Synthesis and antitumor activity of novel alkynyl (phosphine) digold(I) complexes

Article abstract of DOI:10.1007/s11243-021-00467-3

A series of 1,4-disubstituted digold–alkynyl complexes, [(PPh₃)Au]₂(μ-C≡C–Ar–CH≡C)], in which the 1,4-diethenylbenzene bridge contains two alkyl or oligo(ethylene glycol)methylether side chains at different positions (2,5- and 2,3-positions), have been synthesized and structurally characterized by spectroscopic techniques. The structure of [(AuPPh₃)₂{μ-C≡C–C₆H₂(OC₆H₁₃)₂-2,5-C≡C}] (2c) has been established by X-ray crystallography. Their antitumor activities in vitro were investigated by MTT assay against four tumor cell lines. Compared to alkyl-functionalized complexes, the oligo(ethylene glycol)methylether-functionalized complexes showed significant antitumor activity, which may be attributed to the improvement of the hydrophilicity of the complex to achieve the appropriate lipophilicity. In particular, complex [(AuPPh₃)₂{μ-C≡C–C₆H₂(OCH₂CH₂OCH₂CH₂OCH₃)₂-2,3-C≡C}] (2j) displayed high activity against the A549 cell line and low cytotoxicity toward normal cell lines. Notably, further investigations are required if complex 2j is to undergo trials as a new potential antitumor agent.

Full text of DOI:10.1007/s11243-021-00467-3

Transition Metal Chemistry
https://doi.org/10.1007/s11243-021-00467-3
Synthesis and antitumor activity of novel alkynyl (phosphine) digold(I)
complexes
Qiu Mei Chen1 · Yi Chen1 · Xiang Hua Wu1
Received: 14 April 2021 / Accepted: 15 June 2021
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021
Abstract
A series of 1,4-disubstituted digold–alkynyl complexes, [(PPh3)Au]2(μ-C≡C–Ar–CH≡C)], in which the 1,4-diethenylbenzene
bridge contains two alkyl or oligo(ethylene glycol)methylether side chains at diferent positions (2,5- and 2,3-positions),
have been synthesized and structurally characterized by spectroscopic techniques. The structure of [(AuPPh3)2{µ-C≡C–
C6H2(OC6H13)2-2,5-C≡C}] (2c) has been established by X-ray crystallography. Their antitumor activities in vitro were inves-
tigated by MTT assay against four tumor cell lines. Compared to alkyl-functionalized complexes, the oligo(ethylene glycol)
methylether-functionalized complexes showed signifcant antitumor activity, which may be attributed to the improvement
of the hydrophilicity of the complex to achieve the appropriate lipophilicity. In particular, complex [(AuPPh3)2{µ-C≡C–
C6H2(OCH2CH2OCH2CH2OCH3)2-2,3-C≡C}] (2j) displayed high activity against the A549 cell line and low cytotoxicity
toward normal cell lines. Notably, further investigations are required if complex 2j is to undergo trials as a new potential
antitumor agent.
Introduction
and sodium aurothiomalate. Firstly, they exhibit reasonably
stable coordinative bonds. Secondly, they improve the bioac-
tivity of the species after ethynylation by suitable ligands, an
example for the water-soluble [Pt(terpy)(glycosylated aryla-
cetylide)]+ (terpy=terpyridine ligand) supported by Che [8].
However, up to now, there are few studies on the bioactivity
of alkynyl gold(I) complexes [9–19]. According to the lit-
erature reviews, the mode of gold complex action is diferent
from that of Pt drugs, which may be the inhibition of thiore-
doxin reductase or the targeting of mitochondrial membrane,
fnally leading to mitochondria-induced apoptosis [20]. The
ability of a complex to permeate the mitochondrial mem-
brane may be decided by its hydrophilic and lipophilic
properties [21, 22], which can be fne-tuned by the ligands.
Here, we carry out a primary research aimed at achieving
the proper lipophilicity of gold phosphine complexes via
fne-tuned by modifcation of a 1,4-diethenylbenzene bridg-
ing ligand. In this paper, ten 1,4-disubstituted digold–alky-
nyl complexes, [(PPh3)Au]2(μ-C≡C–Ar–CH≡C)], in which
the 1,4-diethenylbenzene bridge contains two alkyl or
oligo(ethylene glycol)methylether side chains at diferent
positions (2,5- and 2,3-positions), have been synthesized.
In vitro antitumor activities of these alkynyl gold(I) com-
plexes against human tumor cell lines were described.
Cisplatin, cis-[PtCl2(NH3)2], has been in clinical use for the
treatment of various tumor cell lines for decades. However,
in view of the adverse side efects of cisplatin in clinical
application, a large number of new metal-based drugs have
been developed recently to reduce drug resistance and side
efects. Among novel non-platinum-based antitumor agents,
gold complexes have recently gained attention because of
their strong antiproliferative efects [1–5]. In fact, gold-
based compounds have been used in clinic for a long time,
such as auranofn and sodium aurothiomalate used for the
treatment of rheumatoid arthritis. However, many gold(I)
compounds lose their activity in vivo, which probably due
to their potentiality to exchange ligands with biomolecules
[6]. It is important that they show suitable stability under
physiological conditions in the development of new bioac-
tive gold complexes [7]. In this instance, alkynyl gold(I)
complexes can be considered as alternative bioactive agents
to replace conventional gold(I) complexes such as auranofn
* Xiang Hua Wu
chxhwu@sina.com
1
College of Chemistry and Chemical Engineering,
Yunnan Normal University, Kunming 650500,
People’s Republic of China
Vol.:(0123456789)
1 3

Transition Metal Chemistry
3JCP = 11.25 Hz, m-PPh3), 129.73 (s, Ph), 130.17 (s, Ph),
131.43 (d, 4JCP =2.5 Hz, p-PPh3), 134.29 (s, Ph), 134.40 (s,
Ph), 153.69 (s, Ph). 31P{1H} NMR (200 MHz, CDCl3): δ
42.25 (s). IR (KBr): ν (C≡C) 2098 cm−1.
Experimental section
Materials and methods
All manipulations were carried out at room temperature
under a nitrogen atmosphere by using standard Schlenk
techniques, unless otherwise stated. H, 13C{1H} and
1
Synthesis of [(AuPPh3)2{µ‑C≡C–C6H2(OC6H13)2‑2,5‑
C≡C}] (2c)
31P{1H} NMR spectra were collected on a Varian Mercury
Plus 500 spectrometer (500 MHz) at room temperature. 1H
and 13C{1H} NMR chemical shifts are relative to TMS, and
31P{1H} NMR chemical shifts are relative to 85% H3PO4.
Infrared spectra were obtained on a TENSOR 27 instru-
ment using KBr pellets. Analytical solvents were pre-dried,
distilled and degassed prior to use. The reagent ethynyltri-
methylsilane was purchased from Alfa Aesar. Others were
commercially available. The starting materials AuCl(PPh3)
[23], 1a [24], 1b [25], 1c [26], 1 g–1j [27] and 1,4-diiodo-
2,3-dihydroxybenzene [28] were prepared by the procedures
described in literature methods. The preparation of com-
pounds 1e and 1f can be found in Supporting information.
The synthesis is similar to 2a, with 1a being replaced
1
by 1c. Pale yellow solid, Yield: 94 mg, 75%. H NMR
3
(500 MHz, CDCl3): δ 0.85 (t, J(1H–1H) = 5.0 Hz, 6H,
–CH3), 1.31–1.32 (m, 8H,–CH2), 1.42–1.47 (m, 4H, –CH2),
1.80–1.83 (m, 4H, –CH2), 3.98 (t, 3 J(1H–1H)=5.0 Hz, 4H,
–OCH2), 6.99 (s, 2H, Ph-H), 7.44–7.56 (m, 30H, Ph-H).
13C{1H} NMR (125 MHz, CDCl3): δ 14.08 (s, CH3), 22.62
(s, CH2), 25.56 (s, CH2), 29.06 (s, CH2), 31.61 (s, CH2),
69.47 (s, CH2), 113.96 (s, Ph), 118.18 (s, Ph), 129.02 (d,
3JCP = 11.25 Hz, m-PPh3), 129.69 (s, Ph), 130.13 (s, Ph),
131.41 (d, 4JCP =2.5 Hz, p-PPh3), 134.25 (s, Ph), 134.36 (s,
Ph), 153.67 (s, Ph). 31P{1H} NMR (200 MHz, CDCl3): δ
42.24 (s). IR (KBr): ν (C≡C) 2097 cm−1.
Synthesis of [(AuPPh3)2{µ‑C≡C–
C6H2(OCH3)2‑2,5‑C≡C}] (2a)
Synthesis of [(AuPPh3)2{µ‑C≡C–
C6H2(OCH3)2‑2,3‑C≡C}] (2d)
1,4-dimethoxy-2,5-bis(2-(trimethylsilyl)ethynyl)benzene
(1a) (0.033 g, 0.10 mmol) and an excess of NaOH (0.8 g,
2.0 mmol) were dissolved in methanol solution (15 mL)
and stirred for 30 min. AuCl(PPh3) (0.094 g, 0.19 mmol)
was then added, and the mixture was stirred for 3 h. The
solid was collected by fltration, washed with methanol and
diethyl ether, and dried under vacuum. Pale yellow solid,
Yield: 64 mg, 58%. 1H NMR (500 MHz, CDCl3): δ 3.83 (s,
3H, –OCH3), 7.01 (s, 2H, Ph-H), 7.44–7.56 (m, 30H, Ph-H).
13C{1H} NMR (125 MHz, CDCl3): δ 56.09 (s, CH3), 113.04
(s Ph), 115.79 (s Ph), 129.04 (d, 3JCP =11.25 Hz, m-PPh3),
129.62 (s Ph), 130.07 (s Ph), 131.45 (d, 4JCP = 2.5 Hz, p-
The synthesis is similar to 2a, with 1a being replaced by 1d.
Pale yellow solid, Yield: 75 mg, 68%. 1H NMR (500 MHz,
CDCl3): δ 4.00 (s, 6H, –OCH3), 7.10 (s, 2H, Ph-H),
7.45–7.56 (m, 30H, Ph-H). 13C{1H} NMR (125 MHz,
CDCl3) δ 60.89 (s, CH3), 118.98 (s, Ph), 128.57 (s, Ph),
129.08 (d, 3JCP =11.25 Hz, m-PPh3), 129.67 (s, Ph), 130.11
4
(s, Ph), 131.46 (d, JCP = 2.5 Hz, p-PPh3), 134.27 (s, Ph),
134.38 (s, Ph), 154.26 (s, Ph). 31P{1H} NMR (200 MHz,
CDCl3): δ 42.19 (s). IR (KBr): ν (C≡C) 2096 cm−1.
2
PPh3), 134.26 (s Ph), 134.37 (d, JCP = 13.9 Hz, o-PPh3),
154.08 (s Ph). 31P{1H} NMR (200 MHz, CDCl3): δ 42.22
Synthesis of [(AuPPh3)2{µ‑C≡C–C6H2(OC4H9)2‑2,3‑
C≡C}] (2e)
(s). IR (KBr): ν (C≡C) 2096 cm−1.
The synthesis is similar to 2a, with 1a being replaced by 1e.
Pale yellow solid, Yield: 86 mg, 72%. 1H NMR (500 MHz,
Synthesis of [(AuPPh3)2{µ‑C≡C–C6H2(OC4H9)2‑2,5‑
C≡C}] (2b)
3
CDCl3): δ 0.89 (t, J(1H–1H) = 7.5 Hz, 6H, –CH3),
1.49–1.53 (m, 4H, –CH2), 1.74–1.77 (m, 4H, –CH2), 4.12
(t, 3 J(1H–1H)=5.0 Hz, 4H, –OCH2), 7.03 (s, 2H, Ph-H),
7.40–7.53 (m, 30H, Ph-H). 13C{1H} NMR (125 MHz,
CDCl3): δ 14.12 (s, CH3), 19.35 (s, CH2), 32.41 (s, CH2),
73.39 (s, CH2), 119.46 (s, Ph), 128.21 (s, Ph), 129.06 (d,
3JCP = 11.25 Hz, m-PPh3), 129.74 (s, Ph), 130.19 (s, Ph),
131.44 (d, 4JCP =2.5 Hz, p-PPh3), 134.28 (s, Ph), 134.39 (s,
Ph), 154.09 (s, Ph). 31P{1H} NMR (200 MHz, CDCl3): δ
42.27 (s). IR (KBr): ν (C≡C) 2098 cm−1.
The synthesis is similar to 2a, with 1a being replaced by 1b.
Pale yellow solid, Yield: 60 mg, 50%. 1H NMR (500 MHz,
3
CDCl3): δ 0.94 (t, J(1H–1H) = 7.5 Hz, 6H, –CH3),
1.45–1.50 (m, 4H, –CH2), 1.78–1.84 (m, 4H, –CH2), 3.99
(t, 3 J(1H–1H)=7.5 Hz, 4H, –OCH2), 6.99 (s, 2H, Ph-H),
7.44–7.56 (m, 30H, Ph–H). 13C{1H} NMR (125 MHz,
CDCl3): δ 13.98 (s, CH3), 19.20 (s, CH2), 31.20 (s, CH2),
69.20 (s, CH2), 113.96 (s, Ph), 118.24 (s, Ph), 129.05 (d,
1 3

Transition Metal Chemistry
CDCl3): δ 3.44 (s, 6H,–OCH3), 3.80 (t, 3 J(1H–1H)=5.0 Hz,
Synthesis of [(AuPPh3)2{µ‑C≡C–C6H2(OC6H13)2‑2,3‑
C≡C}] (2f)
3
4H,–OCH2), 4.35 (t, J(1H–1H) = 5.0 Hz, 4H,–OCH2),
7.10 (s, 2H, Ph–H), 7.44–7.55 (m, 30H, Ph–H). 13C{1H}
NMR (125 MHz, CDCl3): δ 58.84 (s, CH3), 71.80 (s, CH2),
72.21 (s, CH2), 119.35 (s, Ph), 128.42 (s, Ph), 129.08 (d,
3JCP = 11.25 Hz, m-PPh3), 129.60 (s, Ph), 130.06 (s, Ph),
131.48 (s, Ph), 132.05 (d, 4JCP =10.0 Hz, p-PPh3), 134.27
(s, Ph), 153.65 (s, Ph). 31P{1H} NMR (200 MHz, CDCl3) δ
42.26 (s). IR (KBr): ν (C≡C) 2097 cm−1.
The synthesis is similar to 2a, with 1a being replaced by 1f.
Pale yellow solid, Yield: 91 mg, 73%. 1H NMR (500 MHz,
CDCl3): δ 0.76 (t, 3 J(1H–1H)=5.0 Hz, 6H, –CH3), 1.22–1.27
(m, 8H, –CH2), 1.47–1.27 (m, 4H, –CH2), 1.74–1.79 (m, 4H,
–CH2), 4.11 (t, 3 J(1H–1H)=5.0 Hz, 4H, –OCH2), 7.03 (s, 2H,
Ph-H), 7.40–7.51 (m, 30H, Ph-H). 13C{1H} NMR (125 MHz,
CDCl3): δ14.13 (s, CH3), 22.76 (s, CH2), 25.86 (s, CH2), 30.28
(s, CH2), 31.84 (s, CH2), 73.72 (s, CH2), 119.42 (s, Ph), 128.24
(s, Ph), 129.05 (d, 3JCP =11.25 Hz, m-PPh3), 129.77 (s, Ph),
130.17 (s, Ph), 131.43 (d, 4JCP =10 Hz, p-PPh3), 134.26 (s,
Ph), 154.03 (s, Ph). 31P{1H} NMR (200 MHz, CDCl3) δ 42.24
(s). IR (KBr): ν (C≡C) 2099 cm−1.
Synthesis of [(AuPPh3)2{µ‑C≡C–C6H2(OCH2CH2OCH2C
H2OCH3)2‑2,3‑C≡C}] (2j)
The synthesis is similar to 2a, with 1a being replaced by 1j.
Pale yellow solid, Yield: 100 mg, 70%. 1H NMR (500 MHz,
CDCl3): δ 3.27 (s, 6H,–OCH3), 3.51 (t, 3 J(1H–1H)=5.0 Hz,
3
4H, –OCH2), 3.77 (t, J(1H–1H) = 5.0 Hz, 4H, –OCH2),
Synthesis of [(AuPPh3)2{µ‑C≡C–
C6H2(OCH2CH2OCH3)2‑2,5‑C≡C}] (2 g)
3
3.89 (t, J(1H–1H) = 5.0 Hz, 4H, –OCH2), 4.37 (t,
3
J(1H–1H) = 5.0 Hz, 4H, –OCH2), 7.09 (s, 1H, Ph–H),
7.46–7.53 (m, 30H, Ph–H). 13C{1H} NMR (125 MHz,
CDCl3): δ 58.93 (s, CH3), 70.32 (s, CH2), 70.45 (s, CH2),
72.12 (s, CH2), 72.52 (s, CH2), 119.31 (s, Ph), 128.61 (s,
The synthesis is similar to 2a, with 1a being replaced by 1 g.
Pale yellow solid, Yield: 90 mg, 69%. 1H NMR (500 MHz,
CDCl3): δ 3.46 (s, 6H, –OCH3), 3.79 (t, 3 J(1H–1H)=5.0 Hz,
3
3
Ph), 129.12 (d, JCP = 11.25 Hz, m-PPh3), 129.69 (s, Ph),
4H, –OCH2), 4.17 (t, J(1H–1H) = 5.0 Hz, 4H, –OCH2),
7.02 (s, 2H, Ph–H), 7.45–7.55 (m, 30H, Ph–H). 13C{1H}
NMR (125 MHz, CDCl3): δ 59.30 (s, CH3), 67.91 (s, CH2),
68.77 (s, CH2), 114.37 (s, Ph), 118.77 (s, Ph), 129.04 (d,
3JCP = 11.25 Hz, m-PPh3), 129.58 (s, Ph), 130.02 (s, Ph),
131.44 (d, 4JCP =1.25 Hz, p-PPh3), 134.21 (s, Ph), 134.32
(s, Ph), 153.77 (s, Ph). 31P{1H} NMR (200 MHz, CDCl3): δ
42.17 (s). IR (KBr): ν (C≡C) 2096 cm−1.
130.13 (s, Ph), 131.50 (s, Ph), 134.26 (s, Ph), 134.37 (s, Ph),
153.55 (s, Ph). 31P{1H} NMR (200 MHz, CDCl3): δ 42.15.
IR (KBr): ν (C≡C) 2096 cm−1.
Crystallographic analysis
Crystals suitable for X-ray difraction were grown from a
dichloromethane of solution 2c layered with hexane. Dif-
fraction intensity data were collected using a Bruker P4 dif-
fractometer with Mo Kα radiation (0.71073 Å). The struc-
ture was solved by direct methods (SHELXS-97) [29] and
refned by full-matrix least squares on F2 using SHELXL-97
integrated in the WINGX program package [30]. The crystal
data and details of the data collection are summarized in
Table S1. Selected bond distances and angles are given in
Table S2.
Synthesis of [(AuPPh3)2{µ‑C≡C–C6H2(OCH2CH2OCH2C
H2OCH3)2‑2,5‑C≡C}] (2 h)
The synthesis is similar to 2a, with 1a being replaced by 1 h.
Pale yellow solid, Yield: 89.5 mg, 70%. 1H NMR (500 MHz,
CDCl3): δ 3.30 (s, 6H,–OCH3), 3.55 (t, 3 J(1H–1H)=5.0 Hz,
3
4H, –OCH2), 3.86 (t, J(1H–1H) = 5.0 Hz, 4H, –OCH2),
3
3.90 (t, J(1H–1H) = 5.0 Hz, 4H, –OCH2), 4.18 (t,
3
J(1H–1H) = 5.0 Hz, 4H, –OCH2), 7.00 (s, 2H, Ph–H),
7.45–7.55 (m, 30H, Ph–H). 13C{1H} NMR (125 MHz,
CDCl3): δ 58.93 (s, CH3), 69.17 (s, CH2), 69.36 (s, CH2),
70.91 (s, CH2), 72.09(s, CH2), 114.18 (s, Ph), 118.23 (s, Ph),
129.07 (d, 3JCP =11.25 Hz, m-PPh3), 129.57 (s, Ph), 130.01
(s, Ph), 131.47 (d, 4JCP =1.25 Hz, p-PPh3), 134.20 (s, Ph),
134.31 (s, Ph), 153.78 (s, Ph). 31P{1H} NMR (200 MHz,
CDCl3): δ 42.19 (s). IR (KBr): ν (C≡C) 2097 cm−1.
Cytotoxicity assay in vitro
Cytotoxic activities were evaluated by the MTT
[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
mide] method using SKOV-3 (a human ovarian cancer cell
line), A549 (a human lung carcinoma cell line), PC12 (a
rat pheochromocytoma cell line), HepG-2 (a human hepa-
tocellular carcinoma cell line), HaCaT (human immor-
tal keratinocyte line), MA-104 (rhesus kidney cell line) and
RAEC (rat aortic endothelial cells) cells [31]. All cell lines
were purchased from American Type Culture Collection
(ATCC, Rockville, MD). Briefy, the cell suspensions (198
μL) were plated in 96-well microtiter plates at a density of
Synthesis of [(AuPPh3)2{µ‑C≡C–
C6H2(OCH2CH2OCH3)2‑2,3‑C≡C}] (2i)
The synthesis is similar to 2a, with 1a being replaced by 1i.
Pale yellow solid, Yield: 70 mg, 54%. 1H NMR (500 MHz,
1 3

Transition Metal Chemistry
5×104 cells/mL and incubated for 12 h at 37 ℃ in a humidi-
fed incubator with 5% CO2. The test compounds of diferent
concentrations were dissolved in DMSO and added to each
well and further incubated for 24 h under the same con-
ditions. Next, 20 μL of the MTT solution (5 mg/mL) was
added to each well and incubated for 4 h. The old medium
(200 μL) containing MTT was then carefully replaced by
100 μL DMSO and pipetted to dissolve any formazan crys-
tals formed. The absorbance was then determined on a Spec-
tra Max Plus plate reader at 570 nm. Dose–response curves
were generated and the IC50 values were calculated as the
concentrations reducing the cellular proliferation in com-
parison with the untreated control by 50% and are given as
the means and errors of 3 independent experiments. Cispl-
atin, a commonly approved agent for the treatment of many
tumors, was used as the positive control.
gave the 2,3-bis(alkyl)-1,4-diiodobenzene derivatives. The
intermediates 1e and 1f were obtained by Palladium-cat-
alyzed coupling between 2,3-bis(alkyl)-1,4-diiodobenzene
derivatives with trimethylsilylethyne in moderate yield.
1
The immediate precursors were characterized by H and
13C{1H} NMR spectroscopy. Other alkynyl compounds
were previously reported [27]. The general synthetic route
for the preparation of binuclear gold(I) alkynyl complexes
is outlined in Scheme 1. The dinuclear gold products were
obtained by the alkynyl derivatives 1a–j reacting with the
gold complex AuCl(PPh3) from moderate to good yield in
the presence of NaOH. These complexes were characterized
by NMR, which are given in the Supporting Information.
Description of the structure
Single crystals of complex 2c suitable for X-ray analysis
were obtained by slow difusion of hexane into a solution of
2c in dichloromethane. The single-crystal X-ray structure of
complex 2c is shown in Fig. 1. The complex contains two
Au(PPh3) units linked by a linear μ-C≡C–C6H2(OC6H13)2-
2,5-C≡C bridge. The molecular structure of 2c is centrosym-
metric, and two gold centers are related by a pseudo-C2 rota-
tion axis. In the structure of 2c, the ≡C−Au−P and C≡C−Au
Results and discussion
Syntheses and characterization
The synthesis of intermediates 1e and 1f is listed in
Scheme S1. Alkylation with 3,6-diiodobenzene-1,2-diol
Scheme 1 Synthesis of triph-
enylphosphine alkynyl bimetal-
lic gold(I) complexes
1 3

Transition Metal Chemistry
angles, which are 177.33(18) and 173.5(6)°, respectively, do
not show substantial deviations from linearity. Moreover, the
carbon atoms of the μ-C≡C−Ar−C≡C units are not copla-
nar, with dihedral angle between the core benzene ring and
the two alkynyl groups of 24(7)°. The Au1···Au1a distance
is 12.040(3) Å. The Au–C(≡C) bond lengths are 2.010(6)
Å, which are in the range of 1.984(15)–2.013(5) Å [12, 15,
25]. Similarly, the Au-P bond distance being 2.2829(17) Å
is comparable to those found in known phosphine gold(I)
σ-acetylide complexes (2.2736–2.290 Å) [12, 15, 25]. The
C≡C bond lengths are typical of disubstituted carbon–carbon
triple bonds spanning the reported range of 1.157–1.206 Å
[12, 15, 25].
2a, 2b and 2c showed no activity on the tumor cell lines
tested, while 2,3-alkyl substituted complexes 2d, 2e and 2f
revealed good antitumor activity. Except for complex 2d,
the IC50 values of complexes 2e and 2f against HeLa cell
Table 1 In vitro antiproliferative activity of bimetallic alkynyl gold(I)
complexes against four cancer cell lines
Complex Antiproliferative activity (IC50a, µM)
Hela
HepG-2
PC12
A549
Cisplatin 3.16 0.36 9.80 0.28
3.01 2.91 1.12 0.12
2a
2b
2c
2d
2e
2f
>100
>100
>100
17.28 0.07 >100
1.74 0.04 >100
1.93 0.08 9.82 0.07
69.77 0.11 >100
7.25 0.03 62.62 0.08
>100
>100
>100
>100
>100
>100
>100
>100
>100
In vitro cytotoxicity
9.46 0.15 69.18 0.18
4.75 0.10 21.91 0.27
2.04 0.07 3.73 0.43
50.26 0.42 55.78 0.69
3.06 0.21 0.69 0.19
In vitro cytotoxicity of bimetallic gold(I) complexes 2a–j
was evaluated against four tumor cell lines (human ovar-
ian tumor cell line SKOV-3, human hepatoma carcinoma
HepG-2, rat pheochromocytoma PC12 cell line and human
lung tumor cell line A549) by using the classical MTT assay.
Cisplatin (CDDP) was used as the reference drug. The IC50
values of bimetallic gold(I) complexes 2a–j are listed in
Table 1.
2 g
2 h
2i
7.99 0.04 25.51
9.47 0.05 17.37 0.05
0.29 4.61 0.16 6.48 0.38
5.61 0.06 0.02 0.01
2j
aAntiproliferative activity was assayed by exposure of the cell lines
for 24 h to complexes 2a–1j and expressed as the concentration
required to inhibit tumor cell proliferation by 50% (IC50). Data are
presented as the mean values from three independent experiments
The in vitro antitumor activity of alkyl-functionalized
complexes indicated that 2,5-alkyl substituted complexes
Fig. 1 Molecular structure of compound 2c with displacement ellipsoids drawn at the 10% probability level for clarity; hydrogen atoms are omit-
ted for clarity
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Transition Metal Chemistry
Table 2 In vitro cytotoxicity (IC50 values in μM) of binuclear alkynyl
gold(I) complex 2j against three normal cell lines
lines are 1.74 0.04 and 1.93 0.08 µM, respectively, which
are about 1.8- and 1.6-fold higher than that of cisplatin
(3.16 0.36 µM). For alkyl-functionalized complexes, only
complex 2f showed good activity (9.82 0.28 µM) against
HepG-2, which is nearly to that of cisplatin (9.82 0.28 µM).
Most interestingly, complex 2f was found to display a broad
spectrum of antitumor activities.
Complex
Cytotoxicity (IC50a, µM)
HaCaT
CDDP (after 24 h) 28.44 4.26
2j (after 24 h) 3990 23.16
CDDP (after 48 h) 8.131 1.67
2j (after 48 h) 431 10.51 10,600 89.25 8670 15.36
MA-104
RAEC
17.67 1.73
33.24 2.36
2710 16.24 2710 9.56
6.695 0.58 33.89 11.07
For oligo(ethylene glycol)methylether-functionalized
series, complexes 2g–j exhibited lower activity than cis-
platin against Hela and HepG-2 cell lines. Aside from
complex 2g, complexes 2h–j showed good antiprolif-
erative activity against the PC12 cell line with IC50 val-
ues below 5.61 0.06 µM, in which the activity of com-
plex 2h (3.06 0.21 µM) is close to that of cisplatin
(3.01 2.91 µM). Remarkably, the complexes 2h–j exhib-
ited promising antiproliferative activity against the A549 cell
lines with the highest activity shown by complex 2j (IC50
0.02 0.01 µM), in which the level of activity was about 56
times higher than that of cisplatin (1.12 0.12 µM). This
may be due to the fact that the hydrophilicity of the complex
was improved after functionalization with oligo(ethylene
glycol)methylether [22]. It also rarely found that the alkynyl
(phosphine) digold(I) complex showed the high efciency
toward A549 cell line. It is also rare to fnd that the alkynyl
(phosphine) digold(I) complex showed excellent cytotoxicity
on the A549 cell line.
aCytotoxicity was assayed by exposure of the cell lines for 24 h or
48 h to complex 2j and expressed as the concentration required to
inhibit tumor cell proliferation by 50% (IC50). Data are presented as
the mean values from three independent experiments
2,3-positions), have been synthesized and characterized.
Their antitumor activities in vitro have been investigated
against four tumor cell lines and three normal cell lines.
The 2,3-alkyl substituted complexes 2e (1.74 0.04 µM)
and 2f (1.93 0.08 µM) against HeLa cell lines revealed
higher activity than cisplatin (3.16 0.36 µM). In addi-
tion, complex 2f was found to display a broad spectrum of
antitumor activities. The activity of 2,3-oligo(ethylene gly-
col)methylether substituted complex 2 h (3.06 0.21 µM)
against the PC12 cell line is close to that of cisplatin
(3.01 2.91 µM). It was also found that the level of activ-
ity of complex 2j (0.02 0.01 µM) against the A549
cell line was about 56 times higher than that of cisplatin
(1.12 0.12 µM). At the same time, the cytotoxicity of the
complex 2j toward three normal cell lines was much lower
than that of cisplatin. Complex 2j displayed high activ-
ity against the A549 cell line and low cytotoxicity toward
normal cells because of the improvement of the hydrophi-
licity of the complex to achieve the proper lipophilicity.
As indicated by this work, complex 2j compound exhibits
great potential in the application of antitumor agents.
For HeLa cell lines, only complexes 2e and 2f were more
active than cisplatin. Except for complex 2f, the activity of
other complexes against HepG-2 cell lines was lower than
that of cisplatin. The activity of complex 2f against PC12
cell lines was superior to that of cisplatin, and the activity
of complex 2h was up to that of cisplatin. In addition, the
activity of the corresponding complexes also increased with
the increase in the length of substituent chain, as shown in
Table 1, which is consistent with the reported literature [22].
In view of the strong activity of 2,3-position functional-
ized complex 2j toward A549 cell lines, the cytotoxicity of
the complex 2j against three normal cell lines in vitro was
investigated. The IC50 values of bimetallic gold(I) complex
2j are summarized in Table 2. These data indicated that
the cytotoxicity of the complex toward normal cell lines
was much lower than that of cisplatin. These studies sug-
gested that the alkynyl (phosphine) digold(I) complexes
showed low cytotoxicity against normal cell lines, which
may be a kind of promising lead for antitumor metallodrug
development.
Appendix
CCDC 1,019,402 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary Information The online version contains supplemen-
Conclusions
tary material available at https://doi.org/10.1007/s11243-021-00467-3.
Ten 1,4-disubstituted alkynyl (phosphine) digold com-
plexes, in which two groups were introduced into the
1,4-diethenylbenzene bridge at diferent positions (2,5- and
Acknowledgements The authors acknowledge financial sup-
port from Natural Science Foundation of Yunnan Province (No.
202001AT070068).
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Transition Metal Chemistry
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