Organometallic binuclear Pd(II) complex: Synthesis, crystal structure and in-vitro antitumor activity study

Article abstract of DOI:10.1016/j.inoche.2019.05.017

A novel planar chiral ferrocene cyclopalladated compound (C2) was synthesized and fully characterized. The absolute configuration of C2 has been determined by single-crystal X-ray analysis. The cytotoxic activities of C2 and cisplatin were evaluated against liver (MHCC97 and HepG2), mouse breast (4 T1) and ovarian granulosa (KGN) cancer cell lines. C2 was about 23 times more potent than cisplatin in the suppression of KGN cells.

Full text of DOI:10.1016/j.inoche.2019.05.017

InorganicChemistryCommunications105(2019)199–202
Contents lists available at ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Short communication
Organometallic binuclear Pd(II) complex: Synthesis, crystal structure and in-
vitro antitumor activity study
Guidong Gong, Xingxing Gao, Xianhong Yu, Huiya Zhang, Jiaqi Yang, Zhonghui Zhang,
Guoyuan Du, Yuan Cao, Gang Zhao⁎
The school of chemistry engineering, Sichuan University, Chengdu 610064, Sichuan, PR China
G R A P H I C A L A B S T R A C T
A R T I C L E I N F O
A B S T R A C T
Keywords:
A novel planar chiral ferrocene cyclopalladated compound (C2) was synthesized and fully characterized. The
absolute configuration of C2 has been determined by single-crystal X-ray analysis. The cytotoxic activities of C2
and cisplatin were evaluated against liver (MHCC97 and HepG2), mouse breast (4 T1) and ovarian granulosa
(KGN) cancer cell lines. C2 was about 23 times more potent than cisplatin in the suppression of KGN cells.
Planar chiral
Ferrocene Cyclopalladated compound
Crystal structure
Antitumor activity
Cancer seriously threatened human health, the reason of which may
be the difficulty in developing new highly active anticancer drugs [1].
Synthesizing new compounds and using them as anticancer drug can-
didates was an effective way to solve this problem [1,2]. Platinum-
based compounds like cisplatin, carboplatin and oxaliplatin play key
roles in cancer therapeutics because of their high anticancer activity
[3]. However, side effect and drug resistance limited their use in on-
cotherapy [4]. Under this consideration, palladium-based compounds
attracted attention due to the similarly chemical characteristic of pla-
tinum and palladium.
anticancer activities were evaluated [5–9]. Structure-activity relationship
(SAR) study illustrated that the anticancer activity of cyclopalladated
compounds was highly related to the C-N cycle, the N-group and the
bridge anion [9–11]. Besides, the chirality part also plays a very im-
portant role in the anticancer ability of cyclopalladated compounds [8].
It has reported that some cyclopalladated compounds could oxidize the
thiol-group of the proteins in organelle membrane and then induce
cancer cell apoptosis [5,7]. However, the target of cyclopalladated
compounds used as anticancer drug candidates is still unclear. As a result,
more cyclopalladated compounds should be synthesized and further
mechanization of them inducing cancer cell apoptosis should be studied.
Some cyclopalladated compounds were synthesized and their
⁎ Corresponding author.
E-mail address: gzhao@scu.edu.cn (G. Zhao).
https://doi.org/10.1016/j.inoche.2019.05.017
Received 19 April 2019; Received in revised form 10 May 2019; Accepted 10 May 2019
Availableonline11May2019
1387-7003/©2019ElsevierB.V.Allrightsreserved.

G. Gong, et al.
InorganicChemistryCommunications105(2019)199–202
Scheme 1. Overview of synthesized compound C2. i) C6H5CH3, 110 °C, 24 h. ii) Pd(OAc)2, MeOH, r.t., 24 h. iii) KSCN, MeOH, r.t., 2 h.
Fig. 1. X-ray crystal structures of C2 presented as ellipsoid models.
Ferrocene is an eye-catching modified group because of its unique
was tested by X-ray single crystal diffraction. The antiproliferation
ability of C2 on KGN, MHCC91, HepG2 and 4 T1 cancer cell lines was
evaluated, taking cisplatin as a positive control.
three-dimensional (3D) structure and chemical property [9,12–14].
Some ferrocene cyclopalladated compounds were synthesized and their
catalytic activities or anticancer activities were evaluated [8,9,15,16].
However, the involute structure of ferrocene cyclopalladated com-
pounds limited their use. Consequently, synthesizing new ferrocene
cyclopalladated compounds and clearing their 3D structures are needful
for expanding their use.
The structural formulas and the numbering of the compounds under
study are presented in Scheme 1. The compound C2 was synthesized as
a reported way [9]. In brief, C1 was obtained from combing acet-
ylferrocene and (+)-(R)-1-amino-2-(methoxymethyl)-pyrrolidine in dry
toluene with a quite high yield. C1 mixed with equivalent Pd(OAc)2 in
MeOH, stirred at 25 °C for 24 h and then excess KSCN was added. C2
was obtained after separated with a column chromatography. C2 was
Hence, a novel binuclear plane chirality ferrocene cyclopalladated
C2 was synthesized and fully characterized. The absolute configuration
200

G. Gong, et al.
InorganicChemistryCommunications105(2019)199–202
Table 1
Table 3
Crystal data and structures refinement for C2.
IC50 values of C2 and cisplatin against HepG2, MHCC97, 4T1 and KGN cell
lines.
Cell lines
Identification code
C2
38H46Fe2N6O2Pd2S2
1007.43
IC50 [μM] value
Cisplatinb
SDa
Empirical formula
C
Formula weight
Temperature/K
293.15
C2
Crystal system
triclinic
Space group
P1
HepG2
MHCC97
4T1
4.6
5.6
1.8
0.2
0.5
0.3
0.71
0.69
0.43
0.60
0.2
a/Å
10.6199(4)
11.1823(4)
19.9004(8)
93.488(3)
95.138(3)
97.897(3)
2325.04(15)
2
0.03
0.07
0.07
b/Å
4.85
14
c/Å
KGN
α/°
a
β/°
The values are shown as the mean values of more than two experiments in
γ/°
triplicate; the cells were incubated with C2 or cisplatin for 72 h.
Volume/Å3
Z
b
Cisplatin was used as a positive control.
ρ
calcg/cm3
1.439
μ/mm−
F(000)
1
1.498
activity of C2 [20,21]. The CCK8 assay was used to measure the cell
viability after treated by C2 or cisplatin respectively. As shown in
Table 3, C2 illustrated different antiproliferation to different cancer cell
lines, and the IC50 to these 4 cancer cell lines were lower than 1 μM.
Besides, the IC50 of C2 to these 4 cancer cell lines was much lower than
the positive control cisplatin, which meaned that C2 shows high po-
tential as an anticancer drug candidate. The reason for the high anti-
proliferation ability of C2 showed in CCK8 assay may be the co-working
of the palladium part and the ferrocene part with different anti-
proliferation mechanisms [6,7,22,23].
1016.0
Crystal size/mm3
0.35 × 0.3 × 0.25
Radiation
MoKα (λ = 0.71073)
5.866 to 52.746
2Θ range for data collection/°
Index ranges
−13 ≤ h ≤ 12, −13 ≤ k ≤ 13, −24 ≤ l ≤ 22
19,193
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indexes [I ≥2σ (I)]
Final R indexes [all data]
Largest diff. Peak/hole / e Å−3
Flack parameter
13,548[Rint = 0.0243. Rsigma = 0.0522]
13,548/6/927
0.997
R1 = 0.0406, wR2 = 0.0930
R
1 = 0.0500, wR2 = 0.0990
0.63/−0.43
In conclusion, a novel planar chiral ferrocene cyclopalladated
compound C2 was synthesized and fully characterized. The absolute
configuration of C2 was confirmed by X-ray single crystal diffraction.
The X-ray analysis showed that C2 exhibits a triclinic form with the
space group P1. The antiproliferative activity assays showed that C2
were antiproliferative to four cancer cell lines with different potencies.
The mechanism of C2 against tumor cells is proceeding.
−0.002(15)
fully characterized by 1H NMR, 13C NMR, optical rotation, elemental
analysis and high resolution mass spectrum.
Single crystal of C2 (CCDC 1909320, Fig. 1) was obtained by slowly
evaporation of the solvents from dichloromethane/n-hexane. The
crystal and experimental data of C2 were summarized in Table 1. Se-
lected bond distances and angles for C2 were showed in Table 2. X-ray
analysis shows that the complex exhibits a triclinic form with the space
group P1. The pair of coordinating N atoms bear a trans relationship,
and each palladium atom in the metallacycle is slightly distorted
square-planar coordination environment. The two palladium atoms are
bond to two thiocyanato groups. The two thiocyanato groups respec-
tively adopts nearly linear configuration [the angle of N(5)-C(19)-S(1)
and N(6)-C(20)-S(2): 179.7(10) and 179.5(9)°]. The two palladacycles
are approximately co-planar, the relevant dihedral angle being 173.06.
All bonds are normal except the PdeC bond lengths, Pd(1)-C(6) and Pd
(2)-C(21) are slightly longer than those of the other dimers, but sub-
stantially shorter than the predicted value of 2.05 Å due to the metal-to-
ligand back-bonding [17–19].
Acknowledgements
GZ is grateful for the support from Sichuan Province Science and
Technology Support Program (No. 19YYJC2612). GDG is grateful for
the support from Sichuan Province Science and Technology Support
Program (No. 2019JDRC0106) and the invaluable support received
from Shelly Chen over these years. We are grateful for the Analytical &
Testing Center of Sichuan University for X-ray diffraction work and we
are also grateful to Dr. Luo for his help of single crystal analysis. We are
grateful for ceshigo (www.ceshigo.com) for NMR test.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.inoche.2019.05.017.
Taking cisplatin as a positive control, Mouse breast cancer cell line
4 T1, human liver cancer cell lines HepG2 and MHCC97, human ovarian
granulosa cell line KGN were used to evaluate the antiproliferation
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