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Ferrocenium SaltsЧThe First Antineoplastic Iron Compounds.

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ligand is detected by 'H-NMR spectroscopy (60 MHz) at
high temperature (AA'BB'X-rkX pattern, AG:osOc= 19.1
kO.3 kcal/mol, as estimated from the coalescence of the
methylene
Photolysis of 6 (Philips HPK 125, Pyrex filter, toluene,
- 40°C) leads to 7 in practically quantitative yield. Formation of this isomer can be monitored by the appearance of
a new C p singlet shifted to lower &values. Both the (s-cisq4-butadiene) ligand as well as the n-ally1 moiety can be
assigned by NMR[*]. According to the NMR data and the
'H-NMR-NOE difference spectra, 6 and 7 are principally
different with regard to the arrangement of the allyl and
butadiene moieties relative to the C p group: Both openchain d i g a n d s in 7 open towards the base of the pyramidal framework (Scheme 2)['".91.
Scheme 2.
7 is only observed at sufficiently low temperature. Upon
heating, 6 is re-formed in a smooth reaction. The thermally
induced isomerization 7 + 6 follows a first-order rate law
= 22.1 f0.2 kcal/mol.
with AG $
Reaction of CpZr(allyl)Clz 4 with "butadiene-magnesium" 5 below -30°C features a somewhat different result: even in the dark reaction 7 is formed in addition to 6
(55 :45). Presumably, this reaction proceeds via intermediate Srlol, which under kinetic control is stabilized by
forming both isomers 6 and 7 with an almost equal probability (Scheme 3). It is possible that the thermally induced
isomerization 7 + 6 might also proceed via 8. However,
from the experimental material presented it cannot unequivocally be distinguished between this mechanism of
diene rotation and one involving a ring inversion process[7'
111.
6
8
Ferrocenium SaltsThe First Antineoplastic Iron Compounds**
I
A
I
-400c
Scheme 3
As shown by the example of the isolated complexes 6
and 7 in Scheme 1, a system of isomeric mono(q-cyclopentadienyl)zirconium(n) compounds of a square-pyramidal
structural type has become readily available. These compounds become chiral~"] upon substitution at C1, C2, or
C3 (see Fig. 1). Therefore their use in catalytic C C coupling reactions of the Ziegler-Natta type should be of particular interest.
Received: February 13, 1984 [Z 708 IE]
German version: Angew. Chem. 96 (1984) 445
[I] a) H.-J. Kablitz, R. Kallweit, G. Wilke, J. Organomet. Chem. 44 (1972)
C49; H.-J. Kablitz, G. Wilke, ibid. 51 (1973) 241; L. Stehling, G. Wilke,
456
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
unpublished, cited in G. Wilke, Fundam. Res. Homogen. Catal. 3 (1979)
I ; G . Wilke, J. Organomet. Chem. 200 (1980) 349; b) J. Blenkers, H. J.
deLiefde Meijer, J. Teuben, Keel. Trau. Chim. Pays-Bas 99 (1980) 216; J.
Organomet. Chem. 218 (1981) 383: OrganometaNics 2 (1983) 1483; c) P.
T. Wolczanski, J. E. Bercaw, ibid. I (1982) 793; J. R. Wengrovius, R. R.
Schrock, J . Organomet. Chern. 205 (1981) 319.
[21 G. Erker, K. Berg, L. Treschanke, K. Engel, Inorg. Chem. 21 (1982)
1277.
131 3, 'H-NMR ([D&oluene, -78°C): 6=5.10 (s, 5H, Cp), 2.95 (d, 12H),
5.27 (m, 3 H, allyl dynamic); IR (cyclohexane comp., 7C): v = 1535 (x-allyl), 1595 e m - ' (u-allyl), cf. [ea].
[41 a) E. G. Hoffmann, R. Kallweit, G. Schroth, K. Seevogel, W. Stempfle,
G. Wilke, J. Organomet. Chem. 97(1975) 183; b) K. Fujita, Y. Ohnuma,
H. Yasuda, H. Tani, ibid 11.1 (1976) 201.
151 A. Immirzi, G. Allegra, Acta Cry.sta/logr. B25 (1969) 120; C. Kruger, Y.H. Tsay, J. Organomet. Chem. 33 (1971) 59: D. A. Whiting, Cryst. Struct.
Commun. I (1972) 379; C. van Soest, A. van der Ent, E. C. Royers, ibid.
3 (1973) 527; G . Huttner, D. Neugebauer, A. Razavi, Angew. Chem. 8 7
(1975) 353: Angew. Chem. I n / . Ed. Engl. 14 (1975) 352; S. S. Wreford, J.
F. Whitney, Inorg. Chem. 20 (1981) 3918; J:Z. Liu, R. D. Ernst, J. Am.
Chem. SOC.104 (1982) 3737: R. L. Harlow, P. J. Krusic, R. J. McKinney,
S. S. Wreford, Organometallic,%I (1982) 1506: b) Exceptions: A. N. Nesmeyanov, 1. 1. Kritskaya, J . Organomet. Chem. 14 (1968) 387: A. Bond,
B. Lewis, M. Green, J . Chem. SOC.Dalton Trans. 1975, 1109; H. Yasuda,
K. Mashima, T. Okamota, A. Nakamura, X I . Int. Conf. Organomet.
Chem., Pine Mountain, GA (USA) 1983, Abstr. 79.
[6] G. Erker, K. Engel, U. Dorf, J. L. Atwood, W. E. Hunter, Angew. Chem.
94 (1982) 915; Angew. Chem. Int. Ed. Engl. 21 (1982) 913; Angew. Chem.
Suppl. 1982, 1974; Y . Kai, N . Kanehisd, K. Miki, N. Kasai, K. Mashima,
K. Nagasuna, H. Yasuda, A. Nakamura, Chem. Lett. 1982, 1979; D. J.
Brauer, C. Kriiger, First European Crystallogr. Conf (Bordeaux) 1973,
A 5.
[7] G. Erker, K. Engel, C. Kruger, A.-P. Chiang, Chem. Ber. 115 (1982)
331 1; R. Benn, G. Schroth, J. Organomet. Chem. 228 (1982) 71 ; G. Erker, K. Engel, C. Kruger, G. Muller, Organometalhcs 3 (1984) 128.
[8] 6, 'H-NMR ([D&oluene): h'=6.04 (Cp), -0.67 (HlA), 2.15 (HIS), 5.34
(H2), 1.23 (H3A), 1.81 (H3S), 6.05 (H4); *J(HlA,HlS)= -7.6 Hz,
'J(H2,H2*)= 8.7, 'J(HIS,H2) =9.4, 'J(H IA,H2)= 11.0,
*J(H3A,H3S) = 1.4, 'J(H3S, H4) = 9.1, 'J(H3A,H4) = 14.6; "C-NMR:
6=108.8 (Cp), 45.8 (dd, 143, 154 Hz, CI), 112.5 (d, 160, C2), 56.8 (dd,
160, 146, C3), 125.5 (d, 153, C4). - 7, 'H-NMR ([D,]toluene, -50°C):
&=4.62 (Cp), - 1.57 (HIA), 3.62 (HIS), 5.12 (H2), 0.94 (H3A), 3.26
(H3S), 6.08 (H4); 'J(tIIA,HlS)= -7.4
Hz, 'J(H2,H2*)=9.0,
'J(HIS,H2)=9.6,
'J(HIA,H2)= 14.0,
*J(H3A,H3S)= 1.8
Hz,
'J(H3S,H4)=8.7, 'J(H3A,H4)= 15.8: I3C-NMR: 6=100.2 (Cp), 48.4
(dd, 142, 158 Hz, CI), 99.9 (d, 156, C2), 55.6 (dd, 150, 160 Hz, C3), 117.2
(d, 148, C4).
[9] Cf. W. J. Highcock, R. M. Mills, J. L. Spencer, P. Woodward, I . Chem.
Soc. Chem. Commun. 1982. 128.
[lo] U. Dorf, K. Engel, G. Erker, OrganometaNics 2 (1983) 462.
I l l ] J. W. Faller, A. M. Rosan, J Am. Chem. Soc. 99 (1977) 4858.
[12] K. Berg, G. Erker, J. Organornet. Chem. 263 (1984) 37, and literature
cited therein.
By Petra Kopf-Maier*, Hurtrnut KOpJ and
Eberhard W. Neuse
Dedicated to Professor Ernst Otto Fischer
Metallocene dihalides of d-electron deficient transition
metals such as (q5-C5H5)2MXZ
with M=Ti, V, Nb, MoI'.']
or octahedral complexes such as cis-dihalobis( 1-phenyl1,3-butanedionato)titaniurn(r~)[~~,
for which antineoplastic
activity has previously been detected, are neutral complexes and contain a cis-configurated MXZgroup; they are
[*I Priv.-Doz. Dr. P. Kopf-Maicr
Institut fur Anatomie der Freien Universitat
Konigin-Luise-Strasse 15, D- 1000 Berlin 33
Prof. Dr. H. Kopf
Institut fur Anorganische iind Analytische Chemie der Technischen
Universitat Berlin
Prof. Dr. E. W. Neuse
Department of Chemistry, llniversity of the Witwatersrand
Johannesburg (South African Republic)
[**I This work was supported by the Fonds der Chemischen Industrie.
0570-0833/84/0606-0456 $02.50/0
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 6
capable of releasing two neighboring coordination vacancies at the site of action, and, hence, fulfill structural conditions recognized as essential for cytostatic action and
which are also realized by other inorganic or organometallic c y t o ~ t a t i c s [ ~ . ~ ~ .
In contrast, the ferrocenium salts (q5-C5H5)2Fe@Xe
1 [6*71, with the d-electron richer transition-metal iron as
central atom, represent another type of coordinatively
largely saturated complex in which the cyclopentadienyl ligands are not inclined to each other, but rather are arranged parallel to one another[’]. We have now surprisingly
found that the cation in the salts 1 has antineoplastic activity.
Q
0
I
Fe
X@
l a : Xo=C1,CCOOo .2C13CCOOH[91
l b : Xe=2,4,6-(N0~)3C6HzOQ”’
l c : X Q = FeCbQ[”l
(20,40,60 . .. 500 mg/kg; six animals per dose); the salts,
which are readily soluble in water, were applied i.p. in
physiological saline solution. Twelve control animals received an i.p. injection of 0.5 m L pure saline solution 24 h
after implantation of the tumor cells. The animals were observed for 90 days after tumor transplantation ; evaluation
of the experiment was carried out as described in [41.
All three ferrocenium salts investigated had an inhibiting effect towards Ehrlich ascites tumor and, in optimal
doses, cure 60 to 100%of the animals treated (cf. Fig. 1 and
Table 1; for comparison, cis-(NH3)2PtC12,10 mg/kg: 100%
cure rate14]); in the optimal dose range, the increase in
mean survival time until the key-date is statistically highly
significant (two-sided U-test, after Wilcoxon) relative to
that of the untreated animals ( I 5.3 d). Antineoplastic properties were neither detected for ferrocene (q5-C,H5),Fe 2
itself,
nor
for
the
tetrachloroferrates(II1)
[(CH3)4N]@[FeC141Q
3a and [C6H5CH2(C2H5)3Nl@[FeC14]Q
3b.
Our results permit the following conclusions to be
drawn: 1) Not only metallocenes of the “early”, but also of
“middle” transition elements, such as iron, can effect cytostatic activity. 2) A coordination-gap releasing MX2
group is not absolutely necessary for the realization of antineoplastic properties by metal complexes. 3) For this purpose, the occurrence as a neutral complex is also not a
conditio sine qua non; in contrast, the excellent solubility
of the salts in water, caused by the ionic character of 1,
proves to be propitious for applications in biological systems.
To test the antineoplastic activity, we intraperitoneally
(i.p.) implanted female CFl mice with approximately
6 x lo6 Ehrlich ascites tumor cells. After 24 h, the animals
were administered various doses of l a , l b , or l c
100
100
Received: February 10, 1984;
supplemented: April 9, 1984 [Z 707 IE]
German version: Angew. Chem. 96 (1984) 446
2
u
-s
80
ga
60
60
40
40
20
In
80
m
0
Y
V
4
3
20
0
100
200
-
300
400
500
Dose [mg/kg]
Fig. I . Dose-effect curve ( A - A ) and dose-lethality curve ( A
0 surviving animals o n day 90. LDSoof l a : 400 mg/kg.
~
A ) for
la;
;.
:
1
[ I ] H. Kopf, P. Kopf-Maier, Angew. Chem. 91 (1979) 509; Angew. Chem.
Int. Ed. Engl. 18 (1979) 417.
[2] Review: H. Kopf, P. Kopf-Maier, ACS Symp. Ser. 209 (1983) 315.
[3] H. J. Keller, B. Keppler, D. Schtnihl, J. Cancer Res. Clin. Oncol. 105
(1983) 109.
[4] P. Kopf-Maier, B. Hesse, H. Kopf, .I. Cancer Res. Clin. Oncol. 96 (1980)
43.
[5] M. J. Cleare, J. D. Hoeschele, Rioinorg. Chem. 2 (1973) 187; M. J.
Cleare, P. C. Hydes, B. W. Malerhi, D. M. Watkins, Biochimie 60 (1978)
835; A. J. Crowe, P. J. Smith, G. Atdssi, Chem.-Biol. Interacr. 32 (1980)
171.
[6] E. 0. Fischer, W. Pfah, 2. Nafur/or.vch.E 7 (1952) 377.
[7] G. Wilkinson, M. Rosenblum, M. C . Whiting, R. B. Woodward, J. Am.
Chem. Soc. 74 (1952) 2125.
[8] M. R. Churchill, A. G. Landers, A. L. Rheingold, Inorg. Chem. 20 (1981)
849, and literature cited therein.
[9] D. N. Hendrickson, Y. S. Sohn, 1). M. Duggan, H. B. Gray, J. Chem.
Phys. 58 (1973) 4666.
[lo] A. N. Nesmejanow, E. G . Perewalowa, L. P. Jurjewa, Chem. Ber. 93
(1960) 2729.
Table 1. Pharmacological data for the iron complexes investigated against Ehrlich ascites tumor in mice.
Compound
la
lb
lc
2
3a
3b
Solvent
[dl
S
S
S
P
S
S
Dose range
studied
[mg/kgl
Optimum dose
range (=OD)
[mg/kgl
Cure rate
in the OD
[0/01
Mean survival
time in the OD
I dl
20, 40, . . ., 500
20, 40, ..., 500
20, 40, ..., 500
20, 40, ..., 500
4, 8, 12, 16;
20, 40, . .., 500
4, 8, 12, 16;
20, 40, ..., 500
220-300
220-240
180-200
100
100
61
90
LDso
[mg/kgl
~
~
-
-
400
340
240
440
80
-
-
120
‘)O
65
[a] s = 0.9% NaCl solution (max. 0.4 mL/mouse); p = propylene glycol (max. 0.1 mL/mouse).
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 6
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
0570-0833/84/0606-0457 $02.50/0
451
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