(2,2′:6′,2″-terpyridine)platinum(II) complexes containing (thioalkyl)dicarba-closo-dodecaborane(12) ligands

Article abstract of DOI:10.1021/ic050265k

A series of novel platinum(II)-2,2′:6′,2″-terpyridine (trpy) complexes containing (thioalkyl)dicarba-closo-dodecaborane(12) (closo-carborane) derivatives were prepared by treatment of the labile precursor species [Pt(MeCN)-(trpy)](OTf)₂ with R(CH₂)_nSH (R = closo-1,2-carborane, n = 0-3; R = closo-1,7-carborane, n = 1; R = closo-1,12-carborane, n = 1) in the presence of NEt₃ to afford brightly colored complexes of the type [PtS(CH₂)_nR(trpy)] OTf. All products were characterized by means of multinuclear (¹H, ¹³C, ¹¹B, and ¹⁹⁵Pt) 1D- and 2D-NMR spectroscopy, ESI-MS, and, for the 1,7-carborane derivative, X-ray crystallography. Preliminary in vitro cytotoxicity studies of selected complexes against human ovarian carcinoma cells are also reported.

Full text of DOI:10.1021/ic050265k

Inorg. Chem. 2005, 44, 6401−6408
(2,2′:6′,2′′-Terpyridine)platinum(II) Complexes Containing
(Thioalkyl)dicarba-closo-dodecaborane(12) Ligands
Jean A. Todd,† Peter Turner,‡ Erin J. Ziolkowski,‡ and Louis M. Rendina*,‡
School of Chemistry, The UniVersity of Sydney, Sydney, NSW 2006, Australia, and School of
Chemistry and Physics, The UniVersity of Adelaide, Adelaide, South Australia 5005, Australia
Received February 21, 2005
A series of novel platinum(II)
borane(12) (closo-carborane) derivatives were prepared by treatment of the labile precursor species [Pt(MeCN)-
(trpy)](OTf)2 with R(CH2)nSH (R closo-1,2-carborane, n 3; R closo-1,7-carborane, n 1; R closo-
1,12-carborane, n 1) in the presence of NEt3 to afford brightly colored complexes of the type [PtS(CH2)nR(trpy)]OTf.
−2,2′:6′,2′′-terpyridine (trpy) complexes containing (thioalkyl)dicarba-closo-dodeca-
)
)
0−
)
)
)
)
All products were characterized by means of multinuclear (1H, 13C, 11B, and 195Pt) 1D- and 2D-NMR spectroscopy,
ESI-MS, and, for the 1,7-carborane derivative, X-ray crystallography. Preliminary in vitro cytotoxicity studies of
selected complexes against human ovarian carcinoma cells are also reported.
Introduction
(II)-trpy (trpy ) 2,2′:6′,2′′-terpyridine) possess interesting
biological activities which may eventually lead to their
exploitation as potential antiprotozoal agents7 and anticancer
drugs.8,9 Complexes of the type [PtL(trpy)]n+ (e.g., L ) Cl,
2-hydroxyethanethiolate (het), Me (n ) 1); L ) 4-picoline
(n ) 2)) are capable of binding strongly to DNA by inter-
calation and competitively inhibiting the binding of the well-
known intercalator ethidium bromide to DNA.10-13 While
[PtCl(trpy)]+ intercalates and, through the loss of the chloro
ligand, also covalently binds to DNA,12 complexes such as
[Pt(het)(trpy)]+ interact predominantly by intercalation, as
covalent binding is negligible due to the inert character of
the Pt-S bond.13 Recent work reported by our group included
the development of a series (thioalkyl)-closo-carborane
ligands and their corresponding cationic platinum(II)-trpy
complexes, some of which have the capacity to bind to calf-
10B-containing compounds that have the capacity to target
DNA are potentially useful agents in the treatment of cancer
by means of boron neutron capture therapy (BNCT),1,2 and
numerous classes of compound have been identified. We
recently reported a new class of DNA-binding agents that
incorporated both platinum and a boron-rich carborane entity,
the first examples of platinum(II)-amine complexes contain-
ing boron.3,4 As well as the potential for additive or perhaps
synergistic biological effects associated with the DNA-
binding reactions of the Pt-B agent coupled with the neutron
capture reactions of the 10B nucleus, there is an additional
advantage that such agents can be radiolabeled by the use
of isotopes such as 195mPt which would allow their tumor
uptake and biodistribution characteristics to be monitored
by means of γ imaging following administration into the
body (t1/2 ) 4 d).5
(6) Erkkila, K. E.; Odom, D. T.; Barton, J. K. Chem. ReV. 1999, 99, 2777-
2795.
DNA metallointercalators are the subject of current
research interest,6 and complexes such as those of platinum-
(7) Lowe, G.; Droz, A. S.; Vilaivan, T.; Weaver, G. W.; Tweedale, L.;
Pratt, J. M.; Rock, P.; Yardley, V.; Croft, S. L. J. Med. Chem. 1999,
42, 999-1006.
(8) McFadyen, W. D.; Wakelin, L. P. G.; Roos, I. A. G.; Hillcoat, B. L.
Biochem. J. 1986, 238, 757-763.
* To whom correspondence should be addressed. E-mail: rendina@
chem.usyd.edu.au. Telephone: 61 2 9351 4781. Fax: 61 2 9351 3329.
† The University of Adelaide.
(9) Lowe, G.; Droz, A. S.; Vilaivan, T.; Weaver, G. W.; Park, J. J.; Pratt,
J. M.; Tweedale, L.; Kelland, L. R., J. Med. Chem. 1999, 42, 3167-
3174.
‡ The University of Sydney.
(1) Hawthorne, M. F.; Lee, M. W. J. Neuro-Oncol. 2003, 62, 33-45.
(2) Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F. G.; Barth, R.
F.; Codogni, I. M.; Wilson, J. G. Chem. ReV. 1998, 98, 1515-1562.
(3) Woodhouse, S. L.; Rendina, L. M. Chem. Commun. 2001, 2464-
2465.
(4) Woodhouse, S. L.; Rendina, L. M. Dalton Trans. 2004, 3669-3677.
(5) Dowell, J. A.; Sancho, A. R.; Anand, D.; Wolf, W. AdV. Drug DeliVery
ReV. 2000, 41, 111-126.
(10) Arena, G.; Monsu Scolaro L.; Pasternack, R. F.; Romeo, R. Inorg.
Chem. 1995, 34, 2994.
(11) McCoubrey, A.; Latham, H. C.; Cook, P. R.; Rodger, A.; Lowe, G.
FEBS Lett. 1996, 380, 73-78.
(12) Howe-Grant, M.; Wu, K. C.; Bauer, W. R.; Lippard, S. J. Biochemistry
1976, 15, 4339-4346.
(13) Jennette, K. W.; Lippard, S. J.; Vassiliades, G. A.; Bauer, W. R. Proc.
Nat. Acad. Sci. U.S.A. 1974, 71, 3839-3843.
10.1021/ic050265k CCC: $30.25
Published on Web 08/09/2005
© 2005 American Chemical Society
Inorganic Chemistry, Vol. 44, No. 18, 2005 6401

Todd et al.
purification. nido-Decaborane was obtained from Strem Chemicals
(Newburyport, US), and it was freshly sublimed in vacuo prior to
use.
thymus DNA presumably by intercalation of the Pt(trpy)
unit.14 It was the purpose of this research to extend this series
to other mononuclear platinum(II)-trpy complexes incor-
porating (thioalkyl)-closo-carborane ligands and to examine
the cytotoxicity of selected complexes against tumor cells
in vitro. A preliminary communication of this work was
reported recently.14
Preparation of Compounds. 1-(Methanedithiolate)-1,7-car-
borane (1). This preparation was adapted from a related procedure
reported by Nachman et al.20 To a stirred solution of 1,7-carborane
(780 mg, 5.40 mmol) in THF (10 mL) at -10 °C was added nBuLi
(3.2 mL, 1.6 M in hexane, 5.12 mmol) dropwise. The reaction
mixture was stirred for 1.5 h before a solution of CuBr (149 mg,
1.28 mmol) and LiBr (183 mg, 1.72 mmol) in THF (20 mL) was
slowly added. The yellow solution was stirred for 15 min at -10
°C, and then the temperature was reduced to -15 °C and CS2 (0.4
mL, 6.63 mmol) was added dropwise. The red solution was then
allowed to warm to -10 °C. After the solution was stirred for 1.5
h, MeI (0.35 mL, 5.62 mmol) was added, and the reaction mixture
was warmed to room temperature and stirred for a further 1.5 h.
After workup with KCN (310 mg, 4.76 mmol) and water (10 mL),
the solution was extracted with diethyl ether (4 × 5 mL). The
combined organic layers were washed with brine and dried over
Na2SO4, and the solvent was removed in vacuo to give the crude
product as yellow crystals. After flash column chromatography (n-
hexane, Rf ) 0.52), 1 was obtained as bright-orange crystals (710
Experimental Section
General Synthetic and Analytical Methods. All reactions were
performed under an inert atmosphere of dry N2 utilizing standard
Schlenk techniques. All reaction solvents were dried and distilled
prior to use. Diethyl ether, dimethoxyethane (DME), and tetrahy-
drofuran (THF) were dried by distillation from sodium benzophe-
none ketyl. Toluene and benzene was predried with anhydrous
CaSO4, followed by distillation from sodium. CH2Cl2 and n-hexane
were dried by distillation from CaH2. N,N-dimethylformamide
(DMF) was predried with MgSO4 and anhydrous CuSO4, followed
by distillation at reduced pressure.
1H and 13C{1H} NMR spectra were recorded on a Varian Gemini
2000 NMR spectrometer or a Bruker DPX300 with Oxford 300
MHz magnet at 298 K, except where otherwise indicated. The 200
1
mg, 59%). Mp: 51.5-53.5 °C. H NMR (300.13 MHz, CDCl3):
δ 3.04 (br, 1H, CcageH), 2.58 (s, 3H, SMe). 13C{1H} NMR (74.48
MHz, CDCl3): δ 220 (CcageCSSCH3), 54.4 (CcageH), 22.8 (SMe),
1
MHz H NMR spectra were recorded on a Varian Gemini 200
instrument. 11B{1H} and 195Pt{1H} NMR were recorded on a Bruker
DPX400 NMR spectrometer. 2-D NMR spectroscopy experiments
were performed on a Bruker Avance DRX 400 MHz NMR
instrument. All chemical shifts are reported in ppm, and coupling
constants are reported in Hz. 1H and 13C{1H} NMR chemical shifts
are relative to tetramethylsilane (TMS). 195Pt{1H} and 11B{1H}
NMR chemical shifts were referenced relative to a sealed external
standard of 0.1 M Na2[PtCl6] in D2O and BF3‚OEt2, respectively
(δ 0.00).
C
cageCSS was not observed. 11B{1H} NMR (400.21 MHz, CDCl3):
δ -4.3 (1B), -7.4 (1B), -10.9 (4B), -13.3 (2B), -16.9 (2B).
ESI-MS: m/z 187.0 (1,7-B10C2H11CS+, 100%), 219.0 (1,7-B10C2-
H11CSS+, 42%), 234.9 (M+, 24%).
1-(Thiomethyl)-1,7-carborane (2). This preparation was adapted
from a related procedure reported by Nachman et al.20 To a stirred
solution of 1 (310 mg, 1.28 mmol) in toluene (10 mL) was added
a solution of 2 M BH3‚SMe2 in THF (0.85 mL, 1.7 mmol). The
resulting solution was refluxed under an inert atmosphere for 5 h,
after which time the orange solution became colorless. When the
solution had cooled to room temperature, an excess of concentrated
HCl was added (8 mL, 32%) and the mixture was stirred at reflux
for 16 h. After cooling, the layers were separated and the aqueous
layer was extracted with n-hexane (3 × 5 mL). The combined
organic extracts were washed with brine (3 × 5 mL) and dried
over anhydrous Na2SO4. The solvent was removed in vacuo, and
the crude material was purified by flash column chromatography
(n-hexane, Rf ) 0.44) to give 2 as a colorless, low-melting solid
Melting points (uncorrected) were determined using a Kofler hot-
stage apparatus equipped with a Reichert microscope. Elemental
analyses were performed by CMAS (Chemical and Microanalytical
Services Pty. Ltd.), Belmont, Victoria, Australia. Electrospray
ionization mass spectra (ESI-MS) were obtained by means of a
Finnegan LCQ mass spectrometer equipped with Finnegan data
processing software, using HPLC grade methanol or 5% DMF/
methanol.
Thin layer chromatography (TLC) was performed on Merck DC-
Alufolien Kieselgel 60 F254 sheets. Visualization of plates was
achieved using 254 nm UV light or by staining with either I2 vapor
or a KMnO4 dip solution, followed by heating. Squat and flash
column chromatography were performed on Merck Kieselgel 60
(230-400 mesh ATSM) silica gel.
Materials and Methods. [Pt(MeCN)(trpy)](OTf)2,15 [PtCl(trpy)]-
Cl‚2H2O,16 1-thiol-1,2-carborane (18),17 1-(benzylthio)-3-bromo-
ethane (6),18 1-(benzylthio)-3-bromopropane (7),19 and 1-(thiomethyl)-
1,12-carborane (19)20 were prepared according to the literature
procedures. 1,2-, 1,7-, and 1,12-carborane were obtained from
Katchem (Prauge, Czech Republic) and used without further
1
(42 mg, 40%). Mp: 25-27 °C. H NMR (300.13 MHz, CDCl3):
δ 2.95 (br, 1H, CcageH), 3.15 (d, 3JHH ) 9.0 Hz, 2H, CH2SH), 1.82
3
(t, JHH ) 8.5 Hz, 1H, SH). 13C{1H} NMR (74.48 MHz, CDCl3):
δ 55.3 (CcageH), 31.0 (CH2SH); CcageCH2 not observed. 11B{1H}
NMR (400.12 MHz, CDCl3): δ -3.8 (1B), -9.6 (1B), -10.8 (4B),
-13.4 (2B), -15.5 (2B). ESI-MS: m/z 189.0 ([M - H]+, 100%).
1-(Benzylthio)-2-propyne (3). Sodium (2.50 g, 109 mmol) was
dissolved in absolute EtOH (100 mL), and the resulting solution
was stirred for 30 min at room temperature. The temperature was
then lowered to 0 °C, and benzyl mercaptan (1 mL, 8.48 mmol)
was added dropwise to the solution. After stirring of the mixture
for 30 min at this temperature, propargyl bromide (8 mL, 85.0
mmol) was added slowly. The solution was then allowed to return
to room temperature and stirred for a further 3 h. The reaction was
quenched by pouring the cloudy yellow solution into a solution of
2 M HCl (100 mL), and the mixture was extracted with n-pentane
(4 × 20 mL). The organic extracts were washed with a saturated
solution of NaHCO3 (4 × 20 mL) and dried over anhydrous Na2-
SO4. The crude yellow oil was purified by column chromatography
(14) Todd, J. A.; Rendina, L. M. Inorg. Chem. 2002, 41, 3331-3333.
(15) Bu¨chner, R.; Field, J. S.; Haines, R. J.; Cunningham, C. T.; McMillin,
D. R. Inorg. Chem. 1997, 36, 3952-3956.
(16) Howe-Grant, M.; Lippard, S. J. Inorg. Synth. 1980, 20, 101-105.
(17) Vinas, C.; Benakki, R.; Teixidor, F.; Casabo, J. Inorg. Chem. 1995,
34, 3844-3845.
(18) Trujillo, D. A.; McMahon, W. A., Jr.; Lyle, R. E. J. Org. Chem. 1987,
52, 2932-2933.
(19) Palmer, D. C.; Taylor, E. C. J. Org. Chem. 1986, 51, 846-850.
(20) Ujvary, I.; Nachman, R. J. Tetrahedron Lett. 1999, 40, 5147-5149.
1
(n-hexane, Rf ) 0.19) to give 3 as a yellow oil (1.08 g, 78%). H
6402 Inorganic Chemistry, Vol. 44, No. 18, 2005

(2,2′:6′,2′′-Terpyridine)platinum(II) Complexes
n
NMR (300.13 MHz, CDCl3): δ 7.35-7.23 (m, 5H, Ph), 3.87 (s,
added BuLi (1.6 M in hexane, 3.8 mL, 6.1 mmol) dropwise with
4
4
2H, PhCH2), 3.08 (d, JHH ) 2.4 Hz, 2H, SCH2), 2.29 (t, JHH
)
stirring. The mixture was then stirred for 30 min at 0 °C, followed
by 30 min at room temperature. The mixture was cooled to 0 °C,
and 7 (1.56 g, 6.32 mmol) in DME (10 mL) was added dropwise.
The colorless solution immediately became pale yellow. The
solution was allowed to return to room temperature and stirred for
a further 40 h. After being quenched with H2O (20 mL), the two
layers were separated and the aqueous layer was extracted with
diethyl ether (4 × 10 mL). The combined organic extracts were
washed with brine (3 × 10 mL) and dried with Na2SO4, and the
solvent was removed in vacuo to give a crude yellow oil. After
purification by flash column chromatography (20% diethyl ether/
n-hexane, Rf ) 0.48), 9 was obtained as a yellow oil (717 mg,
46%). 1H NMR (300.13 MHz, CDCl3): δ 7.35-7.23 (m, 5H, Ph),
2.4 Hz, 1H, CtCH). 13C{1H} NMR (74.48 MHz, CDCl3): δ 137.5
(Ph), 129.0 (Ph), 128.6 (Ph), 127.2 (Ph), 79.9 (CtCH), 71.3
(CtCH), 35.3 (PhCH2S), 22.7 (SCH2CtCH).
1-((Benzylthio)methyl)-1,2-carborane (4). A mixture of nido-
decaborane (769 mg, 6.29 mmol), 3 (978 mg, 6.15 mmol), and
MeCN (5 mL, 66 mmol) in toluene (30 mL) was refluxed for 24
h. After cooling the red solution to room temperature, the solvents
were reduced in vacuo, and the yellow viscous oil was dissolved
in MeOH (15 mL) and left to stand for 18 h at room temperature.
After the solvent was removed in vacuo, 4 was obtained as a golden
1
oil (1.65 g, 95%). H NMR (300.13 MHz, CDCl3): δ 7.38-7.27
(m, 5H, Ph), 3.90 (br, 1H, CcageH), 3.75 (s, 2H, SCH2Ph), 3.16 (s,
2H, CcageCH2S). 13C{1H} NMR (74.48 MHz, CDCl3): δ 136.4 (Ph),
128.9 (Ph), 128.7 (Ph), 127.8 (Ph), 74.4 (CcageC), 59.5 (CcageH),
37.4 (SCH2Ph), 36.9 (CcageCH2S). 11B{1H} NMR (400.21 MHz,
CDCl3): δ -2.4 (2B), -5.4 (2B), -8.96 (1B), -10.8 (1B), -13.1
(4B).
3
3.72 (s, 2H, SCH2Ph), 3.52 (br, 1H, CcageH), 2.38 (t, JHH ) 5.2
Hz, 2H, CH2S), 2.17 (m, 2H, CH2CH2CH2), 1.78 (t, JHH ) 6.0
3
Hz, 2H, CcageCH2). 13C{1H} NMR (74.48 MHz, CDCl3): δ 138.0
(Ph), 129.2 (Ph), 128.0 (Ph), 127.6 (Ph), 74.7 (CcageC), 61.2 (CcageH),
36.4 (CH2S), 33.7 (SCH2Ph), 28.8 (CcageC), 28.5 (CH2CH2CH2).
11B{1H} NMR (400.21 MHz, CDCl3): δ -2.3 (1B), -5.71 (1B),
-9.29 (2B), -11.6 (4B), -13.1 (2B). ESI-MS: m/z 307.9 ([M -
H]-, 100%).
1-(Thiomethyl)-1,2-carborane (5). A suspension of freshly
sublimed AlCl3 (2.6 g, 19.5 mmol) in benzene (30 mL) was stirred
at 50 °C for 30 min, after which time the AlCl3 had completely
dissolved. A solution of 4 (1.11 g, 3.95 mmol) in benzene (20 mL)
was then added dropwise. The reaction mixture was stirred at 50
°C for 24 h, by which time it had become red. The solvent was
removed in vacuo, and the residue was dissolved in CH2Cl2 (20
mL). A saturated solution of potassium sodium tartrate (20 mL)
was added to the solution and stirred for 30 min. The layers were
separated, the aqueous layer was extracted with CH2Cl2 (3 × 8
mL), and the combined organic layers were washed with brine
(3 × 8 mL). The crude yellow oil was purified by flash column
chromatography (10% ethyl acetate/n-hexane, Rf ) 0.28) to yield
5 as a yellow, low-melting solid (252 mg, 33%). Mp: 44-45 °C.
1H NMR (300.13 MHz, CDCl3): δ 4.12 (br, 1H, CcageH), 3.29 (d,
1-(2-Thioethyl)-1,2-carborane (10). A procedure similar to that
used for the synthesis of 5 was followed, using 8 (1.97 g, 6.69
mmol) instead of 4. The crude yellow oil was purified by flash
column chromatography (10% ethyl acetate/n-hexane, Rf ) 0.42)
to give 10 as a colorless solid (315 mg, 23%). Mp: 102-107 °C.
1H NMR (300.13 MHz, CDCl3): δ 3.67 (br, 1H, CcageH), 2.62 (m,
2H, CH2SH), 2.52 (m, 2H, CcageCH2), 1.47 (t, 3JHH ) 8.1 Hz, 1H,
SH). 13C{1H} NMR (74.48 MHz, CDCl3): δ 74.9 (CcageC), 66.7
(CcageH), 40.8 (CH2SH), 29.3 (CcageC). 11B{1H} NMR (400.21 MHz,
CDCl3): δ -2.4 (1B), -5.9 (1B), -9.2 (2B), -11.6 (4B), -14.4
(2B). ESI-MS: m/z 169.2 ([M - H]-, 100%).
1-(3-Thiopropyl)-1,2-carborane (11). A procedure similar to
that used in the synthesis of 5 was followed, using 9 (354 mg,
1.14 mmol) instead of 4. The crude yellow oil was purified by
flash column chromatography (30% diethyl ether/n-hexane, Rf )
0.35) to give 11 as a low-melting solid (82 mg, 33%). Mp: 52-55
°C. 1H NMR (300.13 MHz, CDCl3): δ 2.93 (br, 1H, CcageH), 2.51
3
3JHH ) 9 Hz, 2H, CcageCH2), 1.87 (t, JHH ) 9 Hz, 1H, SH). 13C-
{1H} NMR (74.48 MHz, CDCl3): δ 75.1 (CcageC), 59.7 (CcageH),
31.7 (CH2). 13C{1H} NMR (CDCl3): δ 74.1 (CcageC), 69.8 (CcageH),
59.8 (CH2SH). 11B{1H} NMR (400.21 MHz, CDCl3): δ -2.4 (1B),
-5.4 (1B), -8.9 (2B), -11.1 (4B), -12.8 (2B). GCEI-MS: m/z
189.2 ([M - H]-, 100%).
(q, 3JHH ) 5.8 Hz, 2H, CH2SH), 2.37 (t, 3JHH ) 5.7 Hz, 2H, Ccage
-
CH2), 1.81 (m, 2H, CH2CH2CH2), 1.36 (t, 3JHH ) 5.8 Hz, 1H, SH).
13C{1H} NMR (74.48 MHz, CDCl3): δ 75.1 (CcageC), 61.4 (CcageH),
36.8 (CH2SH), 27.1 (CcageC), 25.5 (CH2CH2CH2). 11B{1H} NMR
1-(2-(Benzylthio)ethyl)-1,2-carborane (8). 1,2-Carborane (960
mg, 6.65 mmol) was dissolved in DME (25 mL). The solution was
cooled to 0 °C, and a solution of nBuLi (4.32 mL, 1.6 M in hexane,
6.77 mmol) was added slowly. The mixture was stirred at this
temperature for 30 min, after which time it was warmed to room
temperature and stirred for a further 30 min. The mixture was then
cooled to 0 °C, and a solution of 6 (1.02 g, 4.42 mmol) in DME
(10 mL) was added dropwise. The resulting yellow solution was
allowed to warm to room temperature and stirred for 45 h, by which
time the solution had become deep red. After quenching with water,
the solution was extracted with diethyl ether (3 × 8 mL) and washed
with brine (8 mL), and the solvent removed in vacuo to give a
crude golden oil, which was purified by flash column chromatog-
raphy (n-hexane, Rf ) 0.35) to give 8 as a colorless solid (612 mg,
47%). 1H NMR (300.13 MHz, CDCl3): δ 7.34-7.25 (m, 5H, Ph),
3.92 (s, 2H, SCH2Ph), 3.20 (br, 1H, CcageH), 2.86 (t, 3JHH ) 6 Hz,
2H, CH2S), 2.80 (t, 3JHH ) 5.8 Hz, 2H, CcageCH2). 13C{1H} NMR
(74.48 MHz, CDCl3): δ 136.7 (Ph), 127.5 (Ph), 127.1 (Ph), 126.8
(Ph), 72.4 (CcageC), 56.5 (CcageH), 38.1 (SCH2Ph), 36.4 (CH2SCH2-
Ph), 24.5 (CcageCH2). 11B{1H} NMR (400.21 MHz, CDCl3): δ -2.3
(2B), -5.4 (2B), -9.1 (2B), -10.8 (4B), -13.4 (2B).
(400.21 MHz, CDCl3): δ -2.3 (1B), -5.8 (1B), -9.4 (2B), -11.7
(4B), -13.3 (2B). ESI-MS: m/z 185.1 (1,2-B10C2H11CH2CH2CH2
100%).
+
,
(1,2-Carborane-1-thiolato)(2,2′:6′,2′′-terpyridine)platinum-
(II) Triflate (12). To a stirred suspension of [PtCl(trpy)]Cl‚2H2O
(100 mg, 0.19 mmol) in DMF (1 mL) was added a solution of
AgOTf (94 mg, 0.36 mmol) in DMF (0.5 mL). The mixture was
stirred at room temperature in the absence of light for 48 h. The
mixture was then filtered through Celite filter aid to remove the
AgCl. A solution of 18 (33 mg, 0.19 mmol) in DMF (1 mL) was
then added and the mixture stirred for 2.5 h. Diethyl ether was
then added to give an orange precipitate, which was collected by
centrifugation, washed with additional diethyl ether, and dried in
vacuo to give 12 as an orange powder (61 mg, 45%). H NMR
(599.89 MHz, acetone-d6): δ 9.47 (d, JHH ) 5.4 Hz, JPtH
27.6 Hz, 2H, H6, H6′′), 8.74 (m, 2H, H3′, H5′), 8.68 (m, 3H, H3,
H3′′ + H4′), 8.58 (td JHH ) 1.8 Hz, JHH ) 7.8 Hz, H4, H4′′),
1
3
3
)
3
3
3
3
4
8.10 (ddd JHH ) 1.8 Hz, JHH ) 5.4 Hz, JHH ) 7.2 Hz, 2H, H5,
H5′′), 4.96 (br, CcageH). 13C{1H} NMR (150.86 Hz, acetone-d6): δ
159.61 (C2, C2′′), 155.38 (C2′, C6′), 153.84 (C6, C6”), 144.30
1-(3-(Benzylthio)propyl)-1,2-carborane (9). To a solution of
1,2-carborane (900 mg, 6.23 mmol) in DME (20 mL) at 0 °C was
Inorganic Chemistry, Vol. 44, No. 18, 2005 6403

Todd et al.
(C4′), 143.6 (C4, C4′′), 130.2 (C5, C5′′), 126.7 (C3, C3′′), 125.1
(C3′, C5′), 71.0 (CcageH). 11B{1H} NMR (96.30 MHz, DMF/
benzene-d6): δ -8.0 (2B), -14.2 (br, 6B), -18.1 (2B). 195Pt{1H}
NMR (64.34 MHz, DMF/benzene-d6): δ -3140. ESI-MS: m/z
603.2 (M+). Anal. Calcd for C18H22B10F3N3O3PtS2: C, 28.72; H,
2.95; N, 5.58. Found: C, 28.81; H, 2.85; N, 5.60.
(1,2-Carborane-1-(3-propanethiolato))(2,2′:6′,2”-terpyridine)-
platinum(II) Triflate (15). To a stirred solution of 11 (30.2 mg,
0.145 mmol) in acetone (5 mL) was added [Pt(MeCN)(trpy)](OTf)2
(155 mg, 0.201 mmol). After the solution had been stirred at room
temperature for 20 min, NEt3 (0.5 mL, 0.201 mmol) was added,
and the solution was stirred for a further 18 h. Diethyl ether
(5 mL) was added to afford 15 as dark-red crystals (60 mg, 67%).
(1,2-Carborane-1-methanethiolato))(2,2′:6′,2”-terpyridine)-
platinum(II) Triflate (13). Method A. To a stirred solution of 5
(12.5 mg, 0.066 mmol) in acetone (5 mL) was added [Pt(MeCN)-
(trpy)](OTf)2 (49.9 mg, 0.065 mmol). After the solution had stirred
at room temperature for 20 min, NEt3 (0.5 mL, 0.201 mmol) was
added and the solution stirred for a further 18 h. Diethyl ether (5
mL) was added to precipitate the complex from solution to give
13 as a bright-red, microcrystalline solid (31 mg, 62.5%).
3
1H NMR (300.13 MHz, acetone-d6): δ 9.59 (dd, JHH ) 1.5 Hz,
3
3
3JHH ) 5.7 Hz, JPtH ) 49 Hz, 2H, H6, H6′′), 8.80 (d, JHH ) 4
Hz, 2H, H3′, H5′), 8.71 (d, 3JHH ) 2.1 Hz, 2H, H3′, H3′′), 8.61 (t,
3JHH ) 3.5 Hz, 1H, H4′), 8.58 (td, 3JHH ) 1.5 Hz, 3JHH ) 3.5 Hz,
1H, H4, H4′′), 8.01 (td, 3JHH ) 3 Hz, 3JHH ) 6 Hz, 2H, H5, H5′′),
3
2.97 (br, 1H, CcageH), 2.74 (t, 2H, JHH ) 7.2 Hz, CH2S), 2.61 (t,
2H, 3JHH ) 6 Hz, CcageCH2), 1.96 (m, 2H, CH2CH2CH2). 13C{1H}
NMR (74.48 MHz, acetone-d6): δ 161.1 (C2, C2′′), 153.4 (C2′,
C6′), 154.5 (C6, C6′′), 144.5 (C4, C4′′ + C4′), 128.7 (C5, C5′′),
126.3 (C3, C3′′), 125.1 (C3′, C5′), 77.8 (CcageC), 62.6 (CcageH),
37.0 (CH2S), 33.7 (CcageC), 30.2 (CH2CH2CH2). 11B{1H} NMR
(400.21 MHz, acetone-d6): δ -2.1 (1B), -5.0 (1B), -9.0 (2B),
-11.1 (4B), -13.8 (2B). 195Pt{1H} NMR (85.69 MHz, acetone-
d6): -3142. ESI-MS: m/z 645.3 (M+, 100%). Anal. Calcd for
C21H28B10F3N3O3PtS2: C, 30.21; H, 3.55; N, 5.29. Found: C, 30.17;
H, 3.59; N, 5.40.
Method B. To a stirred suspension of [PtCl(trpy)]Cl‚2H2O (100
mg, 0.19 mmol) in DMF (1 mL) was added a solution of AgOTf
(94 mg, 0.36 mmol) in DMF (0.5 mL). The mixture was stirred at
room temperature in the absence of light for 48 h. The mixture
was then filtered through Celite filter aid to remove the AgCl. A
solution of 5 (36 mg, 0.19 mmol) in DMF (1 mL) was then added
to the solution, and the mixture was stirred for 1.5 h at room
temperature. Diethyl ether was added to the solution, precipitating
an off-white solid, which was filtered off and discarded. Additional
diethyl ether was added to precipitate the product, which was
collected by centrifuging, washed with diethyl ether, and dried in
vacuo to give 13 as a bright-red, microcrystalline solid (86 mg,
70%). 1H NMR (599.89 MHz, acetone-d6): δ 9.27 (d, 3JHH ) 5.9
(1,7-Carborane-1-methanethiolato)(2,2′:6′,2”-terpyridine)-
platinum(II) Triflate (16). Method A. To a stirred solution of 2
(40 mg, 0.210 mmol) in acetone (5 mL) was added [Pt(MeCN)-
(trpy)](OTf)2 (185 mg, 0.244 mmol). The solution was stirred at
room temperature for 20 min, and NEt3 (0.5 mL, 0.201 mmol) was
added. The solution was then stirred for a further 18 h. Diethyl
ether (5 mL) was added to afford 16 as red needles (79 mg, 49%).
Method B. To a stirred suspension of [PtCl(trpy)]Cl‚2H2O (68
mg, 0.13 mmol) in DMF (0.5 mL) was added a solution of AgOTf
(64 mg, 0.25 mmol) in DMF (0.5 mL). The mixture was stirred at
room temperature in the absence of light for 48 h and then filtered
through Celite filter aid to remove the AgCl. A solution of 2 (23
mg, 0.12 mmol) in DMF (0.5 mL) was added to the orange filtrate
to give a dark-red solution which was stirred for 5 h at room
temperature. Diethyl ether was then added to the solution to
precipitate a tan solid, which was removed by filtration. Additional
diethyl ether was added to the filtrate, and it was allowed to stand
for 12 h at room temperature. The mixture was centrifuged to give
dark-red needles of 16, which were washed with diethyl ether and
dried in vacuo (40 mg, 45%). 1H NMR (599.89 MHz, acetone-d6):
δ 9.18 (d, 3JHH ) 5.4 Hz, 3JPtH ) 37.5 Hz, 2H, H6, H6′′), 8.63 (m,
2H, H3′, H5′), 8.58 (m, 3H, H3, H3′′ + H4′), 8.49 (td, 3JHH ) 1.2,
3
Hz, JPtH ) 37.5 Hz, 2H, H6, H6′′), 8.62 (m, 2H, H3′, H5′), 8.59
(m, 2H, H3, H3′′ + H4′), 8.52 (td, 3JHH ) 7.8 Hz, 3JHH ) 1.8 Hz,
3
3
4
2H, H4, H4′′), 8.00 (ddd, JHH ) 1.8 Hz, JHH ) 5.9 Hz, JHH
)
9.6 Hz, 2H, H5, H5′′), 4.87 (br, 1H, CcageH), 3.49 (s, 3JPtH ) 37.8,
2H, CH2S). 13C{1H} NMR (50.3 MHz, acetone-d6): δ 160.0 (C2,
C2′′), 154.7 (C2′, C6′), 153.3 (2JPtC ) 30.0 Hz, C6, C6′′), 143.6
(C4, C4′′ + C4′), 130.4 (3JPtC ) 41.9 Hz, C5, C5′′), 127.0 (3JPtC
)
31.4 Hz, C3, C3′′), 125.4 (C3′, C5′), 66.1 (CcageC), 62.2 (CcageH),
37.6 (CH2S). 11B{1H} NMR (96.30 MHz, DMF/benzene-d6): δ
-7.8 (1B), -10.6 (1B), -14.1 (2B), -15.6 (2B), -16.8 (2B),
-17.5 (2B). 195Pt{1H} NMR (64.34 MHz, DMF/benzene-d6): δ
-3135. ESI-MS: m/z 618.2 (M+), 429.4 (C15H11N3Pt+). Anal.
Calcd for C19H24B10F3N3O3PtS2: C, 29.76; H, 3.15; N, 5.48.
Found: C, 29.77; H, 3.10; N, 5.43.
(1,2-Carborane-1-(2-ethanethiolato))(2,2′:6′,2”-terpyridine)-
platinum(II) Triflate (14). To a stirred solution of 10 (48.3 mg,
0.221 mmol) in acetone (5 mL) was added [Pt(MeCN)(trpy)](OTf)2
(106.1 mg, 0.206 mmol). The solution was stirred at room
temperature for 20 min, and NEt3 (0.5 mL, 0.201 mmol) was added.
The solution was then stirred for a further 18 h. Diethyl ether
(5 mL) was added to afford 14 as a microcrystalline, red-orange
3
3
3JHH ) 7.5 Hz, 2H, H4, H4′′), 7.98 (ddd, JHH ) 1.2 Hz, JHH
)
5.4 Hz, 4JHH ) 7.8 Hz, 2H, H5, H5′′), 3.56 (CcageH), 3.10 (CH2S).
13C{1H} NMR (75.48 MHz, acetone-d6): δ 154.3 (C2′ + C6′),
159.7 (C2, C2′′), 153.0 (2JPtC ) 21.6 Hz, C6, C6′′), 143.5 (C4,
C4” + C4′), 130.2 (3JPtC ) 43.1 Hz, C5, C5′′), 127.0 (3JPtC ) 32.3
Hz, C3, C3′′), 125.4 (3JPtC ) 21.6 Hz, C3′, C5′), 56.2 (CcageH),
37.1 (CH2S). 11B{1H} NMR (96.30 MHz, acetone-d6): δ -3.3 (1B),
-10.5 (5B), -3.0 (2B), -14.4 (2B). 195Pt{1H} NMR (64.34 MHz,
acetone-d6): δ -3152. ESI-MS: m/z 618.2 (M+), 429.4 (C15H10N3-
Pt+). Anal. Calcd for C19H24B10F3N3O3PtS2: C, 29.76; H, 3.16; N,
5.48. Found: C, 29.74; H, 3.16; N, 5.52.
1
solid (27 mg, 59%). H NMR (300.13 MHz, acetone-d6): δ 9.31
(d, 3JHH ) 7.0 Hz, 2H, H6, H6′′), 8.63 (d, 3JHH ) 7.3 Hz, 2H, H3′,
3
3
H5′), 8.51 (d, JHH ) 7.5 Hz, 2H, H3, H3′′), 8.47 (t, JHH ) 7.2
3
3
Hz, 1H, H4′), 8.42 (td, JHH ) 1.5 Hz, JHH ) 7.8 Hz, 2H, H4,
H4′′), 7.79 (td, 3JHH ) 1.6 Hz, 3JHH ) 7.3 Hz, 2H, H5, H5′′), 3.74
3
(br, 1H, CcageH), 2.71 (d, 2H, JHH ) 5.7 Hz, CH2S), 2.59 (d, 2H,
3JHH ) 5.4 Hz, CcageCH2). 13C{1H} NMR (74.48 MHz, acetone-
d6): δ 161.8 (C2, C2′′), 155.2 (C2′, C6′), 154.3 (C6, C6′′), 141.0
(C4, C4′′ + C4′), 129.5 (C5, C5′′), 127.3 (C3, C3′′), 123.5 (C3′,
C5′), 72.8 (CcageC), 57.9 (CcageH), 38.1 (CH2S), 30.6 (CcageC).
11B{1H} NMR (400.21 MHz, acetone-d6): δ -2.2 (1B), -6.1 (1B),
-9.6 (2B), -12.6 (4B), -15.8 (2B). 195Pt{1H} NMR (85.69 MHz,
acetone-d6): δ -3108. ESI MS: m/z 631.6 (M+, 100%). Anal. Calcd
for C20H26B10F3N3O3PtS2‚0.5CH3CN: C, 31.48; H, 3.46; N, 6.12.
Found: C, 31.36; H, 2.94; N, 6.08.
(1,12-Carborane-1-methanethiolato)(2,2′:6′,2′′-terpyridine)-
platinum(II) Triflate (17). To a stirred solution of 19 (47.9 mg,
0.250 mmol) in acetone (5 mL) was added [Pt(MeCN)(trpy)](OTf)2
(193 mg, 0.251 mmol). After the solution had stirred at room
temperature for 20 min, NEt3 (0.5 mL, 0.201 mmol) was added,
and the solution was stirred for 18 h. Diethyl ether (5 mL) was
added to afford 17 as an orange microcrystalline solid (98 mg, 71%).
6404 Inorganic Chemistry, Vol. 44, No. 18, 2005

(2,2′:6′,2′′-Terpyridine)platinum(II) Complexes
3
1H NMR (300.13 MHz, DMSO-d6): δ 9.28 (dd, JHH ) 0.6 Hz,
3
3
3JHH ) 6 Hz, JPtH ) 45 Hz, 2H, H6, H6′′), 8.83 (dd, JHH ) 0.9
3
3
Hz, JHH ) 6 Hz, 2H, H3′, H5′), 8.68 (d, JHH ) 9 Hz, 2H, H3,
3
3
H3′′), 8.64 (t, JHH ) 6 Hz, 1H, H4′), 8.49 (td, JHH ) 1.5 Hz,
3JHH ) 9 Hz, 2H, H4, H4′′), 8.00 (td, 3JHH ) 1.5 Hz, 3JHH ) 6 Hz,
2H, H5, H5′′), 3.25 (s, 2H, CH2S), 2.83 (s, 2H, CcageH). 13C{1H}
NMR (74.48 MHz, DMSO-d6): δ 160.3 (C2, C2′′), 155.7 (C2′,
C6′), 153.4 (C6, C6′′), 143.5 (C4, C4′′ + C4′), 130.1 (C5, C5′′),
127.2 (C3, C3′′), 124.9 (C3′, C5′), 55.4 (CH2S), 31.5 (CcageH),
C
cageC not observed. 11B{1H} NMR (400.21 MHz, DMSO-d6): δ
-12.2 (5B), δ -14.5 (5B). 195Pt{1H} NMR (64.34 MHz, acetone-
d6): δ -3132. ESI-MS: m/z 459.0 (C15H11N3Pt+, 100%). Anal.
Calcd for C19H24B10F3N3O3PtS2: C, 29.87; H, 3.16; N, 5.48.
Found: C, 29.94; H, 2.97; N, 5.60.
X-ray Structure Determination of 16. A red and poorly formed
bladelike crystal was attached with Exxon Paratone N to a short
length of fiber supported on a thin piece of copper wire inserted in
a copper mounting pin. The crystal was quenched in a cold nitrogen
gas stream from an Oxford Cryosystems Cryostream. A Bruker-
Nonius ApexII-FR591 diffractometer employing graphite-mono-
chromated Mo KR radiation generated from a rotating anode was
used for the data collection. Cell constants were obtained from a
least-squares refinement against 8340 reflections located between
5 and 57° in 2θ. Data were collected at 150(2) K with ω and φ
scans to 57° in 2θ. The data integration and reduction were
undertaken with SAINT and XPREP,21 and subsequent computa-
tions were carried out with the WinGX22 and XTAL23 graphical
user interfaces. A Gaussian absorption correction21,24 was applied
to the data. The structure was solved in the space group P1h (No.
1) by direct methods with SIR9725 and extended and refined with
SHELXL-97.26 The asymmetric unit contains three crystallographi-
cally independent complex molecules together with three triflate
counterions. Significant residual electron density close to the
platinum and sulfur sites has been modeled as minor occupancy
sites associated with unresolved orientation disorder of the complex
molecules. The fully occupied non-hydrogen sites were modeled
with anisotropic displacement parameters, and the rest were modeled
with isotropic displacement parameters. A riding atom model with
group displacement parameters was used for the hydrogen atoms.
An ORTEP27 depiction of one of the cations in 16 with 50%
displacement ellipsoids is provided in Figure 1. Crystallographic
data are summarized in Table 1.
Figure 1. 1H COSY NMR spectrum of 16 showing key couplings and
peak assignments for the trpy ligand (solvent ) d7-DMF).
Table 1. Crystallographic Parameters for 16
formula of the refinement model
model Mr
C19H24B10F3N3O3.33PtS2
772.06
cryst system
triclinic
space group
a
b
c
P1h (No. 1)
16.3529(8) Å
17.0884(9) Å
17.9759(9) Å
73.450(3)°
R
â
76.772(3)°
γ
63.437(2)°
V
4276.6(4) Å3
1.799 g cm-3
6
Dc
Z
cryst size
cryst color
cryst habit
temp
0.437 × 0.198 × 0.076 mm
red
blade
150(2) K
λ(Mo KR)
µ(Mo KR)
T(Gaussian)min,max
2θmax
hkl range
N
0.710 73 Å
5.119 mm-1
0.347, 0.727
57.46°
In Vitro Cytotoxicity Studies. All anticancer screening was
performed in the Andrew Durant Drug Testing Facility, Peter
MacCallum Cancer Institute (Melbourne, Australia). Details of the
sulforhodamine (SRB) assay have been reported previously.4
-22/22, -23/23, -24/24
104 700
Nind
Nobs
Nvar
22 046 (Rmerge 0.0980)
15 963 (I > 2σ(I))
1162
residsa R1(F), wR2(F2)
GoF(all)
resid extrema
0.0421, 0.1180
1.147
Results and Discussion
-2.351, 2.962 e Å-3
Preparation and Characterization of (Thioalkyl)car-
borane Ligands. A two-step synthesis for 1-(thiomethyl)-
2
a R1 ) ∑||Fo| - |Fc||/∑|Fo| for Fo > 2σ(Fo); wR2 ) (∑w(Fo2 - Fc )2/
2
2
∑(wFc )2)1/2 for all reflections w ) 1/[σ2(Fo ) + (0.05P)2 + 2.0P], where
2
2
(21) APEX, SAINT, and XPREP. Area detector control and data integration
and reduction software; Bruker-Nonius Analytical X-ray Instruments
Inc.: Madison, WI, 2003.
P ) (Fo + 2Fc )/3.
1,12-carborane was recently reported by Nachman et al.,20
and it therefore appeared suitable for adaptation using 1,2-
and 1,7-carborane (Scheme 1).
The 1,7-carborane was deprotonated with nBuLi and
treated with CuBr and LiBr followed by CS2. Addition of
MeI, followed by workup and column chromatography gave
the dithioester 1 in 59% yield. The 11B{1H} NMR spectrum
of the product contained five peaks in the range δ -4.3 to
-16.9 in the ratio 1:1:4:2:2, which was consistent with a
closo-1,7-carborane structure. The dithioester 1 was then
(22) Win, G. X.; Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837-838.
(23) Hall, S. R., du Boulay, D. J., Olthof-Hazekamp, R., Eds. Xtal3.6
System; University of Western Australia: Perth, Australia, 1999.
(24) Coppens, P.; Leiserowitz, L.; Rabinovich, D. Acta Crystallogr. 1965,
18, 1035-1038.
(25) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giaco-
vazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1998, 32, 115-119.
(26) Sheldrick, G. M. SHELX97 Programs for Crystal Structure Analysis;
Institu¨t fu¨r Anorganische Chemie der Universita¨t, University of
Go¨ttingen: Tammanstrasse 4, D-3400 Go¨ttingen, Germany, 1998.
(27) Johnson, C. K. ORTEPII. Report ORNL-5138; Oak Ridge National
Laboratory: Oak Ridge, TN, 1976.
Inorganic Chemistry, Vol. 44, No. 18, 2005 6405

Todd et al.
Scheme 1
Scheme 3
Scheme 2
Scheme 4
reduced with BH3‚SMe2 to afford the thiol 2 in 40% yield.
The 1,2-carborane isomer was also prepared by this method,
but its yield was found to be consistently less than 5% and
a more appropriate synthesis was sought. An alternative
three-step synthesis was devised on the basis of the well-
known condensation reaction between terminal alkynes and
nido-decaborane in the presence of MeCN (Scheme 2).28 In
these reactions, protection of the thiol group proved necessary
to minimize unwanted side reactions. A benzyl-protecting
group was used instead of the tert-butyl group,29 as previous
work within our group has demonstrated that higher yields
of product may be obtained upon removal of the benzyl
group compared with the removal of a tert-butyl group.30
As shown in Scheme 2, the alkyne 3 was refluxed with the
MeCN adduct of nido-decaborane to afford the carborane
A solution of 6 or 7 in DME was added dropwise to a
solution of 1,2-carborane which had been treated with 1 equiv
of nBuLi, to give 8 or 9, respectively, following workup and
column chromatography (Scheme 3). 1H, 13C{1H}, and
11B{1H} NMR spectra supported the identity of the purified
products. In particular, the signal due to the CH2Br group in
the H NMR spectra was shifted upfield by ca. 0.5 ppm,
consistent with the replacement of the electronegative
halogen atom with a C-bonded carborane.
The benzyl-protected thiol 8 or 9 was then added to a
solution of freshly sublimed AlCl3 in benzene to deprotect
the thiol group. Following workup and purification by means
of flash column chromatography, the ligands 10 and 11 were
obtained in reasonable yield. The 1H, 13C{1H}, and 11B{1H}
NMR spectra supported the structures of 10 and 11, with
the 11B{1H} NMR spectra containing five peaks in the range
δ -2 to -14 in the ratio 1:1:2:4:2, consistent with a closo-
1,2-carborane cage. ESI-MS also confirmed the nature of
the products.
1
derivative 4 in high purity and yield. The H, 13C{1H}, and
11B{1H} NMR spectra all agreed with the expected product,
and the compound was then treated with freshly sublimed
AlCl3 in benzene to remove the S-benzyl protecting group
by using an adaptation of the method reported by Herma´nek
et al.29 The thiol 5 was obtained in 33% yield after column
chromatography. The appearance of a triplet at δ 1.87 in
1
1
the H NMR spectrum coupled to a doublet at δ 3.29
(3JHH ) 9 Hz), corresponding to the thiol and methylene
protons, respectively, confirmed the removal of the benzyl
protecting group. This was also verified by the absence of
1
aromatic signals in both the H and 13C{1H} NMR spectra.
The 11B{1H} NMR spectrum showed that the closo-carborane
had remained intact, and GCEI-MS revealed the molecular
ion peak (m/z 189.2, [M - H]-).
Preparation and Characterization of Platinum(II)-
trpy Derivatives. Some of the target platinum(II)-trpy
complexes 12-17 were originally prepared from [Pt(trpy)-
(dmf)](OTf)2.14 However, the relative ease of preparation of
[Pt(MeCN)(trpy)](OTf)2 makes it a superior precursor to the
related [Pt(dmf)(trpy)]2+ species.15 Thus, the addition of [Pt-
(MeCN)(trpy)](OTf)2 to acetone solutions containing the
ligands 2, 5, 10, 11, 18, or 19 containing triethylamine
base resulted in an immediate color change from pale-yellow
to orange or dark-red, depending on the nature of the thiol
ligand, to afford 12-17 as microcrystalline solids (Scheme
4).
Following the same method used to prepare 5, the
carborane derivatives 10 and 11 were synthesized from
B10H12(MeCN)2 and 1-(benzylthio)-3-butyne (n ) 2) or
1-(benzylthio)-4-pentyne (n ) 3), respectively, but this
method afforded only low yields of products in our hands.
An alternative approach was to incorporate a protected thiol
group into the parent 1,2-carborane via its monolithiated
intermediate. In this reaction, protection of the thiol group
with a benzyl or tert-butyl group was required to prevent
the slightly acidic thiol from reacting with the lithiated
carborane intermediate.
1
Complexes 12-17 were fully characterized by H, 13C-
(28) Bregadze, V. I. Chem. ReV. 1992, 92, 209-223.
(29) Plesek, J.; Hermanek, S. Collect. Czech. Chem. Commun. 1979, 44,
2769-2771.
{1H}, 11B{1H}, and 195Pt{1H} NMR spectroscopy, as well
1
(30) Woodhouse, S. L.; Rendina, L. M. Unpublished results.
as ESI-MS and microanalysis. In the H NMR spectra for
6406 Inorganic Chemistry, Vol. 44, No. 18, 2005

(2,2′:6′,2′′-Terpyridine)platinum(II) Complexes
Table 2. IC50 (µM) Values for 13 and 15-17 (n ) 2)a
complex
2008 cell line
C13 cell line
13
15
16
17
1.7
5.3
4.6
26
2.1
4.1
5.1
21
cisplatin
0.6
10
a Cell lines were assayed by means of a sulforhodamine B (SRB) assay.
of metallointercalators to DNA can result in considerable
cytotoxic effects.8,9 The concentrations (µM) required to
achieve 50% inhibition of cell growth (IC50) in each line
are presented in Table 2; cisplatin was used as a control.
Although cytotoxic effects in the absence of thermal
neutrons are not as important for BNCT as an ability to
concentrate within tumor cells and bind to DNA,2 the
cytotoxic properties of the complexes may result in an
additive or synergistic effect during thermal neutron irradia-
tion. In contrast, a high cytotoxicity is undesirable as this
would result in cell death at low platinum concentrations,
prior to accumulation of sufficient levels of 10B nuclei within
the cells.
Table 2 shows that complexes 13, 15, and 16 displayed a
consistently higher cytotoxicity than 17 in the 2008 tumor
line. This is likely to be a consequence of the significantly
lower solubility of 17 in polar environments, as any
precipitation of the complex from solution during the
incubation period would result in a reduced cytotoxic effect.
By comparison of the cytotoxicity of the three isomeric
complexes 13, 16, and 17, which differ only in the nature of
the carborane, it can be seen that 13 is the most active in
these cell lines. This provides strong evidence that subtle
changes in the nature of the carborane cage can significantly
affect the biological activity of the complexes, probably as
a result of the decreased aqueous solubility observed in the
complexes on moving from closo-1,2- and 1,7- to 1,12-
carborane (13, 16, and 17, respectively). An unexpected result
was the lower biological activity of 15 compared with 13. It
was expected that the longer alkyl linker between the
carborane and platinum(II)-trpy groups in 15 would facili-
tate DNA binding by reducing unfavorable steric interactions
between the closo-carborane cage and DNA.14 However the
lower activity of 15 suggests that this is not the case. Again,
the diminished solubility of 15 in polar solvents due to the
aliphatic alkyl chain is consistent with this result. Alterna-
tively, another mechanism of action may be responsible for
the cytotoxicity of the complexes, e.g. enzyme inhibition.33
The similar IC50 values obtained for each complex in both
the cisplatin-sensitive and cisplatin-resistant lines suggests
that, as expected, the mechanism of cytotoxicity differs from
that of cisplatin. However, the causes of the observed IC50
values cannot be identified until the exact mechanism(s) of
cytotoxicity has been determined.
Figure 2. ORTEP34 depiction and atomic numbering scheme of one of
the three crystallographically independent cations in 16 with 50% displace-
ment ellipsoids. Selected bond distances (Å): Pt(1)-N(2) ) 1.968(4), Pt-
(1)-N(3) ) 1.987(5), Pt(1)-N(1) ) 2.018(4), Pt(1)-S(1) ) 2.2967(16).
Selected bond angles (deg): N(2)-Pt(1)-N(3) ) 80.46(17), N(2)-Pt(1)-
N(1) ) 80.89(17), N(3)-Pt(1)-N(1) ) 161.33(17), N(2)-Pt(1)-S(1) )
177.62(13), N(3)-Pt(1)-S(1) ) 101.65(13), N(1)-Pt(1)-S(1) ) 96.99-
(13), C(16)-S(1)-Pt(1) ) 102.98(17).
12-17, there were six distinct aromatic signals observed in
addition to the aliphatic and carborane C-H proton reso-
nances. The assignments for the aromatic protons were based
on 2-D NMR (COSY, HMBC, and HSQC) methods, and a
1
representative H COSY NMR spectrum is presented in
Figure 1. 195Pt{1H} NMR spectroscopy also proved useful
in characterizing selected complexes. Previous studies have
shown that 195Pt{1H} NMR resonances for complexes with
a PtN3S core appear between δ -3100 and -3200 ppm;31
e.g., the signal for 15 is located at δ -3142 ppm.
Complex 16 was further characterized by means of single-
crystal, X-ray diffraction methods (Figure 2), the parameters
of which are given in Table 1. The three crystallographically
independent complexes are square planar, with metal devia-
tions of 0.018(17), 0.023(18), and 0.038(17) Å from the least-
squares planes defined by the four coordinating atoms. In
each case the carborane bearing the thioalkyl ligand is canted
slightly with respect to the least-squares plane, such that the
torsion angles N(3)-Pt(1)-S(1)-C(16), N(6)-Pt(2)-S(2)-
C(34), and N(9)-Pt(3)-S(3)-C(52) are 66.7(2), 64.8(2), and
74.3(2)°, respectively. The deviation of the torsion angles
from 90° appears to be the result of the proximity of
neighboring carborane groups on adjacent complexes. The
Pt-N bond lengths range from 1.968(4) to 2.035(4) Å, and
the Pt-S bond lengths are 2.2967(16), 2.3005(16), and
2.3006(16) Å. These bond lengths, and the three atom
coordination sphere bond angles, are unremarkable with
respect to equivalent bonds and angles in platinum complexes
having the same coordination motif.32
In Vitro Cytotoxicity Studies of Complexes 13 and 15-
17. Complexes 13 and 15-17 were screened against 2008
human ovarian cancer cells and the cisplatin-resistant variant
2008/C13 in vitro. It was expected that some degree of
cytotoxicity would be observed in the absence of thermal
neutrons if the complexes entered the cells, as the binding
Conclusion
In this work, a series of (thioalkyl)-closo-carborane ligands
were synthesized with varying alkyl chain lengths and
(31) Fazlur-Rahman, A. K.; Verkade, J. G. Inorg. Chem. 1992, 31, 2064-
2069.
(32) Allen, F. H. Acta Crystallogr. 2002, B58, 380.
(33) Becker, K.; Herold-Mende, C.; Park, J. J.; Lowe, G.; Schirmer, R.
H., J. Med. Chem. 2001, 44, 2784-2792.
Inorganic Chemistry, Vol. 44, No. 18, 2005 6407

Todd et al.
isomeric carboranes, and a series of novel, brightly colored
platinum(II)-trpy complexes containing these ligands were
also prepared and fully characterized by means of multi-
nuclear (1H, 13C, 11B, and 195Pt) 1D- and 2D-NMR spectros-
copy, ESI-MS and, in the case of 16, X-ray crystallography.
We are currently evaluating the DNA-binding and tumor cell
uptake characteristics of selected complexes, and the results
of this work will be reported in due course.
11B{1H} and 195Pt{1H} NMR spectra and Dr. K. Fisher
(University of Sydney) for recording the ESI-MS. We are
grateful to Johnson-Matthey for the generous loan of K2-
[PtCl4]. Finally, we acknowledge funding from the Australian
Research Council and Anti-Cancer Foundation of South
Australia.
Supporting Information Available: X-ray crystallographic data
files for 16, including atomic coordinates, bond distances and angles,
and thermal parameters, in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to Dr. C. Cullinane
(Peter MacCallum Cancer Institute, Melbourne, Australia)
for the cytotoxicity data. We also thank Dr. I. Luck
(University of Sydney) for assistance with the recording of
IC050265K
6408 Inorganic Chemistry, Vol. 44, No. 18, 2005