Novel cis- and trans-configured bis(oxime)platinum(II) complexes: Synthesis, characterization, and cytotoxic activity

Article abstract of DOI:10.1021/ic100584b

Novel cis- and trans-configured bis(oxime)platinum(II) complexes have been synthesized and characterized by elemental analyses, IR, electrospray ionization mass spectrometry, multinuclear (¹H, ¹³C, and ¹⁹⁵Pt) NMR spectroscopy, and, in five cases, by X-ray diffraction. Their cytotoxicity was studied in the cisplatin-sensitive CH1 cell line as well as in inherently cisplatin-resistant SW480 cancer cells. Remarkably, every single dihalidobis(oxime)platinum(II) complex (with either a cis or trans configuration) shows a comparable cytotoxic potency in both cell lines, indicating a capacity of overcoming cisplatin resistance. Particularly strong cytotoxicities were observed in the case of trans-[PtCl₂(R ₂C=NOH)₂] (R = Me, n-Pr, i-Pr) with IC₅₀ values in the high nanomolar concentration range in both CH1 and SW480 cancer cells. These complexes are as potent as cisplatin in CH1 cells and up to 20 times more potent than cisplatin in SW480 cells. In comparison to transplatin, the novel compounds are up to 90 (CH1) and 120 times (SW480) more cytotoxic. The previously reported observation that the trans geometry yields a more active complex in the case of [PtCl₂(Me₂C=NOH)₂] could be confirmed for at least two structural analogues.

Full text of DOI:10.1021/ic100584b

Inorg. Chem. 2010, 49, 5669–5678 5669
DOI: 10.1021/ic100584b
Novel Cis- and Trans-Configured Bis(oxime)platinum(II) Complexes: Synthesis,
Characterization, and Cytotoxic Activity
†
†
†,‡
†
Yulia Yu. Scaffidi-Domianello, Kristof Meelich, Michael A. Jakupec, Vladimir B. Arion,
§
,†
,†,‡
Vadim Yu. Kukushkin, Markus Galanski,* and Bernhard K. Keppler*
†
‡
Institute of Inorganic Chemistry and, Research Platform “Translational Cancer Therapy Research”,
§
University of Vienna, W a€ hringer Strasse 42, A-1090 Vienna, Austria, and Department of Chemistry,
St. Petersburg State University, 198504 Stary Petergof, Russian Federation
Received March 29, 2010
Novel cis- and trans-configured bis(oxime)platinum(II) complexes have been synthesized and characterized
1
13
195
by elemental analyses, IR, electrospray ionization mass spectrometry, multinuclear ( H, C, and Pt) NMR
spectroscopy, and, in five cases, by X-ray diffraction. Their cytotoxicity was studied in the cisplatin-sensitive CH1 cell
line as well as in inherently cisplatin-resistant SW480 cancer cells. Remarkably, every single dihalidobis(oxime)platinum-
(
II) complex (with either a cis or trans configuration) shows a comparable cytotoxic potency in both cell lines, indicating
a capacity of overcoming cisplatin resistance. Particularly strong cytotoxicities were observed in the case of trans-
PtCl (R CdNOH) ] (R = Me, n-Pr, i-Pr) with IC values in the high nanomolar concentration range in both CH1 and
[
2
2
2
50
SW480 cancer cells. These complexes are as potent as cisplatin in CH1 cells and up to 20 times more potent than
cisplatin in SW480 cells. In comparison to transplatin, the novel compounds are up to 90 (CH1) and 120 times
(SW480) more cytotoxic. The previously reported observation that the trans geometry yields a more active complex in
the case of [PtCl (Me CdNOH) ] could be confirmed for at least two structural analogues.
2
2
2
Introduction
more investigators turn their attention toward nonclassic
7-11
structures
that may help to overcome the drawbacks of
Over 40 years have passed since the serendipitous discov-
ery of the biological activity of cisplatin, which has become
one of the most usedanticancer drugs today. Since then, great
efforts have been concentrated on the development of novel
platinum drugs possessing therapeutic properties compar-
able to those of cisplatin but showing reduced side effects
along with a broader spectrum of activity.
ever new drug candidates among the complexes complying
with the classical structure-activity relationships led to
the achievements of carboplatin and oxaliplatin but then
seemed to become gradually exhausted. Therefore, nowadays
1
platinum-based chemotherapy. Moreover, the development
of platinum compounds being structurally different from
cisplatinand forming different types of Pt-DNA adducts may
lead to a drug with a spectrum of clinical activity different
from those of classic platinum drugs.
2-4
For decades, trans-configured platinum complexes at-
tracted little interest because of the classic structure-activity
The search for
5
,6
5,6
relationships according to Cleare and Hoeschele, based on
cisplatin/transplatin and their analogues. The presence of
two monodentate or one bidentate exchangeable ligand(s)
(leaving groups) coordinated in cis geometry was declared a
requirement for antitumor activity. The significantly lower
cytotoxicity of transplatin compared to that of cisplatin in
vitro as well as its inactivity in vivo has been ascribed to its
disfavored chelation reactions with DNA due to the trans-
standing leaving groups. Consequently, the formation of 1,2-
intrastrand cross-links, the predominant DNA adducts
formed by cisplatin and believed to account for its cytotoxic
*
To whom correspondence should be addressed. E-mail: markus.
galanski@univie.ac.at (M.G.), bernhard.keppler@univie.ac.at (B.K.K.).
Phone: þ43-1-4277-52603 (M.G.), þ43-1-4277-52602 (B.K.K.). Fax: þ43-
1
-4277-52680 (M.G.), þ43-1-4277-52680 (B.K.K.).
(
(
1) Rosenberg, B.; Van Kamp, L.; Crigas, T. Nature 1965, 205, 698–699.
2) Jakupec, M. A.; Galanski, M.; Keppler, B. K. Rev. Physiol. Biochem.
Pharmacol. 2003, 146, 1–54.
3) Galanski, M.; Jakupec, M. A.; Keppler, B. K. Curr. Med. Chem. 2005,
2, 2075–2094.
4) Galanski, M.; Arion, V. B.; Jakupec, M. A.; Keppler, B. K. Curr.
Pharm. Des. 2003, 9, 2078–2089.
(
12
1
activity, is greatly hindered. It was shown that transplatin-
DNA adducts are more rapidly repaired and cannot be
(
(
(
(
(
5) Cleare, M. J.; Hoeschele, J. D. Plat. Met. Rev. 1973, 17, 2–13.
6) Cleare, M. J.; Hoeschele, J. D. Bioinorg. Chem. 1973, 2, 187–210.
7) Aris, S. M.; Farrell, N. P. Eur. J. Inorg. Chem. 2009, 10, 1293–1302.
8) Kalinowska-Lis, U.; Ochocki, J.; Matlawska-Wasowska, K. Coord.
(10) Hall, M. D.; Hambley, T. W. Coord. Chem. Rev. 2002, 232, 49–67.
(11) Farrell, N. In Platinum-Based Drugs in Cancer Therapy; Kelland,
L. R., Farrell, N. P., Eds.; Humana Press: Totowa, NJ, 2000; pp 321-338.
(12) Liu, Y.; Vinje, J.; Pacifico, C.; Natile, G.; Sletten, E. J. Am. Chem.
Soc. 2002, 124, 12854–12862.
Chem. Rev. 2008, 252, 1328–1345.
9) Natile, G.; Coluccia, M. Coord. Chem. Rev. 2001, 216-217, 383–410.
(
r 2010 American Chemical Society
Published on Web 05/11/2010
pubs.acs.org/IC

5
670 Inorganic Chemistry, Vol. 49, No. 12, 2010
Scaffidi-Domianello et al.
3
5,36
recognized by the high-mobility group proteins HMG1,
recognizing specifically 1,2-intrastrand cross-links and
shielding them from repair. Moreover, the higher reactivity
of transplatin compared to that of cisplatin may favor its
deactivation, resulting in the lack of anticancer activity.
In the past few years, some exceptions from the classic rules
have been reported. Several classes of trans complexes
exhibiting higher cytotoxicity than or at least equal to that
groups,
and (vii) platinum(II) complexes with acetimine
3
7
ligands. Interestingly, most of the listed complexes are
similarly or even more cytotoxic than cisplatin and all of
them proved to be non-cross-resistant to cisplatin in cellular
models of acquired cisplatin resistance. Furthermore, for the
first four of the above-mentioned classes, the antitumor
activity was confirmed in an in vivo model. Moreover, some
of the complexes even displayed a lack of cross-resistance to
13-16
20,29
of the corresponding cis isomer are (i) platinum(II)
/
cisplatin in vivo.
17
platinum(IV) complexes with pyridine-like ligands, (ii) plati-
Very recently, a new intriguing class of trans-configured
platinum compounds exhibiting antitumor activity was re-
ported. Almost simultaneously two independent groups of
researcher published the fascinating results of in vitro bio-
logical investigations for two acetoxime-containing plati-
num(II) complexes, namely, trans-[PtCl
CH(CH
According to these investigations, the former complex, but
not its cis isomer, causes cell death by apoptosis, even though
the overall cytotoxicity was found to be higher for the cis-
configured complex. Differently, trans-[PtCl (Me CdNOH) ]
18-21
num(II) complexes with iminoether ligands,
(iii) plati-
num(II) complexes with nonplanar heterocyclic ligands, such
2
2-25
26-28
as piperidine or piperazine,
(iv) platinum(II)
/
29,30
platinum(IV) complexes with aliphatic amines, (v) plati-
num(II) carboxylato complexes with planar amines,
azole and isopropylamine, azole and ammine ligands, (vi)
platinum(II) complexes containing various phosphoric
31,32
(Me
)] as well as trans-[PtCl (Me CdNOH) ].
2 2
CdNOH)(NH -
2
2 2
33
34
38
39
)
2
3
2
(
13) Farrell, N.; Ha, T. T. B.; Souchard, J. P.; Wimmer, F. L.; Cros, S.;
Johnson, N. P. J. Med. Chem. 1989, 32, 2240–2241.
14) Farrell, N.; Kelland, L. R.; Roberts, J. D.; Van Beusichem, M.
2
2
2
(
was found to be 16 times more cytotoxic than its cis isomer
and as cytotoxic as cisplatin in cisplatin-sensitive ovarian
carcinoma cells (CH1). Moreover, it appeared to be 15 times
more cytotoxic than both cisplatin and its cis isomer
in intrinsically cisplatin-resistant colon carcinoma cells
Cancer Res. 1992, 52, 5065–5072.
(
15) Van Beusichem, M.; Farrell, N. Inorg. Chem. 1992, 31, 634–639.
(
16) Farrell, N.; Povirk, L. F.; Dange, Y.; DeMasters, G.; Gupta, M. S.;
Kohlhagen, G.; Khan, Q. A.; Pommier, Y.; Gewirtz, D. A. Biochem.
Pharmacol. 2004, 68, 857–866.
(
17) Martinez, A.; Lorenzo, J.; Prieto, M. J.; de Llorens, R.; Font-Bardia,
M.; Solans, X.; Aviles, F. X.; Moreno, V. ChemBioChem 2005, 6, 2068–2077.
18) Coluccia, M.; Nassi, A.; Loseto, F.; Boccarelli, A.; Mariggio, M. A.;
Giordano, D.; Intini, F. P.; Caputo, P.; Natile, G. J. Med. Chem. 1993, 36,
10–512.
19) Zaludova, R.; Zokovska, A.; Kasparkova, J.; Balcarova, Z.; Vrana,
O.; Coluccia, M.; Natile, G.; Brabec, V. Mol. Pharmacol. 1997, 52, 354–361.
20) Coluccia, M.; Nassi, A.; Boccarelli, A.; Giordano, D.; Cardellicchio,
N.; Locker, D.; Leng, M.; Sivo, M.; Intini, F. P.; Natile, G. J. Inorg. Biochem.
999, 77, 31–35.
21) Casini, A.; Gabbiani, C.; Mastrobuoni, G.; Pellicani, R. Z.; Intini, F.
(SW480).
(
In this context, it is worthwhile mentioning that oximes are
attractive ligands in view of their potential to act as donors or
5
(
acceptors for hydrogen bonds or even serve as weak acids
40
(
pK 3-8), which could play an important role in the
a
(
41
binding of platinum compounds to DNA. In addition,
the biological relevance of oximes appreciably favors their
use as ligands for potential metal-based drugs, which may
yield increased cytotoxicity by virtue of synergistic effects
between the platinum center and the coordinated oxime. For
instance, it was reported that oxime complexes and other
species bearing the oxime functional group caused biological
effects such as endothelium-independent relaxation in blood
1
(
P.; Arnesano, F.; Natile, G.; Moneti, G.; Francese, S.; Messori, L. Biochem-
istry 2007, 46, 12220–12230.
(
22) Najajreh, Y.; Perez, J. M.; Navarro-Ranninger, C.; Gibson, D.
J. Med. Chem. 2002, 45, 5189–5195.
23) Nguewa, P. A.; Fuertes, M. A.; Iborra, S.; Najajreh, Y.; Gibson, D.;
Martinez, E.; Alonso, C.; Perez, J. M. J. Inorg. Biochem. 2005, 99, 727–736.
24) Najajreh, Y.; Prilutski, D.; Ardeli-Tzaraf, Y.; Perez, J. M.; Khazanov,
(
(
42
E.; Barenholz, Y.; Kasparkova, J.; Brabec, V.; Gibson, D. Angew. Chem., Int.
Ed. 2005, 44, 2885–2887.
vessels, an increase in the targeting of specific nuclear bases
4
3
44
of DNA, and oxidative DNA cleavage.
(
25) Najajreh, Y.; Khazanov, E.; Jawbry, S.; Ardeli-Tzaraf, Y.; Perez, J.
M.; Kasparkova, J.; Brabec, V.; Barenholz, Y.; Gibson, D. J. Med. Chem.
006, 49, 4665–4673.
26) Montero, E. I.; Diaz, S.; Gonzalez-Vadillo, A. M.; Perez, J. M.;
Alonso, C.; Navarro-Ranninger, C. J. Med. Chem. 1999, 42, 4264–4268.
27) Montero, E. I.; Perez, J. M.; Schwartz, A.; Fuertes, M. A.; Malinge,
J. M.; Alonso, C.; Leng, M.; Navarro-Ranninger, C. ChemBioChem 2002, 3,
1–67.
28) Prokop, R.; Kasparkova, J.; Novakova, O.; Marini, V.; Pizarro, A.
M.; Navarro-Ranninger, C.; Brabec, V. Biochem. Pharmacol. 2004, 67,
097–1109.
29) Kelland, L. R.; Barnard, C. F. J.; Evans, I. G.; Murrer, B. A.;
On the basis of the promising results obtained with
2
trans-[PtCl (Me CdNOH) ] and with the aim to estab-
2
2
2
(
lish structure-activity relationships, we report on a series
of novel dihalidobis(oxime)platinum(II) complexes, i.e.,
(
trans-[PtX (R CdNOH) ] (X = Cl, Br, I; R = Me, Et, n-
2
2
2
6
Pr, i-Pr), of which at least two exhibit higher cytotoxicity
than the corresponding cis species in both CH1 and SW480
cells. Moreover, the corresponding cis/trans couples of
(
1
(
Theobald, B. R. C.; Wyer, S. B.; Goddard, P. M.; Jones, M.; Valenti, M.;
Bryant, A.; Rogers, P. M.; Harrap, K. R. J. Med. Chem. 1995, 38, 3016–3024.
(37) Boccarelli, A.; Intini, F. P.; Sasanelli, R.; Sivo, M. F.; Coluccia, M.;
Natile, G. J. Med. Chem. 2006, 49, 829–837.
(
30) Perez, J. M.; Kelland, L. R.; Montero, E. I.; Boxall, F. E.;
Fuertes, M. A.; Alonso, C.; Navarro-Ranninger, C. Mol. Pharmacol.
003, 63, 933–944.
31) Ma, E. S. F.; Bates, W. D.; Edmunds, A.; Kelland, L. R.; Fojo, T.;
Farrell, N. J. Med. Chem. 2005, 48, 5651–5654.
32) Quiroga, A. G.; Perez, J. M.; Alonso, C.; Navarro-Ranninger, C.;
Farrell, N. J. Med. Chem. 2006, 49, 224–231.
33) van Zutphen, S.; Pantoja, E.; Soriano, R.; Soro, C.; Tooke, D. M.;
Spek, A. L.; den Dulk, H.; Brouwer, J.; Reedijk, J. Dalton Trans. 2006, 1020–
023.
34) Bulluss, G. H.; Knott, K. M.; Ma, E. S. F.; Aris, S. M.; Alvarado, E.;
Farrell, N. Inorg. Chem. 2006, 45, 5733–5735.
35) Ramos-Lima, F. J.; Quiroga, A. G.; Perez, J. M.; Font-Bardia, M.;
Solans, X.; Navarro-Ranninger, C. Eur. J. Inorg. Chem. 2003, 1591–1598.
36) Kalinowska, U.; Matlawska, K.; Checinska, L.; Domagala, M.;
Kontek, R.; Osiecka, R.; Ochocki, J. J. Inorg. Biochem. 2005, 99, 2024–2031.
(38) Quiroga, A. G.; Cubo, L.; de Blas, E.; Aller, P.; Navarro-Ranninger,
C. J. Inorg. Biochem. 2007, 101, 104–110.
(39) Zorbas-Seifried, S.; Jakupec, M. A.; Kukushkin, N. V.; Groessl, M.;
Hartinger, Ch. G.; Semenova, O.; Zorbas, H.; Kukushkin, V. Yu.; Keppler,
B. K. Mol. Pharmacol. 2007, 71, 357–365.
(40) Kukushkin, V. Yu.; Tudela, D.; Pombeiro, A. J. L. Coord. Chem.
Rev. 1996, 156, 333–362.
(41) Reedijk, J. Inorg. Chim. Acta 1992, 198-200, 873–881.
(42) Vetrovsky, P.; Boucher, J.-L.; Schott, C.; Beranova, P.; Chalupsky,
K.; Callizot, N.; Muller, B.; Entlicher, G.; Mansuy, D.; Stoclet, J.-C.
J. Pharm. Exp. Ther. 2002, 303, 823–830.
2
(
(
(
1
(
(
(43) Hambley, T. W.; Ling, E. C. H.; O’Mara, S.; McKeage, M. J.;
Russell, P. J. J. Biol. Inorg. Chem. 2000, 5, 675–681.
(44) Saglam, N.; Colak, A.; Serbest, K.; Duelger, S.; Guener, S.;
Karaboecek, S.; Belduez, A. O. BioMetals 2002, 15, 357–365.
(

Article
Pt(NH ) (R CdNOH) ](NO ) (R = Me, Et, n-Pr) were
synthesized and investigated. In accordance with the classic
structure-activity relationships, stating that platinum com-
plexes with four nitrogen donor ligands are devoid of
cytotoxicity, the IC50 values of the diamminebis(oxime) series
were proven to be very high.
Inorganic Chemistry, Vol. 49, No. 12, 2010 5671
[
(SP-4-2)-Bis(acetone oxime-KN )diiodidoplatinum(II) (3c).
Potassium iodide (406 mg, 2.45 mmol) was added to a solution
of K [PtCl ] (203 mg, 0.49 mmol) in 2 mL of H O, and the
2 4 2
mixture was stirred at room temperature for 2 h. After the
addition of acetone oxime (72 mg, 0.98 mmol), the reaction
mixture was left to stand at the same temperature without
stirring for 2 days, and the crystals of 3c were filtered off,
washed twice with 0.5 mL of ice-cold water, and dried in vacuo.
3
2
2
2
3 2
Experimental Section
Yield: 233 mg (80%). Anal. (C
6
H
14
N
2
I
2
O
2
Pt) C, H, N. ESI-
þ
þ
þ
Solvents were obtained from commercial sources and used
as received. Acetone oxime was purchased from Fluka, while
MS in acetone: m/z 545 [M - Me
2
CdNOH þ Na] , 618 [M þ
þ
-
Na] , 634 [M þ K] . ESI-MS in acetone: m/z 521 [M -
-
-
3
-pentanone, 4-heptanone, and 2,4-dimethyl-3-pentanone
for the synthesis of the corresponding oximes were obtained
from Aldrich. The complexes cis- and trans-[PtBr (Me Cd
Me
[10:1 (v/v) CHCl
bands): ν 3242 s (νOH), 1653 m (νCdN) cm . H NMR in
2
CdNOH - H] , 594 [M - H] . Mp 220 °C (dec). TLC
3
/Me CO]: R = 0.52. IR in KBr (selected
2
f
-1 1
2
2
53
54
55
13
1
acetone-d : δ 2.65 (s, 3H, CH ), 2.19 (s, 3H, CH ) ppm. C{ H}
NOH)], cis-[PtI
prepared according to the published methods. For thin-layer
chromatography (TLC), Merck UV 254 SiO plates were
2 3 2 2 3 2
(NH ) ] , and trans-[PtCl (NH ) ]
were
6
3
3
6 3 3
NMR in acetone-d : δ 164.6 (CdN), 24.6 (CH ), 17.9 (CH )
1
95
ppm. Pt NMR in acetone-d : δ -1729 (600 Hz) ppm. Crystals
6
2
for X-ray study were obtained by slow evaporation of an
aqueous solution.
used. Fluka silica gel 60 (220-440 mesh) was used for column
chromatography. C, H, and N elemental analyses were car-
ried out by the Microanalytical Laboratory of the University
of Vienna and are within (0.4% of the calculated values,
confirming their g95% purity. Melting points were deter-
mined with a B u€ chi B-540 melting point apparatus and
are uncorrected. Electrospray ionization mass spectrometry
(SP-4-1)-Bis(acetone oxime-KN )diiodidoplatinum(II) (3t).
The powder of 3c (230 mg, 0.39 mmol) was refluxed in 5 mL
of MeNO at 95-100 °C for 3 h. A small amount of a brown
precipitate was filtered off, and the yellow filtrate was reduced to
1.5 mL at 40 °C using a rotary evaporator, resulting in the
precipitation of a yellow solid. The precipitate was collected by
2
(
ESI-MS) spectra were obtained with a Bruker Esquire 3000
-
1
instrument. Mid-infrared (MIR; 4000-400 cm ) spectra
were recorded with a Perkin-Elmer Fourier transform infra-
red (FTIR) instrument in KBr pellets. H, C, and Pt
NMR spectra were measured with a Bruker Avance III
filtration, washed twice with 1 mL of MeNO , and dried in
2
vacuo. Yield: 114 mg (50%). Anal. (C H N I O Pt) C, H, N.
6
14 2 2
2
1
13
195
þ
þ
ESI-MS in acetone: m/z 618 [M þ Na] . Mp 200 °C (dec). TLC
[
15:1 (v/v) CHCl
3 2 f
/Me CO]: R = 0.50. IR in KBr (selected
1
13
00 MHz NMR spectrometer at 500.32 ( H), 125.81 ( C),
-
1 1
5
bands): ν 3329 s (νOH), 1661 m (νCdN) cm . H NMR in DMF-
195
195
a
b
and 107.55 MHz ( Pt), correspondingly, at 298 K. Pt
chemical shifts are given relative to external K [PtCl ], and
the half-height line width is given in parentheses.
d : δ 11.88 (s, br, 1H, OH ), 11.71 (s, br, 1H, OH ), 2.72 (s, 3H,
7
b
a
b
a
2
4
CH
3 3 3
), 2.68 (s, 3H, CH ), 2.39 (s, 3H, CH ), 2.32 (s, 3H, CH )
3
13
1
b
ppm. C{ H} NMR in DMF-d : δ 164.8 (CdN ), 162.6
CdN ), 24.87 (CH ), 24.86 (CH ), 17.9 (CH ), 17.5 (CH )
3 3 3 3
7
a
a
b
b
a
Synthesis of Ligands. 3-Pentanone oxime, 4-heptanone
oxime, and 2,4-dimethyl-3-pentanone oxime were synthesized
(
1
95
ppm. Pt NMR in DMF-d : δ -1800 (320) ppm. Crystals for
7
45-47
by known procedures
ponding ketones were treated with hydroxylamine hydrochloride
in a MeOH/H O mixture (1:1), while K CO was used for
with some modifications: the corres-
X-ray study were obtained by slow evaporation of an acetone
solution.
2
2
3
(
SP-4-2)-Dichloridobis(3-pentanone oxime-KN )platinum(II)
4c) and (SP-4-1)-Dichloridobis(3-pentanone oxime-κN )plati-
num(II) (4t). 3-Pentanone oxime (113 mg, 1.12 mmol) was added
to a solution of K [PtCl ] (239 mg, 0.58 mmol) in 1.5 mL of H O,
neutralization. The reaction mixture was stirred at 65-70 °C
for 24 h, and then the solvent was removed and the product
purified by column chromatography (1:4 ethyl acetate/hexane,
first fraction). The yields were 87-92%.
(
2
4
2
and the mixture was stirred at 70 °C for 0.5 h. Then, the reaction
mixture was left to stand without stirring at room temperature
for 2 days, resulting in the formation of pale-yellow crystals. The
precipitate was filtered off, washed twice with 1 mL of ice-cold
water, and dried at room temperature in air, whereupon isomers
Synthesis of Complexes. (SP-4-2)-Bis(acetone oxime-KN)dibro-
midoplatinum(II) (2c). The complex was prepared according to the
published method from K [PtCl ] (191 mg, 0.46 mmol), an excess of
2
4
KBr (274 mg, 2.30 mmol), and 2 equiv of acetoxime (67 mg, 0.92
5
3
6 14 2 2 2
mmol) in water. Yield: 138 mg (60%). Anal. (C H N Br O Pt) C,
4c and 4t were separated by column chromatography [8:1 (v/v)
CHCl /Me CdO] and dried in vacuo. Yields: 148 mg (55%) and
-
1 1
H, N. IR in KBr (selected bands): ν1656 m (νCdN) cm . HNMRin
3
2
þ
D
2
O: δ 2.69 (s, 3H, CH
3
), 2.22 (s, 3H, CH ) ppm. ESI-MS in
3
1
08 mg (40%), respectively.
4
þ
þ
MeOH: m/z 524 [M þ Na] , 560 [M þ HCl þ Na] .
þ
c. Anal. (C10
H
22
2
N Cl
2
O
2
Pt) C, H, N. ESI-MS in MeOH:
þ
þ
(SP-4-1)-Bis(acetone oxime-KN )dibromidoplatinum(II) (2t).
The synthesis was performed by thermal isomerization of the
corresponding cis complex. 2c (175 mg, 0.35 mmol) was kept at
40 °C for 6 h; the resulting gray powder was suspended in 2 mL
of acetone and filtered through a small amount of SiO , which
m/z 491 [M þ Na] , 507 [M þ K] , 533 [M þ Et
2
CdNOH -
CdNOH - HCl -
H] , 467 [M - H] . Mp 153 °C (dec). TLC [7:1 (v/v) CHCl /
þ
-
-
Cl] . ESI-MS in MeOH: m/z 330 [M - Et
2
5
3
-
3
1
Me
1
3
2
CO]: R
3
649 m (νCdN) cm . H NMR in CDCl : δ 9.04 (s, br, 1H, OH),
3
f
= 0.46. IR in KBr (selected bands): ν 3255 s (νOH),
-
1 1
2
3
was washed three times with 2 mL of acetone. Then the solvent
was partially evaporated under reduced pressure, and bright
yellow crystals of the product were formed. The crystals were
collected, washed with 0.5 mL of acetone, and dried in vacuo.
Yield: 35 mg (20%). Anal. (C H N Br O Pt) C, H, N. IR in
.18 (q, 2H, CH
2 2
, JH,H = 7.6 Hz), 3.60 (q, 2H, CH , JH,H =
3
.6 Hz), 1.26 (t, 3H, CH , J
7
= 7.6 Hz), 1.09 (t, 3H, CH3,
H,H
3
3
13
1
H,H = 7.6 Hz) ppm. C{ H} NMR in CDCl
J
3
: δ 176.2 (CdN),
195
2
9.8 (CH ), 23.4 (CH ), 10.9 (CH ), 10.3 (CH ) ppm.
3
2
2
3
Pt
6
14
2
2
2
NMR in CDCl : δ -441 (380 Hz) ppm. Crystals for X-ray
3
-
1
1
KBr (selected bands): ν 1664 m (νCdN) cm
.
), 2.19 (s, 3H, CH
H NMR in
) ppm. ESI-
study were obtained by slow evaporation of a chloroform/ethyl
acetate solution.
acetone-d
6
: δ 2.62 (s, 3H, CH
3
3
þ
þ
þ
þ
MS in MeOH: m/z 524 [M þ Na] , 560 [M þ HCl þ Na] .
4
t. Anal. (C10
H
22
N
2
Cl
2
O
2
Pt) C, H, N. ESI-MS in MeOH:
þ
-
m/z 491 [M þ Na] . ESI-MS in MeOH: m/z 330 [M - Et Cd
CdNOH - H] . Mp: 204 °C
dec). TLC [7:1 (v/v) CHCl /Me CO]: R = 0.54. IR in KBr
2
-
-
(
45) Portela-Cubillo, F.; Lymer, J.; Scanlan, E. M.; Scott, J. S.; Walton,
J. C. Tetrahedron 2008, 64, 11908–11916.
46) Alcalde, E.; Mesquida, N.; Alvarez-Rua, C.; Cuberes, R.; Frigola, J.;
Garcia-Granda, S. Molecules 2008, 13, 301–318.
47) Wang, K.; Fu, X.; Liu, J.; Liang, Y.; Dong, D. Org. Lett. 2009, 11,
015–1018.
NOH - HCl - H] , 366 [M - Et
2
(
(
3
2
f
(
-1
1
selected bands): cm : ν 3254 s (νOH), 1658 m (νCdN). H NMR
3
(
in CDCl : δ 3.10 (q, 2H, CH , J
3
2
H,H
= 7.6 Hz), 2.58 (q, 2H, CH2,
3
3
1
3
JH,H = 7.6 Hz), 1.33 (t, 3H, CH , JH,H = 7.6 Hz), 1.13 (t, 3H,

5
672 Inorganic Chemistry, Vol. 49, No. 12, 2010
Scaffidi-Domianello et al.
3
, JH,H = 7.6 Hz) ppm. C{ H} NMR in CDCl
13
1
CH
(
3
3
: δ 176.2
precipitation of a white solid. The precipitate was filtered off,
washed with acetone (2 ꢀ 1 mL) and ether (3 mL), and dried in
CdN), 29.6 (CH ), 23.5 (CH ), 11.0 (CH ), 10.3 (CH ) ppm.
3
2
2
3
1
95
Pt NMR in CDCl
SP-4-1)-Dichloridobis(4-heptanone oxime-KN )platinum(II)
5t). 4-Heptanone oxime (182 mg, 1.41 mmol) was added to a
solution of K [PtCl ] (292 mg, 0.70 mmol) in 2 mL of H O, and
3
: δ -462 (450 Hz) ppm.
vacuo. Yield: 88 mg (65%). Anal. (C
6
H
20
N
6
O
8
Pt) C, H, N. ESI-
þ
MS in H O/MeOH: m/z 267 [M - 2NH - Me CdNOH -
(
2
3
2
þ
þ
HNO
NH
3
- NO
3
] , 340 [M - 2NH
3
- HNO
3
- NO ] , 357 [M -
3
(
þ
þ
3
- HNO
3
- NO
3
] , 374 [M - HNO
3
- NO ] , 639 [2M -
3
2
4
2
þ
Me CdNOH - 2NH - 3HNO - NO ] , 657 [2M - Me Cd
the mixture was stirred at 85 °C for 2 h. Then, the heating was
switched off, and the reaction mixture was stirred at room
temperature for 2 days, resulting in the formation of a large
amount of lemon-yellow precipitate. The precipitate was filtered
2
3
3
þ
3
2
NOH - NH - 3HNO - NO ] , 696 [2M - 3NH - 3HNO -
3
3
3
3
3
þ
þ
NO
NO
3
] , 713 [2M - 2NH
3
- 3HNO
3
- NO
3
] , 747 [2M - 3HNO
3
-
þ
3
] . Mp: 234 °C (dec). IR in KBr (selected bands): ν 3211 s
-
1 1
(νOH), 1667 m (ν
NH
) cm . H NMR in D O: δ 4.27 (s, br, 3H,
CdN 2
13 1
off, washed twice with 1 mL of H
temperature in air, whereupon it was purified by column
chromatography [10:1 (v/v) CHCl /Me CdO] and then dried
in vacuo. Yield: 240 mg (65%). Anal. (C H N Cl O Pt) C, H, N.
2
O, and dried at room
3
), 2.58 (s, 3H, CH
3
), 2.19 (s, 3H, CH
3
) ppm. C{ H} NMR in
195
D
D
2
O: δ 172.2 (CdN), 23.4 (CH
O: δ -907 (800 Hz) ppm. Crystals for X-ray study were
), 18.0 (CH ) ppm. Pt NMR in
3 3
3
2
2
1
4
30
2
2 2
þ
þ
þ
obtained by slow evaporation of an aqueous solution.
(SP-4-2)-Diamminebis(3-pentanone oxime-KN)platinum(II)
Dinitrate (8c). cis-[PtI (NH ) ] (109 mg, 0.23 mmol) and AgNO
2 3 2 3
2
(77 mg, 0.45 mmol) were suspended in 2 mL of H O, whereupon
the mixture was stirred at room temperature overnight. The
yellow precipitate of AgI was filtered off, and 3-pentanone
oxime (50 μL, 0.45 mmol) in 2 mL of THF was added. After
the reaction mixture was stirred at the same temperature for 2
days, the solvent was removed and the crude product was dried
in vacuo. Then, the white solid was suspended in 10 mL of
acetone, filtered off, washed with acetone (2 ꢀ 1 mL), and dried
ESI-MS in MeOH: m/z 452 [M - HCl - Cl] , 525 [M þ H] ,
þ
þ
-
-
5
47 [M þ Na] , 584 [M þ HCl þ Na] . ESI-MS in MeOH: m/z
3
58 [M - Pr CdNOH - HCl - H] , 394 [M - Pr CdNOH -
2
2
-
H] . Mp: 173 °C (dec). TLC [10:1 (v/v) CHCl /Me CO]: R =
3
2
f
0
cm . H NMR in CDCl
.48. IR in KBr (selected bands): ν 3299 s (νOH), 1672 m (νCdN
)
-
1 1
3
: δ 7.42 (s, br, 1H, OH), 3.04 (m, 2H,
CH ), 2.54 (m, 2H, CH ), 1.78 (m, 2H, CH CH ), 1.58 (m, 2H,
2
2
3
2
3
CH
3
CH
2
3 3
), 1.12 (t, 3H, CH , JH,H = 7.3 Hz), 0.98 (t, 3H, CH ,
3
J
13
H,H = 7.3 Hz) ppm. C{ H} NMR in CDCl
1
3
: δ 173.8 (CdN),
3
(
8.4 (CH
2
), 32.1 (CH ), 20.2 (CH
2
3
CH
2
), 19.5 (CH CH ), 14.3
2
3
1
95
CH ), 13.9 (CH ) ppm. Pt NMR in CDCl : δ -453 (350 Hz)
3
3
3
ppm. Crystals for X-ray study were obtained by slow evapora-
tion of a chloroform/ethyl acetate solution.
in vacuo. Yield: 53 mg (42%). Anal. (C10
H
28
N
6
O
8
Pt) C, H, N.
þ
ESI-MS in H
O/MeOH: m/z 396 [M - 2NH
- HNO
-
2
3
3
þ
þ
NO
NO
690 [2M - Et
3
3
] , 413 [M - NH
3
- HNO
CdNOH - 3NH
CdNOH - 4NH - 3HNO
3
- NO
3
] , 430 [M - HNO
3
-
] ,
(
SP-4-1)-Dichloridobis(2,4-dimethyl-3-pentanone oxime-KN)-
þ
þ
] , 606 [2M - 2Et
2
3
- 3HNO
3
- NO
3
platinum(II) (6t). The synthesis and purification were carried out
as described for 4t, using K [PtCl ] (153 mg, 0.37 mmol) and 2,4-
dimethyl-3-pentanone oxime (95 mg, 0.74 mmol). Yield: 104 mg
þ
2
3
3
- NO
3
] , 724 [2M -
2
4
þ
Et CdNOH - 2NH - 3HNO - NO ] , 808 [2M - 3NH -
2
3
3
3
3
þ
þ
þ
þ
3
3
HNO
3
- NO
3
] , 825 [2M - 2NH
3
- 3HNO
3
- NO
] , 843
] .
(
60%). Anal. (C14
H
30
N
2
Cl
2
O
2
Pt) C, H, N. ESI-MS in acetone:
þ
þ
þ
m/z 452 [M - HCl - Cl] , 510 [M - HCl þ Na] , 547 [M þ
[2M - NH
3
- 3HNO
3
- NO
3
] , 859 [2M - 3HNO
3
- NO
3
þ
-
-
Mp: 158 °C (dec). IR in KBr (selected bands): ν 3194 s (νOH),
Pr CdNOH - Cl] . ESI-MS in acetone: m/z 358 [M - Pr Cd
2
2
-
1 1
-
1
2
666 m (ν
) cm . H NMR in D O: δ 3.00 (m, 2H, CH ),
CdN 2 2
3
NOH - HCl - H] , 394 [M - Pr
2
CdNOH - H] , 487 [M -
HCl - H] . Mp: 185 °C (dec). TLC [10:1 (v/v) CHCl /Me CO]:
R = 0.45. IR in KBr (selected bands): ν 3330 s (νOH), 1662 m
-
2 3
.53 (m, 2H, CH ), 1.12 (t, 3H, CH , JH,H = 7.6 Hz), 0.99 (t,
3
2
3
13
1
3H, CH
(
3 2
195
CdN), 29.5 (CH ), 22.9 (CH ), 9.9 (CH ), 9.3 (CH ) ppm. Pt
, JH,H = 7.6 Hz) ppm. C{ H} NMR in D O: δ 178.9
f
-
1 1
(
ν
CdN) cm . H NMR in CDCl
3
: δ 4.28 (m, 2H, 2CH), 2.67 (m,
2
2
3
3
3
, JH,H = 6.9 Hz), 1.23 (d, 6H, 2CH
NMR in D
(SP-4-1)-Diamminebis(pentanone oxime-KN)platinum(II)
Dinitrate (8t). trans-[PtCl (NH ] (105 mg, 0.35 mmol) and
AgNO (118 mg, 0.70 mmol) were suspended in 4 mL of H O,
2
O: δ -897 (1050 Hz) ppm.
2
H, 2CH), 1.28 (d, 6H, 2CH
3
1
3
,
3
J
13
H,H = 6.9 Hz) ppm. C{ H} NMR in CDCl : δ 180.7 (CdN),
3
195
7.1 (CH), 29.7 (CH), 18.9 (2CH ), 18.5 (2CH ) ppm. Pt NMR
3
in CDCl
2
3 2
)
3
3
3
: δ -441 (420 Hz) ppm.
3
2
(
SP-4-2)-Bis(acetone oxime-KN )diammineplatinum(II) Dini-
trate (7c). cis-[PtI (NH ] (72 mg, 0.15 mmol) and AgNO
51 mg, 0.30 mmol) were suspended in 2 mL of H O, whereupon
whereupon the mixture was stirred at 60 °C overnight. The white
precipitate of AgCl was filtered off, and 3-pentanone oxime
(77 μL, 0.70 mmol) in 2 mL of THF was added. After the
reaction mixture was stirred at room temperature overnight, the
solvent was removed and the yellowish solid was suspended in
10 mL of acetone; the precipitate was then filtered off, washed
with acetone (2 ꢀ 1 mL) and diethyl ether (3 mL), and dried in
2
3
)
2
3
(
2
the mixture was stirred at room temperature overnight. The
yellow precipitate of AgI was filtered off, and acetone oxime
22 mg, 0.30 mmol) was added. After the reaction mixture was
(
stirred at the same temperature for 10 h, the clear colorless
solution was reduced to 0.5 mL and 15 mL of acetone was
added, inducing the precipitation of a white solid. The precipi-
tate was filtered off, washed with acetone (2 ꢀ 1 mL), and dried
vacuo. Yield: 54 mg (45%). Anal. (C10
H
28
6
N O
8
Pt) C, H, N.
þ
ESI-MS in H
O/MeOH: m/z 396 [M - 2NH
- HNO
-
-
2
3
3
þ
þ
NO
NO
3
] , 413 [M - NH
] , 724 [2M - Et
[2M - 3NH
3
- HNO
3
- NO
3
] , 430 [M - HNO
3
þ
þ
in vacuo. Yield: 41 mg (55%). Anal. (C
6
H
20
N
6
O
8
Pt H
2
O) C, H,
3
2
CdNOH - 2NH
3
- 3HNO
3
- NO
3
3
] , 808
3
þ
þ
þ
N. ESI-MS in H O/MeOH: m/z 357 [M - NH - HNO -
NO
NO ] , 713 [2M - 2NH - 3HNO - NO ] , 730 [2M - NH -
HNO
3
- 3HNO
3
- NO
3
] , 859 [2M -3HNO
- NO
3
] .
2
3
3
þ
þ
þ
] , 374 [M - HNO
3
- NO
3
3
] , 696 [2M - 3NH
3
- 3HNO
3
-
Mp: 213 °C (dec). IR in KBr (selected bands): ν 3270 s (νOH),
3
þ
-1 1
1645 m (νCdN) cm . HNMRinD
2
O: δ4.30 (s, br, 3H, NH
3
), 3.02
=
3
3
3
3
þ
þ
3
(m, br, 2H, CH ), 2.58 (m, br, 2H, CH ), 1.17 (t, 3H, CH , J
3
(
3
- NO
3
] , 747 [2M - 3HNO
3
- NO
3
] . Mp: 147 °C
2
2
3
1
H,H
3
7.7 Hz), 1.03 (t, 3H, CH , J
13
dec). IR in KBr (selected bands): ν 3194 s (ν ), 1666 m (ν
)
)
H,H
= 7.6 Hz) ppm. C{ H} NMR
OH
CdN
3
-
1 1
cm . H NMR in D
2
O: δ 2.52 (s, 3H, CH
ppm. C{ H} NMR in D O: δ 172.5 (CdN), 23.8 (CH
) ppm. Pt NMR in D O: δ -907 (1000 Hz) ppm.
SP-4-1)-Bis(acetone oxime-KN )diammineplatinum(II) Dini-
3
), 2.12 (s, 3H, CH
3
in D O: δ 180.2 (CdN), 29.3 (CH ), 23.0 (CH ), 10.0 (CH ), 9.3
2 2 2 3
195
1
3
1
2
3
), 18.2
(CH ) ppm. Pt NMR in D O: δ -914 (1500 Hz) ppm.
3
2
1
95
(
CH
3
2
(SP-4-2)-Diamminebis(4-heptanone oxime-KN )platinum(II)
dinitrate (9c). The synthesis was carried out as described for
7c, using 203 mg (0.42 mmol) of cis-[PtI (NH ) ], 143 mg (0.84
(
trate (7t). trans-[PtCl (NH ) ] (81 mg, 0.27 mmol) and AgNO
2
3 2
3
2
3 2
(
92 mg, 0.54 mmol) were suspended in 2.5 mL of H
2
O, where-
3
mmol) of AgNO , and 122 μL (0.84 mmol) of 4-heptanone
upon the mixture was stirred at 60 °C overnight. The white
precipitate of AgCl was filtered off, and acetone oxime (40 mg,
oxime. Yield: 39 mg (15%). Anal. (C14
N. ESI-MS in H
H
36
N
6
O
8
Pt H
3
2
O) C, H,
Cd
þ
2
O/MeOH: m/z 340 [M - NH
3
- n-Pr
2
þ
þ
0
.54 mmol) was added. After the reaction mixture was stirred at
NOH - HNO - NO ] , 452 [M - 2NH - HNO - NO ] ,
3
3
3
3
3
þ
þ
room temperature overnight, the clear yellowish solution was
reduced to 0.5 mL and 10 mL of acetone was added, inducing the
470 [M - NH
3
- HNO
CdNOH - 4NH
3
- NO
3
] , 486 [M - HNO
- 3HNO
3
- NO
3
] ,
] , 791
þ
774 [2M - n-Pr
2
3
3
- NO
3

Article
Inorganic Chemistry, Vol. 49, No. 12, 2010 5673
Table 1. Crystal Data and Details of Data Collection for 3c, 3t, 4c, 5t, and 7t
3
c
3t
4c
22Cl
5t
30Cl
7t
empirical formula
fw
space group
C
6
H
14
I
2
N
2
O
2
Pt
C
6
H
I
14 2
N
2
2
O Pt
C
10
H
2
N
2
2
O Pt
C
14
H
2
N
O
2 2
Pt
6 20 6 8
C H N O Pt
595.08
P2 /c
7.9315(2)
17.4453(5)
9.6186(2)
595.08
P2
9.0055(4)
9.0841(3)
16.5477(5)
468.29
P1
524.39
Pnma
8.0268(6)
16.3958(13)
14.4299(12)
499.37
P1
1
2
1 1
2
1
˚
a, A
9.1808(2)
9.4940(3)
9.5723(3)
79.582(3)
79.141(2)
72.957(2)
776.38(4)
2
0.710 73
2.003
10 0. 20 1 ꢀ 0.15 ꢀ 0.08
93.74
6.3713(4)
7.6065(5)
8.4282(6)
91.570(4)
105.325(4)
101.662(3)
384.39(4)
1
0.710 73
2.157
10 0. 20 1 ꢀ 0.12 ꢀ 0.10
91.73
˚
b, A
˚
c, A
λ, deg
β, deg
γ, deg
101.752(2)
3
˚
V, A
Z
1303.00(6)
4
0.710 73
3.033
10 0. 20 5 ꢀ 0.10 ꢀ 0.08
154.85
0.0250
0.0543
1.034
1353.72(9)
4
0.710 73
2.920
10 0. 10 2 ꢀ 0.05 ꢀ 0.03
149.05
0.0144
0.0309
0.990
1899.1(3)
4
0.710 73
1.834
10 0. 20 0 ꢀ 0.06 ꢀ 0.06
76.75
0.0187
0.0400
0.989
˚
R, A
-3
F
crystal size, mm
calcd, g cm
T, K
μ, cm
R1
-
1
a
0.0174
0.0354
1.010
0.0195
0.0385
1.000
b
wR2
GOF
c
P
P
P
P
P
a
b
|. wR2 = { [w(F
2
o
2 2
2 2 1/2 c
) ]} . GOF = { [w(F
2
o
2 2
1/2
R1 = ||F
and p is the total number of parameters refined.
o
| - |F
c
||/ |F
o
- F
c
) ]/ [w(F
o
- F ) ] /(n - p)} , where n is the number of reflections
c
þ
3
[
n-Pr
2M - n-Pr CdNOH - 3NH - 3HNO - NO ] , 808 [2M -
3 s over 1° scan width for 3c, 3t, 4c, 5t, and 7t, respectively. The
data were processed using the SAINT software package.
2
3
3
þ
48
2
CdNOH - 2NH
3
- 3HNO
3
- NO
3
] , 920 [2M - 3NH
3
-
] , 955
þ
þ
3
HNO
3
- NO
3
3
] , 937 [2M - 2NH
3
- 3HNO
3
- NO
3
Crystal data, data collection parameters, and structure refine-
ment details for 3c, 3t, 4c, 5t, and 7t are given in Table 1. The
structures were solved by direct methods and refined by full-
matrix least-squares techniques. Non-hydrogen atoms were
refined with anisotropic displacement parameters. Hydrogen
atoms were placed at calculated positions and refined as riding
atoms in the subsequent least-squares model refinements. The
isotropic thermal parameters were estimated to be 1.2 times
the values of the equivalent isotropic thermal parameters of the
non-hydrogen atoms to which the hydrogen atoms were
þ
þ
[
2M - NH
- 3HNO
3
- NO
3
] , 972 [2M - 3HNO
3
- NO
3
] .
Mp: 155 °C (dec). IR in KBr (selected bands): ν 3316 s (νOH),
-
1 1
1
645 m (νCdN) cm . H NMR in D
2
O: δ 2.94 (t, 2H, CH
), 1.55 (m, br, 2H, CH CH
= 7.4 Hz), 0.84
2
,
3
JH,H = 8.0 Hz), 2.51 (t, br, 2H, CH
.45 (m, br, 2H, CH CH ), 0.96 (t, 3H, CH , J
H,H
2
3
2
),
3
1
3
2
3
3
13
1
(
(
t, 3H, CH , J
3
= 7.2 Hz) ppm. C{ H} NMR in D O: δ 177.8
H,H 2
CdN), 38.3 (CH
), 13.34 (CH ), 13.32 (CH
882 (1050 Hz) ppm.
SP-4-1)-Diamminebis(4-heptanone oxime-KN)platinum(II)
Dinitrate (9t). trans-[PtCl (NH ) ] (200 mg, 0.67 mmol) and
2
), 31.7 (CH
2
), 19.5 (CH
3
2
CH ), 18.9 (CH
3
-
O: δ
1
95
CH
2
3
3
) ppm. Pt NMR in D
2
-
4
9
(
bonded. SHELXS-97 was used for structure solution and
SHELXL-97 for refinement, molecular diagrams were pro-
5
0
2
3 2
5
duced with ORTEP, and appropriate scattering factors were
1
AgNO (227 mg, 1.34 mmol) were suspended in 5 mL of H O,
whereupon the mixture was stirred at 60 °C overnight. The white
precipitate of AgCl was filtered off, and 4-heptanone oxime
3
2
5
2
used.
Cell Lines and Culture Conditions. Human CH1 (ovarian
carcinoma) and SW480 (colon carcinoma) cells were kindly
provided by Lloyd R. Kelland (CRC Centre for Cancer Ther-
apeutics, Institute of Cancer Research, Sutton, U.K.) and
Brigitte Marian (Institute of Cancer Research, Department of
Medicine I, Medical University of Vienna, Austria), respec-
(
173 mg, 1.34 mmol) in 1 mL of THF was added. After the
reaction mixture was stirred at room temperature for 3 days, the
yellowish solution was filtered from a small amount of a gray
precipitate. Then the solvent was removed, and the solid was
suspended in 10 mL of acetone; the white precipitate was filtered
off and washed with acetone (2 ꢀ 1 mL) and ether (3 mL). After
that, the solid was suspended in 5 mL of EtOH, filtered off, and
then washed three times with 1 mL of EtOH. The filtrates were
combined, the volume was reduced to 0.5 mL, and 5 mL of Et O
2
was added, inducing the precipitation of a white solid. After
filtration, the product was washed with 0.5 mL of Et
dried in vacuo. Yield: 123 mg (30%). Anal. (C H N -
2
tively. Cells were grown in 75 cm culture flasks (Iwaki/Asahi
Technoglass, Gyouda, Japan) as adherent monolayer cultures in
a complete culture medium, i.e., a minimal essential medium
(MEM) supplemented with 10% heat-inactivated fetal bovine
serum, 1 mM sodium pyruvate, and 4 mM L-glutamine (all
purchased from Sigma-Aldrich, Vienna, Austria). Cultures were
maintained at 37 °C in a humidified atmosphere containing 5%
2
O and
1
4
36
6
þ
O Pt H O) C, H, N. ESI-MS in H O/MeOH: m/z 452 [M -
2
CO and 95% air.
8
3
2
2
þ
þ
2
NH
3
- HNO
3
- NO
3
þ
] , 469 [M - NH
3
- HNO
3
- NO
3
] , 486
Cytotoxicity Tests in Cancer Cell Lines. Cytotoxicity was
determined by means of a colorimetric microculture assay [MTT
[
M - HNO
3
- NO
3
] . Mp: 211 °C (dec). IR in KBr (selected
-1 1
2
bands): ν 3202 s (νOH), 1657 m (νCdN) cm . H NMR in D O: δ
4
.30 (s, br, 3H, NH ), 2.96 (s, br, 2H, CH ), 2.56 (t, 2H, CH ,
(48) SAINT-Plus, version 7.06a, and APEX2; Bruker-Nonius AXS Inc.:
Madison, WI, 2004.
3
2
2
3
J
CH
H,H = 8.0 Hz), 1.63 (m, br, 2H, CH
3
2
CH ), 1.49 (m, br, 2H,
3
, JH,H = 7.3 Hz), 0.87 (t, 3H, CH
(
49) Sheldrick, G. M. SHELXS-97, Program for Crystal Structure Solu-
tion; University of G €o ttingen: G €o ttingen, Germany, 1997.
50) Sheldrick, G. M. SHELXS-97, Program for Crystal Structure Re-
finement; University of G €o ttingen: G €o ttingen, Germany, 1997.
51) Johnson, C. K. Report ORNL-5138; Oak Ridge National Labora-
tory: Oak Ridge, TN, 1976.
52) International Tables for X-ray Crystallography; Kluwer Academic
Press: Dordrecht, The Netherlands, 1992; Vol. C, Tables 4.2.6.8 and 6.1.1.4.
53) Kukushkin, V. Yu.; Tudela, D.; Izotova, Y. A.; Belsky, V. K.; Stash,
A. I. Polyhedron 1998, 17, 2455–2461.
54) Dhara, S. C. Indian J. Chem. 1970, 8, 193–194.
(55) Kauffman, G. B.; Cowan, D. O. Inorg. Synth. 1963, 7, 239–245.
CH ), 1.00 (t, 3H, CH
3 2
3
3
,
3
J
13
1
2
H,H = 7.4 Hz) ppm. C{ H} NMR in D O: δ 178.2 (CdN),
(
3
8.1 (CH ), 31.8 (CH ), 19.6 (CH CH ), 18.9 (CH CH ), 13.4
2
2
3
2
3
2
1
95
(
(
CH
3
), 13.2 (CH
3
) ppm.
2
Pt NMR in D O: δ -906, -914
(
950 Hz) ppm.
Crystallographic Structure Determination. X-ray diffraction
(
measurements were performed with a Bruker X8 APEX II CCD
diffractometer at 100 K. Single crystals were positioned at 40,
(
4
8
0, 40, 40, 40, and 35 mm from the detector, and 930, 2109, 1575,
04, and 1869 frames were measured, each for 5, 30, 30, 50, and
(

5
674 Inorganic Chemistry, Vol. 49, No. 12, 2010
Scaffidi-Domianello et al.
Figure 1. Platinum(II) oxime complexes under investigation.
assay, MTT = 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-
tetrazolium bromide]. For this purpose, CH1 and SW480 cells
were harvested from culture flasks by trypsinization and seeded
in 100 μL aliquots in MEM supplemented with 10% heat-
inactivated fetal bovine serum, 1 mM sodium pyruvate, 4 mM
L-glutamine, and 1% nonessential amino acids (100ꢀ) (all
purchased from Sigma-Aldrich) into 96-well microculture plates
complexes of the type [Pt(NH ) (R CdNOH) ](NO ) , where
R = Me (7c/7t), Et (8c/8t), and n-Pr (9c/9t), which were
anticipated to be inactive (Figure 1).
3
2
2
2
3 2
Synthesis and Characterization of Dihalidobis(oxime)-
platinum(II) Complexes. Synthesis of the target cis-diio-
didoplatinum(II) complex 3c was carried out in analogy to
53
corresponding dibromido species 2c. The reaction be-
tween K [PtI ], obtained in situ by the addition of KI to
(
1
Iwaki/Asahi Technoglass, Gyouda, Japan) in cell densities of
.5 ꢀ 10 and 2.5 ꢀ 10 cells well , respectively, in order to
3
3
-1
2
4
ensure exponential growth of untreated controls throughout
drug exposure. For 24 h, cells were allowed to settle and resume
exponential growth, followed by the addition of dilutions of
the test compounds in aliquots of 100 μL well- in the same
medium. Only for the less water-soluble compounds 5t and 6t,
stock solutions had to be prepared in a dimethyl sulfoxide
an aqueous solution of K [PtCl ], and acetoxime proceeded
2 4
in an aqueous solution at room temperature and led to
precipitation of 3c. Corresponding trans isomer 3t was
obtained via thermal isomerization of 3c in a MeNO2
solution at 95-100 °C for 3 h. The preparation of dichlorido
species 4c and 4t-6t was performed by a one-step reaction
of K [PtCl ] and 2 equiv of the corresponding oxime in an
1
(
2
DMSO)/H O mixture (the stability of the compounds in a
1
DMSO solution was proven by H NMR spectroscopy). The
DMSO content in the actually tested dilutions did not exceed
2
4
aqueous solution at 75-85 °C; a higher temperature was
needed to increase the solubility of the oximes in water. The
formation of a cis/trans isomeric mixture was observed
exclusively in the case of the n-pentanone oxime complex
0
.5%. After continuous exposure for 96 h, drug solutions were
-
1
replaced by a 130 μL well
RPMI 1640 culture medium
supplemented with 10% heat-inactivated fetal bovine serum
(
-
1
and 4 mM L-glutamine) plus 20 μL well MTT solution in
phosphate-buffered saline (5 mg mL ). After incubation for
(
4c/4t), and these isomers could be separated by column
-
1
chromatography. The reactions with n-heptanone oxime as
well as with 2,4-dimethyl-3-pentanone oxime resulted, be-
cause of steric reasons, solely in isomerically pure trans
compounds 5t and 6t, respectively. The final products were
obtained as pale-yellow solids and were isolated in moderate
to good yields (40-65%).
4
h, the medium/MTT mixtures were removed, and the for-
mazan crystals formed by viable cells were dissolved in 150 μL of
DMSO per well. Optical densities at 550 nm were measured with
a microplate reader (Tecan Spectra Classic), using a reference
wavelength of 690 nm to correct for unspecific absorption. The
quantity of vital cells was expressed in terms of T/C values by
comparison to untreated control microcultures, and 50% in-
hibitory concentrations (IC50) were calculated from concentration-
effect curves by interpolation. Evaluation is based on means from at
least three independent experiments, each comprising three repli-
cates per concentration level.
Complexes 3c, 4c, and 3t-6t were characterized by C,
1
H, and N elemental analyses, H, C{ H}, and
13
1
195
Pt
NMR and IR spectroscopy, ESI-MS, and also X-ray
crystallography (for 3c, 3t, 4c, and 5t). All compounds
gave satisfactory C, H, and N elemental analyses. ESI-
þ
Results and Discussion
MS spectra displayed the fragments [M þ Na] and [M þ
þ
-
K] in the positive mode as well as [M - oxime - H] and
Recently, we reported on the intriguing biological proper-
-
[
that were in good agreement with the calculated ones. The
M - H] in the negative mode, having isotopic patterns
ties of an isomeric couple cis/trans-[PtCl (Me CdNOH) ]
2
2
2
39
(1c/1t). In order to establish and learn more about their
structure-activity relationships, a series of novel oximepla-
IR spectra of 3c, 4c, and 3t-6t showed strong-intensity
-
1
tinum(II) analogues were prepared: (i) cis/trans couples of
νOH (3242-3330 cm ) and medium-intensity νCdN
5
3
-1
[
PtX (Me CdNOH) ], where X = Br (2c/2t) or I (3c/3t),
(1649-1672 cm ) stretching vibrations. Interestingly,
only in the case of the trans-configured complex 3t,
displaying sterically demanding iodido ligands, two sets
2
2
2
with the aim of understanding the role of the ionic leaving
ligands and the configuration of the complexes for their
cytotoxic properties, (ii) [PtCl (R CdNOH) ], where R = Et
1
of CH
This circumstance is explainable by a hindered rotation of
signals were detected in the H NMR spectrum.
2
2
2
3
(4c/4t), n-Pr (5t), and i-Pr (6t), to elucidate the influence
of increased lipophilicity and/or steric hindrance, and (iii)
the oxime ligands around the Pt-N bonds as proven via

Article
Inorganic Chemistry, Vol. 49, No. 12, 2010 5675
195
Figure 2. Temperature-dependent Pt NMR spectra of 9t (the region between -1100 and -700 ppm is shown). At low temperatures, the rotation of the
ligands is slowed down, resulting in a splitting of the platinum resonances.
1
the acquisition of H NMR spectra at different temperatures
was broader than that for 7t (the half-height widths were
1500 and 800 Hz, respectively), turning into two signals
(a broad signal with a shoulder) in the case of 9t, which is
most probably the result of a hindered rotation of the
(
278-335 K; Figure S1 in the Supporting Information).
Synthesis and Characterization of Diamminebis-
oxime)platinum(II) Dinitrate Complexes. For the pre-
(
1
95
paration of cis- and trans-[Pt(NH ) (R CdNOH) ]-
3
sterically demanding ligands. To clarify that fact,
Pt
2
2
2
5
4
1
(NO ) (7c/7t-9c/9t), the well-known cis-[PtI (NH ) ]
and trans-[PtCl (NH ) ] complexes were used as start-
(Figure 2) and H NMR (Figure S2 in the Supporting
Information) spectra were measured at different tempera-
tures for 9t. At 283 K, two platinum signals at -914 and
-926 ppm were observed; upon an increase in the tem-
perature to 343 K, only one signal was detected, showing
that the complex exists in temperature-dependent con-
formations.
3
2
2
3 2
5
5
2
3 2
ing materials. First, halide abstraction of the starting
complex by using AgNO was carried out in an aqueous
3
solution at room temperature in the case of the cis species
and at 60 °C for the corresponding trans-configured
complexes. The elevated temperature in the latter case
was necessary for the second chlorido ligand to be
An analogous behavior was monitored in the proton
resonance spectra, measured at the same temperatures
(Figure S2 in the Supporting Information). However, for
the NMR spectra of the corresponding cis-configured
[Pt(NH ) (R CdNOH) ](NO ) complexes 7c, 8c, and
3 2 2 2 3 2
9c, no such features were observed.
X-ray Crystal Structures. The structures of cis-[PtI -
2
3
1
abstracted after the first chloride was already ex-
changed by a water molecule (aqua ligands are known
5
6
for their extremely weak trans effect ). After the formed
AgX (X = Cl, I) precipitate was filtered off, 2 equiv of the
corresponding oxime was added to the in situ generated
2
þ
cis/trans-[Pt(NH ) (H O) ] species, leading to the for-
3
2
2
2
mation of the desired complexes (7c/7t-9c/9t). The com-
pounds were obtained in moderate to good yields
(Me
cis-[PtCl
(5t), and trans-[Pt(NH
2
CdNOH)
2
] (3c), trans-[PtI
] (4c), trans-[PtCl
(Me CdNOH)
2
(Me
2
CdNOH)
(n-Pr CdNOH)
](NO (7t) were
2
] (3t),
(Et CdNOH)
]
2
2
2
2
2
2
(
15-65%) via either precipitation (7c, 7t, and 9c; the
)
3
2
2
2
)
3 2
addition of acetone to the aqueous solution) or solvent
removal and suspension in acetone (8c, 8t, and 9t).
Complexes 7c/7t-9c/9t gave satisfactory elemental
analyses and expected molecular ion/fragmentation pat-
terns in the ESI-MS spectra. The presence of a broad
range of peaks was recognized in the positive mode (see
Experimental Section). Complexes 7c/7t-9c/9t were
determined by X-ray diffraction (Table 1 and Figures 3-5).
In 3c, 3t, 4c, and 5t, the metal center is bound by two
oximic nitrogen atoms and two halogenido ligands, being
in the cis (3c and 4c) or trans (3t and 5t) positions. In 7t,
two ammonia and two oxime ligands are mutually trans.
In the coordinated oximes, the CdN bond lengths
˚
[1.270(7)-1.292(7) A] are similar within 3σ and corres-
pond to previously reported distances in metal-bound
characterized by IR spectroscopy; characteristic ν
OH
3194-3316 cm- ) and νCdN (1645-1667 cm ) bands
1
-1
53,57-60
˚
(
were observed. With respect to the H NMR spectra in
oximes [1.268-1.324 A]. The platinum atom in the
square-planar complex 3t is slightly displaced out of the
1
D O of the trans-[Pt(NH ) (R CdNOH) ](NO ) com-
2
2
3 2
2
3 2
(
57) Kukushkin, V. Yu.; Nishioka, T.; Tudela, D.; Isobe, K.; Kinoshita, I.
Inorg. Chem. 1997, 36, 6157–6165.
58) Kukushkin, N. V.; Ketrush, P. M.; Haukka, M. Acta Crystallogr.
007, E63, m1286.
59) Manivannan, V.; Kumar, B.; Chandan Kumar Pal, D.; Chakravorty,
plexes 7t, 8t, and 9t, it is worth mentioning that the proton
signals become broader with the increased length of R. In
turn, in the Pt NMR spectra, the platinum signal of 8t
(
1
95
2
(
A. Inorg. Chem. 1997, 36, 1526–1528.
(60) Ebeling, G.; Gruber, A. S.; Burrow, R. A.; Dupont, J.; Lough, A. J.;
Farrar, D. H. Inorg. Chem. Commun. 2002, 5, 552–554.
(
56) Chval, Z.; Sip, M.; Burda, J. V. J. Comput. Chem. 2008, 29, 2370–
2
381.

5
676 Inorganic Chemistry, Vol. 49, No. 12, 2010
Scaffidi-Domianello et al.
˚
Figure 3. ORTEP diagram of 3c (left) and 3t (right) displaying thermal ellipsoids at 50% probability. Selected bond lengths (A) and angles (deg) for 3c:
Pt-N1, 2.041(4); Pt-N2, 2.055(4); Pt-I1, 2.5819(4); Pt-I2, 2.5963(4); N1-C2, 1.292(7); N2-C5, 1.270(7); N1-Pt-N2, 89.03(17); N1-Pt-I1, 90.77(12);
˚
N1-Pt-I2, 176.08(12). Selected bond lengths (A) and angles (deg) for 3t: Pt-N1, 2.002(3); Pt-N2, 2.007(3); Pt-I1, 2.5938(3); Pt-I2, 2.6104(2); N1-C2,
1.285(4); N2-C5, 1.291(4); N1-Pt-N2, 174.39(11); N1-Pt-I1, 90.69(8); N1-Pt-I2, 89.63(8).
˚
mean plane through N1-I1-N2-I2, by 0.01A, whereasin
the case of 3c, it lies ideally within the corresponding
N1-I1-N2-I2 plane (Figure 3).
The Pt-I bond distances in complexes 3c and 3t were
˚
found in the range of 2.5819(4)-2.6104(2) A. These
distances agree well with those of previously published
6
1-63
platinum(II) iodide compounds.
tances in the case of cis-configured 3c at 2.041(4) and
2
The Pt-N dis-
˚
.055(4) A for Pt-N1 and Pt-N2, respectively, are
significantly longer than those found in 3t [Pt-
N1, 2.002(3) A; Pt-N2, 2.007(3) A] because of the
more pronounced trans influence of the coordinated
iodide.
˚
˚
Figure 4. ORTEP diagram of 4c displaying thermal ellipsoids at 50%
˚
probability. Selected bond lengths (A) and angles (deg): Pt-N1,
5
6
2.0049(19); Pt-N2, 2.0249(19); Pt-Cl1, 2.2977(6); Pt-Cl2, 2.2957(6);
N1-C3, 1.290(3); N2-C8, 1.287(3); N1-Pt-N2, 92.08(8); N1-Pt-Cl1,
88.35(6); N1-Pt-Cl2, 178.14(5).
In dichloridoplatinum(II) complexes 4c and 5t (Figures
and 5), deviation of the platinum atom from the mean
4
planes through N1-Cl1-N2-Cl2 and N1-Cl1-N1-
cell line CH1 and the intrinsically cisplatin-resistant colon
carcinoma cell line SW480 by means of the colorimetric
MTT assay. IC50 values are listed in Table 2. In general,
both cell lines are similarly sensitive to the halogenido
oxime compounds 2c-4c and 2t-6t, while CH1 cancer
cells are considerably more sensitive to the cationic
diamminebis(oxime) complexes 7c-9c as well as 7t and
˚
I1-Cl2 is not larger than 0.04 A. The Pt-Cl bond
distances in 4c and 5t vary from 2.2821(9) to 2.3208(8) A,
˚
which falls into the range of typical Pt-Cl dis-
64,65
tances.
˚
The Pt-N1 bond length in 4c at 2.0049(19) A
is in the expected range for platinum complexes with a cis
53,57
configuration.
Of note is the relatively long distance
˚
Pt-N2 at 2.0249(19) A, displaying a 7σ difference from the
Pt-N1 bond length. The N1-Pt-N2 angle at 92.08(8)° in
9t than SW480 cells; complex 8t showed no antiprolifera-
tive effect at all.
Specific structural modifications of the previously re-
ported cis/trans-[PtCl (Me CdNOH) ] complexes 1c and
4
c is larger than that in 3c [N1-Pt-N2, 89.03(17)°], depen-
ding on the coordinated halogenido ligand (chlorido versus
iodido).
2
2
2
39
1t
were made in order to investigate the structure-
˚
The Pt-N1 bond of trans-configured 5t at 2.006(2) A is
well comparable with Pt-N distances found in 3t and 7t
at 2.002(3) and 2.006(2) A, respectively. In contrast, the
activity relationships with respect to the effect of (i) the
leaving group, (ii) the carbon chain length of coordinated
oximes in the case of the chlorido complexes, as well as
˚
Pt-N2 distance (coordinated ammine ligand) in 7t at
(iii) an increasing oxime carbon chain length in cationic
diamminebis(oxime) complexes.
˚
.045(2) A is significantly longer.
2
Cytotoxicity and Structure-Activity Relationships. The
cytotoxic potencies of the halogenido oxime complexes
i. Effect of the Leaving Group. Substitution of the
chlorido ligands in 1c/1t for bromides, yielding 2c/2t,
dramatically decreases the cytotoxic potencies by factors
of 9-39. These results were expected and can be explained
by the lower reactivity of bromido complexes compared
2
c-4c and 2t-6t, as well as the diamminebis(oxime) com-
pounds 7c/7t-9c/9t, were compared to those of cisplatin
and transplatin in the cisplatin-sensitive ovarian carcinoma
6
to chlorido analogues. Still, the trans isomer 2t is more
(
61) Berger, I.; Nazarov, A. A.; Hartinger, Ch. G.; Groessl, M.; Valiahdi,
cytotoxic than its cis analogue 2c. However, this trend is
not continued in the iodido counterparts. 3c and 3t
proved to be more cytotoxic than, or at least similarly
cytotoxic to the corresponding bromido species 2c and 2t,
despite a higher stability [hard and soft acids and bases
(HSAB) principle]. This might be caused by the higher
lipophilicity of 3c and 3t, facilitating cellular accumula-
tion of the complexes. Thus, the order of cytotoxicity of
S.-M.; Jakupec, M. A.; Keppler, B. K. ChemMedChem. 2007, 2, 505–514.
(62) Rochon, F. D.; Bonnier, C. Inorg. Chim. Acta 2007, 360, 461–472.
(63) Rochon, F. D.; Buculei, V. Inorg. Chim. Acta 2004, 357, 2218–2230.
(64) Scaffidi-Domianello, Yu.; Nazarov, A. A.; Haukka, M.; Galanski,
M.; Keppler, B. K.; Schneider, J.; Du, P.; Eisenberg, R.; Kukushkin, V. Yu.
Inorg. Chem. 2007, 46, 4469–4482.
(
65) Scaffidi-Domianello, Yu.; Haukka, M.; Kelly, P. F.; Galanski, M.;
Keppler, B. K.; Kukushkin, V. Yu. Z. Kristallogr.;New Cryst. Struct. 2006,
21, 226–228.
2

Article
Inorganic Chemistry, Vol. 49, No. 12, 2010 5677
˚
Figure 5. ORTEP diagram of 5t (left) and 7t (right) displaying thermal ellipsoids at 50% probability. Selected bond lengths (A) and angles (deg) for 5t:
Pt-N1, 2.006(2); Pt-Cl1, 2.2821(9); Pt-Cl2, 2.3208(8); N1-C4, 1.277(3); N1-Pt-N1#1, 174.82(11); N1-Pt-Cl1, 89.09(6); N1-Pt-Cl2, 90.90(6).
˚
Selected bond lengths (A) and angles (deg) for 7t: Pt-N1, 2.006(2); Pt-N2, 2.045(2); N1-C2, 1.288(3); N1-Pt-N2, 89.66(9); N1-Pt-N2i1, 90.34(9);
N1-Pt-N1i1, 180.0(11).
6
6
Table 2. Cytotoxicity of Platinum(II) Oxime Complexes in CH1 and SW480
Cancer Cells (Exposure Time 96 h)
(virtually no leaving groups ) or charged compounds
low cellular accumulation but increased renal elimina-
(
6
tion ) are generally considered to be noncytotoxic. The
reason for the observed (albeit low) cytotoxicity of 7c
and 9t, especially in CH1 cells, is yet unclear.
cis configuration
IC50, μM
trans configuration
IC50, μM
In comparison to cisplatin, the cis-configured halido
complexes 1c-4c are considerably (up to 70 times) less
potent in the cisplatin-sensitive cell line CH1 but almost
completely retain their cytotoxicity in the cisplatin-resis-
tant SW480 cells, as indicated by a comparison of the
resistance factors (RF = IC50 in the cisplatin-resistant
cell line/IC50 in the cisplatin-sensitive cell line) of 1c-4c
(RF = 1.1-1.8; Table S1 in the Supporting Information)
with that of cisplatin (RF = 24).
compound
CH1
SW480 compound
CH1
SW480
1c
2c
3c
4c
2.7 ( 0.7
25 ( 4
1.6 ( 0.2
11 ( 1
3.4 ( 0.3 1t
45 ( 6 2t
1.8 ( 0.5 3t
15 ( 1 4t
0.17 ( 0.09 0.22 ( 0.05
6.7 ( 0.2
3.0 ( 0.5
1.4 ( 0.3
0.18 ( 0.03 0.16 ( 0.02
0.19 ( 0.03 0.21 ( 0.03
468 ( 180 >1000
2.5 ( 0.4
2.8 ( 0.3
1.9 ( 0.6
5
t
6
t
7
8
9
c
c
c
21 ( 7
717 ( 46
162 ( 46
567 ( 39 7t
>1000
>1000
8t
>1000
29 ( 5
>1000
350 ( 30
19 ( 3
9t
In the case of trans-halido compounds 1t-6t, the
resistant factors of 0.4-1.4 show that the complexes are
not cross-resistant with cisplatin either. 1t, 5t, and 6t are
similarly cytotoxic as cisplatin in CH1 cells and up to 20
times more cytotoxic than cisplatin in SW480 cells. In
comparison to transplatin, 1t-6t are up to 90 (CH1) and
cisplatin 0.14 ( 0.03 3.3 ( 0.4 transplatin 15 ( 2
[PtX (Me CdNOH) ]-type agents is dependent on the
2 2 2
halido ligand X as follows: I > Cl > Br (cis geometry) and
Cl > I g Br (trans geometry). Contrary to the chlorido (1c/
1t) and bromido (2c/2t) complexes, the cis isomer 3c is
slightly more cytotoxic than trans-configured 3t, reversing
the structure-activity relationships to a more cis/transpla-
tin-like behavior.
120 (SW480) times more cytotoxic.
Conclusions
ii. Effect of the Oxime Carbon Chain in Dichlorido
Complexes. A series of complexes with chlorido ligands
and a systematically increased carbon chain of the oxime
ligand were investigated. Using n-pentanone oxime in
A series of novel bis(oxime)platinum(II) complexes with
either cis or trans configuration have been synthesized,
characterized, and investigated in two human cancer cell
lines. Structure-activity relationships could be inferred from
these results. The observation that the trans geometry yields a
more active complex in the case of the prototypic oxime
complex [PtCl (Me CdNOH) ] could be confirmed for at
4
c/4t instead of acetoxime in 1c/1t resulted in a 4-8.6-fold
decrease of cytotoxicity. Remarkably, the trans-config-
ured complex 4t is 8 times more cytotoxic than 4c. Further
increasing the length of the oxime carbon chain of the
trans complexes by either n-propyl (5t) or isopropyl (6t)
residues results in similarly enhanced cytotoxicity with
IC50 values in the high nanomolar concentration range in
both the cisplatin-sensitive CH1 and cisplatin-resistant
2
2
2
least two further structural analogues, [PtBr (Me Cd
2
2
NOH) ] and [PtCl (Et CdNOH) ]. Every single cis- or
2
2
2
2
trans-configured halido bis(oxime) complex showed compar-
able cytotoxic potency in both cell lines, the cisplatin-sensi-
tive CH1 and the inherently cisplatin-resistant SW480 cancer
cells. Particularly high cytotoxicities were revealed for the
three trans compounds with chlorido ligands, with IC50
values as low as 0.16-0.22 μM. Given these encouraging
results, their mechanism of action should be studied in more
detail in order to gain an understanding, which, in turn, may
help to optimize their anticancer activity.
SW480 cells. Hence, the cytotoxicity of the trans-[PtCl2-
(
R CdNOH) ]-type complexes depends on the residues
2 2
R as follows: Me ≈ n-Pr ≈ i-Pr > Et.
iii. Effect of the Oxime Carbon Chain Length in Catio-
nic Diamminebis(oxime) Complexes. All six cationic dia-
mminedioxime complexes (7c/7t-9c/9t) displayed either
a low or a negligible cytotoxicity. This is in accordance
with the classic structure-activity relationships, accord-
ing to which complexes with four nitrogen donor ligands
Acknowledgment. The authors are indebted to the
FFG-Austrian Research Promotion Agency (811591),
the Austrian Council for Research and Technology Devel-
opment (IS526001), the FWF (Austrian Science Fund),
COST D39, and Russian Fund for Basic Research (Grant
(
66) Llewellyn, D. R.; O’Connor, C. J.; Odell, A. L. J. Chem. Soc. 1964,
1
96–200.

5
678 Inorganic Chemistry, Vol. 49, No. 12, 2010
9-03-12173-ofim). We thank Nikolay V. Kukushkin (St.
Petersburg State University) for experimental assistance.
Scaffidi-Domianello et al.
0
and 7t. Crystallographic data have been deposited with the
Cambridge Crystallographic Data Center as CCDC 767592-
67596 for 4c, 5t, 3c, 3t, and 7t, respectively. Copies of data can
7
Supporting Information Available: Figures with temperature-
dependent H NMR spectra of 3t and 9t, tables with resistance
factors and elemental analyses of platinum oxime complexes,
and X-ray crystallographic data in CIF format for 3c, 3t, 4c, 5t,
be obtained, free of charge, upon application to CCDC, 12
Union Road, Cambridge CB2 1EZ, U.K. (deposit@ccdc.com.
ac.uk). This material is available free of charge via the Internet at
http://pubs.acs.org.
1