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Simple route to ferrocenylalkyl nucleobases. Antitumor activity in vivo

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Full Paper
Received: 22 December 2008
Revised: 3 March 2009
Accepted: 14 March 2009
Published online in Wiley Interscience: 22 April 2009
(www.interscience.com) DOI 10.1002/aoc.1500
Simple route to ferrocenylalkyl nucleobases.
Antitumor activity in vivo
Alexander A. Simenela∗ , Elena A. Morozovaa, Lubov’ V. Snegura ,
Svetlana I. Zykovaa , Vadim V. Kachalab , Larissa A. Ostrovskayac,
Natalia V. Bluchterovac and Margarita M. Fominac
Ferrocenylalkyl nucleobases (1–14) were prepared via the reaction of the α-(hydroxy)alkyl ferrocenes FcCHR(OH) (Fc =
ferrocenyl; R = H, Me, Et, Ph) with thymine, cytosine, iodo-cytosine and adenine in DMSO at 100 ◦ C, yields being 50–80%.
The antitumor activities of ferrocenylmethyl thymine (1) against solid tumor models, carcinoma 755 (Ca755) and Lewis lung
carcinoma (LLC) were studied in vivo. Therapeutic synergism of antitumor activity against LLC was demonstrated in the case of
c 2009 John Wiley & Sons, Ltd.
combined application of compound 1 with anticancer drug cyclophosphamide. Copyright Keywords: synthesis; ferrocene; α-(hydroxy)alkylferrocenes; nucleobases; adenine; thymine; cytosine; antitumor activity
Introduction
Appl. Organometal. Chem. 2009 , 23, 219–224
Results and Discussion
Synthesis
α-Ferrocenylcarbinols FcCH(R)OH (R = H, Me, Et, Ph) with alkyl
and aryl substituents were used as initial ferrocene compounds.
These alcohols are synthetically accessible compounds and can be
prepared from ferrocene by reduction of its acyl derivatives.[16] The
compounds are stable in air for a long time, under acidic conditions
they form the corresponding ferrocenyl carbenium ions FcCH(R)+ .
The alcohols, ferrocenylmethanol[17] and 1-ferrocenylethanol, are
widely used for introducing ferrocenyl-methyl and -ethyl groups
∗
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. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47
Leninsky Ave, 119991 Moscow, Russian Federation
c N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 4
Kosigin St, 119991 Moscow, Russian Federation
c 2009 John Wiley & Sons, Ltd.
Copyright 219
Iron-containing organometallic compounds, ferrocenes, play an
important role in biological processes exhibiting antianemic,[1]
antiseptic[2] and antitumor[3] activities. Studies of their interaction
with biomolecular targets are significant for the understanding of biological activity mechanisms[4] and for the development of novel drugs.[5] In several reviews DNA is considered
as the probable primary cellular target.[3,6] In this connection, interest in ferrocene-modified DNA,[7] RNA[8] and their
components – nucleobases,[9] nucleosides,[10] nucleotides[11] and
oligonucleotides[11] – has increased in the past 10 years.[12]
The first ferrocene derivatives of nucleobases, 9Nferrocenylmethyl adenine and N6 -ferrocenylmethyl adenine, were
synthesized by S.-C. Chen.[13] In the 1990s ferrocene-modified nucleosides were described.[14] X-ray investigations of a number of
ferrocenyl-methylated adenine, thymine, cytosine and substituted
purines were carried out by A. Houlton and co-workers,[9b,d,e] and
Z.A. Starikova and co-workers.[9a,c] In a recently published paper[15]
ferrocenylmethylated thymidine monophosphate, deoxycytidine
monophosphate, adenine and uridine ferrocene derivatives were
synthesized under conditions close to physiological ones (in water). However, the existent routes of ferrocene-modification of
nucleobases led to the final products in rather low yields, not
exceeding 30–40%. In some cases, the reactions are multistaged,
or require reagents protected by special groups.
In this paper a simple and suitable method is described for the
introduction of ferrocenylalkyl units into nucleobases: adenine,
thymine, cytosine and 5-iodo-cytosine. Equimolar amounts of ferrocenylcarbinols, FcCHR(OH), and nucleobases in DMSO are heated
at 100 ◦ C for 30–40 min. After extraction and column chromatography ferrocenylalkyl nucleobases (with methyl, ethyl or benzyl
bridges) were prepared in 50–82% yields. It is significant that
the process is selective, yielding mono-N-substituted nucleobases
only. Moreover, the reactions with ferrocene carbinoles, viz. ferrocenylmethanol FcCH2 OH, ferrocenylethanol FcCH(CH3 )OH, ferrocenylpropanol FcCH(CH2 CH3 )OH and ferrocenylphenyl methanol
FcCH(Ph)OH, allow the introduction of both the ferrocenyl moiety
and alkyl bridges into the molecules of nucleobases. As a result,
the lipophilicities of the final ferrocenylalkyl nucleobases can be
changed.
The antitumor activities of 1N-ferrocenylmethyl thymine (1)
against some animal tumor systems such as carcinoma 755
(Ca755), melanoma B16 (B16) and Lewis lung carcinoma (LLC)
were studied in vivo. The strong antitumor effect of this drug
against carcinoma 755 was shown. The coefficient of tumor growth
inhibition equaled 70% in comparison with control. Therapeutic
synergism of antitumor activity of combination of compound 1
with the well-known antitumor drug cyclophosphamide against
carcinoma 755 was demonstrated.
A. A. Simenel et al.
Figure 1. Ferrocene derivatives of thymine (1–4), adenine (5–8), cytosine (9 and 10) and iodo-cytosine (11–14).
Figure 2. Fragment of HMBC spectra of 1N-ferrocenylphenyl-5-iodocytosine (14).
220
into various nucleophilic substrates.[18] Previously, ferrocenylmethyl adenine (5) and ferrocenylethyl adenine (6) were obtained
via the reaction of the corresponding alcohols with adenine under acidic conditions, yields being 30 and 40%, respectively.[9a,c]
Adenine, thymine, cytosine and uracil were ferrocene-modified
by ferrocenylmethyltrimethylammonium iodide, FcCH2 N(CH3 )3 I,
as well.[9] Using FcCH2 N(CH3 )3 I as a ferrocenylmethylating agent
in boiling water, ferrocenylmethyl adenine and thymine were
obtained in yields up to 40%. In all these cases, disubstituted derivatives of adenine and thymine, N6 ,9N-bis(ferrocenylmethyl)adenine
and 1N,3N-bis(ferrocenylmethyl)thymine, were obtained as well
(yields 15–20%).
In DMSO solution at 100 ◦ C N-mono-ferrocenylsubstituted
nucleobases 1–14 were obtained in 50–82% yields after purification by column chromatography from the initial carbinols
(Fig. 1). Moreover, an alternative pathway of the synthesis of 1
and 6 is proposed. 1N-(ferrocenylmethyl)thymine (1) and 9N(ferrocenylethyl)adenine (6) were synthesized from sodium salt of
thymine and silver salt of adenine, respectively. The reaction was
carried out regioselectively.
The 1 H NMR spectra of compounds 1–14 in DMSO-d6 shows
several sets of signals assigned, respectively, to the protons of
the substituted and unsubstituted cyclopentadienyl rings, to the
CH(R)-bridge protons and to the protons of the nucleobases and
their substituents. The assignments of the signals of the 13 C NMR
www.interscience.wiley.com/journal/aoc
spectra of Fc-compounds with thymine, adenine, cytosine and
5-iodo-cytosine were based on HSQC spectra.
The structures of compounds were assigned on the basis of
1 H and 13 C NMR spectra and 1 H/13 C heteronuclear correlations.
Particularly in the HMBC spectrum of 1N-ferrocenylphenyl-5iodocytosine (14) (Fig. 2), there are correlations between singlet
at 6.67 ppm attributed to the CH linked to the ferrocene residue,
and C-2 and C-6 carbon atoms of 5-iodocytosine (154.10 and
148.59 ppm respectively) and, vice versa, correlation between
singlet at 7.63 ppm attributed to the C(6)H of the cytosine residue
and CH linkage carbon atom (58.74 ppm).
There are no correlations between proton and carbon atoms of
CH linkage and C(4) atom of 5-iodocytosine; moreover the NOE
experiment exhibited interaction between the H-6 proton of the
pyrimidine base and linkage proton. Thus ferrocenylalkilation
proceeds in 1N-position of cytosine ring. Regioselectivity of
alkylation of the other pyrimidine derivatives was proved in the
same way.
Antitumor Activity Tests
Antitumor effects of ferrocene compounds are well known.[3] The
activities were found for positively charged ferricenium salts,[19,20]
uncharged ferrocene derivatives,[20] potentially anionogenic
Fc-compounds[21] and compounds with negative charge[22] as
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2009, 23, 219–224
Simple route to ferrocenylalkyl nucleobases
Table 1. The results of antitumor activity of 1N-ferrocenylmethyl
thymine (1) on carcinoma 755 and Lewis lung carcinoma solid tumors
in vivo
Tumor strains
Daily dose,
mg kg−1
5.0
2.5
0.8
Control
Carcinoma 755
(12th day)a
Mean
Tumor
tumor
growth
weight (g) inhibition (%)
2.52 ± 0.57
1.26 ± 0.56
2.94 ± 0.20
4.20 ± 0.91
40
70
30
–
Lewis lung
carcinoma (12th day)
Mean
Tumor
tumor
growth
weight (g) inhibition (%)
1.48 ± 0.38
2.16 ± 0.29
–
2.70 ± 0.42
45
20
–
–
Solvent, water–ethanol 90 : 10, percentage by volume; drug administration, intraperitoneal.
a Evaluation of the coefficient of tumor growth inhibition (%), 12th day
after tumor transplantation.
Appl. Organometal. Chem. 2009, 23, 219–224
Compound
Daily dose
(mg kg−1 )
Tumor growth
inhibition (%)a
æ
1 + Cyclophosphamide
1
Cyclophosphamide
5.0 + 20.0
5.0
20.0
50
35
10
0.20
0.11
0.03
Solvents: for compound 1, water–ethanol 90 : 10, percentage by
volume; for cyclophosphamide, water; drug administration, intraperitoneal; æ, kinetic criterion of tumor growth inhibition.
a Coefficient of tumor growth inhibition (%) was evaluated on the 13th
day after tumor transplantation.
of relative rates of tumor growth in groups of treated (ϕT ) and
control animals (ϕC ). As seen from data represented in Table 2, the
synergistic effect of a combination that includes compound 1 and
cyclophosphamide was found. This result is principally important
for the further investigation of ferrrocene compounds as potential
prospective drugs for antitumor polychemotherapy.
The acute toxicity of compound 1 was also studied. It was
established that the meanings of the medium toxic dose (LD50 )
and the maximum tolerated dose (MTD) equaled 40 and 20 mg
kg−1 , respectively, after compound 1 single intraperitoneal
administration. The chemotherapeutic index (TI) for compound
1 was estimated as the ratio between the LD50 and maximum
effective total dose ED70 , as follows: TI = LD50 /ED70 , where ED70 =
daily dose×5 (drug administration, five times every day beginning
from the next day after tumor transplantation). The therapeutic
index was found to be equal to 3.2 (TI = 40/12.5 = 3.2) for mice
with carcinoma 755. For cisplatin, TI = 2.
Ferrocenylmethyl thymine (1) was not effective against experimental test systems L1210 and P388 leukemias. The mean life-span
of treated animals was the same as for controls. The antitumor
activity in vivo of compound 1 on melanoma B16 solid tumor was
not found; the level of the tumor growth inhibition was equal to
controls.
Experimental
1 H and 13 C NMR spectra were obtained on a Bruker Avance-600 at
600.13 MHz and Bruker DRX-500 (A) at 500.13 MHz and 125.76 MHz
for protons and 13 C, respectively, in DMSO-d6 at 30 ◦ C. EI mass
spectra were taken on a Kratos MS-890 spectrometer at 70 eV. IR
spectra were recorded on a UR-20 spectrometer (Karl Zeiss).
Synthesis
Nucleobases were purchased from Acros Organics and used without purification. 1-Ferrocenylethanol, 1-ferrocenylpropanol and
ferrocenylphenyl methanol were synthesized from the corresponding acyl ferrocenes by reduction with lithium aluminum hydride in THF.[16] Ferrocenylmethanol was obtained from trimethylferrocenylmethylammonium iodide according to a well-known
procedure.[17]
As the general procedure, 1.0 mmol of ferrocenylcarbinol was
added to a solution of 1.0 mmol of nucleobase in 25 ml DMSO,
and the mixture was heated at 100 ◦ C with TLC monitoring until
the mass got dark. Then the resulting mass was cooled and 50 ml
water added. After extraction with CHCl3 (3 × 25 ml), the organic
c 2009 John Wiley & Sons, Ltd.
Copyright www.interscience.wiley.com/journal/aoc
221
well. The further development of these investigations included
modification of ferrocene compounds by some cytostatic drugs
and vitamins (sarcolysin,[23] cisplatin,[24] tamoxifen,[5,25] thiamin
and hydroxythiamine[26] ), as well as the synthesis of new original compounds. DNA is considered to be the more probable
cellular target for ferrocene compounds.[3] A radical mechanism
for ferricenium salts[3,27] (note that ferricenium salts are stable
radical cations) and a ‘soft’ ferrocenylalkylation mechanism for
ferrocenylalkyl azoles were suggested.[3b,9d]
The antitumor activity of ferrocenylmethyl thymine (1) on some
solid tumor models such as carcinoma 755 (Ca755) and Lewis lung
carcinoma (LLC) transplanted in BDF1 mice was studied in this
work. The tested doses varied in the interval 0.8–5.0 mg kg−1 .
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 12 days. The results of antitumor effect of compound
1 against the above-mentioned murine tumors are summarized
in Table 1. As seen from Table 1, carcinoma 755 is considerably
more sensitive to compound 1 than Lewis lung carcinoma. This
phenomenon was noted early.[20,22] The maximum level of the
tumor growth inhibition, 70% as compared with controls, was
observed after administration of compound 1 in the dose 2.5 mg
kg−1 . Thus, compound 1 exhibited maximum antitumor effect
(carcinoma 755) at small doses. Such an inverse dose–effect
response was found early for ferrocenylmethyl benzimidazole[20a]
(Lewis lung carcinoma, dose 5.0 mg kg−1 , tumor growth inhibition
70%), ortho-carboxybenzoylferrocene sodium salt[22] (carcinoma
755, dose 2.5 mg kg−1 , tumor growth inhibition 70%) and the other
ferrocene derivatives.[20c] Apparently, the found dose–efficiency
dependence – the achievement of the maximum antitumor effect
after application of the agent in the rather low doses – is typical
for ferrocene compounds of this kind. A preliminary conclusion
can be drawn. 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 effectiveness of combined administration of compound 1
with well-known cytostatic agent cyclophosphamide was studied
in experiments with Lewis lung carcinoma. The kinetic criterion
æ was used for evaluation of tumor growth inhibition activity
of the treatment (Table 2). This criterion allows the comparison
Table 2. Antitumor activity of 1N-ferrocenylmethyl thymine (1) in
combination with cyclophosphamide on Lewis lung carcinoma in vivo
A. A. Simenel et al.
layer was washed with water until the specific odor of DMSO
disappeared, dried over anhydrous magnesium sulfate, and the
solvent removed in vacuo. The solid was chromatographied on a
column with silica gel. Methanol and methylene dichloride were
used as eluents.
1N-(Ferrocenylmethyl)thymine (1)[9b – d]
FcCH2 Thy. Yield 60%. Yellow crystals, m.p. 215 ◦ C with decomposition; m.p. (lit)[9d] 215 ◦ C. EI-MS, m/z: 324 (relative intensity 60%)
[M]+ . C16 H16 FeN2 O2 : calcd C 59.26, H 4.94, Fe 17.28, N 8.64%; anal.
C 59.21, H 4.86, Fe 16.97, N 8.41%. 259 [M − C5 H5 ]+ (40%); 199
[M − Thy] (36%); 126 [ThyH]+ (86%); 121 (FeC5 H5 ) (32%); 56 [Fe]+
(20%). 1 H NMR for 1a (DMSO-d6 , δ, ppm): 1.73, 1.76 (d, J = 7.5 Hz,
3H, CH3 ); 4.06–4.31 (m, 4H, C5 H4 ); 4.20 (s, 5H, C5 H5 ); 4.55 (s, 2H,
CH2 ); 7.55 [s, 1H, C(6)H]; 11.14 (s, 1H, NH). 13 C NMR (δ, ppm): 11.67
(CH3 ); 45.84 (CH2 ); 67.25, 67.91, 68.58, 69.50 (C5 H4 ); 68.25 (C5 H5 );
82.86 [C(C5 H4 )CH2 ], 108.30 (C-5), 140.66 (C-6), 150.46 (C-2), 170.27
(C-4). IR (KBr, ν, cm−1 ): 3259–2840, 2960, 1750, 1700, 1110, 1010,
950, 880, 825, 480.
Variant B
Compound 1 was synthesized from sodium salt of thymine,
Na+ Thy− , and ferrocenylmethanol in methylene dichloride in
the presence of 45% fluoroboric acid as was described for
ferrocenylalkyl benzotriazoles.[20b] Yield 80%, m.p. 215 ◦ C with
decomposition. EI-MS, m/z: 324 [M]+ . C16 H16 FeN2 O2 . Sodium salt
of thymine was prepared from thymine and sodium hydride in
boiling THF.
1N-(Ferrocenylethyl)thymine (2)
FcCH(CH3 )Thy. Yield 55%. Yellow crystals, m.p. 192 ◦ C. EI-MS, m/z:
338 [M]+ . C17 H18 FeN2 O2 . 273 [M − C5 H5 ]+ (15%); 212 [M − Thy]+
(93%); 126 [ThyH]+ (40%); 121 (FeC5 H5 ) (72%); 56 [Fe]+ (54%). 1 H
NMR (DMSO-d6 , δ, ppm): 1.32 (s, 3H, CH3 ); 2.13 (d, J = 6.9 Hz, 3H,
CH3 ); 4.15–4.33 (m, 9H, Fc); 4.87 (m, 1H, CH); 7.67 [s, 1H, C(6)H];
11.13 (s, 1H, NH). IR (KBr, ν, cm−1 ): 3090–2940, 2900, 1700, 1490,
1110, 1008, 950, 878, 825, 485.
1N-(Ferrocenylbenzyl)thymine (4)
Yield 50%. Brown crystals, m.p. 180 ◦ C. EI-MS, m/z: 400 [M]+ .
C22 H20 FeN2 O2 . 335 [M − Cp]+ (16%); 275 [M − Thy]+ (46%); 126
[ThyH]+ (52%); 121 [FeCp]+ (75%); 56 [Fe]+ (49%). 1 H NMR (DMSOd6 , δ, ppm): 1.23 (s, 3H, CH3 ); 3.96–4.15 (m, 9H, Fc); 4.98 (m, 1H,
CH); 5.87 (m, 5H, C6 H5 ); 6.84 [s, 1H, C(6)H]; 7.45 (broad s, 1H, NH2 ).
IR (KBr, ν, cm−1 ): 3100–2960, 2940–2870, 1700, 1500, 1475–1350,
1411, 1112, 1010, 950, 882, 830, 483.
9N-(Ferrocenylmethyl)adenine (5)[9,20b]
222
Yield 70%. Yellow crystals, m.p. 242–243 ◦ C. m.p. (lit)[20b]
242–244 ◦ C. EI-MS, m/z: 333 [M]+ . C16 H15 FeN5 . 1 H NMR (DMSOd6 , δ, ppm): 3.95–4.01 (m, 9H, Fc); 4.98 (s, 2H, CH2 ); 7.02 [s, 1H,
C(2)H]; 7.18 [s, 1H, C(8)H]; 7.99 (broad s, 2H, NH2 ). IR (KBr, ν, cm−1 ):
3590–3270, 3130–3090, 1610, 1410, 1110, 1020, 850, 775, 490.
www.interscience.wiley.com/journal/aoc
9N-(Ferrocenylethyl)adenine (6)[9a,c,d,20b]
Yield 65%. Yellow-orange crystals, m.p. 194–195 ◦ C with decomposition. m.p. (lit)[20b] 194–196 ◦ C. EI-MS, m/z: 347 [M]+ . C17 H17 FeN5 .
1 H NMR (DMSO-d , δ, ppm): 1.67 (d, J = 7.1 Hz, 3H, CH ); 4.01–4.37
6
3
(m, 9H, Fc); 5.54 (m, 1H, CH); 7.01 (broad s, 2H, NH 2 ); 7.91 (s, 1H, CH);
7.94 (s, 1H, CH). 13 C (δ, ppm): 20.26 (CH3 ); 48.85 (CH); 66.16, 67.08,
67.28, 67.78, 68.39 (C5 H4 ); 68.40 (C5 H5 ); 138.63 (C-8), 152.03 (C-2).
IR (KBr, ν, cm−1 ): 3505, 3350–3310, 3130, 1490, 1420, 1120, 1010,
988, 838, 805, 497. C17 H17 FeN5 : calcd C 58.79, H 4.90, Fe 16.14, N
20.17%; anal. C 59.09, H 5.04, Fe 15.94, N 20.16%.
Variant B
Compound 6 was obtained via the reaction of 0.24 g (1.0 mmol)
silver salt of adenine and 0.23 g (1.0 mmol) 1-ferrocenylethanol
in 2 ml methylene dichloride in the presence of 0.18 ml 45%
fluoroboric acid at room temperature for 10 min as described
for ferrocenylethyl benzotriazole.[20b] To the dark-green resulting
mass, 50 ml water, 50 ml CH2 Cl2 , and 2–3 mg ascorbic acid were
added then, after stirring, the yellow organic layer was separated,
washed with water, dried over anhydrous magnesium sulfate, and
the solvent removed in vacuo. EI-MS, m/z: 347 [M]+ . C17 H17 FeN5 :
calcd C 58.79, H 4.90, N 20.17%; anal. C 58.81, H 5.01, N 20.07%.
Silver salt of adenine was synthesized from adenine, silver nitrate
and concentrated ammonia by a reported procedure for preparing
silver salt of imidazole.[28]
9N-(Ferrocenylpropyl)adenine (7)
Yield 72%. Yellow-orange oil. EI-MS, m/z: 359 [M]+ . C18 H19 FeN5 .
1
H NMR (CDCl3 , δ, ppm): 0.67 (m, 3H, CH3 ); 2.02 (m, 1H, CH2 ); 2.15
(m, 1H, CH2 ); 3.87 (s, 5H, C5 H5 ); 3.93–4.13 (m, 4H, C5 H4 ); 5.27–5.28
(m, 1H, CH); 6.48 (broad s, 2H, NH2 ); 7.69 [s, 1H, C(8)H]; 8.18 [s,
1H, C(2)H]. 13 C NMR (δ, ppm): 10.62 (CH3 ); 28.54 (CH2 ); 55.24(CH);
66.31, 66.60, 67.35, 67.93 (C5 H4 ); 68.33 (C5 H5 ); 68.83 [C(C5 H4 )CH];
118.51 (C-5); 138.43 (C-8); 149.49 (C-4); 152.27 (C-2); 155.44 (C-6).
IR (KBr, ν, cm−1 ): 3510, 3400–3350, 3100, 1485, 1420, 1110, 1000,
998, 846, 800, 489.
9N-(Ferrocenylbenzyl)adenine (8)
Yield 78%. Orange crystals, m.p. 110–113 ◦ C. EI-MS, m/z: 409 [M]+ .
C22 H19 FeN5 . 1 H NMR (DMSO-d6 , δ, ppm): 3.42–4.15 (m, 9H, Fc);
5.23 (m, 1H, CH); 5.94 (m, 5H, C6 H5 ); 6.37 (broad s, 2H, NH2 ); 7.56 (s,
1H, CH); 8.30 (s, 1H, CH). IR (KBr, ν, cm−1 ): 3690–3210, 3200–3000,
1620, 1480, 1460–1335, 1120, 1040, 850, 730, 450.
1N-(Ferrocenylethyl)cytosine (9)
Yield 80%. Yellow crystals, m.p. 207 ◦ C with decomposition. EI-MS,
m/z: 323 [M]+ . C16 H17 FeN3 O. 258 [M − Cp]+ (23%); 212 [M − Cyt]+
(98%); 121 [FeCp]+ (75%); 111 [CytH]+ (70%); 56 [Fe]+ (52%) 1 H
NMR (DMSO-d6 , δ, ppm): 1.31 (d, J = 6.9 Hz, 3H, CH3 ); 3.98–4.16
(m, 9H, Fc); 5.35–5.42 (m, 1H, CH); 6.72 (broad s, 2H, NH2 ); 7.07 (s,
1H, CH); 7.11 (s, 1H, CH). IR (KBr, ν, cm−1 ): 3410–3350, 3330–3200,
1690–1620, 1510, 1410, 1120, 1010, 810, 730, 450.
1N-(Ferrocenylbenzyl)cytosine (10)
Yield 70%. Orange powder, m.p. 185–187 ◦ C with decomposition.
EI-MS, m/z: 385 [M]+ (25%). C21 H19 FeN3 O. 275 [M − Cyt]+ (20%);
231 [C5 H5 FeCyt]+ (32%); 153 [C5 H4 CPh]+ (100%); 198 [FcCH]+
c 2009 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2009, 23, 219–224
Simple route to ferrocenylalkyl nucleobases
(13%) 1 H NMR (DMSO-d6 , δ, ppm): 4.07 (s, 1H, C5 H4 ); 4.12 (s, 5H,
C5 H5 ); 4.24 (s, 1H, C5 H4 ); 4.27 (s, 1H, C5 H4 ); 4.31 (s, 1H, C5 H4 );
5.68–5.69 [d, J = 7.1 Hz, 1H, C(5)H]; 6.77 (s, 1H, CH); 7.02 (broad s,
1H, NH); 7.11 (broad s, 1H, NH); 7.22–7.23 (d, J = 7.3 Hz, 2H, Ph);
7.30–7.31 (t, J = 7.0 Hz, 1H, Ph); 7.35–7.36 (m, 3H, Ph, C(6)H). 13 C
(δ, ppm): 57.47 (C-5); 67.12, 67.83, 68.63, 69.42 (C5 H4 ); 68.76 (C5 H5 );
87.40 [C(C5 H4 )CH]; 93.45 (CH); 127.29, 127.53, 128.18 (Ph); 140.48
(C-6); 143.16 [C(Ph)CH]; 155.36 (C-2); 165.16 (C-4). IR (KBr, ν, cm−1 ):
3410–3350, 3330–3200, 1690–1620, 1510, 1410, 1120, 1010, 810,
730, 450.
1N-(Ferrocenylmethyl)-5-iodo-cytosine (11)
Yield 73%. Light yellow crystals, m.p. 220 ◦ C. EI-MS, m/z: 435
[M]+ . C15 H14 FeIN3 O. 370 [M − Cp]+ (30%); 199 [M − ICyt]+ (80%);
237 [ICytH]+ (50%); 121 [FeCp]+ (100%); 56 [Fe]+ (35%) 1 H NMR
(DMSO-d6 , δ, ppm): 4.00–4.30 (m, 9H, Fc); 4.45 (s, 2H, CH2 ); 7.46
(broad s, 2H, NH2 ); 8.01 (s, 1H, CH). IR (KBr, ν, cm−1 ): 3485, 3375,
3100, 1660, 1585, 1490, 1110, 830, 790, 640, 485.
1N-(Ferrocenylethyll)-5-iodo-cytosine (12)
Yield 80%. Yellow-orange crystals, m.p. 158–159 ◦ C with decomposition. EI-MS, m/z: 449 [M]+ . C16 H16 FeIN3 OxH2 O: calcd C 42.44,
H 4.19, Fe 11.61, N 8.73%; anal. C 42.10, H 3.75, Fe 11.52, N 8.65%.
1 H NMR (DMSO-d , δ, ppm): 1.58, 159 (d, J = 5.0 Hz, 3H, CH );
6
3
4.10–4.35 (m, 4H, C5 H4 ); 4.18 (s, 5H, C5 H5 ); 5.62, 5.63 (q, J = 5.0 Hz,
1H, CH); 6.11 (broad s, 1H, NH); 7.52 (s, 1H, HC-6), 7.64 (broad s, 1H,
NH). 13 C (δ, ppm): 18.89 (CH3 ); 50.26 (CH); 55.37 (C-5); 66.15, 67.38,
67.58, 68.33 (C5 H4 ); 68.41 (C5 H5 ); 87.83 [C(C5 H4 )CH]; 147.27 (C-6);
153.68 (C-2), 162.79 (C-4).
1N-(Ferrocenylpropyl)-5-iodo-cytosine (13)
Yield 82%. Light yellow crystals, m.p. 186 ◦ C. EI-MS, m/z: 463 [M]+ .
C17 H18 FeIN3 O. 398 [M − Cp]+ (35%); 226 [M − ICyt]+ (80%); 237
[ICytH]+ (60%); 121 [FeCp]+ (73%); 56 [Fe]+ (62%) 1 H NMR (DMSOd6 , δ, ppm): 0.74 (m, 3H, CH3 ); 1.01 (m, 2H, CH2 ); 3.90–4.01 (m, 9H,
Fc); 4.11 (m, 1H, CH); 5.67 (broad s, 2H, NH2 ); 7.65 (s, 1H, CH). IR
(KBr, ν, cm−1 ): 3510, 3405, 3102, 1680, 1588, 1460, 1110, 846, 790,
680, 488.
1N-(Ferrocenylbenzyl)-5-iodo-cytosine (14)
Yield 65%. Brown crystals, m.p. 190 ◦ C. EI-MS, m/z: 511 [M]+ .
C21 H18 FeIN3 O. 446 [M − Cp]+ (23%); 275 [M − ICyt]+ (43%);
237 [ICytH]+ (48%); 121 [FeCp]+ (81%); 56 [Fe]+ (53%).
C21 H18 FeIN3 OxH2 O: calcd C 47.64, H 3.78, N 7.94%; anal. C 47.75, H
3.81, N 7.65%. 1 H NMR (DMSO-d6 , δ, ppm): 4.06 (s, 1H, C5 H4 ); 4.11
(s, 5H, C5 H5 ); 4.27 (s, 1H, C5 H4 ); 4.30 (s, 1H, C5 H4 ); 4.33 (s, 1H, C5 H4 );
6.58 (broad s, 1H, NH); 6.67 (s, 1H, CH); 7.28–7.29 (d, J = 7.6 Hz,
2H, Ph); 7.32–7.33 (t, J = 7.3 Hz, 1H, Ph); 7.37–7.40 (m, 2H, Ph);
7.63 [s, 1H, C(6)H]; 7.80 (broad s, 1H, NH). 13 C (δ, ppm): 55.94 (C-5);
58.74 (CH); 67.52, 68.14, 69.10, 69.42 (C5 H4 ); 68.87 (C5 H5 ); 86.27
[C(C5 H4 )CH]; 127.51, 127.61, 128.27 (Ph), 139.70 [C(Ph)CH]; 148.59
(C-6); 154.10 (C-2), 163.45 (C-4). IR (KBr, ν, cm−1 ): 3400, 3375, 3110,
1700, 1576, 1466, 1110, 856, 789, 636, 485.
Antitumor activity tests
Appl. Organometal. Chem. 2009, 23, 219–224
Acknowledgments
This work was partially supported by the Russian Academy of
Sciences (Presidium Programs ‘Support for Young Scientists’ and
‘Fundamental Sciences – for Medicine’), by the Department of
Chemistry and Materials Science (Project 10) and by the Russian
Foundation for Basic Research (RFBR No 06-03-32219). L.V.S. wish
to thank Dr Yury I. Lyakhovetsky for his kind help in editing the
manuscript.
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