Multinuclear platinum(II)-amine complexes containing bis(aminopropyl) dicarba-closo-dodecaborane(12) ligands

Article abstract of DOI:10.1039/b408801h

Treatment of the bridging bidentate 1,Z-bis(aminopropyl)-1,Z-dicarba-closo- dodecaborane(12) (1,Z-bis(aminopropyl)-1,Z-carborane) ligands of the type 1,Z-{H₂N(CH₂)₃}₂-1,Z-C ₂B₁₀H₁₀ (L¹, Z = 7, 5) or (L ², Z = 12, 6) with two equivalents of trans-[PtClI ₂(NH₃)]^-, followed by halogen ligand metathesis with AgOTf and HCl_(aq) afforded the novel diplatinum(II)-amine species cis-[{PtCl₂(NH₃)}₂Lⁿ] (7 (n = 1) or 8 (n = 2), respectively). Similarly, the reaction of L¹ or L² with the labile trans-[PtCl(dmf)(NH₃)₂] ⁺ afforded trans-[{PtCl(NH₃)₂} ₂Lⁿ](OTf)₂ (9 (n = 1) or 10 (n = 2), respectively) in good yield and purity. However, isolation of the analogous 1,2-carborane complexes was not possible owing to decomposition reactions that led to extensive degradation of the carborane cage and reduction of the metal centre. The mixed dinuclear complex [cis-{PtCl₂(NH ₃)}-L¹-trans-{PtCl(NH₃)₂}]OTf (19) was prepared by treatment of the Boc-protected amine ligand 1-{(Boc) ₂N(CH₂)₃}-7-{H₂N(CH ₂)₃}-1,7-C₂B₁₀H₁₀ (L ³,15) with trans-[PtCl(dmf)(NH₃)₂]⁺ to yield trans-[PtCl(NH₃)₂L³]OTf (16), followed by acid deprotection of the pendant amine group, complexation with trans-[PtClI₂(NH₃)]^-, and halogen ligand metathesis using AgOTf and HCl_(aq). A novel trinuclear species containing 5 was prepared by the addition of two equivalents of 15 to the labile precursor cis-[Pt(dmf)₂(NH₃)₂]²⁺ followed by acid deprotection of the pendant amine groups. Further complexation with two equivalents of trans-[PtClI₂(NH₃)]^- followed by halogen ligand metathesis using AgOTf and HCl_(aq) afforded the triplatinum(II)-amine species [cis-{Pt(NH₃) ₂(L¹)₂}-cis-{PtCl₂(NH ₃)}₂](OTf)₂ (23). Complexes 7-10, 19 and 23 represent the first examples of multinuclear platinum(II)-amine derivatives containing carborane cages. Preliminary in vitro cytotoxicity studies for selected complexes are also reported.

Full text of DOI:10.1039/b408801h

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F U L L P A P E R
Multinuclear platinum(II)–amine complexes containing
bis(aminopropyl)dicarba-closo-dodecaborane(12) ligands
Susan L. Woodhouseb and Louis M. Rendina*a
a
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
E-mail: rendina@chem.usyd.edu.au; Fax: +61 2 9351 3329; Tel: +61 2 9351 4781
School of Chemistry and Physics, The University of Adelaide, Adelaide, South Australia 5005,
b
Australia
Received 11th June 2004, Accepted 22nd September 2004
First published as an Advance Article on the web 6th October 2004
Treatment of the bridging bidentate 1,Z-bis(aminopropyl)-1,Z-dicarba-closo-dodecaborane(12) (1,Z-
bis(aminopropyl)-1,Z-carborane) ligands of the type 1,Z-{H2N(CH2)3}2-1,Z-C2B10H10 (L1, Z = 7, 5) or (L2, Z = 12,
6) with two equivalents of trans-[PtClI2(NH3)]−, followed by halogen ligand metathesis with AgOTf and HCl(aq)
afforded the novel diplatinum(II)–amine species cis-[{PtCl2(NH3)}2Ln] (7 (n = 1) or 8 (n = 2), respectively). Similarly,
the reaction of L1 or L2 with the labile trans-[PtCl(dmf)(NH3)2]+ afforded trans-[{PtCl(NH3)2}2Ln](OTf)2 (9 (n = 1)
or 10 (n = 2), respectively) in good yield and purity. However, isolation of the analogous 1,2-carborane complexes
was not possible owing to decomposition reactions that led to extensive degradation of the carborane cage and
reduction of the metal centre. The mixed dinuclear complex [cis-{PtCl2(NH3)}–L1-trans-{PtCl(NH3)2}]OTf (19) was
prepared by treatment of the Boc-protected amine ligand 1-{(Boc)2N(CH2)3}-7-{H2N(CH2)3}-1,7-C2B10H10 (L3, 15)
with trans-[PtCl(dmf)(NH3)2]+ to yield trans-[PtCl(NH3)2L3]OTf (16), followed by acid deprotection of the pendant
amine group, complexation with trans-[PtClI2(NH3)]−, and halogen ligand metathesis using AgOTf and HCl(aq)
.
A novel trinuclear species containing 5 was prepared by the addition of two equivalents of 15 to the labile precursor
cis-[Pt(dmf)2(NH3)2]2+ followed by acid deprotection of the pendant amine groups. Further complexation with
two equivalents of trans-[PtClI2(NH3)]− followed by halogen ligand metathesis using AgOTf and HCl(aq) afforded
the triplatinum(II)–amine species [cis-{Pt(NH3)2(L1)2}-cis-{PtCl2(NH3)}2](OTf)2 (23). Complexes 7–10, 19 and 23
represent the first examples of multinuclear platinum(II)–amine derivatives containing carborane cages. Preliminary
in vitro cytotoxicity studies for selected complexes are also reported.
are capable of demonstrating persistent DNA-binding within
Introduction
tumour cells in addition to localising adequate concentrations
Boron neutron capture therapy (BNCT) is an experimental
of 10B near chromosomal DNA.
cancer treatment that is currently undergoing Phase I/II clinical
The coordination chemistry of closo-carboranes (di-
carba-closo-dodecaboranes(12)) bearing N-donor groups,
trials in several countries.1–4 The key aspect of the therapy is the
interaction of slow (thermal) neutrons with 10B-containing drugs
e.g. phenylazo 1, N,N-dimethylamino 2, and alkylamino 3
that are localised within malignant cells. The resulting nuclear
(n = 1–3) is an area of increasing interest.19 Zakharkin and
reactions with the 10B nucleus ultimately lead to cell destruction
co-workers reviewed the preparation of a series of cyclometal-
lated Group 7 complexes and a dinuclear palladium(II) species
containing 1 or 2 in which the carborane derivative acts as a
owing to the production of high linear energy transfer (LET)
particles that are accompanied by approximately 2.4 MeV of
kinetic energy. The effectiveness of the neutron capture reac-
chelating ligand and forms a M–B bond that is stabilised by
tion is dramatically enhanced if 10B-containing compounds
intramolecular coordination of the nearby N-donor atom.20
are placed in close proximity to chromosomal DNA,5–7 and the
Kang and co-workers have reported the organometallic
search for new DNA-binding agents with relevance to BNCT
chemistry of 2 with gallium(III),21 tin(IV),22 mercury(II)22 and
remains a major research objective.8
Farrell and co-workers have developed an extensive series of
multinuclear platinum(II) complexes bridged by linear or sub-
stituted aliphatic linkers that possess a greater affinity for DNA
than the archetypal platinum anti-cancer agent cisplatin.9–14
This class of ‘non-classical’ DNA-binding agents has been
comprehensively studied and extended to include variations in
the number of platinum(II) centres, linker lengths, bi-, tri- and
tetra-functionality, and coordination geometry that allow a
diverse array of unique adducts to be formed with DNA. The
study of multinuclear platinum(II) complexes has resulted in
the development of a trinuclear platinum(II) complex known
as BBR3464, the first representative of the ‘non-classical’
class of multinuclear platinum(II) anti-cancer drugs to enter
clinical trials.12,15–17 The rapid DNA binding of complexes
such as the highly-charged BBR3464 results in high levels of
platination.11,18 The DNA adducts persist over time, implying
poor DNA-adduct repair, and thus contribute to a more per-
sistent perturbation of the cell cycle than cisplatin.12 Indeed,
the use of multinuclear complexes as tumour delivery agents
for boron clusters may potentially combine the favourable
aspects of platinum chemotherapy and BNCT if such complexes
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
D a l t o n T r a n s . , 2 0 0 4 , 3 6 6 9 – 3 6 7 7
3 6 6 9

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Group 9 and 10 transition metals23 whereby the carborane is
bonded to the metal centre via one of the carbon atoms rather
than a proximal boron atom. In contrast, the coordination
chemistry of 3 had not been explored until recently when the
first examples of mononuclear platinum(II)–amine complexes
containing this ligand (n = 1, 3) were reported.24 Herein we
report the preparation and characterisation of related di- and
tri-nuclear platinum(II)–amine complexes containing bridging
bidentate diamine ligands that incorporate a closo-1,12- or 1,7-
carborane entity. A preliminary communication of this work has
been reported.25
dichloro geometry, as indicated by the characteristic singlet
resonance in the 195Pt{1H} NMR spectrum at d −2156 that is
consistent with a PtCl2N2 core.28 However, a minor impurity
signal was sometimes observed at d −2462. While the identity of
this impurity remains unconfirmed, the chemical shift is consis-
tent with a PtN3Cl complex,28 e.g. a 1:1 mononuclear complex
containing an N,N-chelate ring. It proved extremely difficult
to purify 7 by recrystallisation methods alone and, in order to
increase its purity, K[PtCl3(NH3)] was treated with an excess of
KI to generate trans-[PtClI2(NH3)]− in situ prior to the reaction
with 5 or 6. Farrell and co-workers have demonstrated that
amine ligands L readily displace either one of the iodo ligands in
trans-[PtClI2(NH3)]− to give the neutral mixed-halogen complex
[PtClI(NH3)(L)] in which L is located trans to the iodo ligand.29
Thus, treatment of [PtClI2(NH3)]− with 5 followed by the
sequential addition of four equivalents of AgNO3 and 0.1 M
HCl afforded the desired 7 with a cis-dichloro geometry. Under
identical conditions, 6 was converted into the corresponding
dinuclear platinum(II) species 8. Once again, the formation
of 7 and 8 was confirmed by a characteristic resonance in the
195Pt{1H} NMR spectrum at d −2156 and −2155, respectively.
Results and discussion
The bis(aminopropyl)carborane ligands 4 and 5 were prepared
from the respective parent carboranes according to the litera-
ture procedure established for the corresponding 1,12-carborane
isomer 6.26 The HCl salts of 4–6 were isolated as stable, colour-
less powders that could be stored at room temperature for
indefinite periods of time. The free amines were freshly prepared
prior to the complexation reactions by treatment of an aqueous
solution containing the corresponding HCl salt with an excess
of K2CO3 in the presence of CH2Cl2.
The preparation of a diplatinum(II)–amine species contain-
ing a closo-1,2-carborane entity was attempted by the reaction
of 4 with two equivalents of K[PtCl3(NH3)] in DMF–H2O or
MeOH–H2O solvent mixtures. However, the isolated yellow
solid proved to be quite unstable and it discoloured upon puri-
fication and/or standing for extended periods of time. 11B{1H}
NMR spectroscopy confirmed extensive degradation of the
closo-carborane cage in 4, a process that was accompanied by
reduction of the platinum(II) centre to afford colloidal platinum
and/or an unidentified dark material that is soluble in organic
solvents and is likely to be a low-valent cluster species containing
Pt–Pt bonding. This phenomenon has recently been described in
detail for related mononuclear complexes,24 and the decomposi-
tion process is most probably initiated by nucleophilic attack
of the amine functionality on the closo-1,2-carborane cage to
generate the corresponding nido species, the rate of which is
greatly enhanced by the presence of water.27 The decomposition
of the platinum(II) complex containing 4 was found to be slower
than that observed for the related mononuclear complexes,24
especially under anhydrous conditions, demonstrating that the
bifunctionalisation of 1,2-carborane somewhat increases the
stability of the platinum(II)–amine derivatives perhaps due to
steric factors. It was also found that the degradation process
could be retarded significantly by lowering the pH of the solu-
tion (pH < 2). However, under such conditions the free amines
are fully protonated and the complexation did not proceed to
completion.
Treatment of the diamine ligand 5 or 6 with two equivalents
of the labile trans-[PtCl(dmf)(NH3)2]+ afforded the correspond-
ing dinuclear complexes 9 and 10 with characteristic resonances
in the 195Pt{1H} NMR spectrum at d −2410 and −2409, respec-
tively. The chemical shifts of these resonances are consistent
with a complex possessing a PtN3Cl core.28
The platinum derivatives 7–10 display an extensive broaden-
1
ing of the 11B NMR signals (both H-coupled and decoupled)
at room temperature which does not allow the determination of
11B–1H coupling constants, or indeed, adequate resolution of the
individual resonances in the case of 1,7-carborane derivatives
such as 7 and 9. This effect is most likely attributed to the slow
The reaction of 5 with two equivalents of K[PtCl3(NH3)]
afforded the corresponding dinuclear complex 7 with a cis-
3 6 7 0
D a l t o n T r a n s . , 2 0 0 4 , 3 6 6 9 – 3 6 7 7

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tumbling in solution of these large molecular entities contain-
ing quadrupolar 11B nuclei which would increase the molecular
correlation time (sc) and thus shorten T1.30
genation conditions, e.g. reduction of the metal centre. Typically,
a Cbz group was removed in an acidified polar solvent such as
EtOH in the presence of a Pd catalyst under a high-pressure H2
atmosphere, although acidic conditions would have resulted in
the loss of the Boc protecting groups in 13 and 14. Using related
hydrogenation conditions to those described by Sjöberg and
co-workers,31 15 was successfully obtained in quantitative yield
by means of a Pd–C catalyst in a buffered NH4HCO2/AcOH
solution. Due to the tendency of the free amine to degrade the
closo-carborane cage,27 15 was freshly prepared prior to reaction
with the platinum(II) precursors.
The preparation of di- and tri-nuclear complexes
containing mixed platinum(II) centres required that the
amine groups in 5 were protected using both Boc (tert-
butoxycarbonyl) and Cbz (benzyloxycarbonyl) thus allowing
their selective removal by means of different deprotection
protocols.26,31–34 The Cbz protecting group can be removed
under standard hydrogenation conditions and it is stable in the
presence of acid. In contrast, the Boc protecting group can be
removed under acidic conditions and it is stable under (non-
acidic) hydrogenation conditions. In both cases, the structural
integrity of the carborane cage is preserved.
The reaction of the diiodo species 11 with one equivalent
of HN(Cbz)2 under phase-transfer conditions gave the Cbz-
protected monoamine 12 in moderate yield (Scheme 1). The
reaction time was limited to 5 h as longer periods resulted
in the dissociation of one of the Cbz groups.26 Due to the
tendency of the Cbz protecting groups to dissociate under
phase-transfer conditions, the Boc-protected amine group
in 13 was incorporated by gently warming a DMF solu-
tion containing 12 with one equivalent of HN(Boc)2 in the
presence of K2CO3 to afford 13 in moderate yield. If the
reaction temperature exceeded 60 °C or the reaction was
allowed to proceed for long periods of time (> 48 h), one of
the Cbz groups was dissociated to give the mono-Cbz protected
amine 14. However, 13 and 14 were readily separated by flash
chromatography and both compounds underwent the sequential
deprotection steps outlined as follows.
The labile species trans-[PtCl(dmf)(NH3)2]+ readily reacted
with 15 to afford the mononuclear platinum(II) species 16
(Scheme 2). The product of this reaction is unusual as it is
soluble in solvents such as MeOH and EtOAc, thus allowing
the facile separation of any unreacted trans-[PtCl2(NH3)2] pre-
cursor from solution. The coordination of the primary amine in
15 to the platinum(II) centre was confirmed by a characteristic
resonance in the 195Pt{1H} NMR spectrum at d −2409, consis-
tent with a PtN3Cl core. There was also a marked change in the
13C{1H} NMR spectrum with the CH2NH2 signal shifting from
d 40.4 to d 47.4 upon coordination. The Boc protecting groups
in 16 were readily removed by treatment of the complex with
3 M HCl affording 17·HCl which contained a pendant amine
group that could be used in further complexation reactions.
In an effort to prepare the diplatinum(II) complex 19
containing both cis-[PtCl2(NH3)(amine)] and trans-[PtCl(NH3)2-
(amine)]+ centres, treatment of K[PtCl3(NH3)] with 17 was
attempted in a mixed DMF–H2O solvent system, essential
for maintaining the solubility of all reactants. However, the
slow rate of ligand substitution in [PtCl3(NH3)]−, particularly
in DMF solution, necessitated the use of iodide ion in order
to enhance the rate of reaction. Indeed, the rate was greatly
enhanced when trans-[PtClI2(NH3)]− was used in the presence
The Cbz protecting group(s) were removed prior to the Boc
groups from 13 and 14. This order of deprotection was chosen
in order to eliminate any potential complications that may have
occurred if a platinum(II) derivative was subjected to hydro-
Scheme 1 Reagents: (i) HN(Cbz)2, Bu4NHSO4, 2 M NaOH, CH2Cl2; (ii) HN(Boc)2, K2CO3, DMF.
Scheme 2 Reagents: (i) H2/Pd–C catalyst, NH4HCO2/AcOH; (ii) trans-[PtCl(dmf)(NH3)2]OTf; (iii) 10 M HCl in EtOAc; (iv) trans-[PtClI2(NH3)]−,
K2CO3; (v) AgOTf, 0.1 M HCl.
D a l t o n T r a n s . , 2 0 0 4 , 3 6 6 9 – 3 6 7 7
3 6 7 1

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Table 1 IC50 values (lM) for 7 and 9 (n = 2). L1210 and L1210/DDP
of K2CO3 to afford the dinuclear species 18 containing a mixed-
halogen ligand set. The presence of excess KI also resulted in
the exchange of the chloro ligand at the remote PtN3Cl centre
to form the corresponding PtN3I species. The presence of
two inequivalent coordination spheres in 18 was confirmed
by 195Pt{1H} NMR spectroscopy, with resonances appearing
at d −2652 and d −2851 in a 1:1 ratio corresponding to the
PtN2ClI and PtN3I cores, respectively. Upon treatment of 18
with three equivalents of AgOTf followed by the addition of
HCl(aq) afforded 19 as a bright-yellow complex.
cell lines were assayed by means of a coulter counting (CC) assay. 2008
and C13*5 cell lines were assayed by means of a sulforhodamine B
(SRB) assay
Cell Line
7
9
Cisplatin
L1210
L1210/DDP
2008
2.0
2.5
13
13
1.1
1.4
5.4
5.6
0.5
6.9
0.6
10
C13*5
Once the synthesis of the key amine 15 was successfully
achieved, the synthesis of a novel trinuclear platinum(II)
complex containing 5 could also be realised. The methodology
employed in this work was adapted from that described by
Farrell, Appleton and Hoeschele for the synthesis of (non-
boron containing) trinuclear platinum(II) complexes.35 Treat-
ment of cis-[PtI2(NH3)2] with two equivalents of AgOTf in
DMF afforded the labile species cis-[Pt(dmf)2(NH3)2]2+ which
upon the addition of two equivalents of 15 resulted in the rapid
formation of the platinum(II) species 20 (Scheme 3). The coordi-
nation of the primary amine group in 15 to the metal centre was
supported by a shift in the 13C{1H} NMR signal corresponding
to the CH2NH2 group from d 40.4 to d 46.8 and the appear-
ance of a signal at d −2663 in the 195Pt{1H} NMR spectrum,
characteristic of a PtN4 coordination sphere.28 The mono-
nuclear complex 20 was sufficiently soluble in EtOAc to allow
Boc-deprotection under standard acidic conditions to afford 21.
Removal of the Boc protecting groups in 20 was accompanied
by a significant shift in the 13C{1H} NMR signal from d 46.8 to
d 39.6. As expected, no change was observed in the 195Pt{1H}
NMR spectrum of 21.
The terminal amine groups in 21 were deprotonated by
treatment with K2CO3 prior to the reaction with trans-
[PtClI2(NH3)]−. The coordination of each of the free amine
groups to platinum(II) was confirmed by a characteristic shift
in the 13C{1H} NMR signal from d 39.6 to d 46.0. The forma-
tion of 22 could not be confirmed by 195Pt{1H} NMR spectro-
scopy alone because, coincidentally, both the PtN4 and PtIClN2
centres characteristically display NMR signals at ca. d −2600.29
Consequently, only one peak was observed for 22 at d −2646,
and no signals corresponding to the precursor complex or other
platinum(II) centres were observed. In order to confirm that the
195Pt{1H} NMR spectrum was the result of overlapping signals
attributed to two different platinum(II) centres, 22 was treated
with four equivalents of AgOTf, followed by an excess of HCl(aq)
to afford two new cis-PtCl2N2 centres in 23. This conversion was
confirmed by the observation of two 195Pt{1H} NMR signals at
d −2157 and d −2651 in a 2:1 ratio, corresponding to the cis-
PtCl2N2 and PtN4 centres, respectively.
In vitro cytotoxicity studies
Preliminary in vitro cytotoxicity studies were conducted with the
dinuclear species 7 and 9 which were screened against a range of
tumour cell lines in order to determine whether the complexes
exhibited a cytotoxic effect in the absence of neutrons; the low
solubility of the 1,12-carborane derivatives 8 and 10 and tri-
nuclear 23 precluded an assessment of their cytotoxicity. The cell
lines included L1210 murine leukaemia cells and its cisplatin-
resistant variant (L1210/DDP), along with the cisplatin-sensitive
(2008) and -resistant (C13*5) human ovarian carcinoma. The
concentrations (lM) required to achieve 50% inhibition of cell
growth in each cell line (IC50) are presented in Table 1.
The results of the preliminary anti-cancer screening of 7 and
9 are encouraging. Most importantly, the IC50 values lie within
the same order of magnitude as those observed for cisplatin and
appear to indicate that the compounds are able to enter cells
without difficulty. This is extremely promising as the achieve-
ment of adequate boron uptake by tumour cells is a highly valued
goal in BNCT. The IC50 values also indicate the compounds are
cytotoxic in the absence of neutrons. The mechanism of induc-
ing cell death is unknown at the present time, but it is reasonable
to assume that the effects are the result of avid DNA-binding as
the complexes are capable of binding to plasmid DNA.25 The
cytotoxic effects of 7 and 9 in the absence of neutrons are not
as essential to their proposed application as BNCT agents as is
their ability to bind to DNA. A limited cytotoxicity exhibited
by the complexes is not necessarily undesirable and could, in
some cases, enhance the anti-cancer characteristics of the com-
pounds in the presence of neutrons by an additive or perhaps
synergistic effect. Indeed, if the complexes were potent cytotoxic
agents (i.e. with IC50 values in the nM range) their application
in BNCT would be limited as this would result in cell death at
low platinum(II) concentrations, prior to the accumulation of a
sufficient level of boron within the tumour cell.
Scheme 3 Reagents: (i) cis-[Pt(dmf)2(NH3)2](OTf)2; (ii) 10 M HCl in EtOAc; (iii) trans-[PtClI2(NH3)]−, K2CO3; (iv) AgOTf, 0.3 M HCl.
3 6 7 2
D a l t o n T r a n s . , 2 0 0 4 , 3 6 6 9 – 3 6 7 7

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Complex 9 was consistently more active than 7 in all cell
lines that were examined. This may be due to the di-cationic
nature of 9, which would not only enhance the aqueous
solubility of the complex but perhaps also enhance its DNA-
binding affinity via electrostatic interactions. Additionally, the
cationic charge could potentially assist with the internalisation
of the dinuclear complex by the cells, thereby balancing out
the lipophilicity associated with the carborane cage. In both
cisplatin-sensitive cell lines L1210 and 2008, 7 and 9 were not
as effective as cisplatin at inhibiting cell growth. This could be
attributed to their limited aqueous solubility or perhaps a less
efficient mechanism of cellular internalisation by the complexes
compared with cisplatin. Indeed, the incorporation of the
sterically bulky, lipophilic carborane moiety into the complexes
would modulate their biological activity to some degree.
Finally, the cytotoxicities of 7 and 9 in the cisplatin-resistant
cell lines L1210/DDP and C13*5 were not only greater than
that of cisplatin but were also very similar to those observed
in the respective parent cell lines, indicating the mechanisms of
cisplatin resistance do not adversely affect the biological activi-
ties of 7 and 9. This result is consistent with the observation that
DNA-adducts formed by other dinuclear platinum(II) complexes
appear to be able to overcome many mechanisms associated with
cisplatin resistance.36,37
Unless otherwise stated, reagents were obtained from Aldrich
and were used without further purification. 1,2-, 1,7- and 1,12-
carborane(KatchemandDexsil)andtrans-[PtCl2(NH3)2](Strem)
were obtained commercially and used without further purifica-
tion. The compounds 6·2HCl,26 HN(Cbz)2,38 K[PtCl3(NH3)],39,40
and cis-[PtX2(NH3)2] (X = Cl, I)41 were prepared from literature
procedures.
Syntheses
1,2-Bis(aminopropyl)-1,2-carborane 4. A solution of 30
(2.35 g, 3.57 mmol) in a homogeneous mixture of 10 M HCl
(30 mL) and EtOAc (70 mL) was stirred at room temperature for
6 h. The solvent was removed in vacuo to give a pale-yellow
solid which was purified by recrystallisation from MeOH–
diethyl ether to afford 4·2HCl as a colourless solid (645 mg,
69%) (Found: C, 28.86; H, 8.61; N, 8.50%. C8H28B10Cl2N2
requires C, 29.00; H, 8.51; N, 8.45%). dH (199.98 MHz, D2O)
2.99 (t, 4H, 3JHH = 7.6 Hz, CH2N), 2.37 (m, 4H, CH2Ccage), 1.93
(m, 4H, CH2CH2N); dC (50.29 MHz, CD3OD) 81.0 (Ccage), 40.2
(CH2N), 33.2 (CH2Ccage), 29.0 (CH2CH2Ccage); dB (96.30 MHz,
CDCl3) −3.54 (s, 2B), −9.29 (s, 8B).
To a solution of 4·2HCl (30 mg, 9.06 × 10−5 mol) in H2O
(1 mL) in the presence of CH2Cl2 (2 mL) was added saturated
K2CO3(aq) (1 mL) with vigorous stirring. The organic layer was
dried over anhydrous Na2SO4 and reduced in vacuo to give 4 as
a colourless, unstable oil (10 mg, 43%).
Conclusions
The first examples of multinuclear platinum(II)–amine
complexes containing closo-1,7- and 1,12-carboranes have
been reported in this work. Symmetrical dinuclear platinum(II)
complexes containing 1,7- or 1,12-carborane and either the
cis-[PtCl2(NH3)(amine)] (7 and 8) or trans-[PtCl(NH3)2(amine)]+
(9 and 10) centres were successfully prepared and characterised.
The platinum(II) complexes containing 1,2-carborane could
not be isolated due to the degradation of the closo-carborane
cage with concomitant reduction of the platinum(II) centre.
Novel methods for the preparation of mixed di- and tri-nuclear
platinum(II) complexes containing 1,7-carborane were also
developed. We are currently evaluating the DNA-binding and
cell-uptake characteristics of selected complexes in several
tumour lines, and the results of these studies will be reported
in due course.
1,7-Bis(aminopropyl)-1,7-carborane 5. The compound was
prepared from 29 in a similar manner to that described for 4
to give 5·2HCl as a colourless solid (69%) (Found: C, 29.05; H,
8.67; N, 8.42%. C8H28B10Cl2N2 requires C, 29.00; H, 8.51; N,
3
8.45%). dH (199.98 MHz, CD3OD) 3.05 (t, 4H, JHH = 7.4 Hz,
CH2N), 2.31 (m, 4H, CH2Ccage), 1.91 (m, 4H, CH2CH2N); dC
(50.29 MHz, CD3OD) 76.6 (Ccage), 40.2 (CH2N), 34.9 (CH2Ccage),
29.2 (CH2CH2Ccage); dB (96.30 MHz, CD3OD) −6.05 (s,
2B), −9.77 (s, 6B), −11.78 (s, 2B).
To a solution of 5·2HCl (59 mg, 0.178 mmol) in H2O (2 mL)
in the presence of CH2Cl2 (2 mL) was added saturated K2CO3(aq)
(1 mL) with vigorous stirring. The organic layer was dried over
anhydrous Na2SO4 and reduced in vacuo to give 5 as a colourless
oil (27 mg, 58%).
l-{1,7-Bis(aminopropyl)-1,7-carborane-N,N}bis[cis-ammine-
dichloroplatinum(II)] 7. A solution of KI (108 mg, 0.65 mmol)
in H2O (0.83 mL) was added to a solution of K[Pt(NH3)Cl3]
(75 mg, 0.21 mmol) in H2O (1.04 mL), previously adjusted to
pH 7 with 0.1 M NaOH and the mixture was stirred for 15 min.
A solution of 5 (27 mg, 0.104 mmol) in MeOH (2 mL) was added
and stirring was continued for 4 h. The resulting yellow precipi-
tate was collected by centrifugation and washed successively
with cold H2O, MeOH, diethyl ether and dried under vacuum
to afford the mixed chloro–iodo complex [{Pt(NH3)ClI}2{1,7-
NH2(CH2)3CB10H10C(CH2)3NH2}] (99 mg, 0.098 mmol, 94%).
To a solution of the mixed chloro–iodo complex (99 mg,
0.098 mmol) in DMF (2 mL) was added a solution of AgNO3
(62 mg, 0.366 mmol) in DMF (2 mL). The solution was stirred
in the absence of light for 18 h. AgI and AgCl was removed by
filtration through a pad of Celite filter-aid and washed with
DMF (1 mL). To the filtrate and washings was added an addi-
tional amount of AgNO3 (25 mg, 0.148 mmol) in DMF (1 mL)
and the solution was stirred in the absence of light for 9 h.
Once again, AgI and AgCl were removed by filtration through
a pad of Celite filter-aid. To the filtrate was added 1.0 M HCl
(0.20 mL, 0.20 mmol) to precipitate unreacted Ag+ as AgCl.
The solution was left in a refrigerator overnight and AgCl was
removed by filtration through a pad of Celite filter-aid. To the
filtrate was added 10 M HCl (0.10 mL, 1.0 mmol), followed by
0.1 M HCl (20 mL). The solution was again placed in a refrige-
rator overnight to precipitate a yellow solid. The precipitate was
collected by centrifugation, washed with MeOH, diethyl ether
Experimental
All reactions were performed under an inert atmosphere of dry
N2 using standard Schlenk techniques. Solvents for recrystal-
lisation and chromatography were distilled prior to use. Tetra-
hydrofuran (THF) was dried by fresh distillation from sodium
benzophenone ketyl, CH2Cl2 was freshly distilled from CaH2,
N,N-dimethylformamide (DMF) was pre-dried over anhydrous
MgSO4 followed by distillation under reduced pressure, and
EtOH was freshly distilled from Mg/I2.
All multinuclear 1-D NMR spectra were recorded at 298 K
on a Varian Gemini 2000 NMR spectrometer equipped with an
Oxford 300 MHz magnet (1H at 300.10 MHz, 13C at 75.48 MHz,
11B at 96.30 MHz, and 195Pt at 64.38 MHz) or a Varian Gemini
200 NMR Spectrometer equipped with an Oxford 200 MHz
magnet (1H at 199.98 MHz, 13C at 50.29 MHz). 1H and 13C{1H}
NMR chemical shifts are reported in ppm relative to TMS.
195Pt{1H} and 11B{1H} NMR chemical shifts were referenced
to a sealed external standard of 0.1 M Na2[PtCl6] in D2O and
BF3·OEt2, respectively (0 ppm). Coupling constants are reported
in Hz. Melting points were determined using a Kofler hot-stage
apparatus under a Reichert microscope and are uncorrected.
Thin layer chromatography was carried out on Kieselgel 60
F254 silica (Merck) on aluminium-backed plates. Electrospray
Ionisation (ESI) mass spectra were obtained by means of a
Finnegan LCQ mass spectrometer using 5% (v/v) DMF–MeOH
solution. Elemental analyses were performed by Chemical and
Microanalytical Services Pty Ltd, Belmont, Victoria (Australia).
D a l t o n T r a n s . , 2 0 0 4 , 3 6 6 9 – 3 6 7 7
3 6 7 3

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and air dried. Recrystallisation from DMF–0.1 M HCl gave 7
as a yellow solid (51 mg, 59% overall) (Found: C, 12.33; H, 4.23;
N, 6.94%. C8H32B10Cl4N4Pt2·0.25C3H7NO requires C, 12.47;
H, 4.04; N, 7.06%). dH (199.98 MHz, d7-DMF) 4.63 (br s, 4H,
NH2), 3.89 (br s, 6H, NH3), 2.40 (m, 4H, CH2N), 1.79 (m, 4H,
CH2Ccage), 1.50 (m, 4H, CH2CH2N); dC (75.48 MHz, d7-DMF)
75.6 (Ccage), 45.5 (CH2N), 33.1 (CH2Ccage), 30.4 (CH2CH2Ccage);
dB (96.30 MHz, d7-DMF) −11.40 (br s, 10B). dPt (64.38 MHz,
d7-DMF) −2156.
pad of Celite filter-aid. To the filtrate was added a solution of
6 (19 mg, 7.35 × 10−5 mol) in DMF (3 mL) and stirring was
continued overnight. The solution was reduced to dryness in
vacuo and the residue was recrystallised from DMF–0.1 M HCl
to give 10 as a colourless solid (57 mg, 71%) (Found: C, 10.50;
H, 4.35; N, 8.23%. C10H38B10Cl2F6N6O6Pt2S2 requires C, 11.06;
H, 3.53; N, 7.74%). ESI-MS (5% DMF–MeOH): m/z 394.0
([M − 2OTf]2+); dH (300.10 MHz, CD3OD + drop d7-DMF)
3
2.64 (t, 4H, JHH = 7.5 Hz, CH2N), 1.76 (m, 4H, CH2Ccage),
1.56 (m, 4H, CH2CH2N); dC (50.29 MHz, d7-DMF + CD3OD)
78.3 (Ccage), 49.4 (CH2N), 34.0 (CH2Ccage), 30.7 (CH2CH2Ccage);
dB (96.30 MHz, d7-DMF) −9.15 (br s, 10B); dPt (64.38 MHz,
d7-DMF) −2409.
l-{1,12-Bis(aminopropyl)-1,12-carborane-N,N}bis[cis-
amminedichloroplatinum(II)] 8. A solution of KI (76 mg,
4.58 × 10−4 mol) in H2O (1.0 mL) was added to a solution of
K[Pt(NH3)Cl3] (54.4 mg, 1.52 × 10−4 mol) in H2O (1.0 mL),
previously adjusted to pH 7 with 0.1 M NaOH and the mixture
was stirred for 15 min. A solution of 6 (19.5 mg, 7.54 × 10−4 mol)
in MeOH (4 mL) was added and the stirring was continued
for 2 h. The yellow precipitate was collected by centrifuga-
tion, washed successively with H2O, MeOH, diethyl ether and
dried under vacuum to give the mixed iodo–chloro complex
[{Pt(NH3)ClI}2{1,12-NH2(CH2)3CB10H10C(CH2)3NH2}] (70 mg,
91%).
To a solution of the mixed iodo–chloro complex (70 mg,
6.9 × 10−4 mol) in DMF (2 mL) was added a solution of AgOTf
(70mg, 2.72 × 10−4 mol)inDMF(2mL). Thesolutionwasstirred
overnight in the absence of light. AgI and AgCl were removed
by filtration through a pad of Celite filter-aid. To the filtrate was
added a second portion of AgOTf (23 mg, 8.95 × 10−5 mol) in
DMF (1 mL) and the solution was stirred in the absence of light
for 12 h. Once again, AgI and AgCl were removed by filtration
through a pad of Celite filter-aid and to the filtrate was added
1.0 M HCl (0.20 mL) to precipitate unreacted Ag+ as AgCl which
was removed by filtration through a pad of Celite filter-aid. To
the filtrate and washings was added 0.1 M HCl (20 mL) and the
solution was cooled to 4 °C overnight. The yellow precipitate
8 was collected by centrifugation, washed with MeOH, diethyl
ether and dried in vacuo (29 mg, 46% overall) (Found: C, 12.50%;
H, 4.15; N, 7.00%. C8H32B10Cl4N4Pt2·0.25C3H7NO requires C,
12.47; H, 4.04; N, 7.06%). dH (300.10 MHz, d7-DMF) 4.87 (s,
NH), 4.19 (s, NH), 2.62 (m, 4H, CH2N), 1.76 (m, 4H, CH2Ccage),
1.56 (m, 4H, CH2CH2N); dC (75.48 MHz, d7-DMF) 80.3 (Ccage),
47.2 (CH2N), 35.5 (CH2Ccage), 31.7 (CH2CH2N); dB (96.30 MHz,
d7-DMF) −8.8 (br s, 10B). dPt (64.38 MHz, d7-DMF) −2155.
1,7-Bis(iodopropyl)-1,7-carborane 11.
A solution of 26
(483 mg, 1.25 mmol) and NaI (1.05 g, 7.01 mmol) in acetone
(20 mL) was heated to reflux for 24 h. The solvent was removed
in vacuo from the cooled solution to afford a mixture contain-
ing both yellow and orange solids. The solids were dissolved in
diethyl ether (20 mL) and H2O (20 mL). The aqueous layer was
extracted with diethyl ether (20 mL) and the combined organic
layers were washed with H2O (20 mL), brine (20 mL) and dried
(MgSO4). The solvent was removed in vacuo to give 11 as a
yellow oil (551 mg, 92%) (Found C, 20.04; H, 4.52%. C8H22B10I2
requires C, 20.01; H, 4.62%). dH (300.10 MHz, CDCl3) 3.01
3
(t, 4H, JHH = 6.0 Hz, CH2I), 1.98 (m, 4H, CH2Ccage), 1.78 (m,
4H, CH2CH2Ccage); dC (50.29 MHz, CDCl3) 74.5 (Ccage), 37.6
(CH2Ccage), 33.1 (CH2CH2Ccage), 4.12 (CH2I); dB (96.30 MHz,
CDCl3) −7.48 (s, 2B), −11.30 (s, 6B), −13.86 (s, 2B).
7-(Iodopropyl)-N,N-dibenzyloxycarbonyl-1-(aminopropyl)-
1,7-carborane 12. To a stirred solution of Bu4NHSO4 (790 mg,
2.33 mmol) and 2 M NaOH (2.4 mL, 5.00 mmol) in CH2Cl2
(50 mL) was added a solution of dibenzyl iminodicarboxylate
(664 mg, 2.33 mmol) in CH2Cl2 (20 mL). After stirring for 30 min,
a solution of 11 (1.12 g, 2.32 mmol) in CH2Cl2 (25 mL) was added
dropwise to the mixture. The reaction was then heated to reflux
for6h.TheaqueouslayerwasextractedwithCH2Cl2 (2 × 20mL).
The combined organic extracts were reduced in vacuo to afford a
yellow residue, which was stirred with diethyl ether (100 mL) for
30 min to precipitate the Bu4NI, which was removed by vacuum
filtration. The filtrate was dried over anhydrous Na2SO4 and
reduced in vacuo to afford a yellow oil that was purified by flash
chromatography on silica. Elution with 10–25% diethyl ether in
n-hexane (Rf = 0.35) gave 12 (660 mg, 44%) (Found: C, 45.19;
H, 5.73; N, 2.20%. C24H36B10INO4 requires C, 45.21; H, 5.69;
N, 2.20%). dH (300.10 MHz, CDCl3) 7.36 (s, 10H, Ph), 5.24 (s,
l-{1,7-Bis(aminopropyl)-1,7-carborane-N,N}bis[trans-
diamminechloroplatinum(II)] bis(triflate) 9. A solution of AgOTf
(48 mg, 0.187 mmol) in DMF (0.50 mL) was added dropwise
to a suspension of trans-[PtCl2(NH3)2] (50 mg, 0.167 mmol)
in DMF (0.50 mL). The solution was stirred in the absence of
light for 18 h. AgCl was removed by filtration through a pad of
Celite filter-aid. To the filtrate was added a solution of 5 (19 mg,
0.074 mmol) in DMF (0.50 mL) and stirring was continued for
48 h. 0.1 M HCl (3 mL) was added to the solution and it was
cooled to 4 °C overnight. A colourless precipitate was collected
by centrifugation, washed with H2O, EtOH and diethyl ether and
dried under vacuum to afford 9 (18 mg, 22%) (Found: C, 10.96;
H, 4.09; N, 8.11%. C10H38B10Cl2F6N6O6Pt2S2 requires C, 11.06;
H, 3.53; N, 7.74%). ESI-MS (5% DMF–MeOH): m/z 393.9
([M − 2OTf]2+); dH (300.10 MHz, CD3OD + drop d7-DMF)
2.74 (t, 4H, 3JHH = 7.5 Hz, CH2N), 2.10 (m, 4H, CH2Ccage), 1.78
(m, 4H, CH2CH2N); dC (75.48 MHz, d7-DMF) 75.6 (Ccage), 46.0
(CH2N), 33.4 (CH2Ccage), 30.6 (CH2CH2Ccage); dB (96.30 MHz,
d7-DMF) −11.0 (br s, 10B); dPt (64.38 MHz, d7-DMF) −2410.
3
4H, CH2Ph), 3.61 (t, 2H, JHH = 7.2 Hz, CH2N), 3.07 (t, 2H,
3JHH = 6.6 Hz, CH2I), 2.04 (m, 2H, ICH2CH2CH2), 1.83 (m,
4H, (Cbz)2NCH2CH2CH2, ICH2CH2), 1.62 (m, 2H, NCH2CH2);
dC (75.48 MHz, CDCl3) 153.3 (CO), 135.1 (Ph), 128.7 (Ph),
128.5 (Ph), 128.2 (Ph), 75.0 (Ccage), 74.5 (Ccage), 68.8 (CH2Ph),
45.9 (CH2N), 37.6 (CH2CH2CH2I), 33.9 (CH2CH2CH2N), 33.1
(CH2CH2I), 29.2 (CH2CH2N), 4.2 (CH2I); dB (96.30 MHz,
CDCl3) −7.72 (s, 2B), −11.24 (s, 6B), −13.97 (s, 2B).
N,N-Di-tert-butoxycarbonyl-7-(aminopropyl)-N,N-dibenzyl-
oxycarbonyl-1-(aminopropyl)-1,7-carborane 13 and N,N-Di-
tert-butoxycarbonyl-7-(aminopropyl)-N-benzyloxycarbonyl-
1-(aminopropyl)-1,7-carborane 14. A solution of 12 (1.40 g,
2.20 mmol), K2CO3 (666 mg, 4.82 mmol) and di-tert-butyl-
iminodicarboxylate (528 mg, 2.43 mmol) in DMF (20 mL)
was warmed to 60 °C for 24 h and then reduced to dryness in
vacuo. The colourless solid was dissolved in CH2Cl2 (100 mL)
and H2O (100 mL) and the aqueous solution was extracted with
another portion of CH2Cl2 (100 mL). The combined organic
layers were washed with H2O (100 mL), brine (100 mL), dried
over anhydrous MgSO4 and reduced in vacuo to give a yellow
oil. Flash chromatography on silica (10–50% diethyl ether in
n;-hexane) gave 13 (270 mg, Rf = 0.23, 16%) and 14 (783 mg,
Rf = 0.12, 60%) as colourless oils.
l-1,12-Bis(aminopropyl)-1,12-carborane-N,N-bis[trans-
diamminechloroplatinum(II)]bis(triflate)10.Asolutionof AgOTf
(36 mg, 1.40 × 10−4 mol) in DMF (2.0 mL) was added dropwise
to a suspension of trans-[PtCl2(NH3)2] (44 mg, 1.47 × 10−4 mol)
in DMF (3 mL). The solution was stirred overnight in the
absence of light. AgCl was removed by filtration through a
3 6 7 4
D a l t o n T r a n s . , 2 0 0 4 , 3 6 6 9 – 3 6 7 7

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13: (Found: C, 56.11; H, 7.33; N, 3.90%. C34H54B10N2O8
requires C, 56.18; H, 7.49; N, 3.85%). dH (300.10 MHz, CDCl3)
7.35 (s, 10H, Ph), 5.23 (s, 4H, CH2 Ph), 3.60 (t, 2H, 3JHH = 6.9 Hz,
CH2N(Cbz)2), 3.47 (t, 2H, 3JHH = 6.9 Hz, CH2N(Boc)2), 1.86 (m,
4H, (Cbz)2NCH2CH2CH2, (Boc)2NCH2CH2CH2), 1.62 (m, 4H,
(Cbz)2NCH2CH2, (Boc)2NCH2CH2), 1.50 (s, 18H, C(CH3)3); dC
(75.48 MHz, CDCl3) 153.3 (CO), 152.5 (CO), 135.1 (Ph), 128.7
(Ph), 128.5 (Ph), 128.2 (Ph), 82.5 (C(CH3)3), 75.3 (Ccage), 75.0
(Ccage), 68.8 (CH2 Ph), 45.9 (CH2N(Cbz)2), 45.5 (CH2N(Boc)2),
34.2 (CH2Ccage), 34.0 (CH2Ccage), 29.3 (NCH2CH2), 29.2
(NCH2CH2), 28.1 (C(CH3)3); dB (96.30 MHz, CDCl3) −7.84 (s,
2B), −11.29 (s, 6B), −13.82 (s, 2B).
solution was stirred at room temperature for 3 h and the solvent
was removed in vacuo to give 17 as a colourless solid (96 mg, 99%)
(Found: C, 15.88; H, 4.89; N, 7.99%. C9H33B10Cl2F3N4O3PtS
requires C, 15.26; H, 4.69; N, 7.91%). dC (75.48 MHz, d7-DMF)
76.5 (Ccage), 76.1 (Ccage), 47.0 (CH2NH2Pt), 39.1 (CH2NH2·HCl),
34.0 (CcageCH2), 33.7 (CcageCH2), 31.5 (CH2CH2NH2Pt), 27.9
(CH2CH2NH2·HCl); dB (96.30 MHz, d7-DMF) −7.3 (br s, 10B);
dPt (64.38 MHz, d7-DMF) −2408.
{l-1,7-Bis(aminopropyl)-1,7-carborane}-N-[amminechloro-
iodoplatinum(II)]-N-[trans-diammineiodoplatinum(II)]
triflate 18. To
a solution of K[PtCl3(NH3)] (45.4 mg,
1.27 × 10−4 mol) in H2O (0.20 mL) was added a solution of KI
(63 mg, 3.79 × 10−4 mol) in H2O (0.60 mL). The brown solution
was stirred at room temperature for 15 min, and then added
to a solution of 17 (89 mg, 1.25 × 10−5 mol) in DMF (5 mL)
containing K2CO3 (17 mg, 1.23 × 10−4 mol). The mixture was
stirred overnight at room temperature, reduced in vacuo to
approx. 1 mL and filtered off to remove the insoluble inorganic
salts. The filtrate was evaporated in vacuo to give 18 as an orange
solid (92%) (Found: C, 8.77; H, 3.69; N, 6.52%. C9H35B10ClF3I2
N5O3Pt2S·1.5H2O requires C, 9.28; H, 3.29; N, 6.01%). dPt (64.38
MHz, d7-DMF) −2652, −2851.
14: (Found: C, 52.69; H, 8.10; N, 4.81%. C26H48B10N2O6
requires C, 52.68; H, 8.16; N, 4.73%). dH (300.10 MHz,
CDCl3) 7.35 (m, 5H, Ph), 5.09 (s, 2H, CH2Ph), 4.70 (br s, 1H,
3
NH), 3.46 (t, 2H, JHH = 7.2 Hz, CH2N(Boc)2), 3.11 (q, 2H,
3JHH = 6.6Hz,CH2NH(Cbz)),1.86(m,4H,(Cbz)2NCH2CH2CH2,
(Boc)2NCH2CH2CH2), 1.62 (m, 4H, (Cbz)2NCH2CH2,
(Boc)2NCH2CH2), 1.50 (s, 18H, C(CH3)3); dB (96.30 MHz,
CDCl3) −7.82 (s, 2B), −11.36 (s, 6B), −13.77 (s, 2B).
N,N-Di-tert-butoxycarbonyl-7-(aminopropyl)-1-(amino-
propyl)-1,7-carborane 15. A solution of 13 or 14 (0.413 mmol)
in EtOAc was added to an NH4HCO2 solution (15 mL, 1.02 M
in 80% aqueous AcOH). A slurry of Pd–C (10%, 47 mg) in
NH4HCO2 solution (2 mL) was added with stirring. The mixture
was stirred for 15 h under a H2 atmosphere. The catalyst was
removed by filtration through Celite filter-aid. The filtrate was
reduced in vacuo to give a colourless residue that was dissolved
in EtOAc (100 mL) and H2O (100 mL). The organic layer
was washed with dilute NaHCO3(aq), dried over Na2SO4, and
reduced in vacuo to give 15 as a colourless oil (150 mg, 79%)
(Found: C, 47.69; H, 9.58; N, 5.78%. C18H42B10N2O4 requires
C, 47.14; H, 9.23; N, 6.11%). dH (300.10 MHz, CDCl3) 3.47 (t,
cis-Diamminebis{1-(N,N-di-tert-butoxycarbonylaminopropyl)-
7-aminopropyl-1,7-carborane-N}platinum(II) bis(triflate) 20. To
a solution of cis-[PtI2(NH3)2] (33 mg, 6.8 × 10−5 mol) in DMF
(2 mL) was added a solution of AgOTf (35 mg, 1.36 × 10−4 mol)
in DMF (1 mL). The solution was stirred in the absence of light
at room temperature for 30 min. AgI was removed by filtration
through a pad of Celite filter-aid. The filtrate was added to a
solution of 15 (62 mg, 1.35 × 10−4 mol) in DMF (2 mL). The
solution was stirred overnight and the solvent was removed
in vacuo to yield 20 as a colourless oil (98 mg, 99%) (Found:
C, 31.83; H, 6.07; N, 5.36%. C38H90B20F6N6O14PtS2 requires
C, 31.60; H, 6.28; N, 5.82%). dC (75.48 MHz, d7-DMF) 153.4
(CO), 82.9 (C(CH3)3), 76.9 (Ccage), 76.8 (Ccage), 46.8 (CH2NH2Pt),
46.1 (CH2N(Boc)2), 34.7 (CcageCH2), 34.3 (CcageCH2), 32.2
(CH2CH2NH2Pt), 30.3 (CH2CH2N(Boc)2), 28.3 (C(CH3)3); dPt
(64.38 MHz, d7-DMF) −2664.
3
3
2H, JHH = 6.6 Hz, CH2N(Boc)2), 2.86 (t, 2H, JHH = 7.5 Hz,
CH2NH2), 2.06 (m, 2H, NH2CH2CH2CH2Ccage), 1.92 (m, 2H,
(Boc)2NCH2CH2CH2Ccage), 1.75 (m, 2H, NH2CH2CH2CH2Ccage),
1.61 (m, 2H, (Boc)2NCH2CH2CH2Ccage), 1.50 (s, 18H, C(CH3)3);
dC (75.48 MHz, CDCl3) 152.5 (CO), 82.5 (C(CH3)3), 75.4 (Ccage),
75.0 (Ccage), 45.5 (CH2N(Boc)2), 40.4 (CH2NH2), 34.2 (CH2CH2-
CH2N(Boc)2), 34.0 (CH2CH2CH2NH2), 31.1 (CH2CH2CH2N-
(Boc)2), 29.3 (CH2CH2CH2NH2), 28.1 (C(CH3)3); dB (96.30 MHz,
CDCl3) −7.86 (s, 2B), −11.24 (s, 6B), −13.67 (s, 2B).
cis-Diamminebis{1,7-bis(aminopropyl)-1,7-carborane-N}-
platinum(II) hydrochloride bis(triflate) 21. To solution of
20 (98 mg, 6.8 × 10−5 mol) in EtOAc (2 mL) was added a
homogenous mixture of 10 M HCl (0.5 mL) and EtOAc
(2 mL). The reaction mixture was stirred for 2 h at room
temperature during which time the product separated as a
yellow oil. After the solvent was removed by decantation, the
residue solidified. The residue was dried in vacuo to give 21 as
a pale-yellow solid (56 mg, 74%) (Found: C, 19.48; H, 5.87;
N, 7.31%. C18H60B20Cl2F6N6O6PtS2 requires C, 19.36; H, 5.41;
N, 7.52%). dC (75.48 MHz, d7-DMF) 77.1 (Ccage), 76.7 (Ccage),
46.9 (CH2NH2Pt), 39.6 (CH2NH2·HCl), 34.5 (CH2Ccage), 34.4
(CH2Ccage), 32.3 (CH2CH2NH2Pt), 28.6 (CH2CH2NH2·HCl); dPt
(64.38 MHz, d7-DMF) −2642.
trans-[Diammine{1-(N,N-di-tert-butoxycarbonylaminopropyl)-
7-aminopropyl-1,7-carborane}chloroplatinum(II)] triflate 16.
To a suspension of trans-[PtCl2(NH3)2] (46.6 mg, 0.155 mmol)
in DMF (1 mL) was added a solution of AgOTf (38.4 mg,
0.149 mmol) in DMF (2 mL). The solution was stirred overnight
in the absence of light. AgCl was removed by filtration through
a pad of Celite filter-aid and the filtrate was added dropwise
to a solution of 15 (68.2 mg, 1.49 × 10−4 mol) in DMF (4 mL).
After stirring the solution for 12 h, the solvent was removed in
vacuo to give a pale-yellow residue. The residue was extracted
with MeOH and the supernatant was reduced in vacuo to give 16
as a pale-yellow oil (126 mg, 97%) (Found: C, 25.77; H, 5.03; N,
5.66%. C19H48B10ClF3N4O7PtS·H2O requires C, 25.63; H, 5.66;
N, 6.29%). dH (199.98 MHz, d7-DMF) 5.69 (s, 2H, NH2), 4.20
(s, 6H, NH3), 3.52 (t, 2H, 3JHH = 6.9 Hz, CH2N(Boc)2), 3.22 (s,
2H, CH2NH2Pt), 2.15 (m, 2H, CH2Ccage), 2.05 (m, 2H, CH2Ccage),
1.84 (s, 2H, CH2CH2Ccage), 1.70 (m, 2H, CH2CH2Ccage), 1.53 (s,
18H, C(CH3)3). dC (75.48 MHz, d7-DMF) 153.4 (CO), 83.0
(C(CH3)3), 76.9 (Ccage), 47.4 (CH2NH2Pt), 46.1 (CH2N(Boc)2),
34.7 (CcageCH2), 34.4 (CcageCH2), 32.2 (CcageCH2CH2), 30.3
(CcageCH2CH2), 28.3 (C(CH3)3). dB (96.30 MHz, d7-DMF) −6.15
(br s, 10B). dPt (64.38 MHz, d7-DMF) −2409.
[cis-Bis{l-1,7-bis(aminopropyl)-1,7-carborane-N,N}-
diammineplatinum(II)] bis[ammine(chloro)iodoplatinum(II)] bis-
(triflate) 22. A solution of KI (49 mg, 2.95 × 10−4 mol) in H2O
(0.20 mL) was added to a solution of K[Pt(NH3)Cl3] (36 mg,
1.01 × 10−4 mol) in H2O (0.5 mL). The solution was stirred for
15 min and then it was added to a stirred solution of 21 (56 mg,
5.01 × 10−5 mol) in DMF (5 mL), followed by the addition of
K2CO3 (15 mg, 1.09 × 10−4 mol). After stirring the mixture for
2 h, the solvent was removed in vacuo to give a orange solid.
The crude residue was recrystallised from DMF–0.1 M HCl to
give 22 as an orange solid (41 mg, 46%) (Found: C, 12.05; H,
3.77; N, 5.98%. C18H64B20Cl2F6I2N8O6Pt3S2 requires C, 12.06;
H, 3.60; N, 6.25%). dC (75.48 MHz, d7-DMF) 77.0 (Ccage), 76.8
(Ccage), 46.8 (CH2NH2Pt), 46.0 (CH2NH2Pt), 34.6 (CcageCH2),
34.4 (CcageCH2), 32.0 (CH2CH2NH2), 31.6 (CH2CH2NH2);
trans-Diammine{1,7-bis(aminopropyl)-1,7-carborane-N}-
chloroplatinum(II) triflate hydrochloride 17. To a solution of
16 (126 mg, 0.144 mmol) in EtOAc (2 mL) was added a homo-
genous mixture of 10 M HCl (3 mL) and EtOAc (7 mL). The
D a l t o n T r a n s . , 2 0 0 4 , 3 6 6 9 – 3 6 7 7
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1,2-Bis(bromopropyl)-1,2-carborane 27. The compound
dB (96.30 MHz, d7-DMF) −7.35 (br s, 10B); dPt (64.38 MHz,
was prepared from 25 in a similar manner to that described
for 26. Purification of the orange residue by squat chromato-
graphy on silica (15% EtOAc in n-hexane, Rf = 0.55) gave,
after removal of the solvent in vacuo, 27 (73%) (Found: C,
24.87; H, 5.76%. C8H22B10Br2 requires C, 24.88; H, 5.74%). Mp
d7-DMF) −2646.
[cis-Bis{l-1,7-bis(aminopropyl)-1,7-carborane-N,N}di-
ammineplatinum(II)]bis[cis-amminedichloroplatinum(II)]
bis(triflate) 23. A solution of 22 (72 mg, 4.02 × 10−5 mol)
in DMF (4 mL) was added a solution of AgOTf (41 mg,
1.60 × 10−4 mol) in DMF (1 mL). The solution was stirred in the
absence of light for 3 h. AgI and AgCl were removed by filtra-
tion through a pad of Celite filter-aid and the filtrate was stirred
overnight with 0.3 M HCl (2 mL, 0.6 mmol). HCl (0.1 M) was
added to precipitate 23 as a yellow solid (10 mg, 15%) (Found:
C, 12.96; H, 4.36; N, 6.25%. C18H64B20Cl4F6N8O6Pt3S2·2H2O
requires C, 13.13; H, 4.16; N, 6.81%). dC (75.48 MHz, d7-DMF)
76.7 (Ccage), 76.5 (Ccage), 46.7 (CH2NH2Pt), 46.4 (CH2NH2Pt),
34.2 (CH2Ccage), 34.1 (CH2Ccage), 31.9 (CH2CH2Ccage), 31.4
(CH2CH2Ccage); dB (96.30 MHz, d7-DMF) −7.4 (br s, 10B); dPt
(64.38 MHz, d7-DMF) −2162 (s, [PtCl2N2]), −2653 (s, [PtN4]).
3
49–50 °C. dH (300.10 MHz, CDCl3) 3.42 (t, 4H, JHH = 6.0 Hz,
CH2Br), 2.39 (m, 4H, CH2Ccage), 2.10 (m, 4H, CH2CH2Ccage).
dC (75.48 MHz, CDCl3) 78.7 (Ccage), 33.5 (CH2Br), 32.1
(CH2Ccage), 31.9 (CH2CH2Ccage). dB (96.30 MHz, CDCl3) −4.80
(s, 2B), −10.46 (s, 8B).
1,2-Bis(iodopropyl)-1,2-carborane 28. The compound was
prepared from 27 in a similar manner to that described for
11 to afford 28 as a yellow solid (73%) (Found: C, 20.02; H,
4.66%. C8H22B10I2 requires C, 20.01; H, 4.62%). Mp 63–64 °C.
dH (300.10 MHz, CDCl3) 3.20 (t, 4H, 3JHH = 6.2 Hz, CH2I), 2.35
(m, 4H, CH2Ccage), 2.03 (m, 4H, CH2CH2Ccage). dC (50.29 MHz,
CDCl3) 78.5 (Ccage), 35.8 (CH2Ccage), 32.6 (CH2CH2Ccage), 4.2
(CH2I). dB (96.30 MHz, CDCl3) −4.79 (s, 2B), −10.55 (s, 8B).
1,7-Bis(hydroxypropyl)-1,7-carborane 24. A solution of 1,7-
carborane (860 mg, 5.96 mmol) in THF (30 mL) was stirred
at −78 °C. A solution of n-BuLi (2.5 M, 6 mL, 15 mmol) in
THF (25 mL) was added dropwise over 10 min and the mixture
was stirred for a further 40 min at −78 °C and slowly warmed
to room temperature. Oxetane (1.1 mL, 16.9 mmol) was added
and the mixture was heated to reflux for 4 h. The addition of
2 M HCl (15 mL, 30 mmol) quenched the reaction. The aqueous
layer was extracted with EtOAc (2 × 30 mL), and the combined
organic layers were washed with H2O (50 mL) and dried over
anhydrous MgSO4. The solvent was removed in vacuo to afford a
colourless solid. Purification by flash chromatography on silica
(67% EtOAc in n-hexane, Rf = 0.31) gave 24 (963 mg, 62%)
(Found: C, 36.84; H, 9.18%. C8H24B10O2 requires C, 36.90; H,
9.29%). dH (300.10 MHz, CDCl3 + drop d6-acetone) 3.56 (t, 4H,
3JHH = 6.3 Hz, CH2OH), 2.03 (m, 4H, CH2Ccage), 1.62 (m, 4H,
CH2CH2Ccage); dC (75.48 MHz, CDCl3 + drop d6-acetone) 75.5
(Ccage), 61.4 (CH2OH), 33.4 (CH2Ccage), 32.7 (CH2CH2Ccage); dB
(96.30 MHz, CDCl3 + drop d6-acetone) −7.66 (s, 2B), −11.45 (s,
6B), −13.84 (s, 2B).
N,N-Di-tert-butyloxycarbonyl-1,7-bis(aminopropyl)-1,7-
carborane 29. To a stirred solution of Bu4NHSO4 (4.38 g,
12.9 mmol) and aqueous NaOH (2 M, 13 mL, 26 mmol) in
CH2Cl2 (80 mL) was added a solution of di-tert-butyl imino-
dicarboxylate (2.81 g, 12.9 mmol) in CH2Cl2 (25 mL). After
stirring for 30 min, a solution of 11 (3.09 g, 6.45 mmol) in CH2Cl2
(50 mL) was added dropwise to the mixture. The reaction was
then heated to reflux for 20 h. The aqueous layer was extracted
with CH2Cl2 (3 × 40 mL) and the combined organic extracts
were reduced in vacuo to afford a yellow residue that was stirred
with diethyl ether (100 mL) for 20 min to precipitate Bu4NI,
which was removed by vacuum filtration. The filtrate was dried
over anhydrous Na2SO4 and reduced in vacuo to afford a yellow
oil that was purified by flash chromatography on silica (elution
with n-hexane followed by gradients up to 30% diethyl ether in
n-hexane). Recrystallisation of the residue from n-hexane gave
29 (2.48 g, 58%). Mp 103 °C (Found: C, 51.20; H, 8.96; N,
4.19%. C28H58B10N2O8 requires C, 51.04; H, 8.87; N, 4.25%).
3
dH (199.98 MHz, CDCl3) 3.47 (t, 4H, JHH = 7.0 Hz, CH2N),
1.87 (m, 4H, CH2Ccage), 1.50 (m, 40H, C(CH3)3, CH2CH2N); dC
(50.29 MHz, CDCl3) 152.5 (CO), 82.5 (C(CH3)3), 75.2 (Ccage),
45.5 (CH2N), 34.2 (CH2Ccage), 29.3 (CH2CH2Ccage), 28.1 (CH3);
dB (96.30 MHz, CDCl3) −7.61 (s, 2B), −11.18 (s, 6B), −13.90
(s, 2B).
1,2-Bis(hydroxypropyl)-1,2-carborane 25. The compound
was prepared from 1,2-carborane in a similar manner to
that described for 24 to afford 25 as a colourless solid (76%)
after stirring the crude material in CHCl3 (4 mL) in order
to dissolve the small amount of impurity (Found: C, 36.87;
H, 9.35%. C8H24B10O2 requires C, 36.90, H, 9.29%). Mp
125–126 °C. dH (199.98 MHz, CDCl3 + drop d6-acetone) 3.65
(t, 4H, 3JHH = 5.4 Hz, CH2OH), 2.35 (m, 4H, CH2Ccage), 1.81 (m,
4H, CH2CH2Ccage); dC (50.29 MHz, CDCl3 + drop d6-acetone)
79.6 (Ccage), 61.3 (CH2OH), 32.4 (CH2Ccage), 31.6 (CH2CH2Ccage);
dB (96.30 MHz, CDCl3 + drop d6-acetone) −5.17 (s, 2B), −11.00
(s, 8B).
N,N-Di-tert-butyloxycarbonyl-1,2-bis(aminopropyl)-1,2-
carborane 30. The compound was prepared from 28 in a similar
manner to that described for 29 to afford a yellow oil that was
purified by flash chromatography on silica. Elution with CH2Cl2
followed by gradients up to 5% diethyl ether in CH2Cl2 gave,
after removal of solvent in vacuo, 30 (89%) (Found: C, 51.10;
H, 8.78; N, 4.17%. C28H58B10N2O8 requires C, 51.04; H, 8.87;
N, 4.25%). dH (300.10 MHz, CDCl3) 3.55 (t, 4H, 3JHH = 6.9 Hz,
CH2N), 2.13 (m, 4H, CH2Ccage), 1.84 (m, 4H, CH2CH2N), 1.51
(s, 36H, C(CH3)3); dC (50.29 MHz, CDCl3) 152.4 (CO), 82.5
(C(CH3)3), 82.4 (Ccage), 45.2 (CH2N), 32.3 (CH2Ccage), 28.9
(CH2CH2Ccage), 28.0 (CH3); dB (96.30 MHz, CDCl3) −4.89 (s,
2B), −10.69 (s, 8B).
1,7-Bis(bromopropyl)-1,7-carborane 26. To a solution of
24 (947 mg, 3.64 mmol) and CBr4 (3.145 g, 9.48 mmol) in
CH2Cl2 (40 mL) at 5 °C was added dropwise a solution of
PPh3 (2.89 g, 11.0 mmol) in CH2Cl2 (30 mL) over 30 min. The
reaction mixture was warmed to room temperature and stirred
for a further 2 h. The solvent was removed in vacuo to afford an
orange residue which was stirred with diethyl ether (20 mL) for
30 min, and the undissolved solid was removed by filtration. The
filtrate was reduced to dryness in vacuo to give a yellow residue
which was purified by squat chromatography on silica (2%
diethyl ether in n-hexane, Rf = 0.38) to give 26 as a pale-yellow
oil (1.21 g, 86%) (Found: C, 24.83; H, 5.81%. C8H22B10Br2
requires C, 24.88; H, 5.74%). dH (300.10 MHz, CDCl3) 3.31 (t,
In vitro cytotoxicity studies
All anti-cancer screening was performed in the Andrew Durant
Drug Testing Facility, Peter MacCallum Cancer Institute
(Melbourne, Australia).
Coulter counting (CC) assay
3
4H, JHH = 6.3 Hz, CH2Br), 2.10 (m, 4H, CH2Ccage), 1.91 (m,
4H, CH2CH2Ccage); dC (50.29 MHz, CDCl3) 74.7 (Ccage), 35.4
(CH2Br), 32.5 (CH2Ccage), 31.9 (CH2CH2Ccage); dB (96.30 MHz,
CDCl3) −7.45 (s, 2B), −11.24 (s, 6B), −13.79 (s, 2B).
Cells are placed into the wells of a culture plate. The drugs are
dissolved in DMSO and diluted to a range of concentrations.
5 lL of each drug solution is added to the wells of the plate. Six
3 6 7 6
D a l t o n T r a n s . , 2 0 0 4 , 3 6 6 9 – 3 6 7 7

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12 C. Manzotti, G. Pratesi, E. Menta, R. Di Domenico, E. Cavalletti,
wells are used as controls: 5 lL vehicle is added to four wells
(solvent controls) and the remaining two wells represent blank
controls. The plate is then incubated at 37 °C in a humidified
5% CO2, 95% air atmosphere for 48 h after which the cells are
diluted and counted using a Sysmex particle counter.
The percent cell growth at each drug concentration is
determined as the average cell number in the drug treated
wells/average cell number of the vehicle control wells × 100.
The results are plotted as % cell growth against drug concentra-
tion. The IC50 (read from the dose response curve) is defined as
the drug concentration that results in a 50% reduction in cell
growth.
H. H. Fiebig, L. R. Kelland, N. Farrell, D. Polizzi, R. Supino,
G. Pezzoni and F. Zunino, Clin. Cancer Res., 2000, 6, 2626.
13 Y. Qu, N. Farrell, J. Kasparkova and V. Brabec, J. Inorg. Biochem.,
1997, 67, 174.
14 J. D. Roberts, J. Peroutka and N. Farrell, J. Inorg. Biochem., 1999, 77,
51.
15 P. Perego, C. Caserini, L. Gatti, N. Carenini, S. Romanelli,
R. Supino, D. Colangelo, I. Viano, R. Leone, S. Spinelli, G. Pezzoni,
C. Manzotti, N. Farrell and F. Zunino, Mol. Pharmacol., 1999, 55,
528.
16 P. Perego, L. Gatti, C. Caserini, R. Supino, D. Colangelo, R. Leone,
S. Spinelli, N. Farrell and F. Zunino, J. Inorg. Biochem., 1999, 77,
59.
17 G. Pratesi, P. Perego, D. Polizzi, S. C. Righetti, R. Supino,
C. Caserini, C. Manzotti, F. C. Giuliani, G. Pezzoni, S. Tognella,
S. Spinelli, N. Farrell and F. Zunino, Br. J. Cancer, 1999, 80, 1912.
18 G. Colella, M. Pennati, A. Bearzatto, R. Leone, D. Colangelo,
C. Manzotti, M. G. Daidone and N. Zaffaroni, Br. J. Cancer, 2001,
84, 1387.
19 A. S. Batsanov, A. E. Goeta, J. A. K. Howard, A. K. Hughes and
J. M. Malget, J. Chem. Soc., Dalton Trans., 2001, 1820.
20 V. N. Kalinin, A. V. Usatov and L. I. Zakharkin, Proc. Indian Nat.
Sci. Acad., Part A, 1989, 55, 293.
21 J.-D. Lee, C.-K. Baek, J. Ko, K. Park, S. Cho, S.-K. Min and S. O.
Kang, Organometallics, 1999, 18, 2189.
22 J.-D. Lee, S.-J. Kim, D. Yoo, J. Ko, S. Cho and S. O. Kang,
Organometallics, 2000, 19, 1695.
23 S. O. Kang and J. Ko, Adv. Organomet. Chem., 2001, 47, 61.
24 J. A. Todd and L. M. Rendina, Inorg. Chem. Commun., 2004, 7,
289.
25 S. L. Woodhouse and L. M. Rendina, Chem. Commun., 2001,
2464.
26 H. Ghaneolhosseini, W. Tjarks and S. Sjöberg, Tetrahedron, 1997,
53, 17519.
27 S. D. Wise, W.-S. Au and T. D. Getman, Main Group Met. Chem.,
2002, 25, 411.
Sulforhodamine (SRB) assay
Cells are placed into the wells of two culture plates and
incubated overnight at 37 °C in a humidified 5% CO2, 95%
air atmosphere. One plate is then fixed with TCA (as a
measure of cells present at the time of addition of drug). Drugs
are dissolved in DMSO to make solutions of concentrations
spanning a 4-log range. 100 lL of each drug solution is then
added to wells of the second plate. The plate is then incubated
for a further 72 h after which viable cells are measured using
the sulforhodamine B (SRB) assay.42,43 Cells are measured by
reading the absorbance at 550 nm using an automatic plate
reader. The mean absorbance for time zero growth (Tz), control
growth (C) and test drug growth (Ti) is determined and the %
growth is calculated at each drug concentration as:
[(Ti − Tz)/(C −Tz)] × 100 for concentrations where Ti  Tz
[(Ti − Tz)/Tz] × 100 for concentrations where Ti < Tz
The IC50 is the drug concentration that results in a 50%
reduction in the net cellular protein increase in control cells
following drug incubation.
28 T. G. Appleton, J. R. Hall and S. F. Ralph, Inorg. Chem., 1985, 24,
4685.
29 Y. Qu, N. Farrell, M. Valsecchi, L. de Greco and S. Spinelli, Magn.
Reson. Chem., 1993, 31, 920.
Acknowledgements
30 R. Weiss and R. N. Grimes, J. Am. Chem. Soc., 1977, 99, 1036.
31 H. Ghaneolhosseini, W. Tjarks and S. Sjöberg, Tetrahedron, 1998,
54, 3877.
32 J. Malmquist and S. Sjöberg, Acta Chem. Scand., 1994, 48, 886.
33 J. Malmquist, H. Ghaneolhosseini and S. Sjöberg, Acta Chem.
Scand., 1996, 50, 958.
34 H. Ghaneolhosseini and S. Sjöberg, Acta Chem. Scand., 1999, 53,
298.
35 Y. Qu, T. G. Appleton, J. D. Hoeschele and N. Farrell, Inorg. Chem.,
1993, 32, 2591.
36 N. Farrell, Y. Qu, L. Feng and B. van Houten, Biochemistry, 1990,
29, 9522.
37 Y. Qu, H. Rauter, A. P. S. Fontes, R. Bandarage, L. R. Kelland and
N. Farrell, J. Med. Chem., 2000, 43, 3189.
We thank Dr C. Cullinane for conducting the in vitro cyto-
toxicity studies (Peter MacCallum Cancer Institute, Melbourne,
Australia), and we are grateful to Prof. L. D. Field (University
of Sydney) for valuable advice regarding the 11B NMR spectra.
We thank Prof. N. Farrell (Virginia Commonwealth University,
US) for advice regarding the use of the trans-[PtClI2(NH3)2]−
precursor, and Prof. S. Sjöberg (Uppsala University, Sweden)
for advice regarding the carborane ligand syntheses. We also
thank Johnson Matthey for the generous loan of K2[PtCl4]. This
work was supported by the Anti-Cancer Foundation of South
Australia.
38 L. Grehn, M. L. S. Almeida and U. Ragnarsson, Synthesis, 1988,
992.
39 M. J. Abrams, C. M. Giandomenico, J. F. Vollano and D. A.
Schwartz, Inorg. Chim. Acta, 1987, 131, 3.
40 C. M. Giandomenico, M. J. Abrams, B. A. Murrer, J. F. Vollano,
M. I. Rheinheimer, S. B. Wyer, G. E. Bossard and J. D. Higgins,
Inorg. Chem., 1995, 34, 1015.
41 S. C. Dhara, Indian J. Chem., 1970, 8, 193.
42 P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon,
D. Vistica, J. T. Warren, H. Bokesch, S. Kenney and M. R. Boyd, J.
Nat. Cancer Inst., 1990, 82, 1107.
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