Synthesis, structure and redox potentials of biologically active ferrocenylalkyl azoles

Article abstract of DOI:10.1016/j.jorganchem.2004.05.001

The syntheses, structures, electrochemical properties of the series of ferrocenylalkyl azoles, FcAlkAz, as well as the antitumor activity of ferrocenylmethyl benzimidazole (8) have been studied. Above mentioned compounds were investigated by the method of cyclic voltametry. All of them exhibited a reversible one-electron oxidation-reduction wave owing to the ferrocene-ferrocenium redox couple with a positive shift (0.50-0.65 V) compared with that of ferrocene (0.42 V). The X-ray determination of molecular structures of 1-(ferrocenylmethyl)imidazole (4), 1-(ferrocenylbenzyl)imidazole (7) and 1-(ferrocenylmethyl)bezimidazole (8) was carried out. Compound 4 with imidazolyl substituent was found to be present in N-protonated form. Antitumor activity of 1-(ferrocenylmethyl)benzimidazole (8) against some solid tumor models such as adenocarcinoma 755 (Ca755), melanoma B16 (B16) and Lewis lung carcinoma was studied. The antitumor activity of compound 8 was compared with cisplatin effectiveness against some experimental tumor systems.

Full text of DOI:10.1016/j.jorganchem.2004.05.001

Journal of Organometallic Chemistry 689 (2004) 2473–2479
www.elsevier.com/locate/jorganchem
Synthesis, structure and redox potentials of biologically active
ferrocenylalkyl azoles
a,
a
a
a
Lubovꢀ V. Snegur *, Alexander A. Simenel , Yury S. Nekrasov , Elena A. Morozova
Zoya A. Starikova , Svetlana M. Peregudova , Yuliya V. Kuzmenko
a
a
a
a
Valery N. Babin , Larissa A. Ostrovskaya , Natalia V. Bluchterova ,
b
b
b
Margarita M. Fomina
a
A.N. Nesmeyanov Institute of OrganoElement Compounds, Russian Academy of Sciences, 28 Vavilov St., 119991 Moscow, Russian Federation
b
N.M. Emanuel Institute of Biochemical Physics, 4 Kosigina St., 119991 Moscow, Russian Federation
Received 26 March 2004; accepted 2 May 2004
Abstract
The syntheses, structures, electrochemical properties of the series of ferrocenylalkyl azoles, FcAlkAz, as well as the antitumor
activity of ferrocenylmethyl benzimidazole (8) have been studied. Above mentioned compounds were investigated by the method
of cyclic voltametry. All of them exhibited a reversible one-electron oxidation–reduction wave owing to the ferrocene–ferrocenium
redox couple with a positive shift (0.50–0.65 V) compared with that of ferrocene (0.42 V). The X-ray determination of molecular
structures of 1-(ferrocenylmethyl)imidazole (4), 1-(ferrocenylbenzyl)imidazole (7) and 1-(ferrocenylmethyl)bezimidazole (8) was car-
ried out. Compound 4 with imidazolyl substituent was found to be present in N-protonated form. Antitumor activity of 1-(ferroce-
nylmethyl)benzimidazole (8) against some solid tumor models such as adenocarcinoma 755 (Ca755), melanoma B16 (B16) and
Lewis lung carcinoma was studied. The antitumor activity of compound 8 was compared with cisplatin effectiveness against some
experimental tumor systems.
ꢀ 2004 Elsevier B.V. All rights reserved.
Keywords: Ferrocenylalkyl azoles; Ferrocene derivatives; Electrochemistry (cyclic voltametry); X-ray crystal structure; Antitumor activity; Exper-
imental tumor systems
1. Introduction
and what target organs and cell structures are affected
by the compounds.
The modern investigation of biologically active com-
pounds involves the study of their pharmacokinetics and
mechanisms of action that may be responsible for the
specific pharmacological effects of tested subjects. This
requires the knowledge of what occurs in the first stages
of interaction of the compounds with biological objects
The study of biological activity of ferrocene com-
pounds began since 1960s [1]. The presence of the iron
atom in the ferrocene molecule defined in the certain ex-
tent the direction of these investigations. The biological-
ly active ferrocene derivatives with the antianaemic
properties were among compounds that attracted the
great attention of various research groups [1–5]. Ferro-
cene compounds with N-heterocycle moieties, ferro-
cenylalkyl azoles, FcAlkAz, are of our current interest
due to their antitumor activity combined with low toxic-
ity [6–9]. While discussing possible mechanisms of
*
Corresponding author. Tel.: +7-095-135-9221; fax: +7-095-135-
5085.
E-mail address: snegur@ineos.ac.ru (L.V. Snegur).
0022-328X/$ - see front matter ꢀ 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.05.001

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L.V. Snegur et al. / Journal of Organometallic Chemistry 689 (2004) 2473–2479
action of these compounds on tumors and metabolic
transformation routes in organisms one can assume
one-electron oxidation of the ferrocene nuclei to the fer-
ricenium forms Fc+(Alk)Az [8]. Actually ferricenium
salts Fc+Xꢀ (Xꢀ =CCl3CO2, C6H2(NO2)3, FeCl4 Æ2CH3-
COOH) were the first compounds in the ferrocene series
that demonstrated antitumor activity [10,11]. These salts
have relatively low reduction potentials [12] suitable for
biological processes to occur. The oxidation potentials
for substituted ferrocene compounds depend to a
marked degree on electron-donating or electron-accept-
ing properties of the lateral substituents and can change
in large range [12]. The value of this potential, we be-
lieve, may serve as a measure of ease of FcAlkAz meta-
bolic transformations in organism. On the other hand,
ferrocenylalkyl azoles as cationoid molecules can be
simply protonated to give positively charged particles
Fc(Alk)AzH+. Thus neutral FcAlkAz can be easily
transformed into the positive particles by means of ei-
ther oxidation of the ferrocene nucleus or protonation
of azole.
Here we report on the synthesis, structures and elec-
trochemical behavior of a series of ferrocenylalkyl az-
oles. The antitumor effect of the compound from these
series, 1-(ferrocenylmethyl)benzimidazole (8), was inves-
tigated in vivo. The oxidation processes are one-elec-
tronic and reversible. The oxidation potential values
for the studied compounds (Eopx ¼ 0:50–0:65 V) are
more positive than that for ferrocene (0.42 V). The re-
duction potentials were determined for complexes 3, 6
only (Table 1). The X-ray structure data for 1-(ferroce-
nylmethyl)imidazole (4), 1-(ferrocenylbenzyl)imidazole
(7) and 1-(ferrocenylmethyl)benzimidazole (8) are pre-
sented (Figs. 2–4. For compound 4 in the crystals only
the N-hydrated forms FcCH2ImÆ0.5H2O were found.
The possible routes of biological conversion of ferro-
cenylalkyl azoles are discussed taking into consideration
the electrochemical and structural data, chemical trans-
formations routes and the results of the antitumor activ-
ity tests.
2. Results and discussion
2.1. Synthesis
Ferrocenylalkyl azoles were synthesized accordingly to
three synthetic approaches (Scheme 1). 1-(a-Ferrocenyl-
ethyl)benzotriazole FcCH(CH3)BTr (3) was prepared
from 1-ferrocenylethanol (2) via the reaction with benzo-
triazole in CH2Cl2 in the presence of 45% aqueous fluo-
roboric acid at room temperature within several minutes
[13–15a]. The molecular structure of compound 3 was de-
termined by Starikova [15b]. Since imidazole is a relative-
ly strong base (basic pKa 7.00) it does not undergo
N-ferrocenylalkylation under the acidic conditions readi-
ly forming a salt ImHÆHBF4 instead [15a]. Therefore fer-
rocenylalkyl imidazoles 4–7 were synthesized by a simple
recently published route excluding acidic conditions from
N,N0-carbonyldiimidazole (CDI, ImC(O)Im) and appro-
priate ferrocenylcarbinoles in boiling CH2Cl2 [16a].
Finally, ferrocenylmethyl benzimidazole FcCH2BIm (8)
was prepared according to a classic method from (ferroce-
nylmethyl)three methylammonium iodide FcCH2N-
(CH3)3I [17a] and benzimidazole [17b] in boiling water
with catalytic amount of potassium hydroxide [17c].
Compound 8 was also prepared by a just published proce-
dure from thionyldibenzimidazole BImS(O)BIm and ferr-
ocenylmethanol in methylene dichloride [16b].
2.2. Electrochemistry
It is well known that ferrocene is easily oxidized to
the ferricenium cation by one-electron oxidants [12].
The redox-potentials for the ferrocene–ferricenium cou-
ple range from 0.3 to 0.4 V. The redox potentials for fer-
rocene derivatives change within wider limits. The
potential depends on the electron-donating or electron-
withdrawing ability of the substituents. Thus, the redox
properties can be rather strongly affected by altering the
substituent nature.
Table 1 gives the electrode potentials for ferro-
cenylalkyl azoles and the related compounds, namely,
1-(ferrocenylmethyl)imidazole and 1-(ferrocenylmeth-
yl)benzimidazole in which the ferrocenyl moiety is con-
nected to 1-N atom of the azole ring via a methylene
bridge (compounds 4, 8) or substituted methylene ones:
Me (compounds 3, 5), n-Pr (compound 6) and Ph (com-
pound 7). All the compounds exhibit reversible one-elec-
tron waves. The electrode potentials for compounds 3–8
(0.52, 0.53, 0.56, 0.65, 0.53, and 0.50 V accordingly)
showed a positive shift compared to that of ferrocene
(0.42 V) indicative of the electron withdrawing effect
of the N-heterocycle. The introduction of alkyl groups
decreases potential. As to compounds 5 the slight in-
crease of potential compared to that for compound 4
may be attributed to the different alkyl bridge. In con-
trast with value E0 =0.172 V (in ethanol) for ferroce-
Table 1
The redox potentials for ferrocenylalkyl imidazoles and related
compounds
Compound number
Formula
Eopx ðVÞ
Erped ðVÞ
1
2
3
4
5
6
7
8
FcH
0.42
0.42
0.52
0.53
0.56
0.65
0.53
0.50
–
FcCH(CH3)OH
FcCH(CH3)BTr
FcCH2Im
–
ꢀ2.43
–
FcC(CH3)2Im
FcCH(C3H7)Im
FcCH(C6H5)Im
FcCH2BIm
–
ꢀ2.34
In CH3CN solution with 0.1 M [(n-Bu)4N]BF4, c=2·10ꢀ3 M; Fc –
ferrocenyl, BTr – benzotriazolyl (C6H4N3), Im – imidazolyl (C3H3N2),
BIm – benzimidazolyl (C7H5N2).

L.V. Snegur et al. / Journal of Organometallic Chemistry 689 (2004) 2473–2479
2475
N
R1
R2
N
N
N
N
N
H
Fe
Fe
N
R1
R2
R1
R2
ii
X
N
N
N
H
3
Fe
Fe
CDI
iii
i
R1
R2
N
N
8
i: H2O, KOH, 1000C, X = N(Me)3, R1 = R2 = H 8
ii: HBF4, H2O, CH2Cl2, X = OH, R1 = H, R2 = CH3
iii: CH2Cl2, 400C, X = OH, R1 = R2 = H 4
4 - 7
3
R1 = R2 = CH3
1 = H, R2 = C3H7
5
6
R
R1 = H, R2 = Ph 7
Scheme 1.
nylbutanoic acide Fc(CH2)3CO2H earlier reported by
Professor Neuse [18,19], the oxidation potential for
compound 6 with the imidazolyl fragment connected
ferrocene by the CH-group bearing n-propyl substituent
is significantly harder and amounts to 0.65 V. This fact
is obviously connected with the intramolecular interac-
tion between the C3H7-function and the iron atom.
However, the presence of the condensed benzene rings
in the benzotriazole derivative 3 (E0 =0.52 V) and benz-
imidazole one 8 (E0 =0.50 V) results in the minimum
electron withdrawal from the ferrocenyl groups. A sim-
ilar electrode potential of +0.53 V was obtained for
compound 7. Complex 8 (E0 =0.50 V) is more easily ox-
idized than all the complexes investigated (see Fig. 1).
The same substitution site was found in both the corre-
sponding ferrocenylbenzyl derivative 7, and ferroce-
nylmethyl benzimidazole (8) (Figs. 3 and 4).
The 1N-ferrocenylalkyl substituted molecules in all
three crystal structures 4, 7 and 8 are very similar with
respect to geometrical characteristics of both imidazole
and ferrocenyl moieties. In all three cases the Cp-rings
of ferrocenyl group are in the eclipsed conformations
(Table 2). The dihedral angles between the imidazole
planes and Cp-rings are equal to 111.0ꢁ, 108.5ꢁ and
115.5ꢁ for molecules 4, 7 and 8, respectively. The steric
effects associated with the presence of the phenyl substi-
tuent at the C(6) atom cause slight changes in the bond
angles C(1)–C(6)–N(1), that is minimal for 7.
The heterocycle-ferrocenyl bonds are realized by
means of the triad of atoms: N(heterocycle)–
C(bridge)–C(ferrocenyl). The exocyclic bonds N(1)–
C(6) in molecules 4 and 7 exceed the standard statistical
2.3. Structures of ferrocenylmethyl imidazole (4), ferr-
ocenylbenzyl imidazole (7) and ferrocenylmethyl benz-
imidazole (8)
3
˚
value (1.469 A) for any bond between C(sp ) and a
FcCH2Im (4) is formed as a result of the substitution
of the N-bonded hydrogen atom in the 1N-position of
imidazole by the ferrocenylmethyl fragment (Fig. 2).
three-coordinated nitrogen atom [20]. The variation of
bond lengths N(heterocycle)–C(bridge) correlates with
electronic properties of heterocycles and its substituents
Fig. 1. Cyclic voltamogramms of ferrocenylbutyl imidazole (6) (c=2·10ꢀ3 M, with [(n-Bu)4N]BF4 in acetonitrile and glassy carbon electrode; the
scan rate was 200 mVsꢀ1).

2476
L.V. Snegur et al. / Journal of Organometallic Chemistry 689 (2004) 2473–2479
Fig. 4. Molecular structure of ferrocenylmethyl benzimidazole (8).
˚
Fig. 2. Molecular structure of ferrocenylmethyl imidazole (4). Selected
˚
Selected bond lengths (A) and bond angles (ꢁ): C(1)–C(6)=1.506(10),
bond lengths (A) and bond angles (ꢁ): C(1)–C(6)=1.500(4), C(6)–N(1)=
C(6)–N(1)=1.450(11), N(1)–C(7)=1.338(11), N(1)–C(13)=1.394(10);
C(1)–C(6)–N(1)=113.5(6), C(7)–N(1)–C(13)=106.2(9), C(6)–N(1)–
C(7)=128.9(9), C(6)–N(1)–C(13)=124.6(9).
1.474(4), N(1)–C(7)=1.367(4), N(1)–C(9)=1.357(4), N(2)ꢁ ꢁ ꢁH=2.27(4);
C(1)–C(6)–N(1)=111.0(2), C(7)–N(1)–C(9)=106.7(3), C(6)–N(1)–
C(7)=126.3(3), C(6)–N(1)–C(9)=126.6(3).
Table 2
˚
Some bond lengths (A) and selected angles (ꢁ) in 1-(ferrocenylmeth-
yl)imidazole (4), 1-(ferrocenylbenzyl)imidazole (7) and 1-(ferrocenylm-
ethyl)bezimidazole (8)
Compound
FcCH2Im
(4)
FcCH(Ph)Im FcCH2BIm
(7)
(8)
Fe–C(average)
Fe–Cipso
2.026; 2.043 2.030; 2.029
2.027; 2.028
2.021
1.643
2.031
1.637
1.642
2.036
1.652
1.633
4.2
Fe–(center C5H5)
Fe–(center C5H4)
1.629
1.4
113.5(6)
Angle Cp–Cp eclipse 1.0
Angle 111.0(2)
Cpsubstituted–Het
108.6(3)
Cipso–C
C5H4CH(R)–NHet
1.500(4)
1.474(4)
1.498(5)
1.488(4)
1.506(10)
1.450(11)
of the neutral ferrocenylmethyl benzimidazole (8) in
water. The maximal over-come dose (MD) was found
to be 400 mg/kg. The antitumor activity of compound
8 against solid tumors was studied. These in vivo inves-
tigations were carried out with survival tumors of ani-
mals. Adenocarcinoma Ca755, melanoma B16 and
Lewis lung carcinoma (LLC) were used as experimental
models of solid tumors. The tested doses varied in the
interval 5–50 mg/kg. The results are presented in a
graphic form (Fig. 5). It was found (in general) that
complex 8 provided antitumor effectiveness against all
of three tested solid tumors. The inhibition of tumor
growth was shown to be up to 70% (LLC, curve D, dose
5 mg/kg), which compared with that of cisplatin (posi-
tive control, our data) at the same dose, and also with
the inhibition produced by 8 upon Ca755 at the dose
of 50 mg/kg (curve B).
Fig. 3. Molecular structure of ferrocenylbenzyl imidazole (7). Selected
˚
bond lengths (A) and bond angles (ꢁ): C(1)–C(6)=1.499(5), C(6)–
N(1)=1.487(4), C(6)–C(10)=1.521(5), N(1)–C(7)=1.356(5), N(1)–
C(9)=1.360(5); C(1)–C(6)–N(1)=108.5(3), C(1)–C(6)–C(10)=115.8(3),
N(1)–C(6)–C(10)=109.6(3), C(7)–N(1)–C(9)=105.7(3), C(6)–N(1)–
C(7)=124.8(3), C(6)–N(1)–C(9)=129.1(3).
(see also X-ray studies of ferrocenylalkyl nucleobases
[21,22]). The bond lengths C(bridge)–C(ferrocenyl) for
compounds 4, 7 and 8 are virtually similar (Table 2).
The other nitrogen atom (of pyridine type) in the im-
idazole nucleus, being a potential hydrogen acceptor, ei-
ther does not participate in hydrogen bonding at all
(compounds 7 and 8) or forms the H-bond with water
molecule (compound 4).
2.4. Antitumor activity of 1-(ferrocenylmethyl)benzimid-
azole (8)
With respect to carcinoma 755 (curve B), compound
8 exhibited the approximately direct doze-efficiency de-
pendence. As to the B16 and LLC tumors, the curves
have a maximum and a minimum accordingly (doses
25 mg/kg) and are symmetrically disposed towards the
horizontal axis, the maximum effectiveness being 60%
Preliminary investigations showed the low toxicity of
such type of ferrocene compounds as 8 [7]. LD50 proved
to be impossible to determine due to the small solubility

L.V. Snegur et al. / Journal of Organometallic Chemistry 689 (2004) 2473–2479
2477
(C6H5)OH were prepared by acylation of ferrocene with
corresponding acid chlorides [23] followed by reduction
of the acyl derivatives with lithium aluminium hydride
in diethyl ether [24,15a]. Dimethylferrocenylcarbinol
FcC(CH3)2OH was synthesized by the reaction of ferro-
cene with acetone in the presence of 95% sulfuric acid
[25]. Ferrocenylethyl benzotriazole FcCH(CH3)BTr (3)
was obtained by the reaction of 1-ferrocenylethanol (2)
with benzotriazole in methylene dichloride in the pres-
ence of 45% fluoroboric acid at r.t. for several minutes
[15]. Ferrocenylalkyl imidazoles 4–7 were synthesized
from carbonyldiimidazole (CDI, ImC(O)Im) and appro-
priate a-ferrocenylcarbinols [16]. Ferrocenylmethyl
benzimidazole FcCH2BIm (8) was prepared both from
B
C
D
70
60
50
40
30
20
10
0
0
10
20
30
40
50
(ferrocenylmethyl)threemethylammonium
iodide
Dose, mg/kg
FcCH2N(CH3)3I and benzimidazole in boiling water
[17c] and thionyldibenzimidazole and ferrocenylmetha-
nol in methylene dichloride [16c].
Fig. 5. Dose–antitumor effect of ferrocenylmethyl benzimidazole
FcCH2BIm (8) against adenocarcinoma 755 (curve B), melanoma
B16 (curve C) and Lewis lung carcinoma (curve D) on the 15th day
after treatment.
a-Ferrocenylethyl benzotriazole (3). Yield: 93%. Yel-
low crystals, m.p. 131–132 ꢁC. Anal. C, 65.74; H, 5.24;
Fe, 16.56; N, 12.06%. Calc. for C18H17FeN3: C, 65.28;
H, 5.17; Fe, 16.86; N, 12.69%. EI-MS, m/z: 331 (relative
intensity 100%) [M+]; 303 [M–N2]+; 238 [M–N2–Cp]+;
B
C
D
1
213 [M–C6H4N3]+; 165.5 [M]2+. H NMR (acetone-d6,
d, ppm): 1.31 (d, 3H, CH3); 4,19 (s, 2H, C5H4); 4.23
(s, 5H, C5H5); 4.43 (s, 2H, C5H4); 5.60 (s, 2H, CH2);
7.33–8.00 (m, 4H, Ph). IR (KBr, m, cmꢀ1): 3090, 2985,
2950, 1500, 1460, 1381, 1320, 1276, 1240, 1170, 1150,
1109, 1008, 994, 825.
Ferrocenylmethyl imidazole (4) [16c]. Yield: 80%. Yel-
low crystals, m.p. 65 ꢁC, EI-MS m/z: 266 (100%) [M+].
Ferrocenyl-iso-propyl imidazole (5) [16c]. Yield: 80%.
Yellow crystals, m.p. 104–105 ꢁC, EI-MS m/z: 294
(23%) [M+].
40
20
0
0
10
20
30
40
50
Daily dose, mg/kg
-20
-40
Ferrocenylbutyl imidazole (6) [16c]. Yield: 78%. Dark
brown oil, EI-MS m/z: 308 (100%) [M+].
Fig. 6. Dependence of the life span (% to control) of tumor-bearing
mice with adenocarcinoma 755 (B) melanome B16 (C) and Lewis lung
carcinome (D) from the daily dose of ferrocenylmethyl benzimidazole
FcCH2BIm (8).
Ferrocenylbenzyl imidazole (7) [16c]. Yield: 82%.
Yellow crystals, m.p. 91–92 ꢁC, EI-MS m/z: 342 (75%)
[M+].
Ferrocenylmethyl benzimidazole (8) [17c]. Yield: 73%.
Yellow crystals, m.p. 129–129.5 ꢁC (from hexane), m.p.
119–122 ꢁC [17b]. Anal. C, 68.41; H, 5.11; Fe, 17.68;
N, 8.91%. Calc. for C18H16FeN2: C, 68.38; H, 5.10; Fe,
17.66; N, 8.86%. EI-MS, m/z: 316 [M+]; 199 [FcCH2]+;
195 [C5H4CH2BIm]+; 186 [FcH]+; 121 [FeCp]+; 118
(B16, dose 25 mg/kg,) and 70% (LLC, dose 5 mg/kg), re-
spectively.
The life span of mice with Ca755 and B16 melanoma,
treated with FcCH2BIm increased in compare to control
(Fig. 6). It is note worthy, that compound 8 showed di-
minishing the life span of animals with LLC.
1
[BzImH]+; 78 [C5H4CH2]+; 65[Cp]+; 56 [Fe]+. H NMR
(C6H6, d, ppm): 3.71–3.95 (m, 9H, 2Cp); 4,30 (c, 2H,
CH2); 7.10–7.37 (m, 2H, Ph); 7.65 (c, H, Im); 8.13 (m,
2H, Ph). IR (KBr, m, cmꢀ1): 3150–3080, 1620, 1500,
1450, 1410, 1385–1520, 1290, 1270, 1240, 1210, 1160,
1110, 1035, 1010, 940, 845, 820, 785, 770, 745.
3. Experimental
3.1. Synthesis
3.2. Electrochemistry
The starting ferrocenylmethanol was obtained from
trimethylferrocenylmethylammonium
Carbinols FcCH(CH3)OH (2), FcCH(C3H7)OH, FcCH
iodide
[17a].
The electrochemical (cyclic voltammetry) measure-
ments were performed on a PI-50-1 potentiostat. The

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L.V. Snegur et al. / Journal of Organometallic Chemistry 689 (2004) 2473–2479
Table 3
Details of crystal structure determinations
FcCH2Im
(4)
FcCH(Ph)Im
(7)
FcCH2BIm
(8)
Formula
C14H14FeN20.5H2O
275.13
C20H18FeN2
342.21
C18H16FeN2
316.18
Formula weight
Crystal growth
Crystal appearance
Crystal size (mm3)
Crystal system
Space group
Hexane–acetone 2:1, r.t.
Orange prism
0.50·0.40·0.25
Tetragonal
P43212
Benzene, r.t.
Pale yellow plate
0.50·0.40·0.20
Monoclinic
P21/c
Hexane–acetone 2:1, +7 ꢁC
Yellow prism
0.35·0.20·0.15
Orthorhombic
P212121
Siemens P3/PC
293
Diffractometer
T (K)
Bruker SMART
140
Siemens P3/PC
293
˚
a (A)
8.9107(8)
8.9107(8)
30.742(4)
90
10.188(3)
10.917(3)
14.489(4)
94.93(2)
1605.5(8)
4
9.427(3)
9.460(4)
16.440(7)
90
˚
b (A)
˚
c (A)
b (ꢁ)
3
˚
V (A )
2440.9(4)
8
1.497
1466(1)
4
1.433
Z
Dcalc (gcmꢀ3
l (mmꢀ1
Absorption correction
Tmin/Tmax
)
1.416
0.939
)
1.218
1.022
None
SADABS
None
0.410/0.746
1144
58
–
712
–
656
F(000)
hmax (ꢁ)
50
3031
54
1773
Number of reflections
Independent reflections
Rint
18906
3218
2795
0.0428
208
1731
0.0446
254
0.0557
163
Number of parameters
R1 (I>2r(I))
wR2
0.0515 (2517)
0.1298
0.992
0.0493 (1969)
0.1220
1.035
0.00658 (622)
0.1139
0.808
Goodness-of-fit
ꢀ3
˚
Dqmax, Dqmin (e A
)
1.503/ꢀ0.317
0.414/ꢀ0.248
0.290/ꢀ0.257
working electrode was a glassy carbon disk (s=2 mm),
the auxiliary electrode was a platinum plate. All the po-
tential values are referred to the Saturated Calomel
Electrode (SCE). The experiments were carried out at
c=2·10ꢀ3 M under argon in deoxygenated acetonitrile
solution containing 0.1 M [(n-Bu)4N]BF4, as a support-
The structure was solved by direct method and re-
fined by the full-matrix last-squares technique for non-
hydrogen atoms in the anisotropic approximation. All
H atoms (except the H(N) and H(Ow) atoms) were
placed in the geometrically calculated positions and in-
cluded in the refinement using the riding model approx-
imation with the Uiso(H)=1.2Ueq(C) for the methylene
and Uiso(H)=1.5Ueq(C) for methylene and methyl
groups, where the Ueq(C) is the equivalent isotropic tem-
perature factor of the carbon atom bonded to the corre-
sponding H atom. All calculations were carried out on
IBM PC with the help of SHELXTL program [28].
ing electrolyte. The scan rate was 0.2 Vsꢀ1
.
3.3. Structures
Crystal data for compounds 4, 7 and 8 are in Table 3.
Single-crystal X-ray diffraction experiment for ferroce-
nylmethyl imidazole (4) was carried out with a Bruker
SMART 1000 CCD area detector, using graphite mono-
chromated Mo Ka radiation (x-scans with a 0.3ꢁ step
in x and 10 s per frame exposure) at 140 K. Low tem-
perature of the crystals was maintained with a Cryo-
stream (Oxford Cryosystems) open-flow N2 gas
cryostat. Reflection intensities were integrated using
SAINT software [26] and semi-empirical method SADABS
[27]. X-ray diffraction experiments for ferrocenylbenzyl
imidazole (7) and 1-ferrocenylmethyl benzimidazole (8)
were carried out with a Siemens P3/PC diffractometer
(T=293 K, graphite-monochromated Mo Ka radia-
tion), no absorption correction was applied.
3.4. Antitumor activity tests
Adenocarcinoma Ca755, melanoma B16, Lewis lung
carcinoma were transplanted subcutaneously with the
fragments of tumor tissues to the inbred mice
f1(C57Bl·DBA2), males with the weight 18–20 g. The
were some groups of treated animals as well as the group
of mice served as a control one, and the other one as a
positive control (cisplatin). All groups comprised 5–7
animals each. Oil solutions of the ferrocenylmethyl
benzimidazole (8) were given orally to the each group
of treated animals beginning from the next day after

L.V. Snegur et al. / Journal of Organometallic Chemistry 689 (2004) 2473–2479
2479
transplantation of the tumors. The index of tumor
growth inhibition was calculated as (CꢀT)/C, %, where
C and T – the average sizes of tumors in groups of con-
trol and treated animals, respectively. The mean survival
time of the treated animals (T) was compared with that
of untreated ones (C) and was expressed as the ratio
(TꢀC)/C, %.
[9] (a) L.V. Snegur, V.N. Babin, N.V. Polyakova, V.I. Boev, A.F.
Kolomiets, Yu.S. Nekrasov, K.G. Shitkov, A.A. Pankratov, N.B.
Morozova, A.I. Ilyina, Russian Federation Patent 2089507, 1996;
(b) K.G. Shitkov, L.V. Snegur, N.B. Morozova, A.I. Ilyina, V.N.
Babin, V.I. Borisov, I.G. Rusakov, A.E. Snegireva, N.P. Boro-
dina, G.M. Shaposhnikova, Russian Federation Patent 2098096,
1993.
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446;
Angew. Chem. Int. Ed. 23 (1984) 456.
[11] P. Kopf-Maier, H. Kopf, E.W. Neuse, J. Cancer Res. Clin. Oncol.
108 (1984) 336.
4. Supplementary material
[12] A.J. Deeming, in: G. Wilkinson, F.G.A. Stone, E.W. Abel (Eds.),
Comprehensive Organometallic Chemistry, Pergamon Press, 1982,
p. 481.
Crystallographic data and refinement parameters for
all compounds (4, 7 and 8) are presented in the Table 3.
Atomic coordinates are available from the Cambridge
Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK, deposition numbers:
CCDC-232572, CCDC-232573, and CCDC-232574,
respectively.
[13] L.V. Snegur, V.I. Boev, V.N. Babin, M.Kh. Dzhafarov, A.S.
Batsanov, Yu.S. Nekrasov, Yu.T. Struchkov, Russ. Chem. Bull.
(1995) 554.
[14] N.S. Kochetkova, V.I. Boev, L.V. Popova, V.N. Babin, Bull.
Acad. Sci. USSR, Div. Chem. Sci. 34 (1985) 1278.
[15] (a) L.V. Snegur, V.I. Boev, Yu.S. Nekrasov, M.M. Ilyin, V.A.
Davankov, Z.A. Starikova, A.I. Yanovsky, A.F. Kolomiets,
V.N. Babin, J. Organomet. Chem. 580 (1999) 26;
(b) L.V. Snegur, V.N. Babin, Yu.S. Nekrasov, Z.A. Starikova,
et al., Appl. Organomet. Chem. (in press).
Acknowledgement
[16] (a) A.A. Simenel, E.A. Morozova, Yu.V. Kuzmenko, L.V.
Snegur, J. Organomet. Chem. 665 (2003) 13;
This work has been partially supported by The Scien-
tific Training Center of Biomedical Chemistry (Grant
No. A0078, the Federal Target Program ‘‘Integration’’).
L.V.S. wish to thank Scientific Research Firm ‘‘Ultra-
san’’ for financial assistance, Mrs. Natalia Polonik for
performing some experiments and Dr. Yu.I. Lyakhovet-
sky for his kind help in editing the manuscript.
(b) V.I. Boev, P.M. Betankourt, L.V. Popova, V.N. Babin;
(c) A.A. Simenel, Yu.V. Kuzmenko, E.A. Morozova, M.M. Ilyin,
I.F. Gunꢀko, L.V. Snegur, J. Organomet. Chem. 688 (2003) 138.
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(b) B. Bildstein, M. Malaun, H. Kopacka, K.-H. Ongania, K.
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