Antiproliferative activity of platinum(II) complexes containing triphenylphosphine: Correlation between structure and biological activity

Article abstract of DOI:10.1016/j.poly.2014.10.001

A series of neutral complexes of platinum(II) of general formula [PtCl₂L(PPh₃)] [L = Et₂NC(Me)NH, SOMe₂, CO, Et₂NH, (HOCH₂CH₂)₂NH, Bz₂NH, N-morpholine] was prepared starting from suitable precursors. The syntheses and spectroscopic characterizations of the two new complexes trans-[PtCl₂(N-morpholine)(PPh₃)] and cis-[PtCl₂(SOMe₂)(PPh₃)] are described as well as their X-ray structures. The antiproliferative activity of all the available compounds was tested in vitro against HeLa, H460 and A549 human tumor cell lines. A brief discussion regarding the structure-activity correlation is presented.

Full text of DOI:10.1016/j.poly.2014.10.001

Polyhedron 85 (2015) 685–689
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Antiproliferative activity of platinum(II) complexes containing
triphenylphosphine: Correlation between structure and biological
activity
Daniela Belli Dell’ Amico a, Lisa Dalla Via b, Aída Nelly García-Argáez b, Luca Labella b, Fabio Marchetti b,
Simona Samaritani a,
⇑
a Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Giuseppe Moruzzi 3, 56124 Pisa, Italy
b Dipartimento di Scienze del Farmaco, Università di Padova, Via F. Marzolo 5, 35131 Padova, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of neutral complexes of platinum(II) of general formula [PtCl2L(PPh3)] [L = Et2NC(Me)NH, SOMe2,
CO, Et2NH, (HOCH2CH2)2NH, Bz2NH, N-morpholine] was prepared starting from suitable precursors. The
syntheses and spectroscopic characterizations of the two new complexes trans-[PtCl2(N-morpho-
line)(PPh3)] and cis-[PtCl2(SOMe2)(PPh3)] are described as well as their X-ray structures. The antiprolifer-
ative activity of all the available compounds was tested in vitro against HeLa, H460 and A549 human
tumor cell lines. A brief discussion regarding the structure–activity correlation is presented.
Ó 2014 Published by Elsevier Ltd.
Received 1 August 2014
Accepted 2 October 2014
Available online 12 October 2014
Keywords:
Platinum(II) complexes
Triphenylphosphine
Antiproliferative activity
Structure–activity relationship
Dialkylamino ligands
1. Introduction
In a previous work [9] we have reported interesting antiprolif-
erative activity on human tumor cell lines for derivatives 4–6
In the continuous search for new platinum based anticancer
drugs [1] following the discovery of cis-[PtCl2(NH3)2] (cis-plati-
num) activity [2], many efforts are oriented to overcome drug-
resistance phenomena [3] and serious collateral effects [4] shown
by this still widely used anticancer agent. While the mechanism
of action of cis-platinum has been deeply investigated [5], much
less is known about cis-platinum analogues. In this context, the
building of new libraries of platinum complexes along with the
availability of data correlating the structure of derivatives with
their activity can be of great help.
Among the many platinum(II) derivatives tested over the last
decades, a growing number of phosphine containing complexes
have shown promising antiproliferative properties [6], being in
some cases [6c,e] active towards cis-platinum resistant tumoral
cells. In the course of our studies on platinum(II) derivatives,
[7,8] we have recently developed convenient synthetic procedures
for the preparation of complexes bearing triphenylphosphine [7]
[PtCl2L(PPh3)] [Chart 1, L = Et2NC(Me)NH (1), SOMe2 (2), CO (3),
Et2NH (4), (HOCH2CH2)2NH (5), Bz2NH (6), N-morpholine (7)].
and, for the most active complex 5, we obtained experimental evi-
dence for its capacity to affect mitochondrial functions [9]. With
the aim of getting some information about the role of free hydroxyl
groups in the noteworthy antiproliferative activity shown by 5,
trans-[PtCl2(N-morpholino)(PPh3)] (Chart 1, 7) was prepared;
indeed, this complex, where oxygen in the amine ligand is still
present, can be formally obtained from 5 by elimination of a mol-
ecule of H2O, followed by cyclization; although the reactivities of
terminal primary hydroxyl groups and dialkylethers can be quite
different, in both cases the oxygen atom can be involved in coordi-
nation to metals and/or hydrogen bonding, thus the comparison
between the biological activities shown in vitro by 5 and 7 seemed
interesting. Moreover, a model compound containing PPh3 and
dimethylsulfoxide (DMSO) ligands was prepared (Chart 1, 2). As
a matter of fact, given the coordinating character of DMSO, when
phosphine complexes are dissolved in this solvent for the biologi-
cal tests in vitro, substitution equilibria cannot be excluded a priori;
small amounts of 2 could then form and affect the observed biolog-
ical activity [10]. We report here the synthesis, the characterization
and the X-ray structures of cis-[PtCl2(SOMe2)(PPh3)] (Chart 1, 2),
and trans-[PtCl2(N-morpholino)(PPh3)] (Chart 1, 7) and, for all the
available Pt complexes shown in the Chart 1, the in vitro antiprolif-
erative activity towards HeLa, H460 and A549 human tumor cell
lines.
⇑
Corresponding author. Tel.: +39 0502219261; fax: +39 0502219260.
E-mail address: simona.samaritani@unipi.it (S. Samaritani).
http://dx.doi.org/10.1016/j.poly.2014.10.001
0277-5387/Ó 2014 Published by Elsevier Ltd.

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D. Belli Dell’ Amico et al. / Polyhedron 85 (2015) 685–689
2.3. Synthesis of trans-[PtCl2(N-morpholino)(PPh3)] (7)
2. Materials and methods
A solution of cis-[PtCl2(NCMe)(PPh3)] (0.215 g, 3.77 Â 10À4 mol)
in MeCN (10.0 mL) was refluxed under stirring and treated with a
solution of morpholine in the same solvent ([morpholine]/
[Pt] = 1.2 M ratio). The mixture was stirred until the maximum
conversion of the precursor was observed (31P NMR, 1.5 h). Aceto-
nitrile was removed under vacuum and the residue after being dis-
solved in the minimum amount of 1,2-dichloroethane (5.0 mL) was
crystallized by addition of heptane (7.0 mL). Bright yellow crystals
were recovered by filtration, washed with heptane and dried under
vacuum (0.116 g, 50% yield). A small sample was recrystallized by
slow diffusion of pentane vapors into a chloroform solution of the
complex and single crystals were selected for the X-ray structure
determination. Elemental Anal. Calc. for C22H24Cl2NOPPt: C, 42.9;
H, 3.9; N, 2.3. Found: C, 42.9; H, 3.6; N, 2.3%. IR (ATR): 3197,
1481, 1433, 1098, 1070 cmÀ1; 1H NMR: 7.80–7.35 (m, 15H, Harom),
3.97–3.93 (m, 3H, NH+NCHH), 3.68–3.59 (m, 4H, OCH2), 3.15–3.10
2.1. General
All manipulations were performed under a dinitrogen atmo-
sphere, if not otherwise stated. Solvents and liquid reagents were
dried according to reported procedures [11]. 1H, 13C, 31P and 195Pt
NMR spectra were recorded with a Bruker ‘‘Avance DRX400’’ spec-
trometer, in CDCl3 solution if not otherwise stated. Chemical shifts
were measured in ppm (d) from TMS by residual solvent peaks for
1H and 13C, from aqueous (D2O) H3PO4 (85%) for 31P and from aque-
ous (D2O) hexachloroplatinic acid for 195Pt. A sealed capillary con-
taining C6D6 was introduced in the NMR tube to lock the
spectrometer to the deuterium signal when non-deuterated sol-
vents were used. FTIR spectra in solid phase were recorded with a
Perkin-Elmer ‘‘Spectrum One’’ spectrometer, equipped with an
ATR accessory. Elemental analyses (C, H, N) were performed at
Dipartimento di Scienze e Tecnologie Chimiche, Università di Udine.
cis-[PtCl2(NCMe)(PPh3)] [7a], cis-[PtCl2(Et2NC(Me)NH)(PPh3)] (1
[7b]), cis-[PtCl2(CO)(PPh3)] (3 [7b]), trans-[PtCl2(Et2NH)(PPh3)] (4
[7b]), trans-[PtCl2{(HOCH2CH2)2NH}(PPh3)](5[9]) andtrans-[PtCl2(-
Bz2NH)(PPh3)] (6 [9]) were prepared according to reported
procedures.
1
195
(m, 2H, NCHH); 31P NMR: 4.75, JPAPt = 3542 Hz;
Pt NMR:
1
3
À3663, JPtAP = 3542 Hz; 13C NMR: 134.7 (d, JCAP = 10 Hz), 130.9,
1
2
128.5 (d, JCAP = 64 Hz), 127.9 (d, JCAP = 11 Hz), 67.9, 48.6.
2.4. Inhibition growth assay
2.2. Synthesis of cis-[PtCl2(SOMe2)(PPh3)] (2)
HeLa (cervix adenocarcinoma), H460 (large cell lung carci-
noma), A549 (non-small cell lung cancer) were grown in Nutrient
Mixture F-12 [HAM] (Sigma Chemical Co.), RPMI 1640 (Sigma
Chemical Co.) supplemented with 2.38 g/L Hepes, 0.11 g/L pyru-
vate sodium, 2.5 g/L glucose and Nutrient Mixture F-12-K (Sigma
Chemical Co.), respectively. 10% Heat-inactivated fetal calf serum
cis-[PtCl2(NCCH3)(PPh3)] (0.176 g; 3.1 Â 10À4 mol) was dis-
solved in dimethylsulfoxide (DMSO, 3.0 mL). 31P NMR spectros-
copy on
a sample of the solution showed the complete
conversion of the precursor into a unique product (18.15 ppm,
1JPAPt = 3772 Hz). Colorless crystals separated out from DMSO solu-
tion upon addition of ethanol (5.0 mL), were recovered by filtra-
tion, washed with ethanol (2.0 mL) and dried (0.136 g, 72% yield).
Single crystals were selected for X-ray structure determination:
cis configuration as well as S-coordination were confirmed. Ele-
mental Anal. Calc. for C20H21Cl2OPSPt: C, 39.6; H, 3.5. Found: C,
(Invitrogen), 100 U/mL penicillin, 100
lg/mL streptomycin, and
0.25 g/mL amphotericin B (Sigma Chemical Co.) were added to
l
the media. The cells were cultured at 37 °C in a moist atmosphere
of 5% carbon dioxide in air. H-460 and A-549 cells (3–4 Â 104) were
seeded into each well of a 24-well cell culture plate. After incuba-
tion for 24 h, various concentrations of the test agents were added
to the complete medium and cells were incubated for a further
72 h. HeLa cells (3–4 Â 104) were seeded into each well of a 24-
well cell culture plate. After incubation for 24 h, the medium was
replaced with an equal volume of fresh medium, and various
38.9; H, 3.3%. IR (ATR): 3058, 3000, 2916, 1145 cmÀ1 1H NMR:
;
3
7.75–7.33 (m, 15 H, Harom), 3.30 ppm (s, 6H, SOCH3, JHAPt = 18 -
1
Hz);31P NMR: 16.18 ppm, JPAPt = 3720 Hz; 195Pt NMR À3902 ppm
1JPAPt = 3720 Hz; 13C NMR: 134.4 (d, J = 10.2 Hz), 131.5, 128.2 (d,
J = 60.0 Hz), 128.2 (d, J = 11.7 Hz), 46.0.
Cl
Cl
PPh3
N
Pt
Cl
Cl
PPh3
S
Cl
PPh3
Cl
Pt
PPh3
O
Pt
H
Pt
Et
NH
Et
Cl
N
Et
Cl
CO
Et
Pt
4
1
2
3
Cl
PPh3
Cl
PPh3
Cl
Cl
PPh3
Pt
Pt
NH
Cl
NH
Bz
Cl
NH
Bz
HO
O
O H
5
6
7
Chart 1. Platinum complexes tested in the present work.

D. Belli Dell’ Amico et al. / Polyhedron 85 (2015) 685–689
687
concentrations of the test complex were added. The cells were then
incubated in standard conditions for a further 72 h.
A trypan blue assay was performed to determine cell viability.
Cytotoxicity data were expressed as GI50 values, i.e., the concentra-
tion of the test agent inducing 50% reduction in cell number com-
pared with control cultures.
(NCMe)] [7a]. Compounds 2, 3 and 4 [7b], 5 and 6 [9] and 7 were
prepared by substitution reactions of cis-[PtCl2(PPh3)(NCMe)]
[7a] with the suitable nucleophile under appropriate experimental
conditions. In particular, in the case of DMSO derivative 2, crystals
of the product were obtained from a DMSO solution of the precur-
sor, upon addition of ethanol. S-coordination to platinum could be
inferred by the ipsochromic shift of the S@O stretching observed in
the IR spectrum (1145 versus 1050 cmÀ1 in the free ligand) [15], as
well as by the downfield shift of the CH3 carbon signal in the 13C
NMR spectrum carried out in CDCl3 (46.0 versus 41.0 ppm for the
free ligand in the same solvent) [16]. This hypothesis was con-
firmed by X-ray diffraction studies on single crystals of 2, that also
showed the cis configuration of the complex (Fig. 1).
The molecular structure of complex 2 is shown in Fig. 1 and its
more relevant geometric parameters are listed in Table 2. The
metal shows the usual square planar coordination typical of Pt(II)
derivatives (max dev. 0.11 Å by Cl(2)). The chlorine atoms occupy
two cis positions being in trans to the phosphine ligand and to
the sulfoxide ligand. The sulfoxide oxygen is pointed towards the
phosphine and roughly lies on the Pt coordination plane. The
disposition is very similar to that found in cis-[dichloro(3,6-dihy-
dro-1,2-oxazine)(dimethylsulfoxide)platinum(II)] [17] or in cis-
[dichloro(cyclopentylamine)(S-dimethylsulfoxide-)platinum(II)]
[18], where the phosphino ligand is substituted by the oxazino or
by the cyclopentylamino ones. With respect to these compounds,
however, the two PtACl bonds in 2 differ more in length. That
opposite to the phosphine, consistently with the known structures
of cis-[dichlorobis(triphenylphosphine)platinum(II)] [19], is 2.35 Å
long, while that opposite to the sulfoxide is 2.29 Å long. This last
value represents the lowest limit for the PtACl bond length range
in cis-dichlorodimethylsulfoxide structures [mean value
2.308(2) Å] according to a survey on the Cambridge Structural Data
Base. [20].
2.5. X-ray structure determination
The X-ray single-crystal data of the compounds 2 and 7 were
collected on a Bruker-AXS SMART-Breeze CCD diffractometer at
room-temperature. The crystallographic data, the conditions used
for the intensity data collection and some features of the structure
refinements are listed in Table 1. The intensities of 99% of reflec-
tions of the Ewald sphere with a hmax = 29.5° and 30°, respectively,
were collected with a mean redundancy of about 4. Data process-
ing, Lorentz-polarization and absorption corrections were per-
formed using SMART, SAINT and the SADABS computer programs [12].
The structures were solved by direct methods and refined by
full-matrix least-squares methods on F2, using the SHELXTL [13] pro-
gram package. All non-hydrogen atoms were refined anisotropi-
cally. The hydrogen atoms were located from difference Fourier
maps, assigned with isotropic displacement factors and included
in the final refinement cycles by use of geometrical constraints.
Some other utilities contained in the WINGX suite [14] were also
used. Some reliability factors of the structure refinement are
reported in Table 1.
3. Results and discussion
3.1. Synthesis of the complexes 1–7
The preparation of trans-[PtCl2(N-morpholino)(PPh3)] (7) was
carried out by addition of a slight excess of morpholine to a reflux-
ing acetonitrile solution of cis-[PtCl2(NCMe)(PPh3)]. As already
observed in the case of diethylamine, [7b] under these conditions,
a fast cis to trans isomerization of the precursor occurs, followed by
nitrile substitution by the secondary amine. The complex was
The platinum(II) derivatives prepared and tested in this study
are reported in Chart 1. All the complexes are characterized by
the presence of a triphenylphosphine and two chloride ligands,
while the other ligand is varied in the nature and in the relative
position. Complex 1 [7b] was prepared by low temperature
(À30 °C) addition reaction of diethylamine on cis-[PtCl2(PPh3)
Table 1
Crystal data and structure refinement parameters for compounds 2 and 7.
Formula
Formula weight
T (K)
C20H21Cl2OPPtS
606.39
296(2)
C22H24Cl2NOPPt
615.38
296(2)
Color
colorless
triclinic
P1 (No. 2)
colorless
triclinic
P1 (No. 2)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
ꢀ
ꢀ
10.3041(1)
10.5610(2)
12.5185(2)
95.706(1)
108.445(1)
118.791(1)
1079.35(3)
2
11.3705(6)
14.1820(7)
16.0292(8)
73.375(2)
71.462(2)
71.462(2)
2273.5(2)
4
a
(°)
b (°)
c
(°)
V (Å3)
Z
l
(mmÀ1
)
6.906
6.490
F(000)
584
1.861
1192
1.798
Dcalc (g cmÀ3
)
k(Mo K
h (°)
Reflection collected/unique
Absorption correction
Rint
a
) (Å)
0.71073
2.29–29.50
22139/5989
multi-scan
0.0348
0.71073
2.09–30.07
47322/13171
multi-scan
0.0175
Parameters refined
237
505
R1 [I > 2
r
(I)]
0.0269
0.0202
wR2 (all data)
0.0444
0.969
0.0450
1.026
Goodness-of-fit (GOF) on F2
Fig. 1. View of the molecular structure of cis-[PtCl2(SOMe2)(PPh3)] (2). Thermal
ellipsoids are at 30% probability.

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D. Belli Dell’ Amico et al. / Polyhedron 85 (2015) 685–689
Table 2
Table 4
Selected bond lengths (Å) and angles (°) in 2.
Cell growth inhibition values in the presence of complexes 1–7 and cis-platinum (cis-
Pt) as reference drug.
Pt(1)ACl(1)
Pt(1)AS(1)
S(1)AO(1)
2.3541(8)
2.2215(8)
1.459(2)
Pt(1)ACl(2)
Pt(1)AP(1)
2.2895(8)
2.2624(7)
Complex
Cell line GI50
HeLa
(l
M)a
H460
A549
Cl(1)APt(1)ACl(2)
Cl(2)APt(1)AP(1)
Pt(1)AS(1)AO(1)
88.20(3)
92.12(3)
118.6(1)
Cl(1)APt(1)AS(1)
S(1)APt(1)AP(1)
88.03(3)
90.10(8)
1
2
7.0 1.2
5.7 1.6
>20
5.1 1.5
0.42 0.06
3.3 1.7
9.7 0.7
1.5 0.6
18.5 4.0
>20
>20
6.8 0.6
1.1 0.3
6.6 1.4
4.4 0.3
0.76 0.11
12.1 3.1
15.3 3.7
>20
8.4 0.4
2.3 0.7
7.0 1.2
12.8 0.8
1.6 0.7
3
4b
5b
6b
7
cis-Ptb
a
Mean values SD of at least three independent experiments are reported.
See Ref. [9].
b
rotation angles around the PAC bonds of the phosphine phenyl
groups. The PtACl bond distances (Table 3) are all similar to the
shorter one in compound 2. The PtAN distance is slightly longer
than that reported for the morpholine complex trans-[PtCl2(N-
morpholino)(DMSO)] [23] which shows a distance of 2.09 Å.
3.2. Biological tests and conclusions
The antiproliferative activity of all complexes was evaluated on
three human tumor cell lines: HeLa (cervix adenocarcinoma), H460
(large cell lung carcinoma) and A549 (non-small cell lung cancer).
The results are reported in Table 4 and are expressed as GI50 values,
i.e. the concentration (lM) of complex able to cause 50% of cell
death with respect to the control culture.
The well-known drug cis-platinum was used as reference com-
pound. A notable cytotoxic effect, comparable to that obtained for
the reference drug, is exerted by 5 [9], characterized by a trans con-
figuration and carrying a bis(2-hydroxyethyl)amine ligand coordi-
nated to the platinum. An interesting capacity to inhibit cell
growth is also showed by 4 [9], 6 [9] and 7. Otherwise, cis com-
plexes 1 and 2 showed a low antiproliferative capacity, whereas
3 is ineffective under the same experimental conditions. As far as
the inactivity of 3 is concerned, we did not collect specific data
to explain it, but the high reactivity of platinum(II) carbonyl com-
plexes towards protic nucleophiles [24] such as those found in
aqueous cellular media could be the basis for this behavior. It is
anyway interesting to note that all complexes able to exert a signif-
icant antiproliferative effect are characterized by the trans isomery
and by the presence of a dialkylamine coordinated to the metal
(Chart 1). It has also to be underlined that, despite the structural
similarity between 5 and 7, the cytotoxicity shown by the two
complexes is quite different, with 5 significantly more active than
7 (Table 4). These data suggest that the presence of a dialkylamino
ligand trans to PPh3 as well as the availability of hydroxyl groups
are important for the development of biologically active
complexes.
Fig. 2. View of the molecular structure of trans-[PtCl2(N-morpholino)(PPh3)] (7).
Thermal ellipsoids are at 30% probability.
characterized by spectroscopic analysis and X-ray diffraction stud-
ies on single crystals (Fig. 2).
The molecular structure of compound 7 (Fig. 2) is similar to that
of
trans-[dichloro(pyrrolidine)(triethylphosphine)platinum(II)]
(PRLPTA) [21] or that of trans-[dichloro-((S)-1-methylpropyl-
amine) (triphenylphosphine) platinum(II)] (BAPXOG) [22]. Unlike
these structures, however, the asymmetric unit of 7 is made by a
couple of molecules, as shown in Fig. 2. The two molecules show
very similar conformations and may be distinguished by different
Table 3
Acknowledgments
Selected bond lengths (Å) and angles (°) in 7.
Pt(1)ACl(1)
Pt(1)ACl(2)
Pt(1)AN(1)
Pt(1)AP(1)
2.2913(7)
2.2969(8)
2.128(2)
Pt(2)ACl(3)
Pt(2)ACl(4)
Pt(2)AN(2)
Pt(2)AP(2)
2.2885(8)
2.2997(8)
2.129(2)
The Ministero dell’ Università e della Ricerca Universitaria (MIUR),
Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN 2009) is
gratefully acknowledged for financial support. Thanks are due to
Chimet S.p.A., I-52041 Badia al Pino (Arezzo) for a loan of platinum.
L. Dalla Via and A.N. García-Argáez are grateful to the financial sup-
port provided by Università degli Studi di Padova – Progetti di Ric-
erca di Ateneo 2010 – ‘‘Attività antitumorale di nuovi composti di
coordinazione nel carcinoma del polmone non a piccole cellule
(NSCLC)’’.
2.2498(7)
2.2454(7)
P(1)APt(1)ACl(1)
P(1)APt(1)ACl(2)
N(1)APt(1)ACl(1)
N(1)APt(1)ACl(2)
P(1)APt(1)AN(1)
Cl(1)APt(1)ACl(2)
94.60(3)
91.05(3)
84.09(7)
90.25(7)
178.62(7)
173.99(3)
P(2)APt(2)ACl(3)
P(2)APt(2)ACl(4)
N(2)APt(2)ACl(3)
N(2)APt(2)ACl(4)
P(2)APt(2)AN(2)
Cl(3)APt(2)ACl(4)
96.36(3)
90.03(3)
84.62(7)
88.97(7)
178.69(7)
173.58(3)

D. Belli Dell’ Amico et al. / Polyhedron 85 (2015) 685–689
689
(h) J.-C. Shi, C.-H. Yueng, D.-X. Wu, Q.-T. Liu, B.-S. Kang, Organometallics 18
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Appendix A. Supplementary data
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(2012) 1389;
(b) D. Belli Dell’Amico, C. Broglia, L. Labella, F. Marchetti, F. Marchetti, D.
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[8] D. Belli Dell’Amico, L. Labella, F. Marchetti, S. Samaritani, J. Organomet. Chem.
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[9] L. Dalla Via, A.N. Garcia-Argaez, A. Adami, S. Grancara, P. Martinis, A. Toninello,
D. Belli Dell’Amico, L. Labella, S. Samaritani, Bioorg. Med. Chem. 21 (2013)
6965.
CCDC 950540–950541 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or
from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk.
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