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An Unusual Route to Potential Platinum Antitumor Compounds Synthesis Reactivity and Spectroscopic Properties of the PtIV Complex fac-[PtCl3(NH3)2L]Cl.

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[14] a j A . Hirsch. I . Lamparth. H . R. Karfunkel, Angew. Clirvii. 1994, /Od. 453455: Ai?grw.Chwii. /!I/. Ed. €rig/. 1994, 33. 437-439; h) C. C. Henderson. C .
M . Rohlfing. R. A . Asaink. P. A . Cahill. ihid 1994, iU6.803-805 and 1994.33.
ix6--7xx.
[I51 a) J. M. Hawkins. A . Meyer, T. A. Lewis. S. Loren. F. J. Hollander, S&rice
f Wu.d7tfigio~iD. C., 1883-i 1991. 2.52. 312-313: b j H. Irngartingcr. C:M.
Kiihler. U. Huher-Patr. W. Kritschmer. Cherw Ber 1994, /27, 5x1 584.
[I61 a ) G. Wegner. Pure A ~ / J / C'hrtn.
.
1977. 49.443 454: b) J. D. Wright. Mnirculrrr
Cri , r r t / . r , Cambridge University Press. 1987. p. 116.
[I71 All electrochemical measuremenrs were carried out with ii 0.1 M solution of
Bu,N A P F , in anhydrous dichloromethane as thc supporting electrolyte. A
potentiostat (Bruker E130Mj connected to an x-y plotter (Ifelec IF3802j was
used. Electrolysis was performed in a classical three-electrode cell. The working
clcctrode was a platinum disk electrode. the counter electrode R platinum wire.
and the reference an aqueous Ag 'AgCl electrode. Potentials were relcrenced to
the internal ferroccne.
[18] J. M . Calvert. D. L. Peebles. R . J. Nowak. Inorg. C'hem. 1985. 24. 3111 3119.
[19] For example. with a film-covered Pt electrode. the cyclic voltammograms ofthe
lerrocene:ferricinium couple in Bu,N *PF, :CH2C'1, (0.1 bi) exhibited peaks
at + 0.44 V with respect to Ag;AgCI [(E,,, E,,J2]. and a A€,, of 100 mV
[ = :€ - E;d)
at a sweep rate of 0.1 Vs I : with a hare Pt electrode. peaks \\ere
located at 0.41 V \+ith a AEp of 60 mV.
1201 Foi- previous modifications of electrodes bsith unpolymerized C'*,,. see a ) C.
Jehouler. Y. S. Oheng. Y. T. Kim. F. Zhou. A. J. Bard. J. Atit. Chcn7. SOL.1992.
114.4237-4247, h)W. Koh. D. Duhois. W. Kutner. M.T. Jones, K. M Kadish.
J, P/7yr. C'herri. 1992. 96. 4163 4165: c) R. G. Compron. R. A Spackman, D.
J. Riley. R. G. Wellington. J. C. Eklund. A. V. Fisher. M . L H. Green. R. E.
Doothwaite. A . H. H. Stcpliena. 1. Turner, J. E l ~ irouizu/.
r
C%etri. 1993. 344.
235-241.
[21] C'. 1. Simionescu. M . Grovu, A R ~ I . Macronioi.
.
C ' h w i . 1983. / / / . 149 - 163. C .
1. Simionescu, M. G r o w . A Duca, hid. 1983, I/.?, 47-59.
[22] P. D. Beer. 0 . Kociaii. R. J. Mortimer. C. Ridgway. J. C/rcni. SO<. C/iwii.
Coriiriiurt. 1991. 1460- 1463.
[23] J. Simonet. J. Rault-Berthelot. pro^. S d i d Sr. C h m 1991. 2f. 1-4X.
+
+
compounds have been prepared. Iproplatin, cis,trans,ci.r[PtC1,(OH),(iPrNH,),],[*l
and tetraplatin, [PtCl,(dach)]
(dach = d,i-rruns-l,2-diaminocyclohexane)
,L31 are currently undergoing clinical trials. Acid-stable, lipophilic Pt" complexes
with carboxylato ligands (in the t r a m positions, instead of OHor CI-) are possibly the first active antitumor compounds based
on platinum that can be administered orally.[41Apart from minimization of the undesired toxicity, the development of substances with different activity spectra (tumor specificity) is also
important.['] For this purpose new combinations of ligands are
needed. which d o not necessarily need to exactly follow the
structure-activity relationship (see 2, Scheme 1 ) for secondgeneration Pt" and Pt'" antitumor compounds. We have now
expanded the spectrum of the ligands Y in Pt'" compounds of
type 2 by an S-donor ligand with the regioselective introduction
of a thiourea derivative.
The oxidative dimerization of 1 ,I ,3,3-tetramethylthiourea (3)
leads to a doubly positively charged bis(formamidinium) ion
with a central disulfide bridge (Scheme 2). Its synthetic potential
r
1
L
J
3
4
Scheme 2. Oxidative dimeriration o f 3 (L) to 4 ([L-LICI,
An Unusual Route to Potential Platinum
Antitumor Compounds: Synthesis, Reactivity,
and Spectroscopic Properties of the
Pt'" Complex fuc-[PtC1,(NH3),L]C1**
was first demonstrated by redox substitutions in Fe" complexes,
in which the thiolato ligands (under maintenance of the oxidation state of the central ion) were oxidized to the corresponding
disulfide, which could be replaced by thiourea.["] The 1 : I reaction of 4 with cisplatin yields Sr7](Scheme 3), the parent com-
Ulrich Bierbach* and Jan Reedijk*
The clinical successes in the treatment of malignant tumors
with cisplatin (cis-diamminedichloroplatinum(lr) 1, Scheme 1 ) .
particularly in the urogenital and gynecological areas,"] are
Y
I ..J
*,P~.-'
j\
am ,,,,
H3N
/ a'
1
am/
Y
2
Scheme 1. Cisplatin ( 1 ) and general
formula 2 for potentially active. SECond-generation PI" and Pt" antitumor
compounds. am = nonlecrving groupa
[am(m)ine
Iigands).
X = leaving
groupa (CI-. RCO;). Y = axial ligands in Pt" complexes (CI-, O H - )
'.\
5 (68%)
\
crs.as,trans -[PtUZ(NH&L,]
counterposed by drastic side effects in the digestive tract and
in the kidney region. In attempts to reduce the toxic side
effects, coordinatively saturated. kinetically inert Pt'" antitumor
[*I
[**I
Dr. U Bierhach. Prof. Dr J Reedijk
Leiden Institute or Chemistry. Gorlneua Laboratories
Leiden University. P. 0.
Box 9502
NL-2300 RA Leiden (The Netherlands)
Telefax. I n t . code + (71)274451
L = 1.1.~.~-tetrdmethy~thiourea.
This reiearch w a s supported by the Deutsche
Forschungsgenleinschaft. We thank Johnson Matthey Ltd. (Reading. Engl n n d ) for the generous loan o f platinum.
CIZ
Scheme 3. flr~,-[PtCI,(NH,),L]CI( 5 ) . the product of the oxidative addition o f 4 to
cisplatin ( I ) . A chloride counterion from 4 becomes a ligand in 5 . The following
mechanism seems plausible. 1. electrophilic attack of[L-L]'+ on the Pt d s orbital
with 2e oxidation of the centrill ion; 2. square-pyramidal. positively charged PI"'
transition state with thioureacoordinatioii: 3. completion oftheoctahedral geometry and reduction of the charge by addition of C1- [run.? to sulfur.
pound of a new group of cationic, water-soluble Pt" complexes
(the reaction with [PtCl,(en)] and other cisplatin derivatives
leads to analogous complexes) .[*I The overall reaction can be
described as an oxidative trans addition of a thiourea ligand and
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a chloro ligand. The desired trans addition of two thiourea
ligands was not observed. Consequently the anions in 4 were
exchanged by noncoordinating tetrafluoroborate (BF,) to
avoid an excess of anionic ligands in solution that compete with
L. However, no reaction occurred, even after heating at reflux
for several hours. Thus free chloride in solution must probably
play a role in the mechanism of the oxidative addition (for
details see the legend of Scheme 3).
Complex 5 is unusually acidic in aqueous solution: a 0.01 M
solution has a pH value of 2, which is reached within 10 minutes
after dissolution of the Pt'" complex. A linear relationship was
observed between the p H value and 1gcptIv,which indicates that
independent of the degree of dilution one proton is released per
complex cation. and 5 is thus a strong acid. This hypothesis can
be explained as follows: hydrolysis occurs owing to the labilizing influence of the S donor on the Pt-Cl bond in trans position,
and subsequently the aqua ligand is deprotonated to give a
hydroxo ligand.
In the IR spectrum of 5 the broad stretching bands v,,(NH)
and ~N,~,,,(NH)
of the ammine ligands at i = 3270 and
3010 cm- I , respectively, lie at unusually low wavenumbers.
This observation indicates that hydrogen bonds of the NH-CI
type exist in the solid state. These have previously only been
observed in antitumor complexes of Pt'", in which the N-H
bond is strongly polarized, as confirmed by an X-ray structural
ana1ysis.l" The band of the v,,(CN) stretching vibration of the
thiourea ligand (C = thiocarbonyl carbon) at i = 1586 cm is
shifted to higher wavenumbers by 80 cm- relative to the corresponding band of free 3. This leads to the conclusion that the
ligand coordinates through the sulfur atom, and consequently
the bond order of the C-N bond in the thiourea ligand increases. Three intense vibrational bands in the far-IR spectrum are
assigned as follows: iaS(PtC1)= 341 c m - ' . i,,,(PtCl) =
326 cm for chloride t r a n s to NH,, corresponding to a' and a"
assuming C, symmetry for the complex, and i(PtC1) =
309 cm - for chloride trans to the S-donor ligand.
The 'H N M R spectrum of 5 in [D,]methanol shows, apart
from a singlet for the methyl protons of the thiourea ligand at
S = 3.35, an unusually well-resolved nine-line pattern for the
ammine protons centered at 6 = 5.82 (Fig. 1). This is due to
195Pt- ' H coupling. *f = 48 Hz ("platinum satellites"), and
14N- ' H coupling. ' J = 53 Hz. This latter quadrupole coupling
is observed only in Pt'" complexes.[101Integration of the signals
indicates that the ratio of NH, to CH, protons is 1 : 2 and consequently confirms the presence of only one thiourea ligand in
5. Significant H.D exchange was not observed for the signal of
'
'
for Pt'" complexes with ammine ligands trans to chloro
ligands. This value also points
to the cis influence of the axial
S donor on the 195Pt-14N
coupling.['21 The introduction
of a S-donor ligand, in other
I
words the formal replacement
of a chloro ligand in cis[(NH3),PtC1,]
(hpl = -145
relative to [PtC1,I2 -)["I with a
920
910
900
tetramethylthiourea ligand in
5Pt
5, leads, as expected, to a
Fig. 2. "'Pt('H; N M R 3pectrum
greater shielding of the Pt nuof 5 ( 6 4 M H L [Dalmethanol. ( ' =
cleus and thus to an upfield
~O-'M.
298K. ext. standard
shift Of the 19'Pt resonance.
K2[PtCI,] (aq)) with a scheme of the
The primary target molecule
heteronuclear coupling
in the mechanism of action of
Pt antitumor compounds is
chromosomal DNA.['31 In a model reaction we treated 5 with
5'-guanosine monophosphate (5'-GMP), a simple monomeric
nucleic acid fragment, under physiological conditions. We will
report on the preliminary results of these studies as well as on
current in vivo investigations with 5 on P388 leukemia elsewhere.
(I?
-
Experimental Procedure
The 'H and '"Pt N M R measurements wereconducted on a Bruker WM300 N M R
spectrometer at 300 and 64 MHr respectively; the IR and rar-IR spectra (KBr and
polyethylene pellets, respectively) were recorded on a Bruker IFS 11 3v FT-IR spectrometer.
Synthesis of 5 : To a solution of 0.167g (0.5mmol) 4 [6] in 5 m L anhydrous
methanol was added 0.15 g(0.5 mmol) cisplatin (1) [14]. The suspension was stirred
at room temperature under exclusion of light for 2 h. Diethyl ether was added to
the resultant orange-yellow solution until it became cloudy, and the mixture
was stored for several days in a refrigerator. The resulting orange microcrystalline precipitate W A S filtered oft' and washed with diethyl ether to give 0.176 g
(68%) of 5. The complex crystallized as 5.0.5CH3OH. which was confirmed by
C,H,N analysis.
Received: March 19. 1994 [Z677?1E]
German version: Angew. C h m . 1994, 106. 1701
I
62
6.0
5.6
5.8
6H
A n g m Clwin. I n / . Ed. Engl. 1994. 33. No. 15/16
Fig. 1. ' H N M R signal of
the ammine ligands in 5
(300 MHz. [D,]methanol,
c = 1 0 - ' ~ . 298K, TMS)
with a scheme of the heteronuclear couplings.
C
[ l ] L. R. Kelland, S . J. Clarke, M. J. McKeage. Platinum M p / . Rer. 1992.
36, 178.
[2] V. H. C. Bramwell, D. Crowther, S. O'Malley. R. Swindell, R. Johnson, E.
Creaven, Cuncer Treat. Rep. 1985. 69. 409.
[3] Y . Kido. A. R. Khokhar. Z. H . Siddik, Anti Cuncer Drugs 1993, 4. 251.
[4] L. R. Kelland. G . Abel. M. J. McKeage, M . Jones. P. M Godddrd, M . Valenti.
B. A. Murrer, K . R. Harrdp. Cancer Res. 1993. 53, 2581.
[5] B K. Keppler in Meral Complcws in Cuncer Chemotherupy (Ed.: B. K. Keppler). VCH. Weinheim. 1993. p. 1.
[6] U. Bierbdch, W. Barklage. W. Saak, S. Pohl, %. Nuturforxh. B 1992, 47,
1593.
[7] Systematic name of 5: (OC-6-33)-didmminetrichloro(1.1.3,3-tetrdmethylthiourea-tiS)platinum(rv) chloride.
VCH VL.rlu~.~gP.rellschaft
mbH, 0-69451 Weinheim, 1994
0570-OX33iY4!1515-1633 3 10.00+ .,75:0
1633
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[ X I U. Bierhach. J. Reedijk, unpublished results.
[Y] R. Kuroda. S. Neidle. I. M. Ismail. P. J. Sadlei-. h o r x . ( % m i . 1983. 22. 3620.
[lo] G. Muller. J. Riede. R. Beyerle-Pfnur. B. Lippert. J A m . Clwni. So<,.1984, 106.
7999.
[ I l l S. J. S. Kerricon. P. J. Sadler. J mug^. Rcson. 1978, 3/.321
[12] 1. M. Ismail. P. J. Sadler in Ploiinuin, Goldand Orhw Mrrul ~ / l ~ ~ ~ l l f ~ / / l ~ ~
&!11.s
( A C S Swi?p. Siv. 1983. 209. 171).
[I31 J. Reedijk. Ifforg Chrm. .4rio 1992. 19H-200, 873.
1141 S. C. Dhara. Iniliiiii .1. C'hefii. 1970. K . 193.
~ ~ n l ~ J l ~ l f / ~ i
1 b, M = Hf, Cp' = C5H5
1C. C P ' =
~ Me2Si(lnd)2
Id, C P ' ~= CpH4(lnd)Z
4a - 4d
Scheme 1. Counterion of the complexes 3 and 4 is [B(C,F,),]
Monomer - Dimer Equilibria in Homo- and
Heterodinuclear Cationic Alkylzirconium
Complexes and Their Role in
Polymerization Catalysis**
Manfred Bochmann* and Simon J. Lancaster
Base-free cationic Group 4 metal alkyl complexes of the general formula [Cp,M-R]' (R = alkyl, M = Ti, Zr, Hf) are highly
active catalysts for the polymerization of olefins.[' -'I In conventional homogeneous Ziegler catalyst systems cationic species
of this kind are formed by the reaction of metallocenes with
alkylaluminum activators such as methyIaluminoxane.[". 4. 51
Aluminum-free complexes are best prepared by reacting dialkylated metallocenes [CpZMR2]with triphenylcarbenium salts of
"noncoordinating" anions,[61such as [CPh,][B(C,F,),] (2 in
Scheme 1). It is generally assumed that these reactions lead to
monomeric cationic 14-electron complexes [Eq. (a)] .['I This reaction has found widespread application for the generation o f
cationic polymerization cataIysts.'3. * '1
-
As part of our continuing interest in the characterization of
homogeneous polymerization systems based on cationic alkyl
metal complexes[2.
we have shown recently that monomeric alkyl cations [Cp,ZrR]+ are indeed the only products if
R = CH,Ph. even in the presence of an excess of [Cp,ZrR,],
since the electron deficiency of the metal center is alleviated by
the $-coordination of the benzyl ligand.'', 13' However, we noted earlier in the case of methyltitanium complexes the appearance of a short-lived dimeric intermediate, [(Ind,TiMe),(p-Me)]+ (Ind = indenyl).['0,141 Following the reaction of
methylzirconium and -hafnium complexes with [CPhJ
[B(C,F,),] (2) at low temperature has now shown that the formulation of Equation (a) does not adequately describe the
course of the reaction and that stable dimeric complexes may be
the major products, depending on the reaction conditions.
The reaction of the methyl complexes [Cp;MMe,] ( I a- 1 d)
with 2 at -60°C in CD,CI, led to the formation of dinuclear
methyl-bridged complexes 3 (Scheme 1). The reaction is essentially quantitative. Evidently adduct formation with a neutral
dialkylmetallocene stabilizes the 14-electron cation [CpiMMe]
more effectively than a solvent molecule or anion coordination.
+
[*] Dr. M. Bochmann, S. J. Lancasrer
School of Chemical Sciences. Unkersity of East Anglia
[**I
GB-Norwich N R 4 7TJ ( U K )
Telefix: In[. code + (603)259396
This woi-k was supported by the Science and Engineering Research Council.
We thank Dr. S. Holding (RAPRA Technology Ltd.) for GPC molecular
weight measurements.
1634
3 ' ) VCH Verlugsgesellsrhufi f n h H , 0-69451 Wrifilii+n, 1994
Compounds 3a-[B(C,F5),] and 3b-[B(C,F,),] are obtained
from dichloromethane/hexane mixtures as off-white. very hydrolysis-sensitive needlelike crystals, while the attempted isolation of 3c led to the precipitation of a red oil which could not
be crystallized. For spectroscopic examination the compounds
are generated in situ in CD,C12. Since rac-1 c consists of a mixture of ( R ) and ( S ) enantiomers, the formation of a cationic
dimer results in two diastereomers in a ratio of 2: 1 (Scheme 2).
The cation 3d forms a pair of diastereomers in a ratio of 1.7:1.
2
2
- PhjCMe
rac-1c
0 .a;
%-Me--
Scheme 2 Counterion
3c
g - M e - &
IS [B(Cc,F5)4]-
The stability of the dimers and the rate of reaction with excess
CPh: depends on the nature of the Cp ligands. The reaction of
3a with 2 is essentially complete on warming a solution to
-40 " C ; this gives the monomeric cation 4a.r'51
By contrast, 3c
persists even in the presence of an excess of the triphenylcarbenium salt up to a temperature of about 20°C. Although at
that stage further reaction with 2 does take place, presumably
with formation of 4c, this is quickly followed by decomposition
since 4 c is not stable in chlorinated solvents under these conditions. The cation 3d is slightly less stable than 3c, and conversion to 4d begins already at 0"C.['61 As in the case of 4c, an
unambiguous assignment of the Zr-Me ' H N M R signal of 4d
was not p~ssible.["~The compounds are insufficiently soluble
for N M R studies in toluene.
In the presence of trimethylaluminum the cations
[CpiMMe]' form preferentially the heterodinuclear complexes
[CpiM(p-Me),AlMe,]' (5a-5e) (Scheme 3). The reaction of a
0570-(I#33:94,1515-162'4S 10.00+ , 2 5 0
Angrn. Chem. Inr. Ed. Engl. 1994. 33. No 15/16
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