Synthesis and crystal structure of the first complex containing a chelating selenourea dianion ligand

Article abstract of DOI:10.1016/S0020-1693(03)00298-6

Reaction of N,N′-diphenylselenourea, PhNHC(Se)NHPh, with cis-[PtCl₂(PPh₃)₂] and triethylamine in hot methanol gives the first example of a selenourea dianion complex, [Pt{SeC(=NPh)NPh}(PPh₃)₂] isolated as a yellow solid in high yield. The structure of the complex was determined by X-ray crystallography and found to be similar to the related thiourea dianion complex [Pt{SC(=NPh)NPh}(PPh₃)₂], with a Pt-Se-C-N four-membered ring. The antitumour activity (P388 murine leukaemia cells) of the selenourea dianion complex was determined, together with a small selection of related platinum(II)-thiourea dianion complexes (prepared by an analogous method) for comparison. The complex [Pt{SC(=NMe)NMe}(PPh₃)₂] showed high activity [IC₅₀ 1.0 μM], with the other complexes showing moderate to low activity.

Full text of DOI:10.1016/S0020-1693(03)00298-6

Inorganica Chimica Acta 355 (2003) 428ꢀ431
/
www.elsevier.com/locate/ica
Note
Synthesis and crystal structure of the first complex containing a
chelating selenourea dianion ligand
William Henderson *, Brian K. Nicholson, Maarten B. Dinger
Department of Chemistry, University of Waikato, Private Bag 3105, Hamilton, New Zealand
Received 7 February 2003; accepted 3 March 2003
Abstract
Reaction of N,N?-diphenylselenourea, PhNHC(Se)NHPh, with cis-[PtCl2(PPh3)2] and triethylamine in hot methanol gives the
first example of a selenourea dianion complex, [Pt{SeC(ÄNPh)NPh}(PPh3)2] isolated as a yellow solid in high yield. The structure of
the complex was determined by X-ray crystallography and found to be similar to the related thiourea dianion complex [Pt{SC(Ä
NPh)NPh}(PPh3)2], with a PtÃSeÃCÃN four-membered ring. The antitumour activity (P388 murine leukaemia cells) of the
selenourea dianion complex was determined, together with a small selection of related platinum(II)ꢀthiourea dianion complexes
(prepared by an analogous method) for comparison. The complex [Pt{SC(ÄNMe)NMe}(PPh3)2] showed high activity [IC50 1.0 mM],
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/
with the other complexes showing moderate to low activity.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Platinum complexes; Selenourea dianion; Thiourea dianion; Crystal structures; Anticancer activity
1. Introduction
gether with the anticancer activity of a selection of
thiourea and selenourea dianion complexes.
Thioureas and selenoureas are potentially multiden-
tate ligands, capable of coordination to a range of metal
centres through nitrogen and/or chalcogen atoms, and
thus possess a potentially rich and diverse coordination
chemistry [1]. Most of the examples of platinum or
palladium complexes containing coordinated thioureas
and selenoureas involve the neutral [1,2] or monoanionic
[3,4] ligand. Examples of complexes where a thiourea is
coordinated as a dianion are known, but are much less
common. Thus, thiourea dianion complexes of platinu-
2. Results and discussion
The reaction of cis-[PtCl2(PPh3)2] with one equivalent
of N,N?-diphenylselenourea, PhNHC(Se)NHPh, in hot
methanol with added triethylamine gave, on addition of
water, a yellow precipitate of the air- and moisture-
stable platinum(II) selenourea dianion complex 1. A
previous attempt at synthesising 1, using silver(I) oxide
as the base led to a large number of unidentified
products [12], presumably in part due to oxidation of
the selenium by the silver. Similar observations have
been reported before [5], although it is noted that the
analogous reaction with N,N?-diphenylthiourea and
silver oxide gave the thiourea dianion complex
m(II) [5ꢀ7], palladium(II) [8], rhodium(III) [9], ruthe-
/
nium(II) [9] and molybdenum(IV) [10] are known.
Although complexes of selenoureas have been known
for some time, [1,3,11] to the best of our knowledge
there are no examples of metal complexes containing
coordinated selenourea dianions. In this Note we
describe the synthesis and structure of the first example
[Pt{SC(Ä
/
NPh)NPh}(PPh3)2] (2a) [5]. The 31P{1H}
NMR spectrum of complex 1 shows the expected
doublet of doublets for two inequivalent phosphines,
showing 195Pt coupling of 3068 and 3252 Hz, assigned to
phosphines trans to Se and N, respectively. It is
noteworthy that the phosphorus trans to Se also shows
2J(31P77Se) coupling of approximately 18 Hz, but no
of such a complex, [Pt{SeC(Ä
/
NPh)NPh}(PPh3)2], to-
* Corresponding author. Tel.: ꢁ
/
64-7-838 4656; fax: ꢁ64-7-838
/
4219.
E-mail address: w.henderson@waikato.ac.nz (W. Henderson).
0020-1693/03/$ - see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0020-1693(03)00298-6

W. Henderson et al. / Inorganica Chimica Acta 355 (2003) 428ꢀ
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429
coupling is observed for the cis phosphine. The 1H
NMR spectrum of 1 showed no signal around d 9.3, due
to the NH proton of PhNHC(Se)NHPh, consistent with
deprotonation of the selenourea. The positive-ion elec-
trospray ionisation (ES) mass spectrum of 1 showed a
to the selenium, as also observed in other thiourea
dianion complexes [5ꢀ10].
The PtÃP(1) (trans to N) distance of 2.252(1) A is
shorter than PtÃ
barely different from the equivalent distances of 2.247(1)
˚
and 2.308(1) A in the sulfur analogue 2a. The covalent
˚
radius of Se is 0.12 A longer than that of S and this is
/
˚
/
˚
P(2) (trans to Se) which is 2.303(1) A,
/
single [Mꢁ
H]ꢁ ion at m/z 994, with excellent agree-
ment between observed and calculated isotope distribu-
/
reflected in the PtÃ
/
Se and SeÃ
/
C(7) distances of
˚
2.4395(5) and 1.957(6) A, compared with analogous
tion patterns.
A single-crystal X-ray diffraction study on 1 con-
firmed the N,Se-coordination of the selenourea dianion,
˚
PtÃ
[5]. Other differences are small, with the SeÃ
‘bite’ angle of 71.68 and the N(1)ÃC(7)ÃSe angle of
105.88 being close to the SÃPtÃN and NÃCÃS angles of
70.58 and 107.78, respectively [5].
/
S and SÃ
/
C lengths of 2.331(1) and 1.782(5) A in 2a
/
PtÃN(1)
/
forming a four-membered PtÃ
analogous to the PtÃSÃCÃN ring system of the complex
[Pt{SC(ÄNPh)NPh}(PPh3)2] (2a), which has also been
/
SeÃ
/
CÃ
/
N ring system,
/
/
/
/
/
/
/
/
/
/
structurally characterised [5]. The molecular structure is
shown in Fig. 1, together with the atom numbering
scheme, while selected bond lengths and angles are given
in the caption of the Figure. The crystal structure of 1
reveals two independent molecules in the asymmetric
unit, but these do not differ significantly, other than in
the conformations of the various phenyl rings. The
following discussion is based on averaged parameters.
The structure shows the expected arrangement of cis-
PPh3 ligands, and a selenourea ligand attached to the Pt
via the Se and N(1) amidate atoms. The coordination
˚
0.03 A, and the
In light of the recent interest in the anticancer activity
of platinum(II) thiourea complexes [13] and our ob-
servation that platinum(II) [14] and gold(III) [15]
complexes containing chelating thiosalicylate ligands
(with an S,O donor atom set) can also show good
anticancer activity, we have tested the activity of
complex 1 towards P388 leukaemia cells. For compar-
ison, the diphenylthiourea complex 2a, the di-
methylthiourea complex 2b (which has been previously
synthesised by the silver oxide-mediated route [12]), and
about the Pt atom is planar to within 9
/
entire core [P(1), P(2), Pt, Se, N(1), C(7) and N(2)] is
˚
planar to within 90.05 A. The plane of the phenyl ring
/
on N(1) forms a dihedral angle with the coordination
plane of 888 and 788, respectively for the two molecules,
while the phenyl ring on N(2) is at 538 and 808,
respectively. These overall features are similar to those
found for the corresponding diphenylthiourea complex
2a [5]. The complex has the CÄ
/
N phenyl substituent cis
Fig. 1. The structure of molecule 1 of Pt{SeC(Ä
Some selected average bond parameters: PtÃSe 2.4395(5), PtÃ
PtÃP(2) 97.33(4)8, N(1)Ã
dichloromethane of crystallisation has been omitted for clarity.
/
NPh)NPh}(PPh3)2] (1). That of molecule 2 differs mainly in the conformations of the phenyl rings.
N(1) 2.100(4), PtÃP(1) 2.2525(12), PtÃP(2) 2.3028(11), SeÃC(7) 1.957(5), N(1)ÃC(7)
PtÃSe 71.62(12)8, C(7)ÃSeÃPt 77.60(16)8, N(1)ÃC(7)ÃSe 105.8(3)8. The
/
/
/
/
/
/
˚
1.360(6), N(2)Ã
/
C(7) 1.281(7) A, P(1)Ã
/
/
/
/
/
/
/
/

430
W. Henderson et al. / Inorganica Chimica Acta 355 (2003) 428ꢀ431
/
Table 1
P388 antitumour assay data for selected thiourea- and selenourea-
dianion complexes
dye MTT tetrazolium is reduced by healthy cells to the
purple dye MTT formazan.
[PtCl2(cod)] was prepared by the literature procedure
[17], and cis-[PtCl2(PPh3)2] prepared from it by reaction
with a stoichiometric quantity of PPh3 in dichloro-
methane [18]. N,N?-Dimethylthiourea was prepared by
reaction of methylamine with MeNCS, while N,N?-
diphenylselenourea was prepared by a modification of
the literature procedure [19]. Complex 2c was prepared
by the literature procedure [6].
a
Complex
IC50
ng mlꢂ1
mM
1a
2a
2b
2c
12 639
2955
822
12.7
3.1
1.0
44.5
37 047
a
The concentration of sample required to reduce the cell growth of
the P388 murine leukaemia cell line (ATCC CCL 46) by 50%.
3.2. Synthesis of [Pt{SeC(Ä
/
NPh)NPh}(PPh3)2] (1)
the cyano methylthiourea complex 2c were prepared by
the triethylamine route used for complex 1, and assayed
for P388 activity; results are given in Table 1. The
dimethylthiourea complex 2b shows substantially higher
activity than all the other complexes, though the
triphenylphosphine diphenylthiourea complex 2a also
shows good activity. The other derivatives, including the
selenourea derivative 1, show significantly lower activ-
ity.
In conclusion, we have synthesised and structurally
characterised the first selenourea dianion complex,
which appears to be very similar to the corresponding
thiourea complex. While this complex shows low
activity against P388 leukaemia cells, it appears that
certain related complexes of thiourea dianion ligands
can show high antitumour activity, and more detailed
studies on the biological properties of this class of
compound are clearly warranted.
The complex cis-[PtCl2(PPh3)2] (80 mg, 0.101 mmol),
and N,N?-diphenylselenourea (28 mg, 0.102 mmol) in
methanol (10 ml) with triethylamine (0.5 ml, excess) was
heated to reflux for 10 min, giving a yellow suspension/
solution. Water (10 ml) was added, and the yellow
precipitate filtered, washed with water (5 ml) and diethyl
ether (5 ml) and dried in vacuo to give complex 1 (89
mg, 89%). Found: C, 58.5; H, 4.0; N, 2.9.
C49H40N2P2PtSe requires C, 59.3; H, 4.1; N, 2.8%.
M.p.: 248ꢀ
/
250 8C (with decomposition). 31P{1H}
1 2
NMR, d 14.9 [d, PPh3 trans Se, J(PtP) 3068, J(SeP)
2
18, J(PP) 20] and 11.5 [d, PPh3 trans N, 1J(PtP) 3252].
1H NMR, d 7.51ꢀ
/
6.40 (m, Ph). ESMS (MeCNꢀ
/H2O),
cone voltage 20 V, m/z 994 [Mꢁ
/
H]ꢁ, 100%.
3.3. Synthesis of thiourea dianion analogues
Complexes 2a and 2b were prepared by a similar
method to that of complex 1.
3. Experimental
3.3.1. [Pt{SC(Ä
/
NPh)NPh}(PPh3)2] (2a)
3.1. General experimental details and materials
cis-[PtCl2(PPh3)2] (400 mg, 0.506 mmol) and N,N?-
diphenylthiourea (116 mg, 0.509 mmol) gave a yellow
powder of 2a, 446 mg (93%), identified as 2a by
comparison of its 31P{1H} NMR data with the literature
values [5].
General experimental details were as described pre-
1
viously from these laboratories [12,14,15]. H, 31P{1H}
and 13C{1H} NMR spectra were recorded on a Bruker
AC300P spectrometer, at 300.13, 121.51 and 75.47
MHz, respectively, in CDCl3. Chemical shifts are
reported relative to CHCl3 (1H and 13C NMR) or
external 85% H3PO4 (31P NMR). Calculated isotopic
distribution patterns were obtained using the ISOTOPE
simulation program [16].
3.3.2. [Pt{SC(Ä
/
NMe)NMe}(PPh3)2] (2b)
cis-[PtCl2(PPh3)2] (253 mg, 0.320 mmol) and
MeNHC(S)NHMe (34 mg, 0.326 mmol) gave a yellow
powder of 2b, 250 mg (95%). Found: C, 56.0; H, 4.3; N,
3.5. Calc. for C39H36N2P2PtS C, 57.0; H, 4.4; N, 3.4%.
31P{1H} NMR, d 19.1 [d, 1J(PtP) 3134, 2J(PP) 20.5] and
Assays were carried out by the commercial service
offered by the Marine Chemistry Group, Department of
Chemistry, Canterbury University, New Zealand. Sam-
1
1
15.0 [d, J(PtP) 3121]. H NMR,d 7.48ꢀ7.10 (m, Ph),
/
4
3
ples were dissolved in 3:1 methanolꢀ
/
dichloromethane
2.89 (s, CÄ
approximately 32]. ESMS (MeCNꢀ
20 V, m/z 822 [Mꢁ
H]ꢁ, 100%. The complex was
/NMe) 2.29 [d, PtNMe, J(PH) 4.26, J(PtH)
prior to testing. The concentration of sample in ng mlꢂ1
required to reduce the cell growth of the P388 leukaemia
cell line (ATCC CCL 46) by 50% yielded IC50 values, by
measurement of the absorbance values when the yellow
/
H2O), cone voltage
/
spectroscopically identical to a sample prepared by the
literature procedure involving silver(I) oxide [12].

W. Henderson et al. / Inorganica Chimica Acta 355 (2003) 428ꢀ
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431
3.4. X-ray structure determination of Pt{SeC(Ä
/
Canterbury) is thanked for the antitumour assays, and
NPh)NPh}(PPh3)2] (1)
Assoc. Prof. Cliff Rickard and Allen Oliver (University
of Auckland) are thanked for collection of the X-ray
data set.
Crystals were obtained by diffusion of diethyl ether
into a dichloromethane solution of the complex. Unit
cell parameters and intensity data were collected using a
Siemens SMART CCD diffractometer, using standard
collection procedures, with monochromatic Mo Ka X-
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difference maps revealed three half-molecules of
CH2Cl2 in the lattice, two disordered over one site and
the third one separate. There is also partial disorder of
the phenyl rings of the selenourea ligand of molecule 2
of 1, as shown by excessive anisotropy. All non-
hydrogen atoms were assigned anisotropic temperature
factors, and hydrogen atoms, except for those on the
disordered solvent, were included in calculated posi-
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C49H40N2P2PtSe×
/
0.75CH2Cl2, Mr 1056.51, triclinic, P
/
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¯
1; aꢃ
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13.909(1), bꢃ
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4.187 mmꢂ1, Tmax 0.497, Tmin 0.384, crystal size
0.26ꢄ 203 K.
0.24 mm3. Tꢃ
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/
16.845(1), cꢃ
109.92(1)8, Vꢃ
4, F(000)ꢃ2086, m(Mo
/
21.551(1) A, aꢃ
/
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101.92(1), bꢃ
/
/
/
4431.1(2)
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˚
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0.40ꢄ
ꢃ
/
/
/
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1.96/ꢂ
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Crystallographic data for the structure analysis have
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We thank the University of Waikato for financial
support of this work, and Johnson Matthey plc for a
generous loan of platinum. Gill Ellis (University of
University of Gottingen, Germany, 1997.
¨