Synthesis and characterization of iminophosphineplatinum(II) complexes of the type (κ2-P,N-2-Ph2PC6H4C(H)=NC6H4X)PtCl2 (X?=?OMe, F)

Article abstract of DOI:10.1007/s11243-017-0176-2

A series of iminophosphineplatinum(II) complexes have been prepared from pro-ligands derived from aniline derivatives containing electron-donating methoxy groups or electron-withdrawing fluorides and [PtCl₂(η²???coe)]₂ (coe?=?cis-cyclooctene). All new pro-ligands and metal complexes have been fully characterized, including an X-ray diffraction study for compound 11 (derived from para-methoxyaniline). Additionally, the molecular structure of a di-iminophosphineplatinum dication 11a has been determined. The platinum compounds showed no appreciable cytotoxic properties against two glioma cell lines using the MTT method.

Full text of DOI:10.1007/s11243-017-0176-2

Transit Met Chem
DOI 10.1007/s11243-017-0176-2
Synthesis and characterization of iminophosphineplatinum(II)
complexes of the type (j2-P,N-2-Ph2PC6H4C(H)=NC6H4X)PtCl2
(X 5 OMe, F)
Patrick-Denis St-Coeur1 Meghan E. Adams2 Bryanna J. Kenny2
•
•
•
Darcie L. Stack3 Christopher M. Vogels2 Jason D. Masuda3 Pier Jr. Morin1
Stephen A. Westcott2
•
•
•
•
Received: 27 July 2017 / Accepted: 30 August 2017
Ó Springer International Publishing AG 2017
Abstract A series of iminophosphineplatinum(II) com-
plexes have been prepared from pro-ligands derived from
aniline derivatives containing electron-donating methoxy
groups or electron-withdrawing fluorides and [PtCl2
(g2 - coe)]2 (coe = cis-cyclooctene). All new pro-ligands
and metal complexes have been fully characterized,
including an X-ray diffraction study for compound 11
(derived from para-methoxyaniline). Additionally, the
molecular structure of a di-iminophosphineplatinum dica-
tion 11a has been determined. The platinum compounds
showed no appreciable cytotoxic properties against two
glioma cell lines using the MTT method.
substituted with an N-heterocyclic base of DNA such as
guanine or purine. The cytotoxic mode of action of cis-
platin results from these interactions with DNA, especially
intrastrand crosslink adducts, which activate signal trans-
duction pathways such as those involving ATR, p53, p73
and MAPK, whereupon the end result is activation of
apoptosis [8, 9]. Serious problems such as cisplatin resis-
tance and side effects arising from cisplatin’s poor solu-
bility in physiological media and lack of selectivity for
cancer cells have limited its therapeutic use as an anti-
cancer agent. As such, much research has focused on
designing and testing the second- and third-generation
platinum complexes by varying either the inert amine
groups of the labile chloride ligands. Notable examples of
such derivatives include carboplatin and cis-[PtCl2(1,4-
DACH)] (DACH = diaminocyclohexane). Picoplatin is a
promising candidate for the treatment of a variety of solid
tumours and is unique in that it demonstrates that platinum
complexes do not need to contain primary amine groups to
have antineoplastic activities [10–13]. Indeed, we [14] and
others [15, 16] have shown that complexes containing
iminophosphine ligands are also potential candidates for
metal-based anticancer therapy. Iminophosphines are a
remarkable family of pro-ligands, whereby varying the
organic group of the imine appendage allows for fine-
tuning of the physicochemical properties of the corre-
sponding platinum complexes. As part of our ongoing
research in this area, we have prepared a series of platinum
complexes containing iminophosphine ligands and exam-
ined their initial cytotoxic properties against two glioma
cell lines using the MTT method, the results of which are
presented herein.
Introduction
The discovery that cis-diamminedichloroplatinum(II) (cis-
platin, or cis-DDP) inhibits cellular division in Escherichia
coli spawned an enormous amount of research into the
design and testing of platinum complexes for their potential
ability to treat various cancers [1–7]. The mechanism of
action of cisplatin is believed to result from the initial loss
of the chloride ligands which are readily replaced by a
molecule of water to give either cis-[(H3N)2PtCl(OH2)]? or
cis-[(H3N)2Pt(OH2)2]2?. The aqua ligands can readily be
& Stephen A. Westcott
swestcott@mta.ca
1
´
Departement de chimie et biochimie, Universite de Moncton,
Campus de Moncton, Moncton, NB E1A 3E9, Canada
´
2
3
Department of Chemistry and Biochemistry, Mount Allison
University, Sackville, NB E4L 1G8, Canada
Department of Chemistry, Saint Mary’s University, Halifax,
NS B3H 3C3, Canada
123

Transit Met Chem
(ddd, JHH = 8.2, JHP = 2.7, JHH = 0.9 Hz, 1H, Ar), 6.50
(dd, JHH = 7.8, 0.9 Hz, 1H, Ar), 6.43 (ov dd, JHP = 2.3,
JHH = 1.8 Hz, 1H, Ar), 3.73 (s, 3H, OCH3). 13C{1H}
NMR (CDCl3) d: 160.2, 159.1 (d, JCP = 21.0 Hz), 153.1,
139.1 (d, JCP = 16.2 Hz), 138.7 (d, JCP = 20.0 Hz), 136.5
(d, JCP = 9.5 Hz), 134.3, 134.1, 133.6, 131.0, 129.8, 129.0,
128.8 (d, JCP = 6.7 Hz), 128.3 (d, JCP = 3.8 Hz), 113.0,
112.3, 106.4, 55.4. 31P{1H} NMR (CDCl3) d: -12.4. IR:
3060 (w), 1619 (s, mCN), 1577 (m), 1462 (m), 1434 (m),
1263 (m), 1144 (m), 1035 (m), 744 (m).
Experimental section
Materials and methods
Reagents and solvents used were obtained from Aldrich
Chemicals. [PtCl2(g2-coe)]2 (coe = cis-cyclooctene) [17],
N-(2-(diphenylphosphino)benzylidene)aniline (1) [18], (E)-
N-(2-(diphenylphosphino)benzylidene)-2-methoxyaniline
(2) [19], (E)-N-(2-(diphenylphosphino)benzylidene)-4-
methoxyaniline
(4)
[20],
(E)-N-(2-(diphenylphos-
phino)benzylidene)-4-fluoroaniline (7) [21] and complex 8
[14] have been synthesized previously, and any additional
data have been added below. NMR spectra were recorded
on a JEOL JNM-GSX400 FT NMR (1H: 400 MHz; 13C:
100 MHz; 19F: 376 MHz; 31P: 162 MHz) spectrometer.
Chemical shifts (d) are reported in ppm [relative to residual
solvent peaks (1H and 13C) and external CF3CO2H (19F) or
H3PO4 (31P)]. Multiplicities are reported as singlet (s),
doublet (d), triplet (t), multiplet (m) and overlapping (ov)
with coupling constants (J) reported in Hz. Melting points
were measured uncorrected with a Stuart SMP30 appara-
tus. FTIR spectra were obtained with a Thermo Fisher
Scientific Nicolet iS5 FTIR spectrometer in ATR mode and
are reported in cm-1. Elemental analyses for carbon,
(E)-N-(2-(Diphenylphosphino)benzylidene)-4-methoxyani-
line (4) Yield: 551 mg (81%); m.p.: 116–118 °C.
(E)-N-(2-(Diphenylphosphino)benzylidene)-2-fluoroaniline
1
(5) Yield: 422 mg (64%); m.p.: 110–111 °C. H NMR
(CDCl3) d: 9.17 (d, JHP = 5.5 Hz, 1H, C(H)=N), 8.27
(ddd, JHH = 7.8 Hz, JHP = 4.1 Hz, JHH = 1.4 Hz, 1H,
Ar), 7.46 (app t, JHH = 7.4 Hz, 1H, Ar), 7.38–7.28 (ov m,
11H, Ar), 7.13–7.00 (ov m, 3H, Ar), 6.93 (ddd,
JHH = 7.8 Hz, JHP = 5.0 Hz, JHH = 1.4 Hz, 1H, Ar), 6.70
(ov ddd, JHH = 7.8 Hz, JHF = 7.8 Hz, JHH = 1.4 Hz, 1H,
Ar). 13C{1H} NMR (CDCl3) d: 161.2 (dd, JCP = 23.8 Hz,
JCF = 1.9 Hz), 155.4 (d, JCF = 248.0 Hz), 139.8 (d,
J = 10.5 Hz), 139.1 (d, J = 17.2 Hz), 138.9 (d,
J = 21.9 Hz), 136.2 (d, J = 9.5 Hz), 134.2 (d,
J = 20.0 Hz), 133.6, 131.4, 129.2, 129.1, 128.8 (d,
J = 7.6 Hz), 128.2 (d, J = 3.8 Hz), 126.9 (d, J = 7.6 Hz),
124.5 (d, J = 3.8 Hz), 121.8, 116.2 (d, J = 20.0 Hz).
19F{1H} NMR (CDCl3) d: -126.6. 31P{1H} NMR (CDCl3)
d: -13.5. IR: 3049 (w), 1619 (s, mCN), 1578 (m), 1478 (s),
1453 (m), 1279 (m), 1104 (m), 733 (s), 692 (s).
hydrogen and nitrogen were carried out at Laboratoire
´
´ ´ ´
d’Analyse Elementaire de l’Universite de Montreal
´
(Montreal, QC). All reactions were performed under a
nitrogen atmosphere in a MBraun LabMaster glovebox.
General procedure for the synthesis of pro-ligands
1–6
(E)-N-(2-(Diphenylphosphino)benzylidene)-3-fluoroaniline
1
To
a mixture of 2-(diphenylphosphino)benzaldehyde
(6) Yield: 481 mg (73%); m.p.: 103–104 °C. H NMR
(500 mg, 1.72 mmol) and the appropriate amine
(1.81 mmol) was added formic acid (1 drop) in MeOH
(5 mL). The reaction was allowed to proceed at RT for
18 h, at which point the iminophosphine pro-ligand was
collected by suction filtration as a pale yellow precipitate.
Spectroscopic NMR data were collected in CDCl3 as the
pro-ligands decompose in wet DMSO-d6. The spectro-
scopically pure pro-ligands were used as prepared to make
the corresponding platinum(II) complexes.
(CDCl3) d: 9.01 (d, JHP = 5.5 Hz, 1H, C(H)=N), 8.17
(ddd, JHH = 7.8 Hz, JHP = 4.1 Hz, JHH = 1.4 Hz, 1H,
Ar), 7.46 (ov ddd, JHH = 7.4, 7.4, 0.9 Hz, 1H, Ar),
7.38–7.28 (ov m, 11H, Ar), 7.22 (m, 1H, Ar), 6.93 (ddd,
JHH = 7.8 Hz, JHP = 4.6 Hz, JHH = 0.9 Hz, 1H, Ar), 6.85
(ov dddd, JHH = 7.8 Hz, 7.8 Hz, JHF = 2.3 Hz,
JHH = 1.4 Hz, 1H, Ar), 6.66 (ddd, JHH = 7.8, 1.8, 0.9 Hz,
1H, Ar), 6.55 (ov ddd, JHF = 10.1 Hz, JHH = 1.8 Hz,
JHH = 1.8 Hz, 1H, Ar). 13C{1H} NMR (CDCl3) d: 163.2
(d, JCF = 245.0 Hz), 159.9 (d, JCP = 21.9 Hz), 153.5
(J = 8.6 Hz), 139.0 (d, J = 20.0 Hz), 138.8 (d,
J = 16.2 Hz), 136.3 (d, J = 8.6 Hz), 134.2 (d,
J = 20.0 Hz), 133.6, 131.3, 130.2 (d, J = 8.6 Hz), 129.1,
129.0, 128.8 (d, J = 7.6 Hz), 128.4 (d, J = 3.8 Hz), 116.8
(d, J = 1.9 Hz), 112.7 (d, J = 21.0 Hz), 108.2 (d,
J = 22.9 Hz). 19F{1H} NMR (CDCl3) d: -113.2. 31P{1H}
NMR (CDCl3) d: -12.5. IR: 3053 (w), 1597 (s, mCN), 1583
(m), 1476 (m), 1433 (m), 1252 (m), 945 (m), 695 (s).
(E)-N-(2-(Diphenylphosphino)benzylidene)-2-methoxyani-
line (2) Yield: 449 mg (66%); m.p.: 108–109 °C.
(E)-N-(2-(Diphenylphosphino)benzylidene)-3-methoxyani-
1
line (3) Yield: 490 mg (72%); m.p.: 89–91 °C. H NMR
(CDCl3) d: 9.04 (d, JHP = 5.0 Hz, 1H, C(H)=N), 8.18
(ddd, JHH = 7.8 Hz, JHP = 4.1 Hz, JHH = 1.4 Hz, 1H,
Ar), 7.45 (app t, JHH = 7.3 Hz, 1H, Ar), 7.36–7.28 (ov m,
11H, Ar), 7.18 (t, JHH = 7.8 Hz, 1H, Ar), 6.91 (ddd,
JHH = 7.8 Hz, JHP = 4.6 Hz, JHH = 0.9 Hz, 1H, Ar), 6.72
123

Transit Met Chem
Synthesis of (E)-N-(2-(diphenylphosphino)
benzylidene)-4-fluoroaniline (7)
268–270 °C. 1H NMR (DMSO-d6) d: 8.83 (s,
JHPt = 97.1 Hz, 1H, C(H)=N), 8.11 (m, 1H, Ar), 7.86 (ov
dd, J = 7.8, 7.4 Hz, 1H, Ar), 7.80 (ov dd, J = 7.8, 7.4 Hz,
1H, Ar), 7.62–7.55 (ov m, 6H, Ar), 7.47–7.42 (ov m, 4H,
Ar), 7.24 (ov dd, J = 8.2, 7.8 Hz, 1H, Ar), 7.02 (app t,
J = 7.8, 7.8 Hz, 1H, Ar), 6.94 (d, J = 8.2 Hz, 1H, Ar),
6.88 (s, 1H, Ar), 6.84 (d, J = 8.2 Hz, 1H, Ar), 3.73 (s, 3H,
OCH3). 13C{1H} NMR (DMSO-d6) d: 167.2 (d,
JCP = 6.7 Hz), 159.3, 154.0, 137.9 (d, JCP = 8.6 Hz),
137.1 (d, JCP = 13.4 Hz), 135.2 (d, JCP = 7.6 Hz), 134.2
(d, JCP = 11.4 Hz), 133.4, 133.0, 132.8, 129.5 (d,
JCP = 11.4 Hz), 128.7, 125.8, 125.1, 121.9, 121.3, 117.0,
113.7, 110.5, 56.0. 31P{1H} NMR (DMSO-d6) d: 5.7
(JPPt = 3660 Hz). IR: 3054 (w), 1598 (m, mCN), 1479 (m),
1435 (s), 1289 (s), 1273 (m), 1141 (m), 1102 (m), 693 (s).
Anal. calcd. for C26H22NCl2OPPt (661.42 g/mol) (%): C
47.21, H 3.35, N 2.12; found: C 46.88, H 3.47, N 2.44.
A THF (10 mL) solution of 2-(diphenylphosphino)ben-
zaldehyde (500 mg, 1.72 mmol) and 4-fluoroaniline
(191 mg, 1.72 mmol) was allowed to react in the presence
˚
of activated 3 A molecular sieves (5 g) over a period of
7 days. The mixture was filtered, and solvent was removed
under vacuum to afford an orange oil. The oil was dis-
solved in hexane (5 mL) and stored at -30 °C. The
resulting precipitate was collected by suction filtration to
afford 7 as a pale yellow solid. Yield: 514 mg (78%); m.p.:
83–84 °C. 13C{1H} NMR (CDCl3) d: 161.3 (d,
JCF = 243.1 Hz), 158.7 (d, JCP = 21.0 Hz), 147.7 (d,
J = 2.9 Hz), 139.1 (d, J = 16.2 Hz), 138.7 (d,
J = 20.0 Hz), 136.5 (d, J = 8.6 Hz), 134.2 (d,
J = 20.0 Hz), 133.7, 131.1, 129.1, 128.8, 128.7, 128.3 (d,
J = 3.8 Hz), 122.5 (d, J = 8.6 Hz), 115.8 (d,
J = 21.9 Hz).
Synthesis of 11 Complex 11 was isolated as a yellow
solid by recrystallization from a solution of CH2Cl2: hex-
ane (10 mL: 5 mL) stored at 5 °C. Yield: 211 mg (59%);
m.p.: 262–263 °C. 1H NMR (DMSO-d6) d: 8.78 (s,
JHPt = 87.9 Hz, 1H, C(H)=N), 8.08 (dd, JHH = 6.4 Hz,
JHP = 4.1 Hz, 1H, Ar), 7.84 (ov dd, JHH = 7.8, 7.3 Hz,
1H, Ar), 7.78 (ov dd, JHH = 7.8, 7.4 Hz, 1H, Ar),
7.62–7.54 (ov m, 6H, Ar), 7.47–7.42 (ov m, 4H, Ar), 7.38
(d, JHH = 9.2 Hz, 2H, Ar), 7.03 (dd, JHP = 10.5,
JHH = 7.8 Hz, 1H, Ar), 6.88 (d, J = 9.2 Hz, 2H, Ar), 3.73
(s, 3H, OCH3). 13C{1H} NMR (DMSO-d6) d: 166.1 (d,
JCP = 6.7 Hz), 159.2, 146.4, 137.4, 137.3 (d,
JCP = 22.0 Hz), 134.9 (d, JCP = 8.6 Hz), 134.3 (d,
JCP = 10.5 Hz), 133.4, 132.8 (2C), 129.5 (d,
JCP = 11.5 Hz), 125.7, 125.6, 125.1, 122.0, 121.4, 113.7,
55.9. 31P{1H} NMR (DMSO-d6) d: 5.8 (JPPt = 3660 Hz).
IR: 3057 (w), 1608 (m, mCN), 1504 (m), 1437 (s), 1256 (s),
1020 (m), 765 (m), 692 (s). Anal. calcd. for C26H22NCl2-
OPPt (661.42 g/mol) (%): C 47.21, H 3.35, N 2.12; found:
C 47.38, H 3.55, N 2.54.
General synthesis of iminophosphineplatinum(II)
complexes 9–14
To a stirred THF (5 mL) suspension of [PtCl2(g2-coe)]2
(200 mg, 0.27 mmol) was added a THF (2 mL) solution of
the appropriate iminophosphine pro-ligand (0.55 mmol).
The reaction was allowed to proceed at RT for 18 h, at
which point a yellow–orange precipitate was collected by
suction filtration. The final purification steps for each
complex are detailed below. Spectroscopic NMR data were
collected in DMSO-d6 due to the poor solubility of the
complexes in CDCl3.
Synthesis of 9 Washing with hexane (3 9 5 mL) afforded
9 as a yellow–orange solid. Yield: 296 mg (83%); m.p.:
198–200 °C. 1H NMR (DMSO-d6) d: 8.82 (s,
JHPt = 97.6 Hz, 1H, C(H)=N), 8.04 (m, 1H, Ar), 7.84 (m,
2H, Ar), 7.62–7.54 (ov m, 6H, Ar), 7.49–7.44 (ov m, 4H,
Ar), 7.21 (t, J = 7.3 Hz, 1H, Ar), 7.12 (m, 1H, Ar), 7.08 (d,
J = 7.8 Hz, 1H, Ar), 7.02 (d, J = 8.2 Hz, 1H, Ar), 6.91 (t,
J = 7.8 Hz, 1H, Ar), 3.64 (s, 3H, OCH3). 13C{1H} NMR
(DMSO-d6) d: 168.0 (d, JCP = 6.7 Hz), 152.2, 142.2,
138.1 (d, JCP = 7.6 Hz), 136.8 (d, JCP = 12.4 Hz), 135.4
(d, JCP = 7.6 Hz), 134.2 (d, JCP = 11.4 Hz), 133.6 (d,
JCP = 27.7 Hz), 132.5, 129.3 (d, JCP = 11.4 Hz), 127.2,
126.5, 125.9, 121.5, 120.9, 119.9, 112.6, 56.4. 31P{1H}
NMR (DMSO-d6) d: 3.8 (JPPt = 3720 Hz). IR: 3061 (w),
1613 (m, mCN), 1493 (m), 1436 (s), 1258 (m), 1100 (s),
1018 (m), 690 (s). Anal. calcd. for C26H22NCl2OPPt
(661.42 g/mol) (%): C 47.21, H 3.35, N 2.12; found: C
47.48, H 3.66, N 2.32.
Synthesis of 12 Compound 12 was purified by recrystal-
lization from CH2Cl2 (5 mL) stored at 5 °C. Yield: 238 mg
(68%); m.p.: 241–243 °C. 1H NMR (DMSO-d6) d: 9.01 (s,
JHPt = 85.2 Hz, 1H, C(H)=N), 8.08 (dd, JHH = 8.7 Hz,
JHP = 4.2 Hz, 1H, Ar), 7.84 (dd, JHH = 6.8, JHF = 2.3 -
Hz, 2H, Ar), 7.63–7.53 (ov m, 6H, Ar), 7.50–7.45 (ov m,
4H, Ar), 7.30–7.13 (ov m, 5H, Ar). 13C{1H} NMR
(DMSO-d6) d: 169.6 (d, JCP = 6.7 Hz), 154.8 (d,
JCF = 246.0 Hz), 140.7 (d, J = 11.5 Hz), 138.6 (d,
J = 8.6 Hz), 136.4 (d, J = 13.4 Hz), 135.9 (d,
J = 7.7 Hz), 134.3 (d, J = 10.5 Hz), 133.8 (d,
J = 2.9 Hz), 133.6, 132.7, 129.8 (d, J = 7.7 Hz), 129.4 (d,
J = 12.5 Hz), 126.9, 126.6, 125.9, 124.3 (d, J = 3.8 Hz),
121.6, 121.0, 116.2 (d, J = 19.2 Hz). 19F{1H} NMR
(DMSO-d6) d: -123.4. 31P{1H} NMR (DMSO-d6) d: 4.7
Synthesis of 10 Washing with hexane (3 9 5 mL) affor-
ded 10 as a yellow solid. Yield: 265 mg (74%); m.p.:
123

Transit Met Chem
(JPPt = 3690 Hz). IR: 3058 (w), 1597 (m, mCN), 1493 (m),
1435 (m), 1219 (m), 1103 (s), 690 (s). Anal. calcd. for
C25H19NCl2FPPt (649.39 g/mol) (%): C 46.24, H 2.95, N
2.16; found: C 46.52, H 3.14, N 2.45.
decomposition to starting materials); therefore, they were
not included in the biological testing. As no decomposition
of the platinum complexes 8–14 was observed, biological
studies of these compounds were initiated.
Synthesis of 13 Compound 13 was purified by recrystal-
lization from CH2Cl2 (5 mL) stored at 5 °C. Yield: 252 mg
(72%); m.p.: 253–255 °C. 1H NMR (DMSO-d6) d: 8.88 (s,
JHPt = 85.2 Hz, 1H, C(H)=N), 8.11 (dd, JHH = 6.4 Hz,
JHP = 4.1 Hz, 1H, Ar), 7.89–7.80 (ov m, 2H, Ar),
7.62–7.55 (ov m, 5H, Ar), 7.49–7.44 (ov m, 3H, Ar), 7.42
(m, 1H, Ar), 7.24 (ov dd, JHF = 12.4 Hz, JHH = 8.2 Hz,
2H, Ar), 7.15–7.05 (ov m, 2H, Ar), 7.03–6.96 (ov m, 2H,
Ar). 13C{1H} NMR (DMSO-d6) d: 168.2 (d, JCP = 6.7 -
Hz), 161.7 (d, JCF = 244.4 Hz), 154.3 (d, J = 9.6 Hz),
138.3 (d, J = 8.6 Hz), 136.8 (d, J = 12.5 Hz), 135.5 (d,
J = 8.6 Hz), 134.3 (d, J = 11.4 Hz), 133.5, 133.2 (d,
J = 2.9 Hz), 132.8, 130.3 (d, J = 8.6 Hz), 129.6 (d,
J = 11.5 Hz), 125.9, 125.2, 121.9, 121.3, 121.1, 115.2 (d,
J = 21.1 Hz), 112.2 (d, J = 24.9 Hz). 19F{1H} NMR
(DMSO-d6) d: -107.6. 31P{1H} NMR (DMSO-d6) d: 5.3
(JPPt = 3640 Hz). IR: 3052 (w), 1591 (m, mCN), 1484 (m),
1436 (m), 1255 (m), 1102 (m), 1079 (s), 693 (s). Anal.
calcd. for C25H19NCl2FPPt (649.39 g/mol) (%): C 46.24, H
2.95, N 2.16; found: C 46.66, H 2.53, N 2.57.
X-ray crystallography
Crystals of 11 and 11a were grown from a CH2Cl2/CH3Cl:
hexane solution stored at RT. Crystals were attached to the
tip of a 400 lm MicroLoop with Paratone-N oil. Mea-
surements were made on a Bruker APEXII CCD equipped
diffractometer (30 mA, 50 mV) using monochromatic Mo-
˚
Ka radiation (k = 0.71073 A) at 125 K. The initial ori-
entation and unit cell were indexed using a least-squares
analysis of a random set of reflections collected from three
series of 0.5° wide scans, 10 s per frame and 12 frames per
series that were well distributed in reciprocal space. For
data collection, four x-scan frame series were collected
with 0.5° wide scans, 5 (11) or 30 (11a) second frames and
416 frames per series at varying u angles (u = 0°, 90°,
180°, 270°). The crystal to detector distance was set to
6 cm, and a complete sphere of data was collected. Cell
refinement and data reduction were performed with the
Bruker SAINT software, which corrects for beam inho-
mogeneity, possible crystal decay, Lorentz and polarization
effects. Data processing and a multi-scan absorption cor-
rection were applied using the APEX2 software package
[22]. The structure was solved using direct methods [23].
All non-hydrogen atoms were refined anisotropically. In
general, hydrogen atoms were included at geometrically
idealized positions with coupled isotropic temperature
factors and were fixed (C-H, Ar-H), or in the case of
methyl groups, the dihedral angle of the idealized tetra-
hedral CH3 fragment was allowed to refine. There was a
molecule of dichloromethane that was co-crystallized with
11. Figures were made using Ortep-3 for Windows [24].
In the initial models in the case of 11a, there was sig-
nificant excess electron density around the dichlor-
omethane molecules. After running a variety of models, it
was deduced that the electron density was part of a water
molecule. In the case of the co-crystallized water molecule,
Synthesis of 14 Complex 14 was isolated as a yellow
solid by recrystallization from a solution of CH2Cl2: hex-
ane (10 mL: 5 mL) stored at 5 °C. Yield: 295 mg (84%);
m.p.: 260 °C. 1H NMR (DMSO-d6) d: 8.85 (s,
JHPt = 98.3 Hz, 1H, C(H)=N), 8.10 (dd, JHH = 6.4 Hz,
JHP = 4.1 Hz, 1H, Ar), 7.86 (app t, JHH = 7.3 Hz, 1H,
Ar), 7.81 (app t, JHH = 7.3 Hz, 1H, Ar), 7.63–7.54 (ov m,
6H, Ar), 7.48–7.42 (ov m, 6H, Ar), 7.21 (app t, J = 8.7 Hz,
2H, Ar), 7.06 (dd, JHP = 10.1, JHH = 7.8 Hz, 1H, Ar).
13C{1H} NMR (DMSO-d6) d: 167.5 (d, JCP = 6.7 Hz),
161.6 (d, JCF = 243.1 Hz), 149.5, 138.0 (d, J = 8.6 Hz),
137.0 (d, J = 13.4 Hz), 135.2 (d, J = 8.6 Hz), 134.3 (d,
J = 10.5 Hz), 133.4, 133.1 (d, J = 2.9 Hz), 132.8 (d,
J = 1.9 Hz), 129.5 (d, J = 11.4 Hz), 126.5 (d,
J = 8.6 Hz), 125.9, 125.3, 121.9, 121.3, 115.4 (d,
J = 22.9 Hz). 19F{1H} NMR (DMSO-d6) d: -113.0.
31P{1H} NMR (DMSO-d6) d: 5.5 (JPPt = 3650 Hz). IR:
3061 (w), 1609 (m, mCN), 1502 (s), 1436 (m), 1238 (m),
1160 (m), 1103 (s), 835 (m), 690 (s). Anal. calcd. for
C25H19NCl2FPPt (649.39 g/mol) (%): C 46.24, H 2.95, N
2.16; found: C 46.18, H 2.52, N 2.34.
˚
the O-H bonds were fixed at 0.90 A and the H-H 1,3-
˚
distance was set to 1.40 A and the H atoms were positioned
to have a hydrogen bond interaction with Cl of dichlor-
omethane. Attempts to provide a disorder model to account
for the excess electron density near the Cl atoms of the
dichloromethane molecules were unsuccessful and were
thus left as is.
Stability of compounds in dimethyl formamide
Solutions of the compounds in wet DMF were monitored
by 31P{1H} NMR spectroscopy over a period of 2 days at
37 °C. Evidence of 2-diphenylphosphinobenzaldehyde was
observed in solutions of the pro-ligands (demonstrating
Cell cultures
Human glioma cells Hs683 and T98G were cultured in an
incubator at 37 °C and 5% CO2 in DMEM supplemented
123

Transit Met Chem
Scheme 1 Synthesis of iminophosphineplatinum(II) complexes 8–
14. 1: R1=R2=R3=H; 2: R1=OMe,R2=R3=H; 3: R1=R3=H,R2=OMe; 4:
R1=R2=H,R3=OMe; 5: R1=F,R2=R3=H; 6: R1=R3=H,R2=F; 7:
R1=R2=H,R3=F; 8: R1=R2=R3=H; 9: R1=OMe,R2=R3=H; 10: R1-
=R3=H,R2=OMe; 11: R1=R2=H,R3=OMe; 12: R1=F,R2=R3=H; 13:
R1=R3=H,R2=F; 14: R1=R2=H,R3=F
with 10% FBS (foetal bovine serum) and 1% antibiotics
(Thermo Fisher Scientific) and have been previously
characterized [25]. Hs683 cells were originally provided by
Dr. Adrian Merlo (Basel, Switzerland), while T98G cells
were purchased from American Type Culture Collection
(ATCC, #CRL-1690).
MTT in PBS was added to each well. Cells and MTT were
incubated for 3 h and subsequently removed. Stained cells
were re-suspended in 100 lL of a 1:24 1 M HCl/95%
EtOH solution and read at 560 nm on a Varioskan (Scan-
lab). Experiments were performed as described twice.
LC50 cytotoxicity assays
MTT assays
MTT assays were used to calculate the experimental LC50
values for the compounds. Hs683 or T98G cells were
seeded at a density of 10,000 cells per well in 96-well
plates and cultured as above for 24 h. Cells were then
treated with the complexes at final concentrations of 0.1,
0.5, 1, 10 and 100 lM, 150 and 250 lM. DMF was used to
dissolve the compounds at the appropriate concentrations.
Each compound, at each final concentration, was assessed
in triplicate wells. DMF-only treatment was also assessed
in triplicate and served as a control. Cells were incubated at
37 °C and 5% CO2 for 48 h following treatment. Cells
were then stained, incubated, re-suspended and absorbance
values collected as above. Data were converted to the
percentage of cell viability compared to solvent control
(DMF only) wells from the same experiment. LC50 values
were calculated via the GraphPad Prism 6 software. LC50
experiments were repeated twice.
A total of 10,000 cells were seeded in triplicates in 96-well
plates in 200 lL of cell culture medium. Cells were incu-
bated at 37 °C and 5% CO2 for 24 h. Medium was replaced
with medium containing 1, 10 or 100 lM of the required
complex dissolved in DMF. Cells were incubated for an
additional 48 h. DMF was used instead of complexes in
control wells. Following incubation, 20 lL of 5 mg/mL
Results and discussion
In order to overcome some of the limitations inherent
within cisplatin therapy, a considerable amount of research
has recently focused on the synergistic use of radiotherapy
and platinum chemotherapy for the treatment of glioblas-
tomas [26–33]. This unique combination allows for
reduction in the platinum dosage, and thereby alleviates
some of the problematic side effects. Gliomas are a com-
mon and deadly form of brain cancer which are typically
classified into four clinical grades, of which glioblastoma
multiforme (GBM) is the most aggressive. The median
Fig. 1 The molecular structure of 11 drawn with 50% probability
ellipsoids and hydrogen atoms and a molecule of solvent removed for
clarity
123

Transit Met Chem
Table 1 Crystallographic data
collection parameters
Complex
11
11a
Formula
C27H24Cl4NOPPt
746.33
C112H106Cl20N4O5P4Pt2
Molecular weight
Crystal system
Space group
2811.06
Monoclinic
P2/c
Triclinic
P - 1
˚
a (A)
9.8615(17)
10.6792(19)
14.457(3)
74.828(2)
71.841(2)
70.9912(2)
1345.3(4)
2
12.2694(8)
13.2083(8)
18.5323(12)
90
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
99.4020(10)
90
3
˚
V (A )
2963.0(3)
1
Z
q
calc. (Mg m-3
)
1.842
1.575
Crystal size (mm3)
0.217 9 0.122 9 0.076
125(2)
0.530 9 0.313 9 0.252
125(2)
Temp (K)
˚
˚
Radiation
l (mm-1
Mo-Ka (k = 0.71073 A)
Mo-Ka (k = 0.71073 A)
)
5.694
2.916
Total reflections
Total unique reflections
No. of variables
h range (°)
9040
23648
4808
7239
317
339
2.256–25.242
3.48 and -2.40
2.228–28.864
1.899 and -1.258
Largest difference
-3
˚
peak/hole (e/A
)
S (goodness-of-fit) on F2
R1a (I [ 2 s(I))
wR2b (all data)
0.995
1.197
0.0604
0.1407
0.0290
0.0713
P
P
a
R1 = ||Fo| – |Fc||/ |Fo|
P
P
b
wR2 = ( [w(F2o - F2c)2]/ [wF4o])1/2
,
where w = 1/[r2(Fo2) ? (0.0767P)2] (11) and w = 1/[r2
(F2o) ? (0.0208P)2 ? (9.0344P)] (11a), where P = (max (Fo2, 0) ? 2.F2c)/3
˚
previously, we have found that platinum(II) complexes
bearing iminophosphine ligands containing boronate ester
groups showed moderate anticancer activity against two
glioma cell lines [14]. With this in mind, we have prepared
iminophosphineplatinum complexes 9–14 containing elec-
tron-donating methoxy derivatives and electron-withdraw-
ing fluoride groups along with the aniline derivative 8 and
examined these species for their cytotoxic properties
against two glioma cell lines using the MTT method.
The synthesis of pro-ligands 1–7 was performed under
an atmosphere of dinitrogen, since the resulting
iminophosphines readily decompose back to the starting
materials in the presence of water. Formation of the pro-
ligands was confirmed by multinuclear NMR spectroscopy
where the aldehyde proton at 10.50 ppm disappears and a
new peak is observed at ca. 9 ppm for the imine proton in
Table 2 Selected bond distances (A) and angles (°) for 11
Bond distances
Bond angles
Pt(1)-N(1)
Pt(1)-P(1)
Pt(1)-C1(1)
Pt(1)-C1(2)
N(1)-C(19)
N(1)-C(20)
P(1)-C(1)
2.045(9)
2.204(3)
2.294(3)
2.365(3)
1.321(15)
1.445(14)
1.814(12)
N(1)-Pt(1)-P(1)
N(1)-Pt(1)-Cl(1)
N(1)-Pt(1)-Cl(2)
Cl(1)-Pt(1)-Cl(2)
P(1)-Pt(1)-Cl(1)
P(1)-Pt(1)-Cl(2)
N(1)-C(19)-C(6)
86.4(3)
175.9(3)
90.1(3)
89.41(10)
94.63(10)
171.77(10)
126.7(10)
survival period for patients diagnosed with GBM is only
12 months. The tumours that infiltrate into regions of the
brain complicate surgical extraction so it is understandable
that the quest for efficacious chemotherapeutic agents to
treat GBM is of utmost importance in an effort to improve
this combination of cancer treatment. As mentioned
1
the H NMR spectra. Imine formation is further confirmed
by 13C{1H} NMR data, since the aldehyde C=O resonance
at 191.8 ppm for 2-diphenylphosphinobenzaldehyde
123

Transit Met Chem
JHPt = 92 Hz). Upon coordination, a significant shift is
also observed in the 31P{1H} spectra, from roughly
-13 ppm for the free pro-ligands to around 5 ppm for
complexes 8–14. Furthermore, the 195Pt satellites observed
with these resonances display coupling constants
(JPPt = 3640 to 3720 Hz) which are well within the range
reported for related species. The decrease in the mC=N
stretching vibration band in the IR spectra from
*1619 cm-1 for the free iminophosphines to
*1603 cm-1 is indicative of coordination of the imine
moiety to a metal centre [34, 35]. We carried out a single-
crystal X-ray diffraction study on the para-methoxy
derivative 11 in order to confirm the solid-state structure of
these complexes, the molecular structure of which is shown
in Fig. 1. Crystallographic data are provided in Table 1 and
selected bond distances and angles in Table 2. The mole-
cule assumes a distorted square planar geometry about the
platinum atom as is evidenced by the bond angles N(1)-
Pt(1)-Cl(1) and P(1)-Pt(1)-Cl(2) which are 176.0(2)° and
171.54(7)°, respectively, and are significantly less than
180°. The ligand coordinates to the metal in a j2-P,N
fashion where the stronger trans-effect of the
diphenylphosphino group over the amine is observed, as
˚
the Pt(1)-Cl(1) distance of 2.293(2) A is noticeably shorter
˚
than that of the Pt(1)-Cl(2) distance of 2.372(2) A [36]. The
Fig. 2 The molecular structure of the dication 11a drawn with 50%
probability ellipsoids and hydrogen atoms and solvent molecules
removed for clarity
nitrogen–platinum and phosphorus–platinum bond dis-
˚
tances of 2.051(7) A and 2.197(2), respectively, are similar
˚
Table 3 Selected bond distances (A) and angles (°) for 11a
to those reported in other platinum systems [37–39]. For
instance, the nitrogen–platinum and phosphorus–platinum
bond distances in the related complex (j2-P,N-2-Ph2PC6-
H4C(H) = N-2,6-iPr2C6H3)PtCl2 are 2.0421(18) and
Bond distances
Bond angles
Pt(1)-N(1)
Pt(1)-N(1)#
Pt(1)-P(1)
Pt(1)-P(1)#
N(1)-C(19)
N(1)-C(20)
P(1)-C(1)
2.121(2)
2.121(2)
2.2509(7)
2.2509(7)
1.292(4)
1.438(4)
1.821(3)
N(1)-Pt(1)-P(1)
N(1)#-Pt(1)-P(1)
N(1)-Pt(1)-P(1)#
N(1)#-Pt(1)-P(1)#
P(1)-Pt(1)-P(1)#
N(1)-Pt(1)-N(1)#
N(1)-C(19)-C(6)
83.38(7)
168.16(7)
168.16(7)
83.38(7)
˚
2.2128(6) A, respectively [15]. The corresponding N(1)-Pt-
P(1) bond angle in this related complex is 89.80(5)°,
whereas the same angle in 11 is 86.4(3). The imine N(1)-
˚
C(1) distance of 1.287(11) A in 11 is in the range of
106.35(4)
87.84(13)
125.1(3)
accepted carbon–nitrogen double bonds. A single crystal of
the minor product 11a was also solved by an X-ray
diffraction study. The molecule structure consists of two
ligands coordinated to the platinum dication surrounded by
two outer-sphere Cl- anions and solvent molecules (CHCl3,
CH2Cl2 and H2O). The molecular structure of the dication
is presented in Fig. 2, with crystallographic data in Table 1
and selected bond lengths and angles in Table 3. The Pt(1)-
N(1) distance of 2.121(2) is similar to that of 11, and the
C(19)-N(1) distance of 1.292(4) is indicative of a carbon–
nitrogen double bond. The platinum centre exists in a
slightly distorted square planar configuration, as demon-
strated by the sum of angles around Pt of 360.95(34)°. The
ligands are arranged so that the phosphine and imine
fragments are trans to one another. The Pt-N and Pt-P bond
disappears as the appearance of a new peak at ca. 160 ppm
for the C=N bonds is observed.
Iminophosphineplatinum(II) complexes (8–14) were
prepared in moderate to good yields (Scheme 1) by the
addition of pro-ligands 1–7 to THF suspensions of
[PtCl2(g2-coe)]2 (coe = cis-cyclooctene). The platinum
compounds have been characterized using a number of
physical methods, including multinuclear NMR and FTIR
spectroscopy, as well as elemental analysis. Coordination
of the iminophosphine to the metal centre was confirmed
by 1H NMR spectroscopy where an upfield shift is
observed for the imine proton from around 9 ppm to ca.
8.4 ppm (in CDCl3) with associated 195Pt satellites (avg.
˚
lengths are 2.120(2) and 2.2509(7) A, respectively, and are
much longer than observed in 11, presumably due to either
the steric effects of the two iminophosphine ligands, or due
123

Transit Met Chem
University) for his expert technical assistance, and anonymous
reviewers are thanked for their very helpful comments.
to differing trans-effects when compared to the Cl ligands
in 11. Related cis-diaminophosphineplatinum(II) com-
plexes have been reported previously [40–46]. For
instance, the disparate Pt-N and Pt-P bond lengths in
[Pt{(NC5H4)[(Ph2PNH)C(=NH)]-4}{(NC5H4)[(Ph2-
References
PNH)C(=N)]-4}][BF4] [44] are 2.07(2)/2.03(2) and
˚
2.218(6)/2.246(6) A, respectively. The coordination
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