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Ruthenium(II) sulfoxide-maltolato and -nitroimidazole complexes: synthesis and MTT assay.
Inorg. Chem. 2003, 42, 7579−7586
Ruthenium(II) Sulfoxide−Maltolato and −Nitroimidazole Complexes:
Synthesis and MTT Assay
Adam Wu, David C. Kennedy, Brian O. Patrick, and Brian R. James*
Department of Chemistry, The UniVersity of British Columbia, 2036 Main Mall,
VancouVer, British Columbia, Canada V6T 1Z1
Received April 7, 2003
RuII sulfoxide−maltolato complexes, Ru(ma)2(L)2 (L ) DMSO (1a) and TMSO (1b) or L2 ) BESE (1c)), were
synthesized, as well as the analogous ethylmaltolato derivatives, Ru(etma)2(L)2 (2a−c) (ma ) 3-hydroxy-2methylpyran-4-onate, etma ) 2-ethyl-3-hydroxypyran-4-onate, TMSO ) tetramethylene sulfoxide, BESE ) 1,2bis(ethylsulfinyl)ethane). A RuII bidentate sulfoxide−metronidazole complex, RuCl2(BESE)(metro)2 (3), was also
synthesized (metro ) metronidazole ) 2-methyl-5-nitroimidazole-1-ethanol). The complexes were characterized
generally by 1H NMR, UV−vis, and IR spectroscopies, as well as MS, elemental analysis, solution conductivity,
and cyclic voltammetry. The molecular structures of Ru(ma)2(S,R-BESE) (1c) and trans-RuCl2(R,R-BESE)(metro)2
(3) were determined by X-ray crystallography. All sulfoxide ligands are S-bonded. The complexes were tested
against human breast cancer cells (MDA-MB-435S) using an in vitro MTT assay, a colorimetric determination of
cell viability: 2a,b exhibit the lowest IC50 values of 190 ± 10 and 220 ± 10 µM, respectively. Cisplatin exhibits an
IC50 value of 30 ± 5 µM.
Introduction
cis- and trans-RuCl2(DMSO)4 exhibit anticancer activity,1,2
most likely due to DNA coordinating to the Ru via intrastrand
cross-linking between two adjacent purines, and both the cis
and trans isomers have been shown to react in water with
nucleoside and nucleotide components.3 Other potent Ru
complexes include (ImH)[trans-Ru(Im)2Cl4], where the
anticancer mechanism is thought to be transferrin-mediated
(Im ) imidazole),4 and (Na or ImH)[trans-Ru(Im)(DMSO)* To whom correspondence should be addressed. E-mail: brj@
chem.ubc.ca.
(1) Clarke, M. J.; Zhu, F.; Frasca, D. R. Chem. ReV. 1999, 99, 2511.
(2) (a) Alessio, E.; Mestroni, G.; Nardin, G.; Attia, W. M.; Calligaris,
M.; Sava, G.; Zorzet, S. Inorg. Chem. 1988, 27, 4099 and references
therein. (b) Farrell, N. P. Transition Metal Complexes as Drugs and
Chemotherapuetic Agents; Ugo, R., James, B. R., Eds.; Kluwer
Academic Publishers: Dordrecht, The Netherlands, 1989; p 147. (c)
Coluccia, M.; Sava, G.; Loseto, F.; Nassi, A.; Boccarelli, A.; Giordano,
D.; Alessio, E.; Mestroni, G. Eur. J. Cancer 1993, 29A, 1873 and
references therein.
(3) (a) Cauci, S.; Viglino, P.; Esposito, G.; Quadrifoglio, F. J. Inorg.
Biochem. 1991, 43, 739. (b) Esposito, G.; Cauci, S.; Fogolsri, F.;
Alessio, E.; Scocchi, M.; Quadrifoglio, F.; Viglino, P. Biochemistry
1992, 31, 7094. (c) Tian, Y.; Yang, P.; Li, Q.; Guo, M.; Zhao, M.
Polyhedron 1997, 16, 1993. (d) Davey, J. M.; Moerman, K. L.; Ralph,
S. F.; Kanitz, R.; Sheil, M. M. Inorg. Chim. Acta 1998, 281, 10.
(4) (a) Keppler, B. K.; Rupp, W.; Juhl, U. M.; Endres, H.; Niebl, R.;
Balzer, W. Inorg. Chem. 1987, 26, 4366. (b) Kratz, F.; Hartmann,
M.; Keppler, B.; Messori, L. J. Biol. Chem. 1994, 269, 2581.
10.1021/ic030119j CCC: $25.00
Published on Web 10/10/2003
© 2003 American Chemical Society
Cl4] (called NAMI and NAMI-A, respectively) that prevent
tumor metastases via a mechanism thought not to involve
Ru-DNA binding as the complexes lack cytotoxicity.5,6
NAMI-A is currently undergoing phase I clinical trials.7 A
general review on the biological activities of Ru complexes
appeared in 1999.1
Our group was the first to synthesize cis-RuCl2(DMSO)48
but for use as an olefin hydrogenation catalyst, this then
leading to the first chiral sulfoxide systems for asymmetric
hydrogenation.9 We later synthesized RuII sulfoxide-nitroimidazole complexes as potential radiosensitizers, with
RuCl2(DMSO)2(4-NO2Im)2 being the most effective, although the configuration of such complexes was never
(5) (a) Sava, G.; Pacor, S.; Coluccia, M.; Mariggio, M.; Cocchietto, M.;
Alessio, E.; Mestroni, G. Drug InVest. 1994, 8, 150. (b) Sava, G.;
Pacor, S.; Bergamo, A.; Cocchietto, M.; Mestroni, G.; Alessio, E.
Chem.-Biol. Interact. 1995, 95, 109. (c) Sava, G.; Capozzi, I.; Clerici,
K.; Gagliargi, G.; Alessio, E.; Mestroni, G. Clin. Exp. Metastasis 1998,
16, 371. (d) Sava, G.; Gagliardi, R.; Bergamo, A.; Alessio, E.;
Mestroni, G. Anticancer Res. 1999, 19, 969.
(6) (a) Bergamo, A.; Gagliardi, R.; Scarcia, V.; Furlani, A.; Alessio, E.;
Mestroni, G.; Sava, G. J. Pharmacol. Exp. Ther. 1999, 289, 559. (b)
Bergamo, A.; Zorzet, S.; Gava, B.; Sorc, A.; Alessio, E.; Iengo, E.;
Sava, G. Anti-Cancer Drugs 2000, 11, 665.
(7) Sava, G.; Bergamo, A.; Zorzet, S.; Gava, B.; Casarsa, C.; Cocchietto,
M.; Furlani, A.; Scarcia, V.; Serli, B.; Iengo, E.; Alessio, E.; Mestroni,
G. Eur. J. Cancer 2002, 38, 427.
(8) James, B. R.; Ochiai, E.; Rempel, G. L. Inorg. Nucl. Chem. Lett. 1971,
7, 781.
Inorganic Chemistry, Vol. 42, No. 23, 2003 7579
Wu et al.
Chart 1
established by a crystal structure.10 Bidentate-sulfoxide
complexes of the type cis- or trans-RuCl2(S-S)2, where S-S
) sulfur-bonded RS(O)(CH2)nS(O)R (R ) alkyl or aryl),
were then made, and in vitro assays indicated that they
accumulated in Chinese hamster ovary cells without hypoxic
selectivity or toxicity, while the trans species accumulated
in DNA to a greater degree than the cis complexes.11,12
We more recently synthesized several Ru β-diketonatoimidazole complexes, including cis-[Ru(acac)2(L)2](CF3SO3)
(L ) Im or N-MeIm), that exhibit hypoxia-selective toxicity
toward some mouse carcinoma cells.13 We have now
extended our studies by using maltolato ligands (Chart 1) in
place of diketonato; both monoanionic ligand types utilize
similar η2(O-O) bonding modes, giving five- and sixmembered chelate rings, respectively, but maltol is nontoxic
and is used as a food additive.14 The promise of Ru sulfoxide
complexes for anticancer activity encourages us to present
this paper that focuses on the characterization of RuII
maltolato and ethylmaltolato complexes (1 and 2) with
ancillary monodentate (DMSO and TMSO) and bidentate
(BESE) sulfoxide ligands (see Chart 1), as well as a BESE/
metro complex (3); the MTT assay data for 1-3 against a
human breast cancer cell line are also presented. Metro itself
(Chart 1) has been used clinically as a radiosensitizer,15 and
for treating anaerobic bacterial infections.16 We have recently
published related papers on the synthesis and MTT assay
results of RuII p-cymene complexes containing BESE17a and
RuII acac complexes containing sulfoxides.17b
(9) (a) McMillan, R. S.; Mercer, A.; James, B. R.; Trotter, J. J. Chem.
Soc., Dalton Trans. 1975, 1006. (b) James, B. R.; McMillan, R. S.;
Reimer, K. J. J. Mol. Catal. 1975/76, 1, 439. (c) James, B. R.;
McMillan, R. S. Can. J. Chem. 1977, 55, 3927. (d) Davies, A. R.;
Einstein, F. W. B.; Farrell, N. P.; James, B. R.; McMillan, R. S. Inorg.
Chem. 1978, 17, 1965. (e) James, B. R.; McMillan, R. S.; Morris, R.
H.; Wang, D. K. W. AdV. Chem. Ser. 1978, No. 167, 122.
(10) (a) Chan, P. K. L.; Skov, K. A.; James, B. R.; Farrell, N. P. Int. J.
Radiat. Oncol. Biol. Phys. 1986, 12, 1059. (b) Chan, P. K. L.; Chan,
P. K. H.; Frost, D. C.; James, B. R.; Skov, K. A. Can. J. Chem. 1988,
66, 117 and references therein. (c) Chan, P. K. L.; James, B. R.; Frost,
D. C.; Chan, P. K. H.; Hu, H.-L.; Skov, K. A. Can. J. Chem. 1989,
67, 508 and references therein.
(11) Yapp, D. T. T.; Rettig, S. J.; James, B. R.; Skov, K. A. Inorg. Chem.
1997, 36, 5635.
(12) Cheu, E. L. S. Ph.D. Dissertation, The University of British Columbia,
Vancouver, BC, Canada, 2000.
(13) (a) Baird, I. R. Ph.D. Dissertation, The University of British Columbia,
Vancouver, BC, Canada, 1999. (b) Baird, I. R.; Rettig, S. J.; James,
B. R.; Skov, K. A. Can. J. Chem. 1999, 77, 1821.
(14) LeBlanc, D. T.; Akers, H. A. Food Technol. 1989, 43, 78.
(15) (a) Fowler, J. F.; Denekamp, J. Pharmacol. Therapeut. 1979, 7, 413.
(b) Denny, W. A.; Roberts, P. B.; Anderson, R. F.; Brown, J. M.;
Wilson, W. R. Int. J. Radiat. Biol. Oncol. Phys. 1992, 22, 553.
(16) Brogden, R. N.; Heel, R. C.; Speight, T. M.; Avery, G. S. Drugs 1978,
16, 387.
(17) Huxham, L. A.; Cheu, E. L. S.; Patrick, B. O.; James, B. R. Inorg.
Chim. Acta 2003, 352, 238. (b) Wu, A.; Kennedy, D. C.; Patrick, B.
O.; James, B. R. Inorg. Chem. Commun. 2003, 6, 996.
7580 Inorganic Chemistry, Vol. 42, No. 23, 2003
Experimental Section
Materials for Synthesis. Reagent grade solvents (Fisher Scientific) were dried using standard procedures18 under N2 before
use, and deuterated solvents (Cambridge Isotope Laboratories) were
used as received. RuCl3‚3H2O (Colonial Metals), maltol (Cultor
Food Science), ethylmaltol (Pfizer Food Science), KOtBu (Acros
Organics), TMSO, metronidazole, [nBu4N](PF6), FeCp*2, cisplatin,
and silica gel preparative TLC plates with fluorescent indicator (20
× 20 cm2, Uniplate from Analtech) were purchased from Aldrich,
unless stated otherwise. meso-BESE,11,17 K(ma),19,20 cis-RuCl2(DMSO)4,21 cis-RuCl2(TMSO)4,22 and [RuCl(H2O)(BESE)]2(µCl)212 were prepared by literature methods. K(etma) was synthesized
by following the maltol/KOtBu procedure used for K(ma),19,20
except ethylmaltol was used. Standard Schlenk techniques were
used for synthesis of the complexes.
Physical Techniques and Instrumentation. 1H NMR spectra
were recorded at room temperature (rt, ∼20 °C) on Bruker AV300
or AV400 instruments (s ) singlet, d ) doublet, br ) broad, and
m ) multiplet; J values are given in Hz), with chemical shifts being
calibrated using residual proton resonances from deuterated solvents.
Elemental analyses were performed by P. Borda of this department
or by M. K. Yang of the Simon Fraser University Chemistry
Department on Carlo Erba EA 1108 CHN-O analyzers. Mass
spectral data (reported as m/z values) were acquired on a Kratos
Concept IIHQ LSIMS instrument using a thioglycerol matrix or
on a Bruker Esquire ES spectrometer in this department (c/o G.
Eigendorf). UV-vis spectra were recorded at rt on a HewlettPackard 8452A diode-array spectrometer, and data are presented
as λmax, nm ( × 10-3 M-1 cm-1). IR spectra (KBr) were recorded
on ATI Mattson Genesis or Bomem-Michelson MB-100 FT-IR
spectrometers; selected ν values (cm-1) are given with assigned
functional groups.23 Conductivity measurements, carried out on a
RCM151B Serfass conductance bridge (A. H. Thomas Co. Ltd.)
with a 3403 cell (Yellow Springs Instrument Co.), were calibrated
using 0.01000 M aqueous KCl solution (ΛM ) 141.3 Ω-1 cm2
mol-1 at 25 °C, cell constant ) 1.016 cm-1), and data are given in
units of Ω-1 cm2 mol-1.24 CV was performed in CH2Cl2 containing
0.1 M [nBu4N](PF6) as supporting electrolyte, voltammograms being
(18) Gordon, A. J.; Ford, R. A. The Chemist’s Companion: A Handbook
of Practical Data, Techniques, and References; John Wiley & Sons:
New York, 1972; p 429.
(19) Fryzuk, M. D.; Jonker, M. J.; Rettig, S. J. Chem. Commun. 1997,
377.
(20) Jonker, M. J. M.Sc. Dissertation, The University of British Columbia,
Vancouver, BC, Canada, 1993.
(21) Evans, I. P.; Spencer, A.; Wilkinson, G. J. Chem. Soc., Dalton Trans.
1973, 204.
(22) (a) Alessio, E.; Milani, B.; Mestroni, G.; Calligaris, M.; Faleschini,
P.; Attia, W. M. Inorg. Chim. Acta 1990, 177, 255. (b) Yapp, D. T.
T.; Jaswal, J.; Rettig, S. J.; James, B. R.; Skov, K. A. Inorg. Chim.
Acta 1990, 177, 199.
(23) Pavia, D. L.; Lampman, G. M.; Kriz, G. S. Introduction to Spectroscopy, 2nd ed.; Harcourt Brace & Co: Orlando, FL, 1996.
(24) (a) Geary, W. J. Coord. Chem. ReV. 1971, 7, 81. (b) Huheey, J. E.
Inorganic Chemistry: Principles of Structure and ReactiVity, 3rd ed.;
Harper Collins Publishers: New York, 1983; p 362.
Ruthenium(II) Sulfoxide Complexes
Table 1. Crystallographic Data for 1c‚H2O and 3
formula
fw
cryst color, habit
cryst size (mm)
cryst system
space group
a (Å)
b (Å)
c (Å)
R (deg)
β (deg)
γ (deg)
V (Å3)
Z
Dcalcd (g cm-3)
F000
no. of observns
(I > 0.00σ(I))
no. of variables
µ(Mo KR) (cm-1)
R1a
wR2b
goodness of fit
1c‚H2O
3
C18H26O9S2Ru
551.59
orange, prism
0.15 × 0.10 × 0.05
triclinic
P1h (No. 2)
7.5998(3)
9.8229(4)
15.3305(4)
71.618(6)
82.902(8)
89.238(8)
1077.34(8)
2
1.700
564
4403
C18H32N6O8S2Cl2Ru
696.58
orange, platelet
0.25 × 0.10 × 0.04
orthorhombic
Pbca (No. 61)
13.4946(7)
19.628(1)
20.746(1)
90.00
90.00
90.00
5495.1(5)
8
1.684
2848
6361
271
9.69
0.029 (I > 3σ(I),
3396 observns)
0.076
0.88
366
9.70
0.042 (I > 2σ(I),
3674 observns)
0.099
0.87
a R1 ) ∑||F | - |F ||/∑|F | (observed data). b wR2 ) (∑(F 2 - F 2)2/
o
c
o
o
c
∑w(Fo2)2)1/2 (all data).
recorded on a Pine Bipotentiostat (model AFCBP1) and PineChem
v2.00 software; the scan rate was 200 mV s-1 using a Pt working
electrode, a Pt wire counter electrode, and a Ag wire reference
electrode, with FeCp*2 (-0.13 V vs SCE in CH2Cl2) used as an
internal calibrant.25 E1/2 values are given vs SCE.
X-ray Crystallography. Measurements were made at 173(1) K
on a Rigaku/ADSC CCD area detector with graphite-monochromated Mo KR radiation (0.710 69 Å). Some crystallographic data
for 1c‚H2O and 3 are shown in Table 1. The final unit-cell
parameters were based on 6720 reflections with 2θ ) 4.4-55.7°
for 1c and 20 589 reflections with 2θ ) 4.2-55.8° for 3. The data
were collected and processed using the d*TREK program,26 and
the structures were solved using direct methods27 and expanded
using Fourier techniques.28 The non-hydrogen atoms were refined
anisotropically, and the H atoms were included but not refined.
For 3, one Et of the BESE ligand, C(1)-C(2), was disordered and
was subsequently modeled in two orientations, the populations of
the disordered fragments being refined to roughly 0.58 and 0.42.
Ru(ma)2(DMSO)2 (1a). Complex 1a was synthesized by a
literature procedure19 but using EtOH rather than toluene as solvent.
A suspension of cis-RuCl2(DMSO)4 (100 mg, 0.21 mmol) and
K(ma) (85 mg, 0.52 mmol) in EtOH (20 mL) was refluxed in air
at 80 °C for 16 h to give a dark red solution. The solvent was
removed under vacuum, and the residue was then extracted with
C6H6 (2 × 20 mL); the extract was filtered through Celite, the
filtrate was reduced to 10 mL, and then hexanes (60 mL) was added
to yield a yellow precipitate that was collected under N2 and dried
in vacuo at rt. The hygroscopic product was stored in a desiccator
over anhydrous CaSO4.
(25) Connelly, N. G.; Geiger, W. E. Chem. ReV. 1996, 96, 877.
(26) d*TREK: Area Detector Software, version 7.1I; Molecular Structure
Corp: The Woodlands, TX, 2001.
(27) Altomare, A.; Burla, M. C.; Cammalli, G.; Cascarano, M.; Giacovazzo,
C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, A. J.
Appl. Crystallogr. 1999, 32, 115.
(28) Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; de
Gelder, R.; Israel, R.; Smits, J. M. M. The DIRDIF-94 Program
System; Technical Report of the Crystallography Laboratory; University of Nijmegen: Nijmegen, The Netherlands, 1994.
Yield: 55 mg (53%). 1H NMR (C6D6; δ): 2.07, 2.13, 2.14, 2.18
(s, 6H, CH3-ma); 2.77, 2.86, 2.87, 2.94, 2.98, 3.07, 3.13, 3.19, 3.21,
3.28, 3.30, 3.34 (s, 12H, CH3-DMSO); 6.03-6.15 (multiple d, 2H,
H(5), 3JHH ) 5.1); 6.47-6.59 (multiple d, 2H, H(6), 3JHH ) 5.1).
Anal. Calcd for C16H22O8S2Ru: C, 37.86; H, 4.37. Found: C, 38.00;
H, 4.55. LR-MS (+LSIMS): 508 (M+), 430 (M+ - DMSO), 352
(M+ - 2 DMSO). UV-vis (H2O): 212 (32.0), 270 (10.7), 356
(6.03). IR (KBr): νSdO 1094; νCdO + νCdC 1547; νCdO 1595. ΛM
(H2O) ) 8 (nonconducting). E1/2(RuIII/II) ) 0.52 V. The NMR and
IR (νSdO) data agree with those reported.19,20
Ru(etma)2(DMSO)2 (2a). The complex was synthesized as for
1a, except K(etma) (92 mg, 0.52 mmol) was used.
Yield: 50 mg (45%). 1H NMR (C6D6; δ): 1.02 (m, 6H, CH3etma); 2.49-2.85 (br m, 4H, CH2); 2.79, 2.88, 2.95, 2.99, 3.07,
3.09, 3.13, 3.18, 3.20, 3.28, 3.30, 3.36 (s, 12H, CH3-DMSO); 6.026.16 (multiple d, 2H, H(5), 3JHH ) 5.1); 6.51-6.64 (multiple d,
2H, H(6), 3JHH ) 5.1). Anal. Calcd for C18H26O8S2Ru: C, 40.36;
H, 4.89. Found: C, 40.38; H, 4.88. LR-MS (+LSIMS): 536 (M+),
458 (M+ - DMSO), 380 (M+ - 2 DMSO). UV-vis (H2O): 212
(29.5), 272 (10.1), 356 (5.82). IR (KBr): νSdO 1097; νCdO + νCdC
1546; νCdO 1592. ΛM (H2O) ) 15 (essentially nonconducting).
E1/2(RuIII/II) ) 0.51 V.
Ru(ma)2(TMSO)2 (1b). The complex 1b was synthesized as for
1a, except cis-RuCl2(TMSO)4 (100 mg, 0.17 mmol) and K(ma)
(70 mg, 0.43 mmol) were used.
Yield: 50 mg (53%). 1H NMR (C6D6; δ): 1.50-2.50 (br m,
8H, CH2CH2S); 2.07, 2.18, 2.20, 2.24 (s, 6H, CH3-ma); 3.00-4.60
(br m, 8H, CH2CH2S); 6.05-6.25 (multiple d, 2H, H(5), 3JHH )
5.1); 6.45-6.65 (multiple d, 2H, H(6), 3JHH ) 5.1). Anal. Calcd
for C20H26O8S2Ru‚H2O: C, 41.59; H, 4.89. Found: C, 41.49; H,
4.71. LR-MS (+LSIMS): 560 (M+), 456 (M+ - TMSO), 352 (M+
- 2 TMSO). UV-vis (H2O): 210 (31.0), 270 (9.60), 354 (5.44).
IR (KBr): νSdO 1056, 1117; νCdO + νCdC 1549; νCdO 1594. ΛM
(H2O) ) 30. E1/2(RuIII/II) ) 0.52 V.
Ru(etma)2(TMSO)2 (2b). The complex was synthesized as for
1b, except that K(etma) (76 mg, 0.43 mmol) was used.
Yield: 50 mg (50%). 1H NMR (C6D6; δ): 1.00 (m, 6H, CH3etma); 1.40-2.10 (br m, 8H, CH2CH2S); 2.40-2.90 (br m, 4H,
CH2-etma); 3.00-4.50 (br m, 8H, CH2CH2S); 6.00-6.25 (multiple
d, 2H, H(5), 3JHH ) 5.1); 6.45-6.70 (multiple d, 2H, H(6), 3JHH )
5.1). Anal. Calcd for C22H30O8S2Ru: C, 44.96; H, 5.15. Found: C,
44.78; H, 5.08. LR-MS (+LSIMS): 588 (M+), 484 (M+ - TMSO),
380 (M+ - 2 TMSO). UV-vis (H2O): 214 (31.0), 272 (10.6),
358 (5.95). IR (KBr): νSdO 1055, 1116; νCdO + νCdC 1546; νCdO
1592. ΛM (H2O) ) 20. E1/2(RuIII/II) ) 0.52 V.
Ru(ma)2(BESE) (1c). The complex was made exactly as for
1a, except that [RuCl(H2O)(BESE)]2(µ-Cl)2 (100 mg, 0.13 mmol)
and K(ma) (110 mg, 0.67 mmol) in EtOH (20 mL) were used.
Crystals suitable for X-ray analysis were grown by slow evaporation
of an acetone solution of the complex layered with hexanes.
Yield: 57 mg (40%). 1H NMR (yellow product, D2O; δ): 1.151.50 (br m, 6H, CH3-BESE); 2.23, 2.26, 2.34, 2.37 (s, 6H, CH3ma); 2.60-3.90 (br m, 8H, CH2S(O)CH2); 6.47-6.71 (multiple d,
2H, H(5), 3JHH ) 5.0); 7.82-7.95 (multiple d, 2H, H(6), 3JHH )
5.0). 1H NMR (crystal, D2O; δ): 1.20-1.50 (m, 6H, CH3-BESE);
2.35, 2.39 (s, 6H, CH3-ma); 2.60-3.90 (m, 8H, CH2S(O)CH2); 6.53,
6.55 (d, 2H, H(5), 3JHH ) 5.1); 7.84, 7.88 (d, 2H, H(6), 3JHH )
5.1). Anal. Calcd for C18H24O8S2Ru: C, 40.52; H, 4.53. Found:
C, 40.39; H, 4.53. LR-MS (+LSIMS): 534 (M+), 352 (M+ BESE). UV-vis (H2O): 208 (34.7), 266 (13.9), 354 (6.94). IR
(KBr): νSdO 1079, 1113; νCdO + νCdC 1549, 1560; νCdO 1595.
ΛM (H2O) ) 4 (nonconducting). E1/2(RuIII/II) ) 0.55 V.
Inorganic Chemistry, Vol. 42, No. 23, 2003
7581
Wu et al.
Ru(etma)2(BESE) (2c). The complex was synthesized as for 1c,
except K(etma) (120 mg, 0.52 mmol) was used.
Yield: 50 mg (33%). 1H NMR (D2O; δ): 1.06 (m, 6H, CH3etma); 1.15-1.50 (br m, 6H, CH3-BESE); 2.55-3.95 (br m, 12H,
CH2-etma and CH2S(O)CH2); 6.50-6.70 (multiple d, 2H, H(5), 3JHH
) 5.1); 7.83-7.97 (multiple d, 2H, H(6), 3JHH ) 5.1). Anal. Calcd
for C20H28O8S2Ru: C, 42.77; H, 5.03. Found: C, 43.03; H, 5.00.
LR-MS (+LSIMS): 562 (M+), 380 (M+ - BESE). UV-vis
(H2O): 210 (32.1), 268 (13.1), 358 (6.71). IR (KBr): νSdO 1079,
1114; νCdO + νCdC 1545, 1559; νCdO 1593. ΛM (H2O) ) 9
(nonconducting). E1/2(RuIII/II) ) 0.55 V.
RuCl2(BESE)(metro)2 (3). A suspension of [RuCl(H2O)(BESE)]2(µ-Cl)2 (150 mg, 0.20 mmol) and metronidazole (207 mg, 1.2 mmol)
in MeOH (60 mL) was refluxed in air at 75 °C for 16 h to give a
yellow mixture. The volume was reduced to 5 mL, and the mixture
was loaded onto a preparative TLC plate. The solvent was allowed
to evaporate, and product separation was achieved using CH2Cl2/
MeOH (90:10). The major (yellow) band was extracted with MeOH
(3 × 20 mL), and the mixture then filtered through Celite. The
filtrate was reduced to 5 mL, and Et2O (60 mL) was added to give
a product that was collected and dried in vacuo at rt. Crystals
suitable for X-ray analysis were grown from evaporation of MeOH/
Et2O solutions.
Yield: 72 mg (26%). 1H NMR (D2O; δ): 1.00-1.60 (br m, 6H,
CH3-BESE); 2.34, 2.47, 2.60, 2.79 (s, 6H, CH3-metro); 3.15-4.00
(br m, 12H, CH2S(O)CH2 and CH2OH); 4.30-4.80 (br m, 4H,
N-CH2CH2OH); 8.09, 8.14, 8.30, 8.49 (s, 2H, H(4)-metro). Anal.
Calcd for C18H32N6O8Cl2S2Ru‚2H2O: C, 29.51; H, 4.95; N, 11.47.
Found: C, 29.87; H, 4.70; N, 10.69. LR-MS (+ES ion trap,
MeOH): 661 (M+ - Cl), 491 (M+ - Cl - metro), 456 (M+ - 2
Cl - metro). UV-vis (H2O): 310 (13.9). IR (KBr): νSdO 1079,
1114; νNdO(symm) 1364; νNdO(asymm) 1480; νOH 3422. ΛM (H2O)
) 180 (5 min), 200 (30 min), 210 (3 h), 220 (24 h) (2:1 electrolyte).
E1/2(NO2/NO2-) ) -1.16 V. E1/2(RuIII/II) ) 1.18 V.
MTT Assay. All reagents were handled in a sterile fume hood.
Leibovitz’s L-15 medium with L-glutamine (L-15), fetal bovine
serum (FBS), Zn bovine insulin, phosphate-buffered saline 7.4
(PBS), trypsin-EDTA (0.25% trypsin and 1 mM Na4(EDTA)), and
trypan blue stain (0.4%) were purchased from Gibco. MTT (3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was an
Aldrich product. The growth medium (L-15 medium with 10% FBS
and 0.01 mg/mL insulin), Zn bovine insulin, and MTT were stored
at 4 °C, while trypsin-EDTA and FBS were stored frozen at -10
°C and thawed before use; PBS was stored at rt.
Human breast cancer cells (MDA-MB-435S),29 purchased from
American Type Culture Collection (ATCC), were plated in a T-75
flask (Becton Dickinson and Co.) and incubated at 37 °C in air.
The cells were transferred to a new flask biweekly and treated with
trypsin-EDTA to detach them from the flask. Cells were counted
under a microscope using a hemacytometer (Hausser Scientific,
0.100 mm deep), after the addition of trypan blue that stains and
excludes dead cells. Cell solutions were diluted with growth medium
to a concentration of 1 × 105 cells/mL and transferred to a 96-well
plate, by plating the wells in columns C and 1 to 8 (Chart 2) with
100 µL (1 × 104 cells). Growth medium (100 µL) was added to
column B, as a blank. To each of the perimeter wells was added
deionized water (200 µL), and the plate was then incubated at 37
°C for 24 h. PBS solutions (100 µL) of the test Ru complex at 8
different concentrations (4000 to 2 µM) were then added to the
(29) (a) Brinkley, B. R.; Beall, P. T.; Wible, L. J.; Mace, M. L.; Turner,
D. S.; Cailleau, R. M. Cancer Res. 1980, 40, 3118. (b) Siciliano, M.
J.; Barker, P. E.; Cailleau, R. Cancer Res. 1979, 39, 919. (c) Cailleau,
R.; Olive, M.; Cruciger, Q. V. J. In Vitro 1978, 14, 911.
7582 Inorganic Chemistry, Vol. 42, No. 23, 2003
Chart 2. A 96-well Plate Showing Columns B, C, and 1-8 in the
Shaded Wells
Chart 3. Five Possible Stereoisomers of 1a or 2aa
a S represents S-bonded DMSO, and O-O′ represents the chemically
inequivalent hydroxy (O) and carbonyl (O′) oxygen atoms of maltolato or
ethylmaltolato ligands.
well in columns 1 (highest [Ru]) to 8 (lowest [Ru]). PBS (100 µL)
was also added to the wells in column B and C, and the plate was
incubated at 37 °C for 3 days.
A modified procedure of Mosmann was used for the MTT
assay.30 A PBS solution of MTT (50 µL, 2.5 mg/mL) was added
to each well of the plate that was then incubated for 3 h, by which
time a purple precipitate of formazan formed at the bottom of certain
wells. The contents of each well were carefully aspirated off to
leave the formazan that was then dissolved in DMSO (150 µL);
the plate was shaken and analyzed by a plate reader (Spectra Max
190 from Molecular Devices) to determine the absorbance of each
well at 570 nm. The percentage cell viability was calculated by
dividing the average absorbance of the cells treated with a Ru
complex by that of the control; % cell viability vs drug concentration
(logarithmic scale) was plotted to determine the IC50 (drug
concentration at which 50% of the cells are viable relative to the
control), with its estimated error derived from the average of 3
trials.
Results and Discussion
Complexes 1a and 2a. The solid-state molecular structure
of 1a was reported19 to be a cis isomer with S-bonded DMSO
ligands (structure C in Chart 3; the IR νSdO value, 39 cm-1
> that of 1055 cm-1 for free DMSO, supports solely
S-bonded sulfoxide10,31), but the solution structure is more
complex.19,20 Because of the inequivalence of the O atoms
of the maltolato (ma) ligand, three cis and two trans
stereoisomers are possible for the solely S-bonded sulfoxide
species 1a (and 2a) (Chart 3). The 1H NMR spectrum of 1a
in C6D6 exhibits four singlets in the δ 2.1 region, each
assignable to a Me of ma, while two sets of four doublets
centered at ∼ δ 6.1 and 6.5 are assigned to the ma H(5) and
H(6), respectively. These data are consistent with the
presence of the three cis isomers, the inequivalent ma ligands
in C giving rise to two Me singlets and the equivalent Me
groups in D and E each giving rise to one; the doublets are
assigned similarly to H(5) and H(6). The 12 singlets between
(30) Mosmann T. J. Immunol. Methods 1983, 65, 55.
(31) Davies, J. A. AdV. Inorg. Chem. Radiochem. 1981, 24, 115.
Ruthenium(II) Sulfoxide Complexes
δ 2.7 and 3.4 correspond to the Me groups of the S-bonded
DMSO ligands.10,31 The formation of the trans isomers (A
and B), which like D and E also have equivalent ma ligands,
is not favored because the π-accepting sulfoxides would
prefer when possible not to be mutually trans.32 Our
interpretation of the 1H NMR spectrum agrees with that
discussed in an M.Sc. thesis.20 Relative integrations of the
resonances suggest that in solution there is ∼55% of C, with
the other two isomers being present in a ratio of ∼2:1.The
acac analogue of 1a, cis-Ru(acac)2(DMSO)2, exists as a
single isomer in solution and is readily characterized by 1H
NMR.17b All the cis isomers are chiral at Ru, and racemic
mixtures must also be present in solution. Complex 2a also
contains S-bonded DMSO ligands (νSdO ) 1097 cm-1); its
1
H NMR solution spectrum is essentially similar to that of
1a, except for coupling between the etma Me and CH2 groups
that theoretically gives a triplet and a quartet, respectively,
for each isomer, and because of the presence of three cis
isomers, multiplets are observed for overlapping signals. The
CH2 etma multiplets also appear to overlap with the Me
singlets of DMSO. Complexes 1a and 2a are soluble in H2O,
immediately forming yellow, essentially nonconducting
solutions; their UV-vis spectra that do not change over 24
h are considered to refer to a mixture of the cis isomers.
The ma and etma νCdO/νCdC values for 1a and 2a (as well
as for complexes 1b,c and 2b,c discussed below) are between
1545 and 1595 cm-1, ∼60 cm-1 below those of the free
maltolato anions,33 reasonable values for binding via the
carbonyl group.
Complexes 1b and 2b. The IR spectra of the TMSO
complexes show νSdO values greater than that for free TMSO
(1023 cm-1) and again imply the presence of S-bonded
TMSO ligands.22 In the 1H NMR spectrum of cis-RuCl2(TMSO)4, the R-proton signals shift downfield to δ 3.4 and
4.0, while the β-proton resonances shift slightly upfield to
δ 2.3, compared to the signals of free TMSO.22 Similar trends
are seen in the 1H NMR spectra of 1b and 2b, but these are
more complicated because of the presence of multiple
isomers. The 1H signals appear as broad multiplets between
δ 3.0 and 4.5 for the R-protons and between δ 1.5 and 2.5
for the β-protons. The four Me singlets of 1b are centered
at δ 2.2 and give a pattern similar to that observed for 1a.
On the basis of the available spectroscopic data, solution
structures of 1b and 2b in C6D6 are tentatively assigned as
all cis, similar to those of 1a and 2a. Complexes 1b and 2b
dissolve in H2O to give weakly conducting solutions (ΛM )
30 and 20 Ω-1 cm2 mol-1, respectively), presumably because
of partial dissociation of the maltolato ligands.
Complexes 1c and 2c. The crystal structure for 1c and
IR data for 1c and 2c with νSdO values greater than that for
free BESE (1015 cm-1) again reveal S-bonded sulfoxide
moieties.11,31 Of the three stereoisomers possible C′, D′ and
E′, (equivalent to C-E in Chart 3 but with connected S
atoms), the structure of 1c (Figure 1) reveals isomer D′ where
the carbonyl O atoms of ma are mutually trans, in contrast
to structure C determined for 1a (see above);19 the disulfoxide
(32) Calligaris, M.; Carugo, O. Coord. Chem. ReV. 1996, 153, 83.
(33) Greaves, S. J.; Griffith, W. P. Polyhedron 1988, 7, 1973.
Figure 1. ORTEP diagram of Ru(ma)2(S,R-BESE) (1c) with 50%
probability ellipsoids.
is found as the meso form (S1 ) S, S2 ) R; Figure 2), which
is the predominant form used in the synthesis.12,17 The
structure is the first reported for a complex containing both
ma and a bidentate disulfoxide. Selected bond lengths and
angles for 1c are shown in Table 2; 1c and 1a have similar
Ru-S bond lengths (2.18-2.21 Å) and Ru-O bond lengths
(2.08-2.15 Å), and both have distorted octahedral geometries
with the ma ligand having a bite of ∼80°. The geometry of
the coordinated ma is close to that found in RuCl(η6mesitylene)(ma).34 The Ru-S bond lengths in 1c are shorter
than those in cis- and trans-RuCl2(BESE)211,12 and [RuCl(p-cymene)(BESE)]PF6,17 when a S atom is trans to another
S or a hydrocarbon fragment (2.288-2.329 Å) as opposed
to being trans to oxygen in 1c. The bite angle of the BESE
in 1c is 88.27°, close to those noted for the complexes
mentioned above (83.73-87.69°).
Complexes 1c and 2c are very soluble in water, immediately forming yellow, nonconducting solutions, whose
UV-vis spectra do not change over 24 h at rt. The timeindependent 1H NMR spectrum of the crystal of 1c in D2O
shows two, equal-intensity ma-Me singlets, in addition to
two sets of doublets for the H(5) and H(6) protons, consistent
with the presence of just isomer D′, the solid-state structure.
The 1H NMR for the yellow powder product (1c) in D2O
shows four major singlets centered at δ 2.3 for the ma-Me
resonances, and multiple sets of doublets are for the H(5)
and H(6) nuclei centered at δ 6.6 and 7.9, respectively. For
the meso-BESE ligand system, the three possible isomers
(C′, D′ and E′) would exhibit inequivalent ma ligands
(i.e., give six singlets for the Me protons and six sets of
doublets for H(5) and H(6)); the four ma-Me singlets
observed indicate the presence of two major isomers. The
etma-Me and -CH2 groups of 2c give rise to overlapping
(34) Capper, G.; Carter, L. C.; Davies, D. L.; Fawcett, J.; Russell, D. R. J.
Chem. Soc., Dalton Trans. 1996, 1399.
Inorganic Chemistry, Vol. 42, No. 23, 2003
7583
Wu et al.
Figure 3. ORTEP diagram of trans-RuCl2(R,R-BESE)(metro)2 (3) with
50% probability ellipsoids.
Table 3. Selected Bond Lengths and Angles of 3
Figure 2. The 1H COSY NMR spectra of 1c (a) and 2c (b) in D2O.
Table 2. Selected Bond Lengths and Angles of 1c‚H2O
bond
length (Å)
bond
angle (deg)
Ru(1)-O(1)
Ru(1)-O(2)
Ru(1)-O(4)
Ru(1)-O(5)
Ru(1)-S(1)
Ru(1)-S(2)
S(1)-O(7)
S(2)-O(8)
O(1)-C(1)
O(2)-C(2)
2.141(2)
2.082(2)
2.098(2)
2.085(2)
2.2054(7)
2.1807(7)
1.487(2)
1.476(2)
1.318(3)
1.281(2)
S(1)-Ru(1)-O(4)
S(2)-Ru(1)-O(1)
O(2)-Ru(1)-O(5)
O(1)-Ru(1)-O(2)
O(4)-Ru(1)-O(5)
S(1)-Ru(1)-S(2)
Ru(1)-O(1)-C(1)
Ru(1)-O(2)-C(2)
O(7)-S(1)-C(15)
C(13)-S(1)-C(15)
174.52(5)
172.93(6)
168.24(7)
80.37(7)
81.17(7)
88.27(3)
107.9(2)
111.1(2)
105.9(1)
100.9(1)
triplets (∼ δ 1.1) and quartets (∼ δ 2.6), respectively. The
BESE-Me signals of 1c and 2c result in multiplets between
δ 1.2-1.5, while the CH3CH2S(O)CH2 protons, occurring
7584 Inorganic Chemistry, Vol. 42, No. 23, 2003
bond
length (Å)
bond
angle (deg)
Ru(1)-N(1)
Ru(1)-N(4)
Ru(1)-S(1)
Ru(1)-S(2)
Ru(1)-Cl(1)
Ru(1)-Cl(2)
S(1)-O(1)
S(2)-O(2)
O(4)-N(3)
O(5)-N(3)
2.139(3)
2.143(3)
2.2267(11)
2.2174(11)
2.4148(10)
2.4006(11)
1.477(3)
1.495(3)
1.238(5)
1.214(5)
N(1)-Ru(1)-S(1)
N(4)-Ru(1)-S(2)
Cl(2)-Ru(1)-Cl(1)
S(2)-Ru(1)-S(1)
N(1)-Ru(1)-N(4)
N(1)-Ru(1)-S(2)
N(1)-Ru(1)-Cl(1)
S(1)-Ru(1)-Cl(1)
O(1)-S(1)-C(1)
C(3)-S(1)-C(1)
177.93(9)
179.03(8)
179.41(4)
87.23(4)
89.26(12)
90.86(9)
90.69(8)
90.11(4)
108.4(3)
92.6(3)
as overlapping multiplets between δ 2.6-4.0, have been
assigned from 1H COSY NMR data (Figure 2). Qualitatively,
the NMR data for 2c appear consistent also with the presence
of two major isomers. The C′, D′, and E′ isomers are all
chiral at Ru, and so the racemic mixtures are present as well;
more complex spectra would be expected if the R,R or S,S
form of BESE were present in 1c or 2c.
The presence of maltolato ligands certainly increases the
water solubility of Ru sulfoxide complexes; e.g., 1c is much
more water-soluble than either cis- or trans-RuCl2(BESE)2,11,12
and this represents a potential advantage for medicinal use,
with the added benefit that maltol itself is approved for
therapeutic use because of its nontoxicity as a food additive.14
The incorporation of maltolate ligands does not always give
water solubility as Ru(ma)2(PPh3)2 (cis or trans geometry
unknown) and Ru(ma)2(COD) are reported to be waterinsoluble.19
Complex 3. The structure of 3 is shown in Figure 3, with
selected bond lengths and angles given in Table 3. The
essentially octahedral structure reveals trans chlorides and
S-bonded BESE, as indicated also by the IR νSdO values.
The conformation at both S atoms is R, an unexpected result
as the complex [RuCl(H2O)(BESE)]2(µ-Cl)2, from which 3
was made, contained meso-BESE.17 It is possible that the
product (obtained in 26% yield) contains meso-BESE, while
the crystal investigated happens to contain R,R-BESE. The
Ruthenium(II) Sulfoxide Complexes
Chart 4. Three Stereoisomers of [Ru(D2O)2(BESE)(metro)2]2+ a
a S-S and N represent S-bonded BESE and metronidazole, respectively.
other possibility, that epimerization at a S-atom occurs during
the synthesis of 3, is unlikely. An equal amount of the S,S
conformer must also be present in the crystallographic unit
cell of 3. The Ru-S bonds, where the S atoms are trans to
N atoms, and the bite angle are very similar to those found
for 1c (see above). The Ru-Cl lengths are in the range noted
for other RuII-BESE complexes (2.385-2.449 Å).11,12,17
The νNdO values (symm and asymm) of the coordinated
metro are within 5 cm-1 of those for free metro; shifts of
∼20 cm-1 are seen when coordination via the NO2 group
occurs.10b,c Complex 3 represents the first structurally
characterized Ru complex containing both nitroimidazole and
sulfoxide ligands, which is significant in view of the
biological properties of such species (see Introduction).10
Complex 3 rapidly dissociates both chlorides in aqueous
solutions, based on conductivity data (180 Ω-1 cm2 mol-1
after 5 min) showing an approximate 2:1 electrolyte; in D2O,
three isomers of the putative [Ru(D2O)2(BESE)(metro)2]2+
(F-H in Chart 4) are possible. The 1H NMR spectrum in
D2O shows four major singlets for Me and H(4) protons of
metro, centered at δ 2.6 and 8.3, respectively. The nature of
the BESE within the sample used for the 1H NMR is unclear.
If the BESE is meso, all three isomers would exhibit
inequivalent metro ligands, and six singlets for each of these
two sets of protons would be expected; thus, the NMR data
would indicate the presence of mainly two isomers. If the
BESE is racemic, the two H(4) protons in F and G would
be equivalent and those in H inequivalent; thus, the observed
singlets could correspond to the presence of all three isomers.
The CV data in CH2Cl2 (below) are not definitive in drawing
conclusions about possible isomer mixtures. The BESE-Me
1
H NMR signals are seen at δ 1.0-1.6, while the CH3CH2S(O)CH2 signals overlap with those of the metro-CH2OH
protons, giving multiplets between δ 3.2-4.0; the metroCH2CH2OH resonance (δ 4.3-4.8) partially overlaps with
the residual D2O solvent signal. The 1H NMR data show no
dissociation of either BESE or metro ligands over 24 h.
Cyclic Voltammetry. The cyclic voltammograms for 1
and 2 in CH2Cl2 do not reveal the presence of isomers: the
observed waves were about twice as broad as that for the
[FeCp*2]+/[FeCp*2] couple and are thought to result from
mixtures of the cis formulations discussed. The RuIII/II
reduction potentials of the ma- and etma-sulfoxide complexes
are very similar, with the BESE-containing complexes
exhibiting a 40-50 mV more positive value than the DMSO
and TMSO complexes (0.51-0.52 V vs SCE). The potentials
strongly reinforce the conclusion that the DMSO and TMSO
exist as cis isomers (as for the BESE complexes), because
within Ru systems cis isomers have reduction potentials ∼0.2
V higher than those of the corresponding trans isomers.35
Figure 4. MTT plots for 2a (a) and 2b (b), with IC50 values equal to 190
( 10 and 220 ( 10 µM, respectively. The error bars indicate one standard
deviation of the averaged cell percent viability.
Table 4. IC50 Values
complex
IC50 (µM)
complex
IC50 (µM)
1a
2a
1b
2b
370 ( 20
190 ( 10
370 ( 20
220 ( 10
1c
2c
3
cisplatin
1300 ( 100
1100 ( 100
860 ( 30
30 ( 5
The 0.6 V more positive RuIII/II potential of 3 (i.e., favoring
the lower oxidation state) possibly results from the π-acceptor
ability of the metro ligands relative to the electron donor
ability of the ma type ligands in 1 and 2. Again, just a single
broad wave is seen for 3, and it is not clear how this relates
to a possible mixture of F-H, although the all cis isomer H
might be expected to have a higher potential than the other
two isomers that have one set of trans ligands. The NO2/
NO2- couple (reduction potential) of metro on coordination
to RuII is increased by ∼60 mV.
MTT Assay. The Ru complexes were examined on human
breast cancer cells (MDA-MB-435S) using the MTT assay
(Table 4), a colorimetric determination of cell viability during
in vitro treatment with a drug.36 The assay, developed as
an initial stage of drug screening, measures the amount of
MTT reduction by mitochondrial dehydrogenase and assumes
that cell viability (corresponding to the reductive activity)
(35) (a) Siebald, H. G. L.; Fabre, P.-L.; Dartiguenave, M.; Dartiguenave,
Y.; Simard, M.; Beauchamp, A. L. Polyhedron 1996, 15, 4221. (b)
Queiroz, S. L.; Batista, A. A.; Oliva, G.; do P. Gambardella, M. T.;
Santos, R. H. A.; MacFarlane, K. S.; Rettig, S. J.; James, B. R. Inorg.
Chim. Acta 1998, 267, 209.
(36) Alley, M. C.; Scudiero, D. A.; Monks, A.; Hursey, M. L.; Czerwinski,
M. J.; Fine, D. L.; Abbott, B. J.; Mayo, J. G.; Shoemaker, R. H.;
Boyd, M. R. Cancer Res. 1988, 48, 589.
Inorganic Chemistry, Vol. 42, No. 23, 2003
7585
Wu et al.
is proportional to the production of purple formazan that is
measured spectrophotometrically.37 A low IC50 is desired and
implies cytotoxicity or antiproliferation at low drug concentrations.38
The MTT plots for 2a,b (Figure 4) reveal the lowest IC50
values of ∼200 µM, while the value for cisplatin was ∼30
µM; 3 is not as potent as 2a,b. The IC50 values for
noncoordinated maltol and ethylmaltol are ∼1600 and 1200
µM, respectively, while those of DMSO, TMSO, BESE, and
metronidazole are >2000 µM; thus, the Ru complexes exhibit
lower IC50 values than those of the corresponding free
ligands. Of note, the etma complexes invariably have
significantly lower IC50 values than those of the corresponding ma complexes. That the BESE species (1c, 2c) are less
active than the DMSO (1a, 2a) and TMSO species (1b, 2b)
may reflect the presence of the chelating ligand that less
readily dissociates than the monodentate sulfoxides, and this
could inhibit subsequent binding to DNA. The nature of the
Ru species present in the phosphate-buffered saline solutions
is, of course, uncertain. The corresponding IC50 values for
[RuCl(p-cymene)(BESE)]PF6 and [RuCl2(p-cymene)]2(µBESE) against the same cell line are 55 and 360 µM,
respectively.17a
(37) (a) Bellamy, W. T. Drugs 1992, 44, 690. (b) Carmichael, J.; DeGraff,
W. G.; Gazdar, A. F.; Minna, J. D.; Mitchell, J. B. Cancer Res. 1987,
47, 936.
(38) (a) Nikolova, A.; Ivanov, D.; Buyukliev, R.; Konstantinov, S.;
Karaivanova, M. Arzneim.-Forsch./Drug Res. 2001, 51, 758. (b)
Galeano, A.; Berger, M. R.; Keppler, B. K. Arzneim.-Forsch./Drug
Res. 1992, 42, 821.
Supporting Information Available: Crystallographic data for
1c and 3 in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
7586 Inorganic Chemistry, Vol. 42, No. 23, 2003
Acknowledgment. We thank Dr. Elena Polishchuk and
Ms. Candice Martins of the Biological Services in this
department and Ms. Helen Wright for assistance with the
MTT assay, Drs. Craig Pamplin and Chi-Wing Tsang for
discussions, and the Natural Sciences and Engineering
Research Council of Canada for financial support.
IC030119J