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Ferrocene-modified thiopyrimidines synthesis enantiomeric resolution antitumor activity.

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Full Paper
Received: 18 February 2010
Revised: 22 April 2010
Accepted: 19 May 2010
Published online in Wiley Online Library: 9 July 2010
(wileyonlinelibrary.com) DOI 10.1002/aoc.1691
Ferrocene-modified thiopyrimidines: synthesis,
enantiomeric resolution, antitumor activity
Alexander A. Simenela∗ , Galina A. Dokuchaevaa , Lubov’ V. Snegura ,
Alexey N. Rodionova , Mikhail M. Ilyina , Svetlana I. Zykovaa ,
Larissa A. Ostrovskayab, Natalia V. Bluchterovab , Margarita M. Fominab
and Valentina A. Rikovab
Ferrocenylalkyl thiopyrimidines (6a–d to 9a–d) were prepared via the reaction of the α-(hydroxy)alkyl ferrocenes, FcCHR(OH)
(1a–d; Fc = ferrocenyl; R = H, Me, Et, Ph), with 2-thiopyrimidines (2–5) in acetone at room temperature in the presence of TFA,
yielding 50–95%. The resulting enantiomers were resolved using HPLC on modified cellulose as chiral selector. The antitumor
activities of S-ferrocenylethyl 2-thiopyrimidine (6b) against two murine solid tumor models, carcinoma 755 (Ca755) and Lewis
lung carcinoma (LLC) were evaluated in vivo. The strong antitumor effect of compound 6b on Ca755 and LLC was demonstrated.
c 2010 John Wiley & Sons,
The index of tumor growth inhibition on Ca755 equaled 95% in comparison with control. Copyright Ltd.
Keywords: synthesis; ferrocene; α-(hydroxy)alkylferrocenes; thiopyrimidines; ferrocenylalkyl thiopyrimidines; enantiomeric resolution;
HPLC; antitumor activity
Introduction
70
Intensive research into novel drugs for chemotherapy for the
treatment of cancer led in the 1960s and 1970s to the
appearance on the pharmaceutical market such well-known drugs
as mercaptopurine, thioguanine and fluorouracil. These drugs
contain in their structures various nucleic bases and have been
classified as substances with antimetabolic activity. During the past
four decades these drugs had been successfully used in clinical
practice.[1] At the same time some negative toxic side-effects of
these drugs were found (mainly hemato- and hepato-toxicities).
Thus, the search for new active, antitumor drugs with lower toxicity
against normal cells and tissues remains one of the most significant
problems of modern antitumor chemotherapy.
It was found that ferrocene units incorporated into some organic
molecules[2,3] or drugs[4] and vitamins[5] significantly decreased
their toxicity. Moreover, the antitumor activities of ferrocenecontaining compounds themselves were extensively studied
in vitro and in vivo.[3,6 – 9] It was demonstrated in experiments in vivo
that ferrocene compounds with heterocyclic systems are effective
against some solid tumors in mice[3,10] and human tumors.[3c]
Ferricenium salts, besides their antiproliferative activity,[11] also
display DNA-cleaving activity[12] and DNA synthesis inhibitory
effect.[13] Recently therapeutic synergism of the antitumor activity
of a combination of ferrocenylmethyl thymine with the wellknown antitumor drug cyclophosphamide against Ca755 was
demonstrated.[10] All these results are important for the further
investigation of ferrocene compounds as prospective drugs for
antitumor polychemotherapy.
The interest in ferrocene-modified purine and pyrimidine
derivatives during the last two decades[14,6d] was caused by the
unique properties displayed by ferrocene, in particular its redox
ability, membrane permeability and low toxicity. The ferrocenyl
units have been successfully introduced into different N-positions
Appl. Organometal. Chem. 2011, 25, 70–75
of the purine and pyrimidine ring systems.[15] Recently we also
synthesized a series of novel ferrocene-modified nucleobases
from nucleobases and ferrocenyl carbinols according to a simple
method using DMSO as a solvent at 100 ◦ C; the significant
antitumor effect of ferrocenylmethyl thymine was evaluated
in vivo.[10]
In this paper we report an approach to thio-derivatives of
pyrimidine ferrocenes (6a–d to 9a–d, Scheme 1). Ferrocenecontaining enantiomers with central chirality were resolved
using HPLC on modified cellulose as chiral selector. The strong
antitumor effects of ferrocenylethyl thiopyrimidine (6b, R = CH3 ,
R1 = R2 = H) were evaluated in experiments in vivo.
Results and Discussion
Synthesis
Ferrocenyl thiopyrimidines (6a–d to 9a–d, Scheme 1) were
obtained via the reaction of the 2-thiopyrimidines with Me, Pr,
Ph and OH groups as substituents, with four different ferrocenyl
carbinols, FcCHR(OH) (Fc = ferrocenyl, C5 H5 FeC5 H4 ; R = H, Me,
Et, Ph) in acetone at room temperature in the presence of
trifluoroacetic acid (TFA) in satisfactory to high yields. Alkylation
∗
Correspondence to: Alexander A. Simenel, A. N. Nesmeyanov Institute of
Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Street,
119991 Moscow, Russian Federation. E-mail: alexsim@ineos.ac.ru
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, Russian Academy of Sciences, 4
Kosigin St, 119991 Moscow, Russian Federation
c 2010 John Wiley & Sons, Ltd.
Copyright Ferrocene-modified thiopyrimidines
R
R2
N
TFA
Fe
OH
+
N
N
Fe
r.t., acetone
S
N
SH
1 a -d
1a R = H
1b R = CH3
1c R = C2H5
1d R = C6H5
R2
R
R1
R1
6 (a-d) - 9(a-d)
2-5
2 R1 = R 2 = H
3 R1 = R2 = CH3
4 R1 = CH3; R2 = C6H5
5 R1 = C3H7;R2 = OH
6a R1 = R2 = H,
7a R1 = R2 = CH3
8a R1 = CH3; R2 = C6H5
9a R1 = C3H7; R2 = OH
yield 74%
95%
92%
50%
Scheme 1. Synthesis of ferrocenylalkyl thiopyrimidines (6a–d to 9a–d) from ferrocenyl carbinols (1a–d) and 2-thiopyrimidines (2–5).
appeared to be regiospecific and S-ferrocenylalkyl thiopyrimidines
were isolated exclusively.
The acid-catalyzed ferrocenylalkylation method for introduction
of ferrocenylalkyl groups into various nucleophilic substrates was
based on the reaction of α-(hydroxy)ferrocenes or ferrocenylalkyl
amines with nucleophiles.[16] The use of equimolar amounts
of strong acids (HBF4 or HClO4 ) or acetic acid allows the
ferrocenylalkylation reaction to be carried out with nitrogencontaining nucleophiles such as azoles.[3b,17] Thiopyrimidines
as nucleophiles are stronger bases than nitrogen-containing
heterocycles and so in this work we used only catalytic
amounts of strong trifluoroacetic acid (TFA) for generation of
ferrocenylcarbenium ions, FcCH(R)+ . The reactions were carried
out in acetone at room temperature with a mole ratio of
ferrocenylcarbinoles (1a–d) and 2-mercaptopirimidines (2–5) of
about 1 : 1 and the products were isolated by filtration. Thus
ferrocenylalkyl thiopyrimidines were synthesized in satisfactory to
high yields (50-95%).
Table 1. Enantiomeric resolution of ferrocenylalky thiopyrimidines
racemic mixtures on column Chiracel OD
Compound
Number
HPLC data
Formula
6b
CH3 N
S
C2H5 N
S
C6H5 N
Enantiomeric Resolution
S
The synthesized twelve ferrocenylalkyl thiopyrimidines (6b–d to
9b–d) contain one asymmetric carbon atom in their structures
and give racemic mixtures of two enantiomers. It is logical
to suppose that the two enantiomers may possess different
biological activities. So we separated the racemic mixtures into
two enantiomers using high-performance liquid chromatography
(HPLC). Earlier, this method of separation was successfully
used for enantiomeric ferrocene compounds with different
simple substituents[18] and ferrocenylalkyl azoles.[17,19] The chiral
sorbents based upon β- and γ -cyclodextrins turned out to be
effective in these cases. To separate mixtures of enantiomeric
ferrocene derivatives having bulky thiopyrimidine substituents
we used modified cellulose as chiral stationary phase. The
enantiomeric resolution analytical data are summarized in Table 1.
We successfully separated the 10 pairs of investigated compounds
6b–d, 7d, 8b–d and 9b–d. Under the conditions applied, there
was no enantiomeric resolution of compounds 7b and 7c. The
recognition mechanism on cellulose is apparently connected,
with formation of specific hydrogen bonds between the strongly
basic nitrogen atom of the corresponding pyrimidine fragments
and carbamate units on the modified cellulose. The introduction
of the hydroxy group into pyrimidine fragments leads to increased
selectivity (see Table 1, for compounds 9b–d α = 1.99, 1.79
and 2.41, respectively). The chromatogram of resolution of
S-(ferrocenylbenzyl)-4-hydroxy-6-propyl-2-thiopyrimidine (9d) is
shown in Fig. 1.
2.89
5.00
1.73
2.79
3.72
1.34
3.75
5.83
1.56
0.76
1.06
0.92
2.03
2.47
1.22
1.68
2.03
1.21
2.11
2.33
1.10
N
Fe
7d
CH3
C6H5 N
S
N
Fe
8b
CH3
C6H5
CH3 N
S
N
Fe
8c
CH3
C6H5
C2H5 N
S
N
Fe
8d
CH3
C6H5
C6H5 N
S
Fe
Antitumor Activity
α
N
Fe
6d
k 2
N
Fe
6c
k 1
N
CH3
Appl. Organometal. Chem. 2011, 25, 70–75
c 2010 John Wiley & Sons, Ltd.
Copyright 71
Antitumor activities of ferrocene-containing compounds are at
this time the subject of intensive investigation by several research
wileyonlinelibrary.com/journal/aoc
A. A. Simenel et al.
Table 1. (Continued)
Compound
Number
HPLC data
k
Formula
9b
OH
k 2
α
1.05
2.10
1.99
0.45
0.80
1.79
1
CH3 N
S
Fe
N
9c
C3H7
OH
C2H5 N
S
Fe
N
9d
C3H7
1.23
OH
2.97
2.41
C6H5 N
S
Fe
N
C3H7
Eluent, hexane–isopropanol 80 : 20 (v/v).
Table 2. The results of antitumor efficiency of S-(ferrocenylethyl)-2thiopyrimidine (6b) on carcinoma 755 and Lewis lung carcinoma solid
tumors in vivo
Daily dose
(mg kg−1 )
20.0
Control
Tumor strains
Carcinoma 755
Lewis lung
(day 14)a
carcinoma (day 22)b
Mean
Tumor
Mean
Tumor
tumor
growth
tumor
growth
weight,
inhibition,
weight,
inhibition,
g
%
g
%
0.50 ± 0.20
8.20 ± 0.60
Figure 1. Chiral chromatographic resolution of S-(ferrocenylbenzyl)-4hydroxy-6-propyl-2-thiopyrimidine (compound 9d). Column, Chiracel
OD, 250 × 4.6 mm, 5 µm. Eluent, hexane–isopropanol, 80 : 20 (v/v),
1.0 ml min−1 . Detector, UV 254 nm.
95
–
3.20 ± 0.50
9.30 ± 0.70
65
–
Solvent, ethanol-water 10 : 90, percentage by volume; drug administration, intraperitoneal.
a Evaluation of the coefficient of tumor growth inhibition (%), day 14
after tumor Ca755 transplantation.
b Evaluation of the coefficient of tumor growth inhibition (%), day 22
after tumor LLC transplantation.
72
groups.[3,6,9,13,20] In 1984 P. Köpf-Maier with colleagues found
antiproliferative effects for ferricenium salts at high doses of
180–300 mg kg−1 against Erlich ascites tumor in mice.[11] At
the same time ferrocene was not active in the range between
20 and 500 mg kg−1 .[11] Later A. Novogrodsky et al. published
results on the antitumor activity of ferrocene.[21] At small daily
doses of 0.05 and 0.20 mg kg−1 the maximal effect of tumor
growth inhibition was achieved on B16 melanoma in mice. At
the same time at higher doses, 1.0 and 5.0 mg kg−1 , the effects
of ferrocene were significantly lower. Such an inverse dose-effect
response was found for ferrocenylmethyl benzimidazole[3b] (Lewis
lung carcinoma, dose 5.0 mg kg−1 , tumor growth inhibition 70%),
o-carboxybenzoylferrocene sodium salt[3d] (carcinoma 755, dose
2.5 mg kg−1 , tumor growth inhibition 70%), feroocenylmethyl
thymine[10] (carcinoma 755, dose 2.5 mg kg−1 , tumor growth
wileyonlinelibrary.com/journal/aoc
inhibition 70%) and the other ferrocene derivatives.[3a] The
anomalies in dose-effect response may be connected to the
increased immunogenicity of the ferrocene derivatives. A large
dose causes enhanced immune response and, as a consequence,
earlier destruction of the compounds.
The antitumor activities of one of the synthesized Fcthiopyrimidines, namely ferrocenylethyl thiopyrimidine (6b), on
two murine solid tumors, carcinoma 755 (Ca755) and Lewis lung
carcinoma (LLC), transplanted in BDF1 mice were evaluated in vivo
in this work. The test dose of 20.0 mg kg−1 was chosen. Tumor
sizes were measured during the whole period of tumor growth.
The index of tumor growth inhibition was calculated at the time
when the antitumor activity of the drug was maximal. This was
after 14 days for carcinoma 755 and after 22 days for LLC. The
results of antitumor effect of compound 6b against the abovementioned murine tumors are summarized in Table 2. As can be
seen from Table 2, a significant antitumor effect of compound 6b
was shown both on carcinoma 755 and Lewis lung carcinoma.
The maximum level of the tumor growth inhibition, 95% as compared with control, was observed on Ca755 after administration
of compound 6b at the dose of 20.0 mg kg−1 day−1 . Moreover
a prolonged effect on Ca755 was found when the level of the
tumor growth inhibition was ≥46% during 13 days after the last
administration of compound 6b.
The antitumor efficiency of the drug against other tested tumor
Lewis lung carcinoma was equal to 65% of the tumor growth
inhibition as compared with controls. As seen from Table 2,
carcinoma Ca755 is considerably more sensitive to compound
6b than LLC.
The acute toxicity of ferrocenylethyl thiopyrimidine (6b) was
characterized by the level of MTD, the maximum tolerated dose,
which was equal to 150 mg kg−1 after compound 6b single
intraperitoneal (i.p.) administration, which allows this compound
to to be categorized as having medium toxicity. The determination
of LD50 turned out to be impossible due to the low solubility of
this compound in water.
Ferrocenylethyl thiopyrimidine (6b) was not effective, as we
found, against murine L1210 and P388 leukemias. The mean
lifespan of treated animals with leukemias was the same as for
controls.
Experimental
Starting Materials and Analytical Instrumentations
The starting ferrocenylmethanol (1a) was obtained from trimethylferrocenylmethylammonium iodide according to a well-known
c 2010 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 70–75
Ferrocene-modified thiopyrimidines
procedure.[22] 1-Ferrocenylethanol (1b), 1-ferrocenylpropanol (1c)
and 1-ferrocenylphenyl methanol (1d) were synthesized from ferrocene by acylation of the corresponding acid chlorides or acid
anhydrides according to the Friedel–Krafts procedure and subsequent reduction with lithium aluminum hydride in diethyl ether or
THF.[23,3b] 2-Thiopyrimidine (2),[24] 4.6-dimethyl-2-thiopyrimidine
(3)[25] and 4-methyl-6-phenyl-2-thiopyrimidine (4)[26] were synthesized from thiourea by standard procedures. 4-Hydroxy-6propyl-2-thiopyrimidine (5) was prepared from thiourea and ethyl
butyrylacetate in methanol in the presence of sodium methoxide
in 57% yield.
1 H NMR spectra were obtained on a Bruker Avance instrument
at 300 MHz. EI mass spectra were taken on a Finnigan Polaris
Q spectrometer at 70 eV. IR spectra were recorded on a UR-20
spectrometer (Karl Zeiss).
Synthesis
4-Hydroxy-6-propyl-2-thiopyrimidine (5)
The mixture of 7.60 g (0.1 mol) thiourea, 15.60 g (0.1 mol) ethyl
butyroacetate and 12.00 g (mol) sodium methoxide were refluxed
in 90 ml methanol for 8 h and then evaporated to dryness. The
residue was dissolved in 100 ml of hot water and filtered. The
filtrate then was treated with 12 ml of acetic acid, the precipitate
was washed with cold water (4×25 ml) and dried. Yield 57%, white
crystals, m.p. 206–208 ◦ C. Anal.: C 48.36; I 6.03; N 16.11; S 18.45%.
Calcd for C7H10N2 OS: C 49.39; I 5.92; N 16.46; O 9.40; S 18.84; Fe
18.00%. 1 H NMR (DMSO-d6 , δ, ppm): 0.99 (t, J = 7.3 Hz, 3H, CH3 );
1.62 (m, 2H, CH2 ); 2.37 (m, 2H, CH2 ); 5.63 (s, 1H, CH); 12.14 (s, 1H,
NH); 12.18 (s, 1H, NH). 13 C NMR (DMSO-d6 , δ, ppm): 13.7 (CH3 ), 21.0
(CH2 ), 33.6 (CH2 ), 103.5 (C-5), 157.1 (C-6), 161.6 (C-4), 176.5 (C-2).
General Procedure
To a solution of ferrocenylcarbinol, FcCHR(OH), (1.0 mmol) and
2-thiopyrimidine (1.0 mmol) in acetone (5.0 ml) two drops of
trifluoroacetic acid were added. The reaction mixture was stirred
overnight until the residue was formed. Then the residue was
filtered, washed with cold ether (2 × 20 ml) and dried in vacuo over
CaCl2 .
S-(Ferrocenylmethyl)-2-thiopyrimidine (6a)
Yield 74%. Orange crystals, m.p. 84–85 ◦ C. Anal.: C 58.09; H 4.60;
N 8.95; S 10.25; Fe 18.4%. Calcd for C15 H14 FeN2 S: C 58.08; H
4.55; N 9.03; S 10.34; Fe 18.00%. EI-MS, m/z (RI, %): 310 (M+ , 29).
IR (KBr, cm−1 ): 3500–3400, 1585, 1405, 1280, 1240–1210, 1120,
1070–1050, 1030, 940, 850, 800, 785–640, 505–430. 1 H NMR
(DMSO-d6 , δ, ppm): 4.13–4.29 (m, 11H, FcCH2 ); 7.17 (t, J = 4.8 Hz,
1H, CH); 8.62 (d, J = 4.8 Hz, 2H, CH). 13 C NMR (DMSO-d6 , δ, ppm):
30.7 (CH2 ), 68.2 (Fc), 69.1 (Fc), 84.6 (Fc), 117.7 (C-5), 158.2 (C-4,6),
171.5 (C-2).
S-(Ferrocenylpropyl)-2-thiopyrimidine (6c)
Yield 43%. Orange crystals, m.p. 64–65 ◦ C. Anal.: C 59.94; H 5.50;
N 8.13; S 9.30; Fe 16.20%. Calcd for C17 H18 FeN2 S: C 60.36; H 5.36;
N 8.28; S 9.48; Fe 16.51%. EI-MS, m/z (RI, %): 324 (M+ , 30). IR
(KBr, cm−1 ): 3550–3400, 2990–2950, 1970, 1585-1570, 1475, 1400,
1270, 1200, 1120, 1080–1050, 1020, 880-870, 845, 835, 770, 640,
510–495. 1 H NMR (DMSO-d6 , δ, ppm): 1.06 (t, J = 7.3 Hz, 3H, CH3 );
2.12 (m, 1H, CH2 ); 2.25 (m, 1H, CH2 ); 4.07–4.28 (m, 9H, Fc); 4.79 (m,
1H, CH); 7.18 (t, J = 4.8 Hz, 1H, CH); 8.62 (d, J = 4.8 Hz, 2H, CH).
13 C NMR (CDCl , δ, ppm): 11.2 (CH ), 29.7 (CH ), 46.1 (CH), 66.3 (Fc),
3
3
2
67.1 (Fc), 68.0 (Fc), 69.0 (Fc), 68.8 (Fc), 90.5 (Fc), 116.3 (C-5), 157.3
(C-4,6), 168.6 (C-2).
S-(Ferrocenylbenzyl)-2-thiopyrimidine (6d)
Yield 83%. Orange crystals, m.p. 116–118 ◦ C. Anal.: C 65.56; H 4.77;
N 7.24; S 8.40; Fe 14.32%. Calcd for C21 H18 FeN2 S: C 65.30; H 4.70;
N 7.25; S 8.30; Fe 14.45%. EI-MS, m/z (RI, %): 386 (M+ , 18). IR (KBr,
cm−1 ): 3580–3520, 3160–3070, 1590, 1460, 1400, 1230–1210,
1120, 1090, 1040, 1020, 980–950, 885–855, 845, 835, 820, 750,
530–490. 1 H NMR (DMSO-d6 , δ, ppm): 4.10–4.20 (m, 9H, Fc); 6.00
(s, 1H, CH); 7.17 (t, J = 4.8 Hz, 1H, CH); 7.22 (t, J = 7.3 Hz, 1H, CH);
7.34 (m, 2H, CH); 7.57 (d, J = 7.3 Hz, 2H, CH); 8.62 (d, J = 4.8 Hz,
2H, CH). 13 C NMR (DMSO-d6 , δ, ppm): 48.9 (CH), 68.1 (Fc), 68.2 (Fc),
68.4 (Fc), 68.6 (Fc), 69.3 (Fc), 89.7 (Fc), 117.8 (C-5), 127.5 (Ph), 128.5
(Ph), 128.6 (Ph), 143.0 (Ph), 158.3 (C-4,6), 170.7 (C-2).
S-(Ferrocenylmethyl)-4,6-dimethyl-2-thiopyrimidine (7a)
Yield 95%. Orange crystals, m.p. 87–88 ◦ C. Anal.: C 60.36; H 5.36;
N 8.28; S 9.48; Fe 16.51%. Calcd for C17 H18 FeN2 S: C 59.10; H 5.32;
N 7.68; S 8.86; Fe 15.9%. EI-MS, m/z (RI, %): 338 (M+ , 27). IR (KBr,
cm−1 ): 3120–2960, 2080, 1600–1560, 1455, 1290–1220, 1125,
1060–1030, 900–865, 845, 780–695, 560, 505, 490–430. 1 H NMR
(DMSO-d6 , δ, ppm): 2.41 (s, 6H, CH3 ); 4.14–4.32 (m, 11H, FcCH2 );
6.98 (s, 1H, CH). 13 C NMR (DMSO-d6 , δ, ppm): 23.9 (CH3 ), 30.5 (CH2 ),
68.1 (Fc), 68.8 (Fc), 69.1 (Fc), 85.1 (Fc), 116.3 (C-5), 167.3 (C-4,6),
170.3 (C-2).
S-(Ferrocenylethyl)-4,6-dimethyl-2-thiopyrimidine (7b)
Yield 65%. Orange oil. Anal.: C 62,60; H 5,64; N 7,69; S 8,76; Fe
15,0%. Calcd for C18 H20 FeN2 S: C 61.36; H 5.68; N 7.95; S 9.09; Fe
15.91%. EI-MS, m/z (RI, %): 352 (M+ , 80). IR (KBr, cm−1 ): 3120,
3000-2950, 1570, 1470, 1390, 1360, 1290, 1210, 1125, 1040, 1000,
970, 910, 870, 845, 830–810, 780–700, 605, 575, 555, 510–450.
1
H NMR (CDCl3 , δ, ppm): 1.85 (d, J = 6.0 Hz, 3H, CH3 ); 2.45 (s, 6H,
CH3 ); 4.17–4.36 (m, 9H, Fc); 4.93 (m, 1H, CH); 6.71 (s, 1H, CH). 13 C
NMR (CDCl3 , δ, ppm): 21.8 (CH3 ), 24.0 (CH3 ), 39.4 (CH), 66.9 (Fc),
67.6 (Fc), 67.7 (Fc), 67.8 (Fc), 68.8 (Fc), 90.4 (Fc), 115.5 (C-5), 166.9
(C-4,6), 171.4 (C-2).
S-(Ferrocenylpropyl)-4,6-dimethyl-2-thiopyrimidine (7c)
S-(Ferrocenylethyl)-2-thiopyrimidine (6b)
Appl. Organometal. Chem. 2011, 25, 70–75
Yield 82%. Orange oil. Anal.: C 62.36; H 6.01; N 7.23; S 9.47; Fe 14.0%.
Calcd for C19 H22 FeN2 S: C 62.30; H 6.05; N 7.65; S 8.75; Fe 15.25%.
EI-MS, m/z (RI, %):366 (M+ , 27). IR (KBr, cm−1 ): 3120, 2990–2960,
2895, 1600, 1560, 1460, 1390, 1355, 1290, 1120, 1050, 1020, 990,
970, 950, 905, 870, 840, 805, 780, 605, 580, 555, 515–495. 1 H NMR
(CDCl3 , δ, ppm): 1.13 (t, J = 6.1 Hz, 3H, CH3 ); 2.03 (m, 1H, CH2 );
2.16 (m, 1H, CH2 ); 2.20 (s, 6H, CH3 ); 4.18–4.32 (m, 9H, Fc); 4.92 (m,
1H, CH); 6.73 (s, 1H, CH). 13 C NMR (CDCl3 , δ, ppm): 11.9 (CH3 ), 23.9
(CH3 ), 29.5 (CH2 ), 46.1 (CH), 67.4 (Fc), 67.5 (Fc), 68.9 (Fc), 90.6 (Fc),
115.4 (C-5), 166.8 (C-4,6), 171.8 (C-2).
c 2010 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
73
Yield 80%. Yellow-orange crystals, m.p. 131–132 ◦ C. Anal.: C 59.21;
H 4.97; N 8.48; S 10.18; Fe 17.20%. Calcd for C16 H16 FeN2 S: C 59.27;
H 4.98; N 8.64; S 9.89; Fe 17.22%. EI-MS, m/z (RI, %): 324 (M+ , 30). IR
(KBr, cm−1 ): 2990, 2115–2080, 1585–1570, 1400, 1205, 1125, 1050,
880, 850, 835, 770–645, 530–455. 1H NMR (DMSO-d6 , δ, ppm): 1.82
(d, J = 6.8 Hz, 3H, CH3 ); 4.17–4.27 (m, 9H, Fc); 4.83 (m, 1H, CH);
7.19 (t, J = 4.8 Hz, 1H, CH); 8.62 (d, J = 4.8 Hz, 2H, CH). 13 C NMR (δ,
ppm): 21.8 (CH3 ), 48.9 (CH), 66.8 (Fc), 68.1 (Fc), 69.1 (Fc), 90.2 (Fc),
117.6 (C-5), 158.3 (C-4,6), 170.8 (C-2).
A. A. Simenel et al.
S-(Ferrocenylbenzyl)-4,6-dimethyl-2-thiopyrimidine (7d)
Yield 68%. Orange crystals, m.p. 119–120 ◦ C. Anal.: C 66.61; H
5.36; N 6.55; S 7.18; Fe 13.20%. Calcd for C23 H22 FeN2 S: C 66.67; H
5.31; N 6.76; S 7.73; Fe 13.53%. EI-MS, m/z (RI, %): 414 (M+ , 16).
IR (KBr, cm−1 ): 3520–3470, 3160–3120, 1970, 1600, 1470–1450,
1360, 1285, 1220, 1120, 1065, 1020, 960, 910, 870, 830, 740, 600,
570, 555, 525, 490, 435–410. 1 H NMR (DMSO-d6 , δ, ppm): 2.40 (s,
6H, CH3 ); 4.12–4.26 (m, 9H, Fc); 5.94 (s, 1H, CH); 6.85 (s, 1H, CH);
7.23 (t, J = 7.1 Hz, 1H, CH); 7.34 (m, 2H, CH); 7.56 (d, J = 7.1 Hz, 2H,
CH). 13 C NMR (DMSO-d6 , δ, ppm): 23.7 (CH3 ), 48.9 (CH), 68.1 (Fc),
68.2 (Fc), 68.4 (Fc), 68.6 (Fc), 69.3 (Fc), 89.6 (Fc), 116.4 (C-5), 127.4
(Ph), 128.3 (Ph), 128.8 (Ph), 143.2 (Ph), 167.3 (C-4,6), 169.6 (C-2).
S-(Ferrocenylmethyl)-4-methyl-6-phenyl-2-thiopyrimidine (8a)
Yield 92%, light-gold powder, m.p. 102–103 ◦ C. Anal.: C 65.03; H
5.13; N 6.89; S 7.89; Fe 13.74%. Calcd for C22 H20 FeN2 S: C 66.01; H
5.04; N 7.00; S 8.01; Fe 13.94%. EI-MS, m/z (RI, %): 400 (M+ , 44).
IR (KBr, cm−1 ): 3240–3100, 1590, 1550, 1470–1420, 1285, 1120,
860–835, 700, 520–458. 1 H NMR (DMSO-d6 , δ, ppm): 3.10 (s, 3H,
CH3 ); 4.08 (s, 2H, CH2 ); 4.20 (s, 5H, Fc); 4.26 (s, 2H, Fc); 4.27 (s, 2H,
Fc); 7.54–7.56 (m, 3H, Ph); 7.57 (s, 1H, CH); 8.19–8.20 (m, 2H, Ph).
13 C NMR (CDCl , δ, ppm): 24.2 (CH ), 30.9 (CH ), 67.7 (Fc), 68.4 (Fc),
3
3
2
68.7 (Fc), 84.5 (Fc), 111.4 (C-5), 127.0 (Ph), 128.7 (Ph), 130.7 (Ph),
136.4 (Ph), 163.3 (C-6), 167.8 (C-4), 171.6 (C-2).
S-(Ferrocenylethyl)-4-methyl-6-phenyl-2-thiopyrimidine (8b)
Yield 85%, orange oil. Anal.: C 65.95; H 5.41; N 6.69; S 7.66; Fe
13.33%. Calcd for C23 H22 FeN2 S: C 66.67; H 5.35; N 6.76; S 7.74; Fe
13.48%. EI MS m/z (RI, %): 414 (M+ , 8). IR (KBr, cm−1 ): 3140–2900,
1590, 1550, 1480, 1340, 1280, 1120, 870–830, 525–490. 1 H NMR
(DMSO, δ, ppm): 1.83 (d, J = 6.5 Hz, 3H, CH3 ); 3.10 (s, 3H, CH3 ); 4.13
(s, 1H, Fc); 4.17 (s, 1H, Fc); 4.22 (s, 5H, Fc); 4.29 (s, 2H, Fc); 4.97 (m,
1H, CH); 7.53–7.55 (m, 3H, Ph); 7.57 (s, 1H, CH); 8.17–8.18 (m, 2H,
Ph). 13 C NMR (CDCl3 , δ, ppm): 21.6 (CH3 ), 24.3 (CH3 ), 39.5 (CH), 66.9
(Fc), 67.5 (Fc), 67.7 (Fc), 67.8 (Fc), 68.7 (Fc), 90.2 (Fc), 111.4 (C-5),
127.0 (Ph), 128.8 (Ph), 130.8 (Ph), 136.6 (Ph), 163.5 (C-6), 167.9 (C-4),
172.0 (C-2).
S-(Ferrocenylpropyl)-4-methyl-6-phenyl-2-thiopyrimidine (8c)
Yield 80%, orange oil. Anal.: C 66.44; H 5.63; N 6.52; S 7.47; Fe
13.01%. Calcd for C24 H24 FeN2 S: C 67.29; H 5.65; N 6.54; S 7.49; Fe
13.04%. EI MS, m/z (RI, %): 428 (M+ , 10). IR (KBr, cm−1 ): 3140–2940,
1590, 1450, 1280, 1120, 850–830, 520–490. 1 H NMR (DMSO-d6 , δ,
ppm): 1.05 (t, J = 7.2 Hz, 3H, CH3 ); 1.95–2.15 (m, 2H, CH2 ); 2.30
(c, 3H, CH3 ); 4.15–4.22 (M, 9H, Fc); 4.81 (m, 1H, CH), 7.50–7.53 (m,
3H, Ph); 7.58 (s, 1H, CH); 8.00–8.04 (M, 2H, Ph). 13 C NMR (CDCl3 , δ,
ppm): 11.2 (CH3 ), 22.8 (CH3 ), 28.5 (CH2 ), 40.4 (CH), 67.4 (Fc), 68.2
(Fc), 68.9 (Fc), 89.1 (Fc), 110.9 (C-5), 127.1 (Ph), 129.0 (Ph), 131.1
(Ph), 136.4 (Ph), 164.1 (C-6), 168.2 (C-4), 172.7 (C-2).
S-(Ferrocenylbenzyl)-4-methyl-6-phenyl-2-thiopyrimidine (8d)
74
Yield 80%, light-red powder, m.p. 128–130 ◦ C. Anal.: C 70.04; H
5.20; N 5.78; S 6.62; Fe 11.53%. Calcd for C28 H24 FeN2 S: C 70.59;
H 5.08; N 5.88; S 6.73; Fe 11.72%. EI-MS, m/z (RI, %): 476 (M+ , 6).
IR (KBr, cm−1 ): 3600–3420, 3220–3080, 1600, 1240–1200, 1120,
860–800, 730, 550. 1 H NMR (DMSO-d6 , δ, ppm.): 2.48 (c, 3H, CH3 );
4.13–4.17 (M, 9H, Fc); 6.06 (c, 1H, CH); 7.22 (m, 1H, Ph); 7.33 (m,
2H, Ph); 7.48 (c, 1H, CH); 7.51–7.53 (m, 3H, Ph); 7.61 (d, J = 7.1 Hz,
wileyonlinelibrary.com/journal/aoc
2H, Ph); 8.00–8.04 (M, 2H, Ph). 13 C NMR (CDCl3 , δ, ppm): 23.6 (CH3 ),
48.5 (CH), 67.5 (Fc), 67.7 (Fc), 68.3 (Fc), 67.6 (Fc), 89.3 (Fc), 111.8
(C-5), 126.9 (Ph), 127.6 (Ph), 128.1 (Ph), 128.5 (Ph), 130.6 (Ph), 136.0
(Ph), 142.4 (Ph), 162.9 (C-6), 167.7 (C-4), 170.1 (C-2).
S-(Ferrocenylmethyl)-4-hydroxy-6-propyl-2-thiopyrimidine (9a)
Yield 50%, yellow crystals, m.p. 129–130 ◦ C. Anal.: C 58.70; H 5.47;
N 7.61; S 8.71; Fe 15.16%. Calcd for C18 H20 FeN2 OS: C 58.29; H
4.46; N 7.73; S 8.79; Fe 15.6%. EI-MS, m/z (RI, %): 368 (M+ , 15).
IR (KBr, cm−1 ): 3150–2900, 1700, 1460–1420, 1240, 1190, 1125,
1070–1050, 1010, 980, 885–830, 780, 600, 520–430. 1 H NMR
(DMSO-d6 , δ, ppm): 1.03 (t, J = 7.3 Hz, 3H, CH3 ); 1.73–1.80 (m, 2H,
CH2 ); 2.24 (m, 2H, CH2 ); 4.20–4.32 (m, 11H, FcCH2); 5.98 (s, 1 H,
CH). 13 C NMR (DMSO-d6 , δ, ppm): 14.0 (CH3 ), 21.1 (CH2 ), 30.3 (CH2 ),
42.4 (CH2 ), 68.3 (Fc), 68.4 (Fc), 69.2 (Fc), 84.6 (Fc), 117.5 (C-5), 147.3
(C-6), 156.3 (C-4); 169.1 (C-2).
S-(Ferrocenylethyl)-4-hydroxy-6-propyl-2-thiopyrimidine (9b)
Yield 52%, orange crystals, m.p. 154 ◦ C. Anal.: C 59.00; H 5.86; N
7.24; S 8.29; Fe 14.44%. Calcd for C19 H22 FeN2 OS: C 59.69; H 5.80;
N 7.33; S 8.39; Fe 14.61%. EI-MS, m/z (%): 382 (M+ , 80%). IR (KBr,
cm−1 ): 3270–3150, 1700, 1560, 1480–1400, 1275, 1120, 895–865,
845–830, 780, 595, 500, 445. 1I NMR (DMSO-d6 , δ, ppm): 1.01 (t,
J = 7.3 Hz, 3H, CH3 ); 1.62 (m, 2H, CH2 ); 1.79 (d, J = 7.3 Hz, 3H,
CH3 ); 2.34 (m, 2H, CH2 ); 4.03–4.44 (m, 9H, Fc); 5.49 (m, 1H, CH); 6.06
(s, 1H, CH). 13 C NMR (DMSO-d6 , δ, ppm): 11.2 (CH3 ), 14.5 (CH3 ), 20.8
(CH2 ), 31.0 (CH2 ), 42.4 (CH), 68.5 (Fc), 69.1 (Fc), 69.7 (Fc), 85.9 (Fc),
118.0 (C-5), 147.4 (C-6), 156.1 (C-4), 170.2 (C-2).
S-(Ferrocenylpropyl)-4-hydroxy-6-propyl-2-thiopyrimidine (9c)
Yield 61%, orange oil. Anal.: C 60.01; H 6.27; N 6.88; S 7.88; Fe
13.72%. Calcd for C20 H24 FeN2 OS: C 60.61; H 6.10; N 7.07; S 8.09;
Fe 14.09%. EI-MS, m/z (RI, %): 396 (M+ , 80%). IR (KBr, cm−1 ):
3190–3080, 2960, 1680, 1585, 1480, 1430, 1360, 1260, 1215, 1020,
985, 905, 840, 770, 565, 550, 495, 425. 1 H NMR (DMSO-d6 , δ, ppm):
0.98 (t, J = 7.3 Hz, 3H, CH3 ); 1.14 (t, J = 5.9 Hz, 3H, CH3 ); 1.67 (m,
2H, CH2 ); 2.14 (m, 1H, CH2 ); 2.27 (m, 1H, CH2 ); 2.38 (m, 2H, CH2 );
4.06–4.22 (m, 9H, Fc); 5.62 (m, 1H, CH); 7.35 (s, 1H, CH). 13 C NMR
(DMSO-d6 , δ, ppm): 10.9 (CH3 ), 21.5 (CH3 ), 22.8 (CH2 ), 28.4 (CH2 ),
31.4 (CH2 ), 36.4 (CH2 ), 42.6 (CH), 68.2 (Fc), 69.7 (Fc), 70.1 (Fc), 86.4
(Fc), 117.5 (C-5), 148.1 (C-6), 157.2 (C-4); 169.9 (C-2).
S-(Ferrocenylbenzyl)-4-hydroxy-6-propyl-2-thiopyrimidine (9d)
Yield 68%, orange crystals, m.p. 112 ◦ C. Anal.: C 63.97; H 5.52; N
6.22; S 7.12; Fe 12.42%. Calcd for C24 H24 FeN2 OS: C 64.86; H 5.44;
N 6.30; S 7.22; Fe 12.57%. EI-MS, m/z (RI, %): 444 (M+ , 8). IR (KBr,
cm−1 ): 3500–3300, 2950–2840, 2120–2070, 1685, 1600, 1515,
1480, 1415–1400, 1330, 1250, 1215, 1100, 1055, 950, 885, 835,
815, 770, 735, 640, 520–495, 445, 435. 1 H NMR (DMSO-d6 , δ, ppm):
1.01 (t, J = 6.6 Hz, 3H, CH3 ); 1.68 (m, 2H, CH2 ); 2.34 (m, 2H, CH2 );
4.03–4.44 (m, 9H, Fc); 6.06 (s, 1H, CH); 6.41 (s, 1H, CH); 7.41–7.48
(m, 5H, Ph). 13 C NMR (DMSO-d6 , δ, ppm): 13.7 (CH3 ), 21.0 (CH2 ),
31.2 (CH), 56.7 (CH), 67.2 (Fc), 67.7 (Fc), 67.8 (Fc), 67.9 (Fc), 69.0 (Fc),
82.0 (Fc), 103.5 (C-5), 127.5 (Ph), 127.9 (Ph), 128.6 (Ph), 142.3 (Ph),
157.1 (C-6), 161.6 (C-4), 176.5 (C-2).
Chromatographic Separation of Enantiomers
A Chiracel OD chiral column (250 × 4.6 mm, 5 µm) was used. The
HPLC system, Bruker LC 31 with a UV 254 detector was operated
at a flow rate of 1.0 ml−1 and ambient temperature.
c 2010 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 70–75
Ferrocene-modified thiopyrimidines
Antitumor Activity Tests
Adenocarcinoma Ca755 and LLC were transplanted subcutaneously with the fragments of tumor tissues to the inbred mice f1
(C57 Bl × DBA2 ), males with weight 18-20g, in accordance with the
standard procedure. The ethanol-water solution (10% by volume)
of compound 6b was administered in daily dose, 20 mg kg−1 ,
intraperitoneally five times every day starting from the next day
after tumor transplantation. Each group comprised five to seven
animals, including the control group of animals.
The kinetics of tumor growth was studied by measurement of
tumor size during the whole period of tumor development. Two
cross-coupling tumor sizes were measured and the volume of the
tumor was calculated as V = ab2 /2, where a is the length and b is
the width and the height of the tumor. As estimated previously,
the density of tumor tissue is equal to 1.0 g cm−3 . Therefore it
is assumed that the weight of tumor in grams is equal to the
volume of tumor in cm3 . The index of tumor growth inhibition
was calculated as (C − T)/C, %, where C and T are the mean tumor
weight in groups of control and treated animals, respectively. The
mean lifespan of treated animals (τexp ) was compared with that of
untreated ones in the control group (τc ) and was expressed as the
ratio τ = (τexp − τc )/τc , %, where τ is the index that characterizes
the increase in mean lifespan of treated mice compared with
controls. The acute toxicity of ferrocenylethyl thiopyrimidine (6b)
was characterized by the level of the MTD after compound 6b
single intraperitoneal (i.p.) administration.
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
Acknowledgments
[15]
This work was supported by the Russian Academy of Sciences
Presidium Programs ‘Fundamental Sciences - for Medicine’ and
‘Support for Young Scientists’, by the Department of Chemistry
and Materials Science (Program ‘Medicinal and Biomolecular
Chemistry’) and by the Russian Foundation for Basic Research
(RFBR no. 09-03-00535). L.V.S. wishes to thank Professor Yu. A.
Belousov for the useful discussions.
[16]
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