Inorganica Chimica Acta 495 (2019) 118964

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Inorganica Chimica Acta

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Synthesis and characterisation of platinum(IV) polypyridyl complexes with T

halide axial ligands
Brondwyn S. McGhiea, Jennette Sakoffb, Jayne Gilbertb, Janice R. Aldrich-Wrighta,c,
⁎

a
School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith South DC, 2751 NSW, Australia
b
Calvary Mater Newcastle, Waratah, NSW 2298, Australia
c
School of Medicine, Western Sydney University, Locked Bag 1797, Penrith South DC, 2751 NSW, Australia

ARTICLE INFO ABSTRACT

Keywords: A series of complexes of the type [Pt(PL)(AL)(X)2]2+ (where PL = 1,10-phenanthroline, 5-methyl-1,10-phenan-

Platinum throline or 5,6-dimethyl-1,10-phenanthroline; AL = 1S,2S-diaminocyclohexane and, X = Cl, Br or I) with an-
N-halogensuccinimide ticancer potency, were synthesised in a one pot reaction using N-halogensuccinimide (NXS) as both the source of
Cell growth inhibition the ligand and the oxidizing reagent. It was determined that 2.4 equivalents of NXS resulted in 100% oxidation
SRCD
of Pt(II) in a solution of equal parts H2O, ethanol and 1 M HCl. This method of oxidation was 24 times faster than
the established peroxide method resulting in the acceleration of the complete synthesis of [Pt(PL)(AL)(X)2]2+. All
structures were confirmed using NMR, ESI-MS, CD and UV, while the purity was confirmed by microanalysis.
The in vitro cytotoxicity assays revealed that they were more active than analogous complexes with hydroxido
axial ligands, and share comparable activity with the corresponding Pt(II) complex.

1. Introduction predominantly cross resistant and operate via similar mechanisms of

Cancer causes the death of approximately 8 million people each
year and that number is predicted to rise by 70% over the next two
decades [1–3]. Unfortunately, current treatments for cancer patients
have low success rates for many cancer types, and especially late stage
cancers [3]. For example, brain cancer is treated with a combination of
surgery, radiotherapy, and chemotherapy and yet the five year survival
rate is just 22% [4,5]. One of the key factors influencing the lack of
success of these treatments is their low specificity for cancer cells which
can result in side effects, reduced dosages, and high incidence of re-
sistance [6–10]. As these issues take a significant toll on both patient
quality of life and the health care system, new treatment strategies are
needed.
The improvement of widely used conventional chemotherapy drugs,
including platinum based drugs such as cisplatin, oxaliplatin and car-
boplatin, has been explored to overcome resistance [3,11–14]. The
mechanism of action of cisplatin requires that the chloride ligands are
substituted with water, allowing the platinum to bind covalently to
DNA and form intra- and interstrand links [3,12,13]. This interaction
distorts the DNA, prevents transcription and, ultimately, leads to
apoptosis [15]. While this process is not specific to cancerous cells, the
rapid division of malignant cancers makes them more susceptible than
normally regulated cells [16]. Cisplatin, oxaliplatin and carboplatin are
action. As such, some cancer cells exhibit both acquired and intrinsic
resistance to all three commonly used compounds [17].
A more potent and cytotoxic platinum complex which can target
cancer cells more effectively to result in a better prognosis is required.
The approach used here to address this need has led to the development
of platinum complexes of the type [Pt(PL)(AL)]2+ which, based on their
unique conformation, may supersede conventional chemotherapy drugs.
Currently, the most cytotoxic [Pt(PL)(AL)]2+ complex developed is
[Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)]2+
(56MESS). The mechanism of 56MESS cytotoxicity is not fully under-
stood, however, these platinum complexes interact intracellularly and
with DNA in ways that are distinct from cisplatin, and can therefore
overcome resistance [18–21]. 56MESS is significantly more potent than
cisplatin in all cell lines tested, indicating the potential of these un-
conventional platinum complexes as viable cancer treatment options
[22]. Improved cytotoxicity reduces the dosage required, treatment time
and reduces the chance of acquired resistance.
Although the in vitro activity of these complexes is exceptional, in
vivo activity has been disappointing due to poor pharmacokinetics [18].
A potential solution that is currently being explored is oxidizing the
compound to platinum(IV) ([Pt(PL)(AL)(OH)2]2+) from the highly cy-
totoxic platinum(II) complexes ([Pt(PL)(AL)]2+) (Fig. 1) [23–25]. The
change in oxidation state allows for two additional axial ligands to be

⁎
Corresponding author at: School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith South DC, 2751 NSW, Australia.
E-mail address: J.Aldrich-Wright@westernsydney.edu.au (J.R. Aldrich-Wright).

https://doi.org/10.1016/j.ica.2019.118964
Received 1 May 2019; Received in revised form 10 June 2019; Accepted 12 June 2019
Available online 13 June 2019
0020-1693/ © 2019 Published by Elsevier B.V.
B.S. McGhie, et al.
Fig. 1. Cytotoxicity comparison of 56MESS, 56MESS(OH)2 with cisplatin, car-
boplatin, and oxaliplatin in multiple cell lines: HT29 colon, U87 glioblastoma,
MCF-7 breast, A2780 ovarian, H460 lung, A431 skin, Du145 prostate, BE2-C
neuroblastoma, SJ-G2 glioblastoma, MIA pancreas and murine glioblastoma
(SMA).
bound to the complex, enabling additional synthetic modifications to
fine tune the pharmacokinetics of the molecule without sacrificing its
cytotoxicity [26]. Once inside the cell, it has been suggested that the
complex will be reduced to the Pt(II) cytotoxic complex (Fig. 2) [27]. It
is necessary to identify and develop ligands which, when coordinated to
56MESS, increase its affinity to cancerous cells so that systemic cyto-
toxicity is reduced. Carboxylic acids [22] coordinate effectively in the
axial positions and are currently being used as a potential method of
attaching other compounds to the basic platinum(IV) ([Pt(PL)(AL)
(OH)2]2+) structure.
It has been hypothesized that replacing the hydroxido group with an
excellent leaving group like a halide, may have a positive effect on the
overall efficacy of the drug [28]. This hypothesis was supported by
evidence that the addition of halides to the axial ligands of cisplatin,
oxaliplatin, and carboplatin significantly influenced their cytotoxicity
[29,30]. Here, we investigated the influence of halide (X) coordination
Fig. 2. Extra- and intracellular reduction of Pt(IV), resulting in the loss of the axial ligands, producing a Pt(II) compound with DNA binding activity.
2
Inorganica Chimica Acta 495 (2019) 118964
Fig. 3. General structure of the synthesised compounds 1–9 where X = Cl, Br
or, I and R = H or CH3 and the stereo-centres (*) are S configuration.
in the axial positions of the platinum(IV) complex ([Pt(PL)(AL)(X)2]2+)
and assessed any relative improvement to their cytotoxicity. Nine
compounds were synthesised in order to evaluate the relative effects of
chlorido, bromido, and iodido as axial ligands when attached to the
platinum(IV) analogues of platinum(II) complexes [Pt(phen)
(SSDACH)]2+ (PHENSS), [Pt(5-methyl-phen)(SSDACH)]2+ (5MESS)
and 56MESS (Fig. 3).
2. Experimental
2.1. Materials and preparation
Reagents were used as received unless otherwise specified. All sol-
vents (supplied by Labserv, Chem-Supply or Merck Chemicals) used
were of analytical grade or higher. Potassium tetrachloroplatinate
(K2PtCl4) was purchased from Precious Metals Online. The chloride
salts of platinum(II) complexes were synthesised using previously
published methods [31]. N-chlorosuccinimide, N-bromosuccinimide, N-
iodosuccinimide and hydrochloric acid were purchased from Sigma-
Aldrich. Methanol was obtained from Honeywell. Deuterated solvents
d6-dimethylsulphoxide (DMSO-d6, 99.9%) and deuterium oxide (D2O,
99.9%) were purchased from Cambridge Isotope Laboratories.
B.S. McGhie, et al.
2.2. Synthesis
Synthesis of c,c,t-[Pt(1,10-phenanthroline)(1S,2S-diaminocyclo-
hexane)(X)2]2+, c,c,t-[Pt(5-methyl-1,10-phenanthroline)(1S,2S-diami-
nocyclohexane)(X)2]2+ and c,c,t-[Pt(5,6-dimethyl 1,10-phenanthro-
line)(1S,2S-diaminocyclohexane)(X)2]2+
[Pt(PL)(AL)](Cl)2 (80 μmol) was combined with N-halosuccinimide (2.4
equivalents) and dissolved in 9 mL of a 1:1:1 H2O, ethanol and 1 M HCl
solution. The mixture was stirred at room temperature (RT) for 2 h before
the volume was reduced under vacuum. A Sep-Pak (20 cc, 5 g) C-18
column connected to a pump apparatus with UV detector (Bio-Rad, EM-1
Econo™ UV Monitor) was used for initial purification. The column was
activated with methanol (10 mL) and then flushed with water (~30 mL)
until the UV absorbance equilibrated. The crude reaction was then loaded
onto the column and eluted with water at a flow rate of 2 mL min−1. A
single yellow coloured peak was detected and collected, and the resulting
fraction was lyophilised. The dry compound was then weighed and loaded
into a paper thimble. The thimble was placed in a soxhlet apparatus and
washed continually with ~200 mL of heated toluene (170 °C) for two
weeks, before being removed and allowed to dry. Any remaining impurities
in the product were removed using flash chromatography. The pure frac-
tions were combined and lyophilised to produce a pale yellow solid.
3. Biophysical characterisation
3.1. Flash chromatography
Samples were purified using the Reveleris X2 flash chromatography
system fitted with a Reveleris reverse phase C-18 4 g column. The column
was equilibrated with 3% MeOH for 2.4 min at 8 mL min−1, and the
samples eluted for 9 min with the UV detector sensitivity on high and
detecting at 230, 254 and 280 nm. Sample masses between 20 and 100 mg
were prepared in ~1–2 mL H2O and injected with a flow rate of
8 mL min−1. The column was eluted with 3% methanol for 6 min then the
methanol concentration was increased to 100% over 1 min, kept steady
for 1 min before returning to 3% over another minute. In each case, only
one peak was detected and this was collected in 10 mL fractions.
3.2. NMR
Spectral data were obtained using a 400 MHz Bruker Avance
Scheme 1. Reaction scheme for the formation of compounds 1–9. Where X is Br, Cl, or I. and where R1 and R2 are either H or CH3 to synthesise compounds 1–9 and
succinimide bound by-products.
3
Inorganica Chimica Acta 495 (2019) 118964
spectrometer at 298 K, using 10 mM samples prepared in D2O. 1H NMR
spectra were obtained using a spectral width of 8250 Hz and 65,536
data points, while 195Pt NMR spectra were acquired using a spectral
width of 85,470 Hz and 674 data points. 1H-195Pt HMQC spectra were
recorded using a spectral width of 214,436 Hz and 256 data points for
the 195Pt nucleus (F1 dimension) and a spectral width of 4808 Hz with
2048 data points for the 1H nucleus (F2 dimension). Chemical shifts are
reported in parts per million (ppm) with J coupling reported in Hz. Spin
multiplicity is reported as: s (singlet), d (doublet), dd (doublet of
doublet) and m (multiplet).
3.3. UV spectroscopy
UV spectra were recorded on a Cary 1E spectrophotometer at RT in
the 200–400 nm range, using a 10 mm quartz cell. All samples were
automatically corrected for solvent baseline. A stock solution (1 mM,
10 µL, 10 aliquots) was titrated into known volume of water and the
absorption measured after each addition to allow the extinction coef-
ficient to be calculated.
3.4. ESI-MS
Electrospray ionisation mass spectroscopy (ESI-MS) experiments,
were performed using a Waters TQ-MS triple quadrupole mass spec-
trometer in positive mode. Sample solutions (final concentration
0.5 mM in H2O) flowrate was 0.1 mL min−1. The desolvation tem-
perature of 300 °C, and desolvation flow rate (nitrogen) of 500 L h−1
remained constant whilst the cone voltage and capillary voltage were
varied for each sample. Spectra were collected over varied m/z ranges
depending on the target mass.
3.5. Circular dichroism (CD)
Circular dichroism spectra were obtained using a Jasco-810 spec-
tropolarimeter at RT. Spectra were obtained in a 10 mm quartz cell, and
measured from 200 to 400 nm with a data pitch of 1 nm, bandwidth of
1 nm and response time of 1 s. For each sample solution (~28 µM), 40
accumulations were collected and a water baseline was subtracted.
 B.S. McGhie, et al.

Table 1
Summary of NMR data of complexes 1–9 showing chemical shift (ppm) with integration, multiplicity and coupling constants. Experiments were performed in D2O, so amine resonances were not observed due to proton
exchange.

Label Complex No.

PHENSS(Cl)2 (1) PHENSS(Br)2 (2) PHENSS(I)2 (3) 5MESS(Cl)2 (4) 5MESS(Br)2 (5) 5MESS(I)2 (6) 56MESS(Cl)2 (7) 56MESS(Br)2 (8) 56MESS(I)2 (9

H4 9.07 (d, 2H: CH,k 9.03 (d, 2H: CH, 9.04 (d, 2H: CH, 8.90 (d, 1H: CH, 8.89 (d, 1H: CH, 8.91 (d, 1H: CH, 9.14 (d, 1H: CH, 9.13 (d, 1H: CH, 9.07 (d, 1H: CH,
J = 8.31 Hz) J = 8.17 Hz) J = 8.43 Hz) J = 8.28 Hz) J = 8.50 Hz) J = 8.44 Hz) J = 8.42 Hz) J = 8.65 Hz) J = 8.58 Hz)
H7 – – – 9.13 (d, 1H: CH, 9.11 (d, 1H: CH, 9.14 (d, 1H: CH, – – –
J = 8.37 Hz) J = 8.50 Hz) J = 8.72 Hz)
H3 8.27 (dd, 2H: CH, 8.26 (dd, 2H: CH, 8.27 (dd, 2H: CH, 8.20 (dd, 1H: CH, 8.17 (dd, 1H: CH, 8.20 (dd, 1H: CH, 8.24 (dd, 1H: CH, 8.21 (dd, 1H: CH, 8.20 (dd, 1H: CH,
J = 5.52, 8.35 Hz) J = 5.47, 8.17 Hz) J = 5.41, 8.22 Hz) J = 5.57, 8.32 Hz) J = 5.83, 7.85 Hz) J = 5.26, 8.21 Hz) J = 5.48, 8.56 Hz) J = 5.55, 8.55 Hz) J = 5.56, 8.56 Hz)
H8 – – – 8.29 (dd, 1H: CH, 8.25 (dd, 1H: CH, 8.29 (dd, 1H: CH, – – –

4
J = 5.57, 8.44 Hz) J = 5.60, 8.56 Hz) J = 2.44, 5.62 Hz)
H2 9.09 (d, 2H: CH, 9.07 (d, 2H: CH, 9.11 (d, 2H: CH, 9.01 (d, 1H: CH, 8.97 (d, 1H: CH, 9.00 (d, 1H: CH, 9.02 (d, 1H: CH, 8.99 (d, 1H: CH, 9.00 (d, 1H: CH,
J = 5.56 Hz) J = 5.56 Hz) J = 5.55 Hz) J = 5.32 Hz) J = 5.33 Hz) J = 5.58 Hz) J = 5.42 Hz) J = 5.43 Hz) J = 5.47 Hz)
H9 – – – 9.10 (d, 1H: CH, 9.05 (d, 1H: CH, 9.09 (d, 1H: CH, – – –
J = 5.49 Hz) J = 5.42 Hz) J = 5.58 Hz)
H5 8.33 (s,2H; CH) 8.33 (s,2H; CH) 8.31 (s,2H; CH) – – – – – –
H6 – – – 8.09 (s,1H; CH) 8.12 (s,1H; CH) 8.12 (s,1H; CH) – – –
CH3 – – – 2.85 (s, 3H; CH3) 2.89 (s, 3H; CH3) 2.86 (s, 3H; CH3) 2.77 (s, 6H; CH3) 2.79 (s, 6H; CH3) 2.67 (s, 6H; CH3)
H1′/2′ 3.35 (m, 2H; CH2) 3.39 (m, 2H; CH2) 3.35 (m, 2H; CH2) 3.35 (m, 2H; CH2) 3.33 (m, 2H; CH2) 3.34 (m, 2H; CH2) 3.33 (m, 2H; CH2) 3.35 (m, 2H; CH2) 3.30 (m, 2H; CH2)
H3′/6′ 2.35 (d, 2H; CH2, 3.34 (d, 2H; CH2 2.36 (d, 2H; CH2 2.36 (d, 2H; CH2 2.32 (d, 2H; CH2 2.36 (d, 2H; CH2 2.36 (d, 2H; CH2 2.33 (d, 2H; CH2 2.33 (d, 2H; CH2
J = 15.56 Hz) J = 11.00 Hz) J = 12.13 Hz) J = 12.09 Hz) J = 11.55 Hz) J = 12.05 Hz) J = 12.57 Hz) J = 11.53 Hz) J = 12.08 Hz)
H4′/5′ 1.72 (m, 2H; CH2) 1.69 (m, 4H; CH2) 1.73 (m, 2H; CH2) 1.72 (m, 2H; CH2) 1.67 (m, 4H; CH2) 1.72 (m, 2H; CH2) 1.72 (m, 2H; CH2) 1.67 (m, 4H; CH2) 1.62(m, 2H; CH2)
H3′/6′ 1.66 (d, 2H; CH2 – 1.66 (d, 2H; CH2 1.66 (d, 2H; CH2 – 1.66 (d, 2H; CH2 1.66 (d, 2H; CH2 – 1.69 (d, 2H; CH2
J = 10.92 Hz) J = 10.40 Hz) J = 10.90 Hz) J = 11.02 Hz) J = 10.71 Hz) J = 9.50 Hz)
H4′/5′ 1.30 (m, 2H; CH2) 1.30 (m, 2H; CH2) 1.30 (m, 2H; CH2) 1.30 (m, 2H; CH2) 1.29 (m, 2H; CH2) 1.30 (m, 2H; CH2) 1.30 (m, 2H; CH2) 1.30 (m, 2H; CH2) 1.26 (m, 2H; CH2)
1
H/195Pt 9.19/−645.8 9.12/−964.3 9.02/−635.2 9.1/−643.1 9.10/−649.7 9.17/−640.7 9.15/−653.5 9.1/−969
−648
9.09/
Yield %
30 21 16 53 20 9 35 46 11
Inorganica Chimica Acta 495 (2019) 118964
B.S. McGhie, et al. Inorganica Chimica Acta 495 (2019) 118964

3.6. Synchrotron radiation circular dichroism (SRCD)

282 (−0.12), 229 (−6.80), 185

Experiments were performed at the AU-CD beamline on ASTRID2

268 (3.85), 216 (−25.5), 183

279 (7.14), 226 (−20.2), 183

270 (3.19), 217 (−24.3), 181

255 (0.93), 215 (−3.60), 185

282 (2.19), 217 (−23.9), 304

290 (4.66), 255 (8.56), 214

[32,33] at ISA, Aarhus University. ASTRID2 operates in top-up mode

CD/λma (nm) (Θ) × 10−8

292 (6.10), 224 (−20.8)

209 (−6.29), 251 (1.63)

with a current of 120 mA. The AU-CD beam-line operates in the wa-
velength range of 125–450 nm, with a bandwidth of 0.6 nm. The beam
size on the sample is 2 (vert.) × 6 mm (horz.), with a sample to detector
distance of 25 mm. All SRCD experiments were performed using a su-
prasil quartz cuvette with a 100 μm path-length. The SRCD data was
processed using OriginPro8.5, and spectra were smoothed using 11

(−1.08)

(−1.04)

(−1.38)

(−0.45)

(−2.31)

(−1.18)

(−3.94)
point smoothing.

3.7. Elemental analysis

278 (579 ± 6.9), 208 (243 ± 3.3)

277 (308 ± 2.9), 207 (168 ± 1.1)

277 (376 ± 1.8), 208 (159 ± 0.7)

282 (165 ± 1.6), 228 (113 ± 1.3)

282 (336 ± 2.3), 209 (153 ± 1.3)

289 (238 ± 2.9), 211 (103 ± 1.5)

289 (226 ± 4.9), 210 (122 ± 1.5)

289 (281 ± 2.0), 211 (119 ± 1.3)

283 (188 ± 4.2), 210 (80 ± 2.4)
Microelemental analysis (C, H and N) was performed at the
Chemical Analysis Facility, Department of Chemistry and Biomolecular

(ε/mol−1.dm3.cm−1) × 102
Sciences, Macquarie University. An Elemental Analyser, Model PE2400
CHNS/O produced by PerkinElmer, USA, was used.

3.8. Assessing cytotoxicity

UV/λmax (nm)
Cytotoxicity assay studies were performed at Calvary Mater
Newcastle Hospital, Waratah, NSW Australia. In vitro studies were
performed according to described methods [34]. Complexes 1–9 were
prepared in DMSO as stock treatment (30 mM) solutions and stored at
−20 °C. All cell lines were cultured in a humidified atmosphere with
5% CO2 at 37 °C and maintained in Dulbecco’s modified eagle’s medium

(37.47)
(DMEM; Trace Biosciences, Australia) supplemented with 10% fetal

(3.39)

(3.72)

(4.27)

(3.57)

(3.57)

(4.61)

(3.70)

(4.51)
3.93

3.47

3.68

4.50

3.68

3.68

4.69

3.86

4.33
bovine serum, sodium bicarbonate (10 mM), penicillin (100 IU mL−1), H
Microanalysis Calc. (Found)

streptomycin (100 μg mL−1), and L-glutamine (4 mM). The non-cancer

MCF10A cell line was cultured in DMEM.F12 (1:1) cell culture media
(Composition in SI). Cytotoxicity was determined by plating cells in (33.36)

(28.85)

(32.76)

(31.94)

(26.83)

(26.83)

(32.71)

(30.26)

(32.53)
duplicate in 100 μL medium at a density of 2500–4000 cells per well in
33.40

28.59

32.17

31.81

26.53

26.53

32.84

30.63

32.55
96-well plates. After 24 h, when cells were in logarithmic growth,
C

media (100 μL) with or without the test agent was added to each well
(Day 0). After 72 h of exposure, growth inhibitory effects were eval-
uated by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium
(8.40)

(7.45)

(8.55)

(7.72)

(6.41)

(6.41)

(7.52)

(6.98)

(7.43)
8.40

7.41

8.53

7.81

6.51

6.51

7.66

7.14

7.91
bromide) assay, and absorbance was read at 540 nm. An eight-point
N

dose-response curve was produced, from which the drug concentration

at which cell growth is inhibited by 50% (GI50) was calculated. These
calculations were based on the difference between the optical density
ESI-MS (m/z) [M−Cl]+ Calc.

values on day 0 and those at the end of drug exposure.

4. Results and discussion

279.54 (280.03)

323.49 (323.35)

371.48 (372.10)

286.55 (285.54)

330.50 (332.99)

293.56 (294.07)

337.51 (337.07)

385.49 (385.89)
378.48(377.81)

4.1. Synthesis and characterisation

The initial method used to synthesise [Pt(1,10-phenanthroline)

(Found)

(1S,2S-diaminocyclohexane)Cl2]2+ was a modification of the procedure

Summary of the characterisation data of complexes 1–9.

described previously [35]. While successful, this method required the in

situ generation of the halide gas so that it could be passed through a Pt
(II) compound suspension. Safety concerns made the N-halogensucci-
Yield

30.4

21.2

16.3

52.9

19.9

9.16

34.7

45.9

10.9

nimide reaction preferable. In the presence of ethanol, N-halogen-

(%)

succinimides (NXS), produced halogen radicals that bound platinum

and oxidized it to Pt(IV). In this reaction, approximately half of the NXS
C18H22Br2N4Pt

C19H24Br2N4Pt

C20H26Br2N4Pt

reacted with ethanol to produce HX (where X is Br, Cl, or I) which then

C18H22Cl2N4Pt

C19H24Cl2N4Pt

C20H26Cl2N4Pt
C18H22I2N4Pt

C19H24I2N4Pt

C20H26I2N4Pt

reacted with the remaining NXS to produce halogen radicals. These

Molecular
Formula

radicals subsequently attacked the platinum(II), and oxidised it to Pt

(IV) to produce [Pt(1,10-phenanthroline)(1S,2S-diaminocyclohexane)
X2]2+ (Scheme 1). However, the introduction of the succinimide re-
sulted in side products where one of the axial ligands was succinimide
5MESS(I)2 (6)

bound through the nitrogen.

PHENSS(Br)2

56MESS(Br)2
PHENSS(Cl)2

56MESS(Cl)2
5MESS(Br)2
PHENSS(I)2

5MESS(Cl)2

56MESS(I)2

The presence of this side product was confirmed both by NMR and ESI-
Complex

MS. The side and intended products had the same solubility and could not
(1)

(2)

(3)

(4)

(5)

(7)

(8)

(9)
Table 2

be separated by filtration, precipitation or column chromatography. In

order to eliminate the formation of PHENSS(X)(succinimide), the method

5
B.S. McGhie, et al.
Fig. 4. The 1H–195Pt HMQC spectrum of PHENSS(Cl)2 (1) in D2O, displaying the correlations between the platinum centre and the protons from each ligand.
was modified with the addition of heat and acid. PHENSSXsuccinimide
was synthesised by refluxing 1 mol equ. of PHENSS with 2.4 mol equ. of
NXS in an ethanol and water solution (50:50, v:v) at 78 °C. NMR was used
to confirm purity (Supplementary Figs. A17) and, the mass was confirmed
by ESI-MS (Table 2). Interestingly, the addition of hydrochloric acid pu-
shed the reaction to favour the production of the dihalogen product.
Presumably, this was due to an interaction between the succinimide by-
product and the acid that prevented the coordination of the succinimide.
Application of this method resulted in the successful synthesis of com-
plexes 1–9 (Fig. 3, Spectra A1–16 in Supplementary data). NMR also re-
vealed the presence of unbound succinimide in high quantities. The pro-
ducts and the succinimide could not be separated by filtration,
precipitation or using a reverse phase C18 column. However, as free suc-
cinimide is slightly soluble in toluene the crude mixture was washed 5
times with toluene, reducing the amount of succinimide in the aqueous
layer. A soxhlet reflux was used for a minimum of two weeks to remove
the remaining succinimide, at which point the succinimide became un-
detectable. In some cases, the soxhlet reflux produced other small uni-
dentified impurities and these were removed using flash chromatography.
The soxhlet reflux and the flash chromatography contributed to product
loss generating a yield of 9–45%.
4.2. Biophysical characterisation
Each complex was characterised using a combination of NMR, CD
and, UV spectroscopy. The NMR spectra produced peaks consistent with
those seen in the literature for similar compounds with little to no
impurities detected (Supplementary Figs. A1–18) [7]. The CD spectra
confirmed that the chirality of the starting materials was retained
during synthesis (Supplementary Figs. C1–15). Additionally, the syn-
chrotron spectra revealed dramatic differences from similar, previously
published Pt(IV) complexes (Supplementary Figs. D1–21). UV spectra
was used to determine the extinction coefficient of each complex.
ESI-MS allowed the correct mass peak to be identified for each
sample, despite the appearance of some break down products. Table 1
shows a summary of the exact masses used and yields for compounds
1–9. Table 2 summarizes the ESI-MS, EA, extinction coefficient and
SRCD data. Break down products were also observed in the HPLC so this
technique was not used to characterise the complexes.
The NMR characterization of complex 1 was achieved using a
6
Inorganica Chimica Acta 495 (2019) 118964
combination of 1H proton NMR spectra and 1H-195Pt heteronuclear
multiple quantum correlation (HMQC) spectra (Figs. 4 and 5). The
HMQC 195Pt peak was significantly different to other polypyridyl pla-
tinum complexes [18]. Typically a Pt(IV) complex of the type [Pt(PL)
(AL)(OH)2]2+ will demonstrate a 195Pt resonance at 450 ppm, the
complexes synthesised in this work had a 195Pt resonance at ~ -
630 ppm (Supplementary Figs. A1, 3, 5, 7, 9, 11, 13, 15, 17). This in-
dicated that the halide axial ligands were present [18]. An example of
the HMQC spectra is shown in Fig. 4, the 195Pt chemical shift of
−645.8 ppm is significantly different to that of the two starting Pt
complexes, [Pt(SS-dach)Cl2] and K2PtCl4 (-3282 and −1650 ppm, re-
spectively). The correlation between the Pt centre and the aromatic
resonance (9.19 ppm) confirms the coordination of the 1,10-phenan-
throline.
The proton chemical shifts were almost identical to similar com-
plexes in the literature, with very minor chemical shifts occurring due
to stacking of the phen ligands in solution [36]. The aromatic region for
PHENSS(Cl)2 (1) was assigned using the following rationale (Fig. 4): the
singlet at 8.33 ppm was assigned to H5 and H6. The H5 and H6 protons
shared the peak location due to the symmetry of the complex and the
absence of protons on the adjacent carbons (Fig. 5). The doublet of
doublets (dd) at 8.27 ppm was assigned to H3 and H8 as the presence of
protons on the adjacent carbons resulted in a dd splitting pattern due to
coupling. The remaining two doublet (d) peaks in the aromatic region
were merged in the spectra. They could still be distinguished however,
due to the smaller coupling constant of H2 and H9 resulting from the
proximity of the nitrogen. The 9.03 ppm doublet J = 8.31 Hz was as-
signed to H4 and H7 and the doublet at 9.09 ppm, J = 5.56 Hz, was
assigned to H2 and H9. The resonances for the aliphatic region were
consistent with NMR spectra of the same ancillary ligands reported in
the literature [18]. The amine proton resonances were not visible due to
exchange with D2O.
The NMR characterization of complexes 2–9 was achieved using the
same rationale. There were some minor differences in the resonances
for these complexes, particularly in the aromatic region where the re-
lative concentration of each solution affected the stacking of the 1,10-
phenanthroline region and, thus, the resonance of the H2,9 and H4,7
peaks. The splitting in the aromatic region was significantly different in
complexes 4–6 due to the asymmetry of those complexes. The aliphatic
region for complexes 4–9 had an additional peak due to the presence of
B.S. McGhie, et al. Inorganica Chimica Acta 495 (2019) 118964

Fig. 5. The 1H NMR spectrum of PHENSS(Cl)2 (1) in D2O, showing proton assignment.

the methyl group on the 1,10-phenanthroline but again, the remaining
peaks were assigned using the rationale described above. The relative
195
Pt resonances of these complexes appear to be more dependent on
the halide ligand than the variations in the PL. For example, bromido
complexes tended to have a much lower ppm of ~-960 ppm while io-
dido complexes tended to have the highest 195Pt peak at ~-640 ppm.
The results of the NMR spectra are summarised in Table 1.
The UV absorption spectra of the nine complexes (minus a water
blank) varied significantly, and the axial ligands had a more pro-
nounced effect on this result than the polypyridyl ligands. Very little
difference is observable between the band shapes at ~290 nm for each
complex whereas for the bands below 250 nm the spectra were quite
distinct (Supplementary Figs. B1–15). At these wavelengths, the spectra
of complexes with chlorido or iodido axial ligands were similar to the
spectra of complexes with hydroxido axial ligands [6]. Complexes with
bromido axial ligands were easily distinguishable with characteristic
broad bands with a shoulder between 220 and 250 nm. The transitions
of the phen analogue at 280–290 nm shifted further (blue) as the
number of methyl groups increased (i.e. PHENSS(X)2 was the most
bathochromic (red) shifted, 5MESS(X)2 was hypsochromic (blue)
shifted and 56MESS(X)2 was the most hypsochromic shifted
(Supplementary Figs. B3). A similar trend was observed for the weak
bands > 300 nm. The 56MESS(X)2 compounds also displayed a
shoulder at approximately 240 nm which was not present in the 5MESS
(X)2 and PHENSS(X)2 spectra. However, this has also been observed
previously with other polypyridyl complexes. Extinction coefficients
were determined from seven data points; the averages and errors are
reported in Table 2 and the spectra are available in Supplementary Figs.
B9–15.
The benchtop CD spectra of all nine complexes was compared to
those of previously published PHENSS(OH)2 complexes [18]. The
spectra of dihydroxido complexes are close to flat until ~270 nm, at
which point there is a sharp drop off that continues for the remainder of
the spectrum (Supplementary Figs. C1–15). While the spectra of

Fig. 6. SRCD spectra of 7 (black), 8 (red) and, 9 (blue); at RT in the 170–400 nm range, using a 100 µm cell, corrected for solvent baseline. (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version of this article.)

7
B.S. McGhie, et al. Inorganica Chimica Acta 495 (2019) 118964

dihalido complexes had a similar sharp drop off, they appeared to reach

0.056 ± 0.0032
0.048 ± 0.0046
0.044 ± 0.0058
0.036 ± 0.0041
0.033 ± 0.0023
0.027 ± 0.0007
a minimum and start to rise before 200 nm. This suggested that further

ADDP Ovarian

0.23 ± 0.026
0.28 ± 0.017
0.25 ± 0.020
peaks would appear at shorter wavelengths. It was thus hypothesised
that unlike the dihydroxido complexes, the SRCD spectra of these di-

n = 3–4
halido species would show additional characteristic peaks < 200 nm.

nd
nd
nd
nd
nd
The SRCD spectra of complexes 1–3 reveal the similarity in po-

0.062 ± 0.0083
0.061 ± 0.0082
0.044 ± 0.0062
0.034 ± 0.0038
0.030 ± 0.0039
0.020 ± 0.005
0.030 ± 0.003
larised light absorption between 1 and 3; the primary difference was

0.094 ± 0.024
0.30 ± 0.0033
MCF10A Breast

0.36 ± 0.032
0.29 ± 0.032
the slightly more intense band at 216 nm for 1. The equivalent peak for
(Normal)

2 was red shifted, and appeared at 226 nm. The second peak at
n = 3–4

~180 nm was similar for the compounds 1–3, although 1 had a large

nd
nd
nd
shoulder at 212 nm (Supplementary Fig. D1–3). For complexes 4–6
0.044 ± 0.0045
0.037 ± 0.0046
0.032 ± 0.0022
0.028 ± 0.0021
0.024 ± 0.0026
0.022 ± 0.0022
0.015 ± 0.002
0.027 ± 0.002
(Supplementary Fig. D4–6), the intensity of the (wavelength) band in-
0.21 ± 0.029
0.25 ± 0.010
0.20 ± 0.013
MIA Pancreas

creased as the size of the ligand increased and as the electronegativity

7.5 ± 1.3
0.9 ± 0.2
decreased; complex 6 had the most intense band followed by 5, and
n = 3–4

> 50
then 4. It can be hypothesised that either the size of the ligand or the
electronegativity of the halide affect the conformation of the complex
such that CD signal is altered. The spectra of 6 had the most intense
0.092 ± 0.039
0.074 ± 0.033
0.067 ± 0.028
0.074 ± 0.018
0.11 ± 0.009
0.34 ± 0.063
0.42 ± 0.071
0.31 ± 0.031
0.18 ± 0.034
0.16 ± 0.044
0.16 ± 0.040
Glioblastoma

absorption band as well as the sharpest, indicating that the iodido li-
0.4 ± 0.1
3.0 ± 1.2
5.7 ± 0.2
n = 3–4

gands had a stronger effect on the structure than the other two ligands.
SJ-G2

Differences in SRCD spectra were also observed for complexes 7–9

(Fig. 6 and Supplementary Fig. D1–3). The negative absorption band at
0.37 ± 0.00000

0.20 ± 0.00000
0.12 ± 0.00000

225 nm for 8 was much more intense than the blue shifted bands of 7
0.087 ± 0.063
0.10 ± 0.016
0.32 ± 0.061
Neuroblastoma

0.44 ± 0.050
0.52 ± 0.025

0.25 ± 0.060
0.20 ± 0.010

0.34 ± 0.18

and 9. Complex 7 appears to have two peaks more than that of 8 with
18.7 ± 1.2
1.9 ± 0.2
0.9 ± 0.2
n = 3–4

additional peaks at 184 and 302 nm. The opposite is true of 9 with only
BE2-C

one true peak which is blue shifted compared to the equivalent peaks of
the bromido and chlorido complexes. This indicated that, overall, this
0.023 ± 0.0030
0.025 ± 0.0053
0.027 ± 0.0027
0.012 ± 0.0017
0.011 ± 0.0031

0.007 ± 0.002
0.009 ± 0.003

compound absorbed equivalent amounts of left and right polarised

0.11 ± 0.0033

0.025 ± 0.017
Du145 Prostate

0.11 ± 0.033
0.18 ± 0.010

light. As noted earlier, the intensity of the peaks for complexes 7–9 did
14.7 ± 1.2
1.2 ± 0.1
2.9 ± 0.4
n = 3–4

not follow a trend that correlated to either size or electronegativity and,

thus, more complex factors are at play.
When the SRCD spectra of chlorido complexes 1, 4 and 7 were
0.037 ± 0.0054
0.051 ± 0.021

compared, 1 and 7 were quite similar in terms of their intensity,

0.10 ± 0.0123
0.062 ± 0.013
0.061 ± 0.011

0.10 ± 0.015
0.44 ± 0.045
0.68 ± 0.023
0.44 ± 0.021
0.13 ± 0.028
0.11 ± 0.015

whereas 4 had featureless-flat spectra (Supplementary Fig. D8). As

24.3 ± 2.2
2.4 ± 0.3
4.1 ± 0.5
A431 Skin
n = 3–4

mentioned previously, these spectral differences were most likely due

to the asymmetry of 5MESS. Although the spectra for 7 and 1 are very
similar, the bands between 275 and 325 nm form negative and positive
0.070 ± 0.0091
0.065 ± 0.0061

0.032 ± 0.0020
0.027 ± 0.0032
0.037 ± 0.009
0.053 ± 0.010

maxima, respectively. The remaining peaks of 7 were red shifted

0.089 ± 0.018

0.048 ± 0.012
0.33 ± 0.0088
0.36 ± 0.029
0.32 ± 0.031
Summary of cytotoxicity results in GI50 = Concentration (µM) that inhibits cell growth by 50%.

compared to the peaks of 1 (Supplementary Fig. D8 & D9). Interest-

H460 Lung

0.9 ± 0.2
1.6 ± 0.1
14 ± 1.0
n = 3–4

ingly, the Cl2 complexes had the least similar SRCD spectra, which was
unexpected as the chlorido ligand is the smallest halogen assessed here
(Supplementary Fig. C4). The spectra of bromido complexes had 2–3
0.037 ± 0.0067

0.030 ± 0.004
0.063 ± 0.016

visible peaks; the peaks of 8 were the most red-shifted followed by 5

0.044 ± 0.012
0.046 ± 0.010

0.035 ± 0.013
0.032 ± 0.017
0.23 ± 0.0058
A2780 Ovarian

0.27 ± 0.023
0.24 ± 0.059
0.25 ± 0.18

and, lastly, 2 (Supplementary Fig. C5). The iodide complexes, 3, 6 and

0.16 ± 0.0
1.0 ± 0.1

9.2 ± 2.9
n = 3–4

9, had the most similar spectra of any of the halogen complexes

(Supplementary Fig. C6). In the instance of the 56MESS(X)2 complex,
unlike the spectra of the dibromido and dichlorido complexes, the
0.033 ± 0.0068
0.050 ± 0.020

diiodido spectra was almost featureless.

0.087 ± 0.032
0.091 ± 0.026
0.060 ± 0.010

0.14 ± 0.000
0.46 ± 0.069

0.11 ± 0.056
MCF-7 Breast

0.53 ± 0.10
0.46 ± 0.10
0.22 ± 0.13

6.5 ± 0.8
0.5 ± 0.1
n = 3–4

4.3. Cytotoxicity
> 50

The complexes 7–9, together with Pt(II) and Pt(IV) dihydroxido

U87 Glioblastoma

0.076 ± 0.014

analogues (56MeSS and 56MESS(OH)2), cisplatin, carboplatin and ox-

0.090 ± 0.012
0.074 ± 0.014

0.14 ± 0.023
0.82 ± 0.090
0.70 ± 0.055
0.23 ± 0.033
0.20 ± 0.029
0.22 ± 0.030
0.12 ± 0.018
0.81 ± 0.15

aliplatin, were screened against 10 human cancer cell lines re-

3.8 ± 1.1
1.8 ± 0.2
n = 3–4

presentative of colon (HT29), glioblastoma (U87 and SJ-G2), breast

> 50

(MCF-7), ovarian (A2780), lung (H460), skin (A431), prostate (Du145),

neuroblastoma (BE2-C), pancreas (MIA) along with normal breast
0.032 ± 0.0036
0.035 ± 0.0058
0.032 ± 0.0035
0.025 ± 0.0020
0.021 ± 0.0023
0.019 ± 0.0032

(MCF10A) and cisplatin resistant ovarian (ADDP) cells. Cytotoxicity

0.076 ± 0.061
0.022 ± 0.004
0.10 ± 0.0033
0.11 ± 0.028
0.16 ± 0.015

was evaluated by means of the MTT test after 72 h of treatment. The

HT29 Colon

11.3 ± 1.9
0.9 ± 0.2

results, expressed as GI50 values calculated from dose-survival curves,

n = 3–4

> 50

are reported in Table 3.

Complexes 1–9 have sub-micromolar GI50 values against all 10 cell
lines making them significantly more potent than cisplatin, carboplatin
PHENSS(Br)2 (2)

56MESS(Br)2 (8)
PHENSS(Cl)2 (1)

56MESS(Cl)2 (7)
5MESS(Br)2 (5)
PHENSS(I)2 (3)
5MESS(Cl)2 (4)

56MESS(I)2 (9)

56MESS(OH)2
5MESS(I)2 (6)

and oxaliplatin. The average GI50 of 1–9 in the ten cancer cell lines was
Carboplatin
Oxaliplatin

0.35, 0.42, 0.33, 0.14, 0.10, 0.10, 0.06, 0.08, 0.04 μM, respectively
Cisplatin
Complex

56MESS
Table 3

compared to 56MESS (0.05 μM) and 56MESS(OH)2 (0.10 μM). Notably,

the average GI50 value for 9 was 87, 40 and 348 fold more potent than

8
B.S. McGhie, et al. Inorganica Chimica Acta 495 (2019) 118964

Table 4 cisplatin (3.69 μM) carboplatin (1.68 μM) and oxaliplatin (14.43 μM) in
Average of GI50 values (Concentration µM) and fold potency against cisplatin, the human cancer cell lines (Table 4), they are also more active than
carboplatin and oxaliplatin. 56MESS or 56MESS(OH)2. While all the complexes are very potent, the
Complex Average* GI50 Cisplatin average GI50 values of 56MeSS(X)2 complexes 7–9 are ordered Br >
values (µM) Cl > I. This same ranking is also evident for PhenSS(X)2 while for
Carboplatin Oxaliplatin 5MESS(X)2 the order is Cl > Br = I.
Changes in both the polyaromatic and axial ligands affected the
PHENSS(Cl)2 (1) 0.35 11 5 41 cytotoxicity of these complexes. When compared based on polyaro-
PHENSS(Br)2 (2) 0.42 9 4 34 matic ligand, cytotoxicity increased with methylation, such that
PHENSS(I)2 (3) 0.33 11 5 44
PHENSS < 5MESS < 56MESS. However, there are some exceptions to
5MESS(Cl)2 (4) 0.14 25 12 100
this overall trend expressed in individual cell lines; for example,
5MESS(Br)2 (5) 0.10 38 17 149
5MESS(I)2 (6) 0.10 38 17 148 amongst the chloride coordinated complexes against the ovarian
56MESS(Cl)2 (7) 0.06 61 28 239 (A2780) cell line, 56MESS (0.037 ± 0.0067 µM) was the most cyto-
56MESS(Br)2 (8) 0.08 46 21 181 toxic, followed by PHENSS (0.23 ± 0.0058 µM) and 5MESS
56MESS(I)2 (9) 0.04 87 40 341 (0.25 ± 0.18 µM). While for [Pt(PL)(AL)(Br)2]2+ complexes, the trend
56MESS 0.05 72 32 280 against breast (MCF-7) cell lines from least to most cytotoxic was
56MESS(OH)2 0.10 38 17 147 PHENSS > 56MESS > 5MESS. There was no deviation from the gen-
Cisplatin 3.69 1 0.5 4 eral trend for the [Pt(PL)(AL)(I)2]2+ complexes as changing the axial
Carboplatin 1.68 2 1 9 ligand appeared to have less effect on the relative cytotoxicity.
Oxaliplatin 14.43 0.3 0.1 1
As complexes 7–9 were the most potent, their cytotoxicity was
*Average of HT29, U87, MCF-7, A2780, H460, A431, Du145, BE2-C, SJ-G2,
compared with that of 56MESS and 56MESS(OH)2, (Fig. 7A–I) against
MIA cell lines. the various cell lines. Against colon (HT29) cells 56MESS was the least
cytotoxic while the GI50 values for 7–9 and 56MESS(OH)2 were

Fig. 7. GI50 values of 7, 8, 9, 56MESS, and 56MESS(OH)2 in multiple cell lines: HT29 colon, U87 and SJ-G2 glioblastoma, H460 lung, A431 skin, BE2-C
neuroblastoma, MIA pancreas, Du145 prostate, A2780 ovarian, MCF-7 breast and MCF10A breast (normal).

9
B.S. McGhie, et al.
comparable (Fig. 7A). In the U87 glioblastoma cell line the GI50 values
of 56MESS(I)2 (0.074 ± 0.014 µM) and 56MESS (0.076 ± 0.014 µM)
were comparable and significantly lower than 56MESS(Cl)2
(0.12 ± 0.018 µM) and 56MESS(OH)2 (0.14 ± 0.023 µM), demon-
strating the contribution of the axial halides. This contribution is also
evident in the SJ-G2 glioblastoma cell line as 56MESS(I)2
(0.067 ± 0.028 µM) was the most cytotoxic of all complexes (Fig. 7B).
The impact of axial halides was also evident against lung (H460), skin
(A431) and neuroblastoma (BE2-C) (Figs. C, D and E) cell lines where
56MESS(I)2 was more potent than 56MESS. This suggests that despite
the theory that 56MESS(I)2 would have reduced to 56MESS within the
cell; the dissociated axial ligand and or the reduction potential must in
some way be contributing to the observed potency. Prostate and
ovarian cancer cell lines were instances where 56MESS(I)2 was not the
most potent complex.
We evaluated the cytotoxic activity of 7–9, 56MESS and 56MESS
(OH)2 against non-tumor human breast MCF10A and cancerous breast
MCF-7 cells (Fig. 7H). Although 9 (0.033 ± 0.0068 µM) was more
cytotoxic than 56MESS (0.050 ± 0.020 µM), the selectivity index
(SI = ratio between average GI50 of non-tumor cells and GI50 of ma-
lignant cells) of 9 (1.1) is lower than that of 56MESS (2.5) or 56MESS
(OH)2 (7.0). This suggested that while the cytotoxicity of 9 was pro-
mising, additional modifications to improve selectivity would maximise
the potential of these complexes.
Overall when examined based on polyaromatic ligand, there was no
identifiable general cytotoxicity trend for the response of individual cell
lines to the complexes 1–3. However, against all cell lines, cytotoxicity
increased based on axial halide Br > Cl > I (Supplementary Fig. E7).
Both ovarian cell lines were the exception to this trend and while the
bromido. The group with the most varied trends was that of complexes
4–6; against Du145 prostate cell line, these complexes were ranked
I > Cl > Br and this ranking was reversed when assessed against
colon (HT29) cells (Br > Cl > I) (Table 3). Against ovarian (A2780),
breast (MCF-7), and neuroblastoma (BE2-C) cell lines, the chlorido
complexes were the most cytotoxic and the bromido, the least (Br >
I > Cl) (Table 3). All data and further figures are provided in the
Supplementary Information.
5. Conclusion
Nine novel Pt(IV) polyaromatic complexes were synthesised and
characterised, using techniques that produced Pt(IV) complexes using
efficient and rapid symmetrical oxidation. The cytotoxicity of these
compounds was determined against several cell lines and their potency
was significantly improved compared to conventional anticancer
agents. In most cell lines, the cytotoxicity of the compounds described
here was also better than previously synthesised Pt(IV) polypyridyl
complexes. Additionally, not only are these complexes potential che-
motherapeutic options themselves, they also offer access to new syn-
thetic pathways as [Pt(AL)(PL)(X)2]2+ can be used as intermediates to
create targeted Pt(IV) species. The influence of the difference in redox
potential between these and other Pt(IV) complexes must also be ex-
plored. The novel and unknown mechanism and efficacy of these
compounds warrants further investigation against cancers that are
difficult to treat and have been associated with increased tumor-
igenicity and poor prognosis, like KRAS mutated cell lines. The tech-
niques and compounds described in this work will continue to add to
the tools at our disposal for effective and inventive cancer treatment.
Acknowledgements
We thank Western Sydney University for providing financial support
through internal research grants. Collection of SRCD data was possible
through granting of beam time from the ISA, Department of Physics &
Astronomy, Aarhus University and an International Synchrotron Access
Program from the Australian synchrotron, AS/IA182/14195. The
10
Inorganica Chimica Acta 495 (2019) 118964
authors also wish to thank Dr Benjamin Pages, Dr Elisé Wright and Mr
Dale Ang for constructive editorial suggestions.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.ica.2019.118964.
References
[1] B.W. Stewart, C.P. Wild, World Cancer Report 2014, in: B.W. Stewart, C.P. Wild
(Eds.), World Cancer Report, World Health Organisation: Lyon Cedex, France, 2014,
pp. 77–619.
[2] F. Bray, et al., Global cancer transitions according to the Human Development Index
(2008–2030): a population-based study, Lancet Oncol. 13 (8) (2012) 790–801.
[3] N.J. Wheate, et al., The status of platinum anticancer drugs in the clinic and in
clinical trials, Dalton Trans. 39 (35) (2010) 8113–8127.
[4] F. Sitas, et al., Cancer incidence and mortality in people aged less than 75 years:
changes in Australia over the period 1987–2007, Cancer Epidemiol. 37 (6) (2013)
780–787.
[5] E.E. Calle, et al., Overweight, obesity, and mortality from cancer in a prospectively
studied cohort of US adults, New England J. Med. 348 (17) (2003) 1625–1638.
[6] Z.H. Siddik, Cisplatin: mode of cytotoxic action and molecular basis of resistance,
Oncogene 22 (47) (2003) 7265–7269.
[7] T.W. Hambley, The influence of structure on the activity and toxicity of Pt anti-
cancer drugs, Coord. Chem. Rev. 166 (1997) 181–223.
[8] M. Kartalou, J.M. Essigmann, Mechanisms of resistance to cisplatin, Mutation Res./
Fundamental Mole. Mech. Mutagen. 478 (1–2) (2001) 23–43.
[9] A. Shikanov, et al., Poly (sebacic acid-co-ricinoleic acid) biodegradable carrier for
paclitaxel: In vitro release and in vivo toxicity, J. Biomed. Mater. Res. Part A 69 (1)
(2004) 47–54.
[10] N.J. Wheate, et al., Novel platinum (II)-based anticancer complexes and molecular
hosts as their drug delivery vehicles, Dalton Trans. 43 (2007) 5055–5064.
[11] M. Pavelka, M.F.A. Lucas, N. Russo, On the hydrolysis mechanism of the second-
generation anticancer drug carboplatin, Chem.-A Eur. J. 13 (36) (2007)
10108–10116.
[12] L. Kelland, The resurgence of platinum-based cancer chemotherapy, Nat. Rev.
Cancer 7 (8) (2007) 573–584.
[13] M. Treskes, W.J. van der Vijgh, WR2721 as a modulator of cisplatin-and carbo-
platin-induced side effects in comparison with other chemoprotective agents: a
molecular approach, Cancer Chemother. Pharmacol. 33 (2) (1993) 93–106.
[14] E. Wong, C.M. Giandomenico, Current status of platinum-based antitumor drugs,
Chem. Rev. 99 (9) (1999) 2451–2466.
[15] S. Dasari, P.B. Tchounwou, Cisplatin in cancer therapy: molecular mechanisms of
action, Eur. J. Pharmacol. 740 (2014) 364–378.
[16] M.A. Fuertes, et al., Cisplatin biochemical mechanism of action: from cytotoxicity to
induction of cell death through interconnections between apoptotic and necrotic
pathways, Curr. Med. Chem. 10 (3) (2003) 257–266.
[17] M. Kartalou, J.M. Essigmann, Recognition of cisplatin adducts by cellular proteins,
Mutat. Res-Fund. Mol. M. 478 (1) (2001) 1–21.
[18] F.J. Macias, et al., Synthesis and analysis of the structure, diffusion and cytotoxicity
of heterocyclic Platinum(IV) complexes, Chem. Eur. J. 21 (47) (2015)
16990–17001.
[19] B.J. Pages, K.B. Garbutcheon-Singh, J.R. Aldrich-Wright, Platinum intercalators of
DNA as anticancer agents, Eur. J. Inorg. Chem. 2017 (12) (2017) 1613–1624.
[20] V.V. Kostjukov, et al., Calculation of the electrostatic charges and energies for in-
tercalation of aromatic drug molecules with DNA, Int. J. Quantum Chem. 111 (3)
(2011) 711–721.
[21] S. Wang, et al., Identification of the molecular mechanisms underlying the cytotoxic
action of a potent platinum metallointercalator, J. Chem. Biol. 5 (2) (2012) 51–61.
[22] K.B. Garbutcheon-Singh, et al., Cytotoxic platinum(ii) intercalators that incorporate
1R,2R-diaminocyclopentane, Dalton Trans. 42 (4) (2013) 918–926.
[23] M.D. Hall, T.W. Hambley, Platinum(IV) antitumour compounds: their bioinorganic
chemistry, Coord. Chem. Rev. 232 (1–2) (2002) 49–67.
[24] F.J. Macias, et al., Synthesis and analysis of the structure, diffusion and cytotoxicity
of heterocyclic platinum(IV) complexes, Chem. – A Eur. J. 21 (47) (2015)
16990–17001.
[25] B.W.J. Harper, et al., Synthesis, characterization and in vitro and in vivo anticancer
activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthro-
line)], Dalton Trans. 46 (21) (2017) 7005–7019.
[26] E. Wexselblatt, D. Gibson, What do we know about the reduction of Pt(IV) pro-
drugs? J. Inorg. Biochem. 117 (2012) 220–229.
[27] Y.-R. Zheng, et al., Pt(IV) prodrugs designed to bind non-covalently to human serum
albumin for drug delivery, J. Am. Chem. Soc. 136 (24) (2014) 8790–8798.
[28] M.D. Hall, et al., Basis for design and development of platinum(IV) anticancer
complexes, J. Med. Chem. 50 (15) (2007) 3403–3411.
[29] Z. Xu, et al., Halogenated PtIV complexes from N-halosuccinimide oxidation of PtII
antitumor drugs: synthesis, mechanistic investigation, and cytotoxicity, Eur. J.
Inorg. Chem. 2017 (12) (2017) 1706–1712.
[30] B. McGhie, N-halogen succinimides: alternative oxidants of platinum anticancer
agents, Aust. J. Chem. 71 (5) (2018) 397–398.
[31] N.J. Wheate, et al., Novel platinum(ii)-based anticancer complexes and molecular
hosts as their drug delivery vehicles, Dalton Trans. 43 (2007) 5055–5064.
B.S. McGhie, et al.
[32] A.J. Miles, et al., Light flux density threshold at which protein denaturation is in-
duced by synchrotron radiation circular dichroism beamlines, J. Synchrotr. Radiat.
15 (4) (2008) 420–422.
[33] A.J. Miles, et al., Synchrotron radiation circular dichroism (SRCD) spectroscopy:
new beamlines and new applications in biology, J. Spectr. 21 (5–6) (2007)
245–255.
[34] M. Tarleton, et al., Library synthesis and cytotoxicity of a family of 2-
11
Inorganica Chimica Acta 495 (2019) 118964
phenylacrylonitriles and discovery of an estrogen dependent breast cancer lead
compound, Med. Chem. Comm. 2 (1) (2011) 31–37.
[35] A. Syamal, R.C. Johnson, Solvent effects in platinum(II)-catalyzed substitution re-
actions of platinum(IV) complexes, Inorg. Chem. 9 (2) (1970) 265–268.
[36] A.M. Krause-Heuer, et al., Diffusion-based studies on the self-stacking and nanorod
formation of platinum(ii) intercalators, Chem. Commun. 10 (2009) 1210–1212.