, 2H), 1.56–1.52
(m, 1H), 1.22–1.03 (m, 6H). HR-MS (m/z):
[C8H16N2O4Pt + H]+ = 400.0831. 13C NMR (151 MHz,
DMSO) δ: 166.47, 166.34, 54.69, 39.97, 39.83, 39.69, 39.55,
39.42, 39.28, 39.14, 33.26, 25.22, 24.41.
I/Cl intermediate (10 mmol) was dissolved in about
300 ml of purified water, bathed at 50ꢀC, and stirred
evenly. AgNO3 (10 mmol) was dissolved in 30 ml of
purified water. The separation funnel was slowly added
into I/Cl intermediate aqueous solution and the reaction
was kept in the dark for 3 hr. After the reaction was fin-
ished, the AgI and AgCl precipitates were removed by
filtration and the pale yellow liquid was collected and
water bathed at 50ꢀC to continue stirring. KCl (10 mmol)
was dissolved in purified water and slowly added to the
reaction system, which was then kept in the dark for
3 hr. After the reaction, cool it in the refrigerator to
below 10ꢀC. Then, G4 sand core funnel filtration, filter
cake purification water run-wash two to three times,
ethanol run-wash once or twice, and dried in an oven at
4.3 | Synthesis of complexes C1 and C2
Pt(II)L1 (10 mmol) and Pt(II)L2 (10 mmol), for com-
plexes C1 and C2 respectively, were dissolved in about
250 mL of purified water, bathed at 50ꢀC, and stirred
evenly. H2O2 (30%; 15 mL) was slowly added to the aque-
ous solution of Pt(II)L1 or Pt(II)L2. The reactions were
conducted in the dark for 5 hr. After the reactions were
finished, a light green (C1) or yellow (C2) solid was
obtained through filtration. Dried after wash-
ing with pure water and ethanol. The filtrate was

6 of 7
ZHONG ET AL.
collected, evaporated, and concentrated to 50–60 ml then
cooled in a refrigerator. After solid precipitation, filtered,
washed by purified water and ethanol and dried to solids.
Combine the solids twice, get the intermediates. The
intermediate products (10 mmol) were dissolved in 20 ml
of N,N-dimethylformamide (DMF) in a water bath at
60ꢀC and evenly stirred. Biotin-NHS ester (10 mmol) was
added and the reactions were kept in the dark for 24 hr.
After the reactions were finished, G4 sand core funnels
were used to filter and collect the clarified yellow liquid.
The filtrate was reversed osmosis by methanol and ether,
and the yellow solids were precipitated by G3 sand-core
funnel filtration and methanol:ethyl ether = 1:1 rinsing
two to three times, vacuum drying at 50ꢀC, and com-
plexes C1 and C2 were obtained. Data for C1: yield
43.02%, yellow solid. IR (ν, cm−1): v(NH) br 3378,
evaporation and concentration, washed by ethanol and
ethyl ether, and vacuum dried at 60ꢀC. The intermedi-
ates
(10
mmol),
O-(Benzotriazol-1-yl)-N,N,N',N'-
tetrafluoroborate (TBTU)
tetramethyluronium
(15 mmol), and triethylamine (10 mmol) were dissolved
in 15 ml dimethyl sulfoxide (DMSO) and the mixture
was evenly stirred in a water bath at 40ꢀC. Biotin-NHS
ester (10 mmol) was added and the reactions were kept
in the dark for the night. After the reactions were fin-
ished, CH2Cl2 was added to the reaction solutions,
mixed evenly, and poured into the separating funnels.
Purified water was added and extracted two to three
times to remove the condensation agent in the reaction
solution. The organic phase was collected and the
water was removed with MgSO4, then the CH2Cl2 was
evaporated and concentrated. The products obtained
were gray and oily. Methanol dissolved, and then
added ether, got solid precipitations. G3 sand core
funnels filter, solids used methanol: ether =1:1 wash
two to three times, and vacuum dried at 60ꢀC. Data for
C3: yield: 43.04%, gray solid. IR (ν, cm−1): v(NH) br
3220 cm−1
,
vs(CH), vas(CH) 2930, 2855 cm−1
,
δ(NH) 1453 cm−1, v(C–O) 1685, 1622 cm−1, v(C–C)
1265 cm−1, v(Pt–O) 891 cm−1, v(Pt–Cl) 675 cm−1, v(Pt–N)
579 cm−1 1H NMR (600 MHz, DMSO) δ: 6.71–6.60
.
(s, 1H), 6.52–6.34 (s, 2H), 5.23–6.04 (m, 3H), 4.36–4.30
(m, 1H), 4.18–4.10 (s, 1H), 3.15–3.02 (m, 1H), 2.85–2.78
(m, 1H), 2.70–2.61 (s, 1H), 2.58–2.54 (m, 2H), 1.25–1.95
(m, 4H), 1.74–0.95 (m, 14H). HR-MS (m/z):
3389, 3224 cm−1, vs(CH), vas(CH) 2932, 2856 cm−1
δ(NH) 1454 cm−1, v(C–O) 1711, 1682 cm−1, v(C–C)
1264 cm−1, v(Pt–O) 897 cm−1, v(Pt–N) 578 cm−1 1H
,
.
[C16H32Cl2N4O4PtS
+
H]+
=
642.1242. 13C NMR
NMR (600 MHz, DMSO) δ: 6.48–6.34 (s, 2H), 4.35–4.29
(m, 1H), 4.22–4.10 (m, 1H), 3.15–3.04 (m, 1H),
2.92–2.90 (s, 1H), 2.85–2.81 (m, 1H), 2.77–2.66 (d, 2H),
2.62–2.54 (d, 1H), 2.32–2.13 (m, 4H), 1.66–1.07 (m,
17H). HR-MS (m/z): [C18H31N4O8PtS + H]+ = 660.1655.
13C NMR (101 MHz, DMSO) δ: 174.42, 162.72, 127.25,
124.45, 119.07, 109.64, 61.05, 59.18, 55.38, 40.11, 39.90,
39.69, 39.48, 39.28, 39.07, 38.86, 33.48, 28.10, 28.02,
24.52. Data for C4: yield 43.68%, gray solid. IR
(151 MHz, DMSO) δ: 181.70, 162.78, 61.11, 59.24, 55.57,
55.54, 53.95, 40.48, 39.98, 39.92, 39.84, 39.71, 39.57, 39.43,
39.29, 39.15, 36.81, 32.45, 31.96, 28.38, 28.19, 25.69, 25.03,
24.74, 24.65. Data for C2: yield 42.00%, yellow solid. IR
(ν, cm−1): v(NH) br 3246, 3071 cm−1
,
vs(CH),
vas(CH) 2933, 2853 cm−1, δ(NH) 1443 cm−1, v(C–O)1697,
1615 cm−1, v(C–C) 1254 cm−1, v(Pt–O) 934 cm−1, v(Pt–Cl)
745 cm−1, v(Pt–N) 534 cm−1. 1H NMR (600 MHz, DMSO)
δ: 7.22–6.97 (s, 1H), 6.48–6.29 (m, 2H), 6.22–5.96 (m, 3H),
4.33–4.24 (s, 1H), 4.16–4.03 (s, 1H), 3.09–3.02 (m, 1H),
2.83–2.77 (m, 1H), 2.72–2.64 (s, 1H), 2.57–2.54 (m, 1H),
2.20–1.98 (m, 4H), 1.70–1.05 (m, 16H). HR-MS (m/z):
(ν, cm−1): v(NH) br 3425, 3250 cm−1
vas(CH) 2933, 2859 cm−1, δ(NH) 1464 cm−1, v(C–O)
1693, 1557 cm−1, v(C–C) 1263 cm−1, v(Pt–O) 869 cm−1
v(Pt–Cl) 743 cm−1 v(Pt–N): 668 cm−1 1H NMR
,
vs(CH),
,
,
.
[C16H32Cl3N4O3PtS
+
H]+
=
660.0903. 13C NMR
(600 MHz, DMSO) δ: 6.78–6.55 (s, 1H), 6.42–6.13 (d,
2H), 4.36–4.24 (t, 1H), 4.13–4.07 (m, 1H), 3.09–3.01 (s,
1H), 2.85–2.77 (m, 2H), 2.76–2.66 (s, 1H), 2.60–2.54 (d,
1H), 2.38–2.09 (m, 4H), 2.05–1.94 (d, 1H), 1.72–1.06 (m,
17H). HR-MS (m/z): [C18H31ClN4O7PtS + H]+ = 678.1340.
13C NMR (151 MHz, DMSO) δ: 170.78, 162.78, 65.41,
61.49, 59.61, 55.43, 40.36, 40.22, 40.08, 39.94, 39.81,
39.67, 39.53, 36.26, 32.50, 31.23, 25.91, 25.69, 25.29,
24.83, 24.79.
(151 MHz, DMSO) δ: 181.03, 164.37, 164.01, 162.79,
61.12, 61.09, 59.23, 55.59, 55.53, 53.97, 40.46, 40.09, 39.97,
39.91, 39.83, 39.69, 39.56, 39.42, 39.28, 39.14, 36.17, 36.14,
31.89, 31.35, 31.33, 28.35, 28.31, 28.19, 28.15, 25.65, 24.97,
24.51, 24.42.
4.4 | Synthesis of complexes C3 and C4
Pt(II)L1 (10 mmol) and Pt(II)L2 (10 mmol), for com-
plexes C3 and C4 respectively, were dissolved in about
200 mL of purified water, bathed at room temperature,
and stirred evenly. N-chlorosuccinimide (10 mmol) was
added to the reactions and reacted overnight. After the
reaction, the yellow solids were obtained by
ACKNOWLEDGMENTS
This work was supported by the Yunnan Applied Basic
Research Projects (Nos. 2018FA047 and 2018FB018) and
the National Natural Science Foundation of China
(NNSFC) (Nos. 21961017, 21642001, 21662021), which
are gratefully acknowledged.

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ORCID
Yunshuang Zhong https://orcid.org/0000-0001-7871-
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Zhong Y, Jia C,
Zhang X, et al. Synthesis, characterization, and
antitumor activity of novel tumor-targeted
platinum(IV) complexes. Appl Organometal Chem.
2020;e5577. https://doi.org/10.1002/aoc.5577