Novel iron complexes bearing N6-substituted adenosine derivatives: Synthesis, magnetic, 57Fe Moessbauer, DFT, and in vitro cytotoxicity studies

Article abstract of DOI:10.1016/j.bmc.2008.07.082

Iron complexes (1-7) involving N6-benzyladenosine derivatives of the predominant composition [Fe(L_n)Cl₃] · H₂O {where L₁ = N6-(2-fluorobenzyl)adenosine (1), L₂ = N6-(4-fluorobenzyl)adenosine (2), L₃ = N6-(2-trifluoromethylbenzyl)adenosine (3), L₄ = N6-(3-trifluoromethylbenzyl)adenosine (4), L₅ = N6-(4-trifluoromethylbenzyl)adenosine (5), L₆ = N6-(4-trifluoromethoxybenzyl)adenosine (6), and L₇ = N6-(4-chlorobenzyl)adenosine (7)} have been synthesized. The compounds have been characterized by elemental analysis, variable-temperature and in-field ⁵⁷Fe Moessbauer, ES+ MS, FTIR, ¹H and ¹³C NMR spectroscopies, magnetochemical and conductivity measurements, thermal (TGA/DSC/DTA) analyses, and DFT calculations. It has been found that the organic molecule is coordinated to iron via N7 atom of the appropriate adenosine derivative and the products are represented by mixtures of complexes with various iron oxidation (Fe^III/Fe^II) and spin states (S = 5/2, 4/2, 3/2, 2/2) and geometries (tetrahedral or trigonal bipyramidal). It is caused by the fact that partial redox processes proceed during the reactions due to the presence of a ribose moiety, which is oxidized to the corresponding 5′-ribotic acid, and simultaneously, a portion of Fe^III cations is reduced to Fe^II ones. Moreover, a significant effect of crystal water molecules on stereochemistry, and hence, on magnetic and spectral properties of the prepared complexes has been found. The compounds have been tested for their in vitro cytotoxicity against the following human cancer cell lines: malignant melanoma (G-361), osteogenic sarcoma (HOS), chronic myelogenous leukemia (K-562), and breast adenocarcinoma (MCF-7). The most important results have been obtained for complex 2 with IC₅₀ values 8-16 μM against HOS, K-562, and MCF-7 cell lines, and for complex 6 with IC₅₀ value 4 μM against MCF-7 cell line.

Full text of DOI:10.1016/j.bmc.2008.07.082

Bioorganic & Medicinal Chemistry 16 (2008) 8719–8728
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Novel iron complexes bearing N6-substituted adenosine derivatives:
Synthesis, magnetic, 57Fe Mössbauer, DFT, and in vitro cytotoxicity studies
a,
a
a
b
a,c
*
ˇ
ˇ
ˇ
ˇ
ˇ
Zdenek Trávnícek , Jirí Mikulík , Michal Cajan , Radek Zboril , Igor Popa
a
ˇ ˇ
Department of Inorganic Chemistry, Faculty of Science, Palacky University, Krízkovského 10, CZ-771 47, Olomouc, Czech Republic
´
b
ˇ
Department of Physical Chemistry, Faculty of Science, Palacky´ University, Tr. Svobody 8, CZ-771 46, Olomouc, Czech Republic
c Laboratory of Growth Regulators, Palacky´ University & Institute of Experimental Botany AS CR, Šlechtitelu˚ 11, CZ-783 71, Olomouc, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Iron complexes (1–7) involving N6-benzyladenosine derivatives of the predominant composition
[Fe(Ln)Cl3]ꢀH2O {where L1 = N6-(2-fluorobenzyl)adenosine (1), L2 = N6-(4-fluorobenzyl)adenosine (2),
Received 7 December 2007
Revised 28 May 2008
Accepted 29 July 2008
Available online 3 August 2008
L3 = N6-(2-trifluoromethylbenzyl)adenosine
(3),
L4 = N6-(3-trifluoromethylbenzyl)adenosine
(4),
L5 = N6-(4-trifluoromethylbenzyl)adenosine (5), L6 = N6-(4-trifluoromethoxybenzyl)adenosine (6), and
7 = N6-(4-chlorobenzyl)adenosine (7)} have been synthesized. The compounds have been characterized
L
by elemental analysis, variable-temperature and in-field 57Fe Mössbauer, ES+ MS, FTIR, 1H and 13C NMR
spectroscopies, magnetochemical and conductivity measurements, thermal (TGA/DSC/DTA) analyses,
and DFT calculations. It has been found that the organic molecule is coordinated to iron via N7 atom of
the appropriate adenosine derivative and the products are represented by mixtures of complexes with
various iron oxidation (FeIII/FeII) and spin states (S = 5/2, 4/2, 3/2, 2/2) and geometries (tetrahedral or tri-
gonal bipyramidal). It is caused by the fact that partial redox processes proceed during the reactions due to
the presence of a ribose moiety, which is oxidized to the corresponding 50-ribotic acid, and simultaneously,
a portion of FeIII cations is reduced to FeII ones. Moreover, a significant effect of crystal water molecules on
stereochemistry, and hence, on magnetic and spectral properties of the prepared complexes has been
found. The compounds have been tested for their in vitro cytotoxicity against the following human cancer
cell lines: malignant melanoma (G-361), osteogenic sarcoma (HOS), chronic myelogenous leukemia (K-
562), and breast adenocarcinoma (MCF-7). The most important results have been obtained for complex
Keywords:
Iron complexes
Adenosine derivatives
57Fe Mössbauer spectroscopy
DFT calculations
Cytotoxicity
2 with IC50 values 8–16
lM against HOS, K-562, and MCF-7 cell lines, and for complex 6 with IC50 value
4
l
M against MCF-7 cell line.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2-[(2-hydroxypropyl)amino]-9-isopropylpurine and Roscovitine =
6-(benzylamino)2-[(2-hydroxymethylpropyl)amino]-9-isopropyl-
purine} demonstrated considerable both in vitro and in vivo
cytotoxicity against some human cancer cell lines, corresponding
to their activities as CDK inhibitors.2 For instance, Cyclacel Pharma-
ceuticals, Inc. announced in June 2006 that Roscovitine (named Seli-
cyclib, CYC202) entered a Phase IIb of clinical trials for evaluation of
the efficacy and safety of the investigated drug for previously trea-
ted non-small cell lung cancer [www.cyclacel.com].
A few years ago, we have found that the cytotoxicity may be
increased after the coordination of the above-mentioned organic
substances, that is both cytokinins and CDK inhibitors, to a suitable
transition metal ion (e.g. PtII, PdII, FeIII, and CoII, CuII, NiII).3–6 Due to
undesirable side-effects of platinum-containing drugs used world-
wide in cancer chemotherapy at present (i.e. cisplatin, oxaliplatin or
carboplatin), the present efforts of chemists are focused on the
preparation of such transition metal complexes which would be
more effective and much less toxic than the above-mentioned
PtII-involving drugs. Among transition metal complexes, which
could meet these requirements, iron complexes bearing CDK
The organic compounds derived from 6-benzylaminopurines
(Bap), belonging to a group of plant growth hormones – called cyto-
kinins, have been intensively studied since the 1960s. The cytoki-
nins represent a group of compounds, which can significantly
affect some of physiological functions, for example, plant cells divi-
sion and senescence.1 Moreover, a suitable substitution on the 6-
benzylaminopurine skeleton can significantly influence biological
function and utilization of these compounds. For that reason, many
types of derivatives have been prepared and studied up to now.
Among them, 2,9-disubstituted derivatives of Bap have been found
to be the most interesting due to their ability to inhibit cyclin-
dependent kinases (CDKs), that is, enzymes playing crucial role in
the cell cycle regulation. Some of these synthetically acquired
CDK inhibitors {such as Olomoucine = 6-(benzylamino)-2-[(2-
hydroxyethyl)amino]-9-methylpurine, Bohemine = 6-(benzylamino)-
* Corresponding author. Tel.: +420 58 563 4944; fax: +420 58 563 4954.
E-mail address: zdenek.travnicek@upol.cz (Z. Trávnícek).
ˇ
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.07.082

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Z. Trávnícek et al. / Bioorg. Med. Chem. 16 (2008) 8719–8728
8720
inhibitors derived from 6-benzylaminopurine could be assigned in
our opinion. Searching within scientific literature databases, only
few complexes or adducts of FeII/III with purine or adenosine
derivatives have been prepared up to now. For instance, Fe2(a-
d)(adH)3Cl3 ꢀ2H2O {adH = adenine},7 Fe2(ado)(ClO4)6 ꢀ4H2O and
Fe(ado)(ClO4)2 ꢀ2H2O {ado = adenosine},8 [Fe(imp)(H2O)5]ꢀ2H2O
{impH2 = inosine-5-monophosphate}.9 Moreover, other N-donor
aromatic and aliphatic heterocycles have been used as ligands for
the syntheses of iron complexes, for example, [Fe(pyO)4Cl2][FeICl4]
and [Fe(pyO)6](ClO4)3 {pyO = pyridine N-oxide derivatives},10 [Fe
(gua)Cl]ꢀ2H2O {guaH = guanine},11 Fe(xa)(xaH)2(ClO4)ꢀH2O and
benzylamine, 3-(trifluoromethyl)benzylamine, 4-(trifluoromethyl)ben-
zylamine, 4-(trifluoromethoxy)benzylamine, 1,10-phenanthroline,
phosphoric acid, L-ascorbic acid, murexide, and solvents used were
purchased from Fluka Co., or Aldrich co. and used without further
purification.
2.2. Methods
IR spectra were measured on a FT-IR Nexus 670 spectrometer
(ThermoNicolet) using polyethylene discs in the region of 150–
600 cmꢁ1 and using KBr discs in the region of 400–4000 cmꢁ1
.
Fe(xa)2(xaH)2(ClO4)ꢀH2O
{xaH = xanthine},12
[Fe(thf)4(H2O)2]
The transmission 57Fe Mössbauer spectra of all complexes were
measured at 300 K in zero applied magnetic field using
(ClO4)3 {thp = tetrahydrofurane),13 and Fe(tc)2(ClO4)2 and Fe(tc)2
(ClO4)3 {tc = tetracycline}.14 While chemical features and physical
properties of these mentioned iron complexes were described
appropriately, their potential biological activity has never been dis-
cussed yet. Recently, two ionic pair complexes of the composition
(H+HL)2[FeCl5]ꢀ2H2O and (H+HL)2[FeCl5]ꢀ3H2O (HL = Bohemine)
have been prepared, characterized, and their in vitro cytotoxicity
has been evaluated.3 Surprisingly, only three X-ray structures of
iron-coordinated purine derivatives and involving Fe–purine moi-
ety have been determined and deposited within the Cambridge
Crystallographic Data Centre up to now:15 [Fe(imp)(H2O)5]ꢀ2H2O,9
[Fe(gmp)(H2O)5]ꢀ3H2O (gmpH2 = guanosine-50-monophosphate)16
and [Fe(mp)3][FeCl4]Cl (mp = 6-mercaptopurine).17
Herein, we report the synthesis, characterization, using a broad
spectrum of physico-chemical techniques, and in vitro cytotoxicity
testing results of a series of high-spin FeIII/FeII complexes involving
differently substituted N6-benzyladenosine derivatives (see
Scheme 1) of a general composition [Fe(Ln)Cl3]ꢀH2O.
a
Mössbauer spectrometer working in constant acceleration mode
with a 57Co(Rh) radioactive source. The iron foil was used as a cal-
ibration standard. The complex 6 was investigated also at 2 K in a
zero external field and in an external field of 7 T applied parallel to
the gamma-ray propagation. 1H and 13C NMR spectra of organic li-
gands Ln and all complexes were measured in various deuterated
solvents (i.e. DMSO-d6, DMFA-d7, methanol-d3, and acetone-d6)
on an Avance 300 MHz NMR spectrometer (Bruker), with an in-
verse probe used. ES+ mass spectra were recorded using a flow
injection mode on the Waters ZMD 2000 mass spectrometer. The
mass-monitoring interval was 40–1300 m/z. The spectra were col-
lected by using 3.0 s cyclical scans and by applying the sample
cone voltage 20, 40 or 60 V and capillary voltage +3.0 kV, at the
source block temperature 100 °C, desolvation temperature
250 °C, cone gas flow rate 50 l hꢁ1 and desolvation gas flow rate
500 l hꢁ1. The mass spectrometer was directly coupled to a Mass-
Lynx data system. Elemental analyses (C, H, N) were carried out
on a Flash EA 1112 CHN(O) analyzer (ThermoFinnigan), the iron
contents were estimated by chelatometric titration (with murexide
as an indicator). UV–Vis spectrometer Lambda40 (Perkin–Elmer)
was used for the determination of a FeIII/FeII ratio in the complexes
by using the method described in the literature.18 The magnetic
susceptibility measurements were carried out for all compounds
by using the Faraday method at 298 K with Hg[Co(SCN)4] as a cal-
2. Experimental
2.1. Materials
FeCl3 ꢀ6H2O, 6-chloro-9-riboside-purine, 4-chlorobenzylamine,
2-fluorobenzylamine, 4-fluorobenzylamine, 2-(trifluoromethyl)-
Scheme 1. N6-(benzyl)adenosine derivatives used as ligands in this study.

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Z. Trávnícek et al. / Bioorg. Med. Chem. 16 (2008) 8719–8728
8721
ibrant. Magnetic properties of the compounds 2, 4 and 6 were also
studied in the temperature range of 80–300 K. The molar suscepti-
bilities were corrected for diamagnetism using Pascal’s con-
washed with a small amount of cold butanol, several times by a
small amount of cold distilled water, and finally by diethyl ether.
The product was recrystallized from ethanol and its composition
and purity were proved by HPLC, elemental analysis, and thin-layer
chromatography (TLC).
stants.19 Conductivity measurements were performed on
a
Cond340i/SET Conductivity Meter (WTW, Germany) at 25 °C using
10ꢁ3 mol dmꢁ3 acetone solutions.20 TGA/DSC analyses were per-
formed on a TGA/DSC XP-10 Thermogravimetric Analyzer (THASS)
in the temperature range of 20–1000 °C with temperature gradient
of 5 °C minꢁ1, DSC analyses were performed in the temperature
range of 20–400 °C with temperature gradient of 5 °C minꢁ1. DTA
analysis of complex 6 was performed with a TGA/DTA 6200 Exstar
thermal analyzer with a sample weight of 12.2 mg and thermal
gradient of 5 °C minꢁ1. All thermogravimetric measurements were
carried out in air atmosphere.
L1: Yield: ꢃ90%. Anal. Calcd for C17H17N5O4F1: C, 54.5; N, 18.7;
H, 4.6. Found: C, 54.7; N, 18.8; H, 4.6%. TLC: one spot. L2: Yield:
ꢃ85%. Anal. Calcd for C17H17N5O4F1: C, 54.5; N, 18.7; H, 4.6. Found:
C, 54.3; N, 18.9; H, 4.7%. TLC: one spot. L3: Yield: ꢃ95%. Anal. Calcd
for C18H17N5O4F3: C, 50.9; N, 16.5; H, 4.0. Found: C, 51.1; N, 16.5; H,
3.9%. TLC: one spot. L4: Yield: ꢃ85%. Anal. Calcd for C18H17N5O4F3:
C, 50.9; N, 16.5; H, 4.0. Found: C, 51.0; N, 16.8; H, 4.0%. TLC: one
spot. L5: Yield: ꢃ90%. Anal. Calcd for C18H17N5O4F3: C, 50.9; N,
16.5; H, 4.0. Found: C, 51.0; N, 16.6; H, 4.1%. TLC: one spot. L6:
Yield: ꢃ85%. Anal. Calcd for C18H17N5O5F3: C, 49.1; N, 15.9; H,
3.9. Found: C, 49.2; N, 15.7; H, 4.0%. TLC: one spot. L7: Yield:
ꢃ85%. Anal. Calcd for C17H17N5O4Cl1: C, 52.2; N, 17.9; H, 4.4.
Found: C, 52.1; N, 17.7; H, 4.4%. TLC: one spot.
2.3. Biological activity testing
Human malignant melanoma cell line G-361, human osteogenic
sarcoma cell line HOS, human chronic myelogenous leukemia cell
line K-562, and human breast adenocarcinoma cell line MCF-7 were
used for vitro cytotoxicity testing of the synthesized compounds by
a calcein acetoxymethyl (AM) assay. The tumor cells were main-
tained in plastic tissue culture flasks and grown on Dulbecco’s
modified Eagle’s cell culture medium (DMEM) at 37 °C in 5% CO2
atmosphere and 100% humidity. The cell suspension of approxi-
mate density 1.25 ꢂ 105 cells mlꢁ1 was reattributed into 96-well
microtitre plates (Nunc, Denmark). After 12 h of preincubation,
2.5. General preparation of the complexes (1–7)
A total amount of 1 mmol of the corresponding organic ligand
{i.e., N6-(2-fluorobenzyl)adenosine, N6-(4-fluorobenzyl)adeno-
sine, N6-(2-trifluoromethylbenzyl)ade-nosine, N6-(3-trifluorom-
ethylbenzyl)adenosine, N6-(4-tri-fluoromethylbenzyl)adenosine,
N6-(4-trifluoromethoxybenzyl)adenosine, and N6-(4-chloroben-
zyl)adenosine} was dissolved in ethanol (30 ml) and added to an
ethanolic solution (15 ml) of FeCl3 ꢀ6 H2O (1 mmol, 270 mg). The
reaction mixture was stirred at 65 °C for 3–4 h. Then, the mixture
was cooled down to room temperature and the orange–brown so-
lid formed. It was filtered off, washed several times with a small
amount of diethylether, and dried in a vacuum desiccator over
the tested compounds (in the 0.5–200 and 0.5–50 lM range,
respectively) were added. The incubation lasted for 72 h. At the
end of this period, the cells were incubated for 1 h with calcein
AM, and the fluorescence of the live cells was measured at 485/
538 nm (ex/em) with a Fluoroskan Ascent (Labsystems, Finland).
IC50 values, the drug concentration lethal to 50% of tumor cells,
were estimated. The presented values are represented by arithme-
tic means determined from three values. The deviations from the
arithmetic mean values not exceed 20%.
P4O10
.
In quest to optimize reaction conditions and pathways regard-
ing the preparation of Fe-complexes, we performed many experi-
ments during which we changed the type of iron-containing
inorganic salts, molar ratio of reactants, temperature, and solvents.
Herein, we present the results which were obtained by the way
described above. In the case that we used Fe(NO3)3 ꢀ9H2O,
Fe(ClO4)3 ꢀxH2O, FeSO4 ꢀ7H2O or Fe(ClO4)2 ꢀxH2O as a starting mate-
rial, and changed molar ratios of the reactants, we obtained mix-
tures of the appropriate iron-containing salt and free ligand, and
FeII/III-complexes. That is why the above-described procedure,
leading to the preparation of the discussed Fe-complexes only,
can be considered as the optimized one.
(1): Yield: ꢃ50%. Anal. Calcd for C17H18N5O4Fe1Cl3F1: C, 37.9; N,
13.0; H, 3.4; Fe, 10.4. Found: C, 37.7; N, 12.8; H, 3.8; Fe, 10.7%. IR
(cmꢁ1): 3401w, 3250w, 3113w, 2975w, 2927w, 2839w, 1655vs,
1616s, 1586m, 1491m, 1455s, 1402m, 1349m, 1313w, 1276w,
1229m, 1181w, 1123m, 1093s, 1035m, 913w, 872w, 832w, 760m,
657w, 639w, 614w, 559w, 533w, 436w. ES+ MS (m/z): 377 [L1]+,
2.4. Preparation of organic ligands L1–L7
All N6-(benzyl)adenosine derivatives (L1–L7) have been synthe-
sized according to the published procedure (see Scheme 2).21 One
millimole of 6-chloro-9-riboside-purine and 4/3 mmol of the appro-
priate substituted benzylamine, that is, 2-(fluoro)benzylamine for
L1, 4-(fluoro)benzylamine for L2, 2-(trifluoromethyl)benzylamine
for L3, 3-(trifluoromethyl)benzylamine for L4, 4-(trifluoro-
methyl)benzylamine for L5, 4-(trifluoromethoxy)benzylamine for
L6, and 4-(chloro)-benzylamine for L7, were dissolved in 20 ml of
butanol in an ultrasonic bath. Then, triethylamine was added drop-
wise while stirring the reaction mixture. The mixture was heated up
to 90 °C and stirred for 4 h. Then, after slow cooling, the solution was
put into the freezer. After 12 h, the white solid was filtered off,
Scheme 2. A general pathway for the synthesis of organic ligands used for the preparation of complexes (1–7).

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Z. Trávnícek et al. / Bioorg. Med. Chem. 16 (2008) 8719–8728
8722
244 [L1–ribose]+. (2): Yield: 55%. Anal. Calcd for C17H20N5O5-
Fe1Cl3F1: C, 36.8; N, 12.6; H, 3.6; Fe, 10.1. Found: C, 37.2; N, 12.2;
H, 3.6; Fe, 10.2%. IR (cmꢁ1): 3382w, 3352w, 3101w, 2929w,
1657vs, 1604s, 1510s, 1452m, 1433m, 1416m, 1403m, 1343m,
1279w, 1221s, 1158m, 1119m, 1094s, 1081s, 1015m, 909w,
893w, 825m, 778w, 743w, 638w, 612w, 561w, 532w, 510w,
483w, 445w. ES+ MS (m/z): 377 [L2]+, 244 [L2–ribose]+. (3): Yield:
ꢃ85%. Anal. Calcd for C18H20N5O5Fe1Cl3F4: C, 35.7; N, 11.5; H, 3.3;
Fe, 8.9. Found: C, 35.8; N, 11.4; H, 3.4; Fe, 9.2%. IR (cmꢁ1): 3414w,
3256w, 3088w, 2929w, 1645vs, 1506w, 1454m, 1426m, 1405m,
1365w, 1315vs, 1218w, 1168m, 1117s, 1059m, 1038m, 909w,
827w, 822w, 771m, 743w, 717w, 625w, 599w, 536w. ES+ MS (m/
z): 426 [L3]+, 294 [L3–ribose]+. (4): Yield: 70%. Anal. Calcd for
C18H18N5O4Fe1Cl3F4: C, 36.8; N, 11.9; H, 3.1; Fe, 9.2. Found: C,
36:5; N, 11.6; H, 3.3; Fe, 9.3%. IR (cmꢁ1): 3292w, 2934w, 1667vs,
1646vs, 1542w, 1506w, 1451m, 1405m, 1328vs, 1201m, 1166s,
1124vs, 1098s, 1074s, 902w, 871w, 802w, 779w, 750w, 702m,
659w, 640w, 611w, 568w, 534w, 505w, 456w. ES+ MS (m/z): 426
[L4]+, 294 [L4–ribose]+. (5): Yield: ꢃ70%. Anal. Calcd for C18H20N5O5-
Fe1Cl3F4: C, 35.7; N, 11.6; H, 3.3; Fe, 8.9. Found: C, 35.5; N, 11.8; H,
3.3; Fe, 9.1. IR (cmꢁ1): 3250w, 3142w, 2925w, 1923w, 1657vs,
1619s, 1580m, 1510m, 1451m, 1418s, 1403m, 1326vs, 1281m,
1212m, 1165s, 1123s, 1066vs, 1018m, 913w, 888w, 864w, 820m,
778m, 637w, 611m, 592w, 537w, 493w. ES+ MS (m/z): 426 [L5]+,
294 [L5–ribose]+. (6): Yield: ꢃ90%. Anal. Calcd for C18H20N5O6-
Fe1Cl3F4: C, 34.8; N, 11.3; H, 3.2; Fe, 8.7. Found: C, 34.8; N, 11.6;
H, 3.2; Fe, 9.0%. IR (cmꢁ1): 3408w, 3241w, 3114w, 2934w,
1657vs, 1615m, 1510m, 1452m, 1419m, 1404m, 1347w, 1263vs,
1220s, 1165m, 1122m, 1106m, 1081m, 1019w, 919w, 890w,
814w, 778w, 744w, 606w, 556w, 530w, 423m. ES+ MS (m/z): 441
[L6]+, 309 [L6–ribose]+. (7): Yield: ꢃ65%. Anal. Calc. for C18H20N5O5-
Fe1Cl4: C, 35.5 (35.7); N, 12.1 (12.2); H, 3.8 (3.5); Fe, 9.7 (9.6).
Found: C, 35.5; N, 12.1; H, 3.8; Fe, 9.7%. IR (cmꢁ1): 3408w,
3249w, 3198w, 3113w, 2975w, 2921w, 2847w, 1656vs, 1615m,
1576m, 1491m, 1448m, 1403m, 1342m, 1278w, 1209m, 1123m,
1089m, 1041m, 1014m, 917w, 885w, 801w, 777w, 723w, 637w,
611w, 557w, 531w, 486w. ES+ MS (m/z): 392 [L7]+, 260 [L7–ribose]+.
Table 1
3. Results and discussion
3.1. General features
Composition, magnetic, and conductivity data for the complexes
a
Complex
leff
/lB
kM (S cm2 molꢁ1
)
[Fe(L1)Cl3]ꢀH2O (1)
[Fe(L2)Cl3]ꢀH2O (2)
[Fe(L3)Cl3]ꢀH2O (3)
[Fe(L4)Cl3]ꢀH2O (4)
[Fe(L5)Cl3]ꢀH2O (5)
[Fe(L6)Cl3]ꢀH2O (6)
[Fe(L7)Cl3]ꢀH2O (7)
5.32
5.40
5.56
5.45
5.32
5.44
5.42
4.2
5.3
5.3
11.9
6.0
5.4
9.7
The reaction between FeCl3 ꢀ6H2O and a substituted N6-benzyl-
adenosine (in a molar ratio of 1:1) in ethanol gave complexes of a
general formula [Fe(Ln)Cl3]ꢀH2O. Chemical composition, magnetic
and conductivity data of the complexes are given in Table 1. All
prepared compounds are hygroscopic and they need to be stored
in vacuum desiccator over P4O10 or NaOH as a drying medium.
a
Measured in acetone.
Table 2
57Fe Mössbauer spectral data of complexes 1—7
Compound
Component
T (K)
d (mm sꢁ1
)
D
EQ (mm sꢁ1
)
C
(mm sꢁ1
)
RA (%)
Assignment
1
Doublet
Singlet
Doublet
Doublet
300
0.33
0.24
1.24
1.04
0.68
—
2.48
2.10
0.68
0.30
0.31
0.45
46
17
15
22
FeIII(HS, TB)
FeIII(HS, Td)
FeII(HS, TB)
FeII(HS, Td)
2
3
4
5
6
Doublet
Singlet
Doublet
Doublet
300
300
300
300
0.33
0.20
1.17
1.06
0.71
—
2.47
1.95
0.57
0.33
0.47
0.49
80
11
5
FeIII(HS, TB)
FeIII(HS, Td)
FeII(HS, TB)
FeII(HS, Td)
4
Doublet
Singlet
Doublet
Doublet
0.32
0.24
1.29
1.09
0.71
—
2.32
1.90
0.49
0.52
0.41
0.47
65
14
11
10
FeIII(HS, TB)
FeIII(HS, Td)
FeII(HS, TB)
FeII(HS, Td)
FeIII(HS, TB)
FeIII(HS, Td)
FeII(HS, TB)
FeII(HS, Td)
FeIII(HS, TB)
FeIII(HS, Td)
FeII(HS, TB)
FeII(HS, Td)
FeIII(HS, TB)
FeIII(HS, Td)
FeII(HS, TB)
FeII(HS, Td)
FeIII(HS, TB)
FeIII(HS, Td)
FeII(HS, TB)
FeII(HS, Td)
Doublet
Singlet
Doublet
Doublet
0.35
0.25
1.19
1.07
0.69
—
2.72
2.07
0.47
0.58
0.29
0.41
63
23
5
9
Doublet
Singlet
Doublet
Doublet
0.33
0.25
1.21
1.03
0.75
—
2.51
1.96
0.39
0.64
0.39
0.25
25
57
12
6
Doublet
Singlet
Doublet
Doublet
Doublet
Singlet
300
2
0.32
0.25
1.19
1.02
0.44
0.37
1.30
1.14
0.72
—
2.44
2.00
0.50
—
0.44
0.58
0.43
0.32
0.48
0.55
0.47
0.36
40
42
12
6
42
36
9
Doublet
Doublet
1.76
1.26
13
7
Doublet
Singlet
Doublet
Doublet
300
0.34
0.25
1.30
1.12
0.70
—
2.40
2.07
0.49
0.58
0.26
0.39
30
45
9
FeIII(HS, TB)
FeIII(HS, Td)
FeII(HS, TB)
FeII(HS, Td)
16
d, isomer shift related to metallic iron ( 0.01 mm sꢁ1);
D C
EQ, quadrupole splitting ( 0.01 mm sꢁ1); , full width of spectral line at a half maximum ( 0.01 mm sꢁ1); RA, relative
spectrum area ( 1%); HS, high-spin; TB, trigonal-bipyramidal arrangement; Td, tetrahedral arrangement.

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Z. Trávnícek et al. / Bioorg. Med. Chem. 16 (2008) 8719–8728
8723
The complexes are soluble in N,N-dimethylformamide (DMFA) and
acetone, partially soluble in methanol and ethanol, and nearly
insoluble in CHCl3 and diethylether. Based on results following
from magnetic, UV/Vis spectral, and mainly from Mössbauer data,
a portion of FeIII cations was reduced to FeII during the synthesis
due to reduction abilities of the ribose molecule, which is attached
to an adenine moiety via N9 nitrogen atom. We have reason to be-
lieve that the ribose was oxidized to the corresponding 50-ribotic
acid. The fact that the FeIII reduction proceeded during the syn-
thetic pathway was supported by a simple UV/Vis spectral mea-
surement.18 The conclusion regarding the reduction process of
FeIII to FeII was proved unambiguously by 57Fe Mössbauer spectros-
copy (see below). As expected, the conductivity data in acetone
illustrated non-ionic features of the compounds in the solvent used
(see Table 1).20
Generally, Mössbauer spectra are very similar and consist of four
subspectra reflecting the presence of four non-equivalent struc-
tural, oxidation, and/or spin states of iron cations in the samples.
Figure 1 shows the representative room temperature Mössbauer
spectrum of the complex 6 including its mathematical deconvolu-
tion. The suggested stereochemical arrangements, valence, and
spin states of the iron ions were assigned to individual subspectra
mainly on the basis of interpretation of their hyperfine parameters
supported by magnetic data and DFT calculations (see below).
These four possible different arrangements are depicted in Figure
2. Following the isomer shift (d) values derived for individual sub-
spectra at room temperature (see Table 2), there may be two
clearly identified high-spin FeIII components in all samples. Sing-
lets with the lowest d values (0.20–0.25 mm sꢁ1) and zero quadru-
pole splitting (
FeIII (S = 5/2). Doublets with higher isomer shifts (0.32–
0.35 mm sꢁ1) and EQ (0.68–0.75 mm sꢁ1) parameters indicate a
DEQ) would be assigned to tetrahedral (Td) high-spin
3.2. 57Fe Mössbauer spectroscopy and magnetic measurements
D
presence of the FeIII species with the higher coordination number
accompanied by decrease in symmetry of the electric charge distri-
bution in the vicinity of the central ion. These doublet components
may be connected with a distorted trigonal-bipyramidal (D3h) or
distorted square-pyramidal (D4v) FeIII arrangement with S = 3/2. It
is worthy to emphasize that these trivalent iron species predomi-
nate in the samples as deduced from their total spectral areas rang-
ing between 63% and 91% (see Table 2). Nevertheless, all the
spectra exhibit two other subspectra with similar d values (1.17–
Mössbauer parameters obtained for all the complexes at room
temperature, and for complex 6 also at 2 K, are given in Table 2.
1.30 and 1.03–1.20 mm sꢁ1), but distinct
DEQ values (2.40–2.72
and 1.90–2.10 mm sꢁ1, respectively). They are ascribable to FeII
ions formed from their FeIII counterparts during the synthetic pro-
cedure due to the reduction effect of the ribose molecule. The dou-
blets with the lower quadrupole splitting parameters probably
originate from a tetrahedral high-spin (S = 4/2) FeII component,
while the next ones with higher
DEQ may be assigned to a distorted
trigonal-bipyramidal or square-pyramidal (S = 2/2) FeII component.
Both FeII tetrahedral and FeII trigonal-bipyramidal species are in
minority, which did not exceed 37% overall. For that reason, effec-
tive magnetic moment values, as presented in Table 1, were not
influenced significantly as compared to a spin only value typical
for five unpaired electrons in tetrahedral FeIII complexes (S = 5/2).
In quest to find more information on the structural and magnetic
Figure 1. 57Fe Mössbauer spectrum of complex 6 measured at room temperature
including the fitted subspectra and assigned states of iron (HS, high-spin; Td,
tetrahedron; TB, trigonal-bipyramid).
Figure 2. Possible geometrical arrangements and compositions of the complex 6, as predicted mainly on the basis of 57Fe Mössbauer data.

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Z. Trávnícek et al. / Bioorg. Med. Chem. 16 (2008) 8719–8728
8724
states of iron in the studied samples, we performed the Mössbauer
measurement of complex 6 at 2 K. As the key magnetic informa-
tion, the sample remains paramagnetic even at such a low temper-
ature. In addition to the temperature shift, we observed
a
significant decrease in the quadrupole splitting of all subspectra
except for that corresponding to tetrahedral FeIII ions preserving
the singlet character (see Table 2). This fact provides an indirect
proof for a considerable distortion of all other local Fe environ-
ments in samples at room temperature. The differences in the rel-
ative spectral areas of individual Fe species, if the room
temperature and the 2 K spectra are compared, are clearly due to
the different f-factors of non-equivalent Fe fractions.
The room temperature effective magnetic moment values of the
complexes 1–7, which can be seen in Table 1, vary from 5.32 to
5.59 leff/lB, while the room temperature vMT values are as fol-
lows: 3.541 cm3 K molꢁ1 (for 1), 3.558 cm3 K molꢁ1 (for 2),
3.762 cm3 K molꢁ1 (for 3), 3.809 cm3 K molꢁ1 (for 4), 3.447 cm3
K molꢁ1 (for 5), 3.599 cm3 K molꢁ1 (for 6), and 3.578 cm3 K molꢁ1
Figure 3. Temperature dependence of leff
line represents the best-fit to the Curie–Weiss law.
/lB and vM for complex 2. The continuous
(for 7). All leff
/lB as well as vMT values are significantly lower than
ond sextet ascribed to the tetrahedral FeII component (S = 4/2) pos-
sesses the larger Beff (46.5 T) and high negative value of eQ
(ꢁ1.0 mm sꢁ1). A type of magnetic ordering induced by a high
external magnetic field can be determined from the intensities of
the 2nd and 5th lines of both sextets. In the used measuring geom-
etry, where the external magnetic field is applied parallel to the
gamma-ray propagation, the zero intensity of these lines unambig-
uously confirms the ferromagnetic ordering in both tetrahedral
high-spin state complexes. The remaining two doublet subspectra
originating from the trigonal-bipyramidal Fe components indicate
the absence of any exchange interactions among these iron ions.
They show almost the same isomer shift parameters as in the
zero-field spectrum, however, the quadrupole shift parameters
are significantly increased (1.65 mm sꢁ1 for FeIII and 2.80 mm sꢁ1
for FeII), which is a probable structural response to the application
of a high external magnetic field. The overall spectrum areas
belonging to trivalent (79%) and divalent iron states (21%) are
nearly the same as those derived from the zero-field spectrum
measured at the same temperature (see Table 2). Let us conclude
this part by a statement that external magnetic field induced weak
ferromagnetic interactions in the framework of the tetrahedral
high-spin FeIII ions as well as in the framework of the tetrahedral
high-spin FeIIspecies, while the FeIII and FeII ions being in the trigo-
nal-bipyramidal arrangements remained in the paramagnetic
states. An exchange between FeIII and FeII ions cannot be supported
from the determined Mössbauer parameters.
those expected for a S = 5/2 spin state (a spin only value is 5.90 leff
/
lB with (4/g2)vT = 4.377 cm3 K molꢁ1).19 The reasons for the de-
crease in effective magnetic moment values may be the presence
of the FeII species, and generally the presence of several structural
arrangements in the vicinity of central atom yielding different oxi-
dation and spin states of iron within each of the complexes as sup-
ported by Mössbauer data. In summary, the probable geometries
and oxidation states, derived from Mössbauer and magnetic data,
can be as follows: high-spin tetrahedral FeIII (S = 5/2), high-spin tri-
gonal-bipyramidal FeIII (S = 3/2), high-spin tetrahedral FeII (S = 4/2),
and high-spin trigonal-bipyramidal FeII (S = 2/2). It should be noted
that such a miscellaneous spectrum of the oxidation and valence
states of iron occurring in the samples is probably related not only
to the above-mentioned partial reduction process, but also to a role
of the water molecule in the system. The presence of the water
molecule may have a significant impact on stereochemistry, and
thus, on magnetic and spectral properties of the complexes
depending on the fact if it acts as a ligand or is situated outside
of the coordination sphere as the crystal water molecule. In the
case of the water bonding as a ligand, the coordination number
of iron changes from four to five. In our systems, this is accompa-
nied by a change of geometries from tetrahedral (Td) to trigonal-
bipyramidal (D3h), resulting in a decrease in spin states from
S = 5/2 to S = 3/2 for FeIII cations and from S = 4/2 to S = 2/2 for FeII
cations. Magnetic properties of complexes 2, 4, and 6 have also
been studied in the temperature interval of 300–80 K. The temper-
ature dependence of leff/lB and vM for the representative complex
2 is displayed in Figure 3. It has been found that the effective mag-
netic moment value is smoothly decreased together with the tem-
perature lowering from 300 to 80 K, that is from 5.45 to 5.11 leff
/
lB
lB
for 2, from 5.38 to 4.99 leff lB for 4, and from 5.59 to 5.14 leff
/
/
for 6. As for a general course of temperature dependence of effec-
tive magnetic moment, it shows one of the typical magnetic fea-
tures of mononuclear high-spin FeIII complexes.
To bring better insight into the different iron states and possible
magnetic interactions among them, we also performed low-tem-
perature (2 K) in-field (7 T) Mössbauer characterization of the rep-
resentative complex 6 (Fig. 4). From such a spectrum it is obvious
that the high external magnetic field induced the magnetic order-
ing (sextet) in the case of tetrahedral FeIII and FeII components. This
assignment is based on the perfect correspondence of the isomer
shift parameters compared to the zero-field spectrum. Sextet cor-
responding to the tetrahedral FeIII state (S = 5/2) reveals the effec-
tive magnetic field (Beff) of 44 T and the zero quadrupole shift (eQ),
proving the preservation of the maximum symmetry of the iron
environment also in the magnetically ordered state (see the zero
Figure 4. 57Fe Mössbauer spectrum of complex 6 measured at 2 K in the external
magnetic field of 7 T including the fitted subspectra and assigned states of iron (HS,
high-spin; Td, tetrahedron; TB, trigonal-bipyramid).
D
EQ in the paramagnetic singlet state – Figure 1, Table 2). The sec-

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Z. Trávnícek et al. / Bioorg. Med. Chem. 16 (2008) 8719–8728
8725
3.3. 1H, 13C NMR and ES+ MS spectral data
purine moiety to iron atom. Other important maxima, observed
in the range of 1448–1455 and 1576–1604 cmꢁ1 may be connected
Low concentrated sample solutions were used for 1H and
C
with the m(C@C)ar vibration. The m(Car–F) vibration appeared at
13
NMR spectra measurements due to paramagnetism of the com-
plexes 1–7. The low concentration of the samples caused the in-
crease in intensities of the deuterated solvent signals and
decrease in intensities of some important signals of the complexes.
In quest to increase quality and quantity of sample signals, the var-
ious deuterated solvents (i.e. DMSO-d6, methanol-d3, DMFA-d7, and
acetone-d6) were used for NMR experiments. The best NMR results
were obtained in the case of complexes 1 and 2 measured in ace-
tone-d6 solutions. Provided that the adenosine derivatives (L1–L7)
are coordinated to the iron atom via N7 atom of a purine moiety,
1229 cmꢁ1 for complex 1 and at 1221 cmꢁ1 for complex 2. The
bands observed at 3382–3414 and 3100–3250 cmꢁ1 can be attrib-
uted to
the bands appearing within the former interval can be also as-
m(N–H) and m
(Car–H) vibration, respectively.22 However,
signed to m(O–H) stretch vibration originating from water mole-
cule. The maxima between 650 and 930 cmꢁ1 are assignable to
the skeletal vibrations of aromatic ring. Pure ribose IR spectrum
shows, apart from others, two maxima which correspond to
m
(Calif–O) stretch vibration. The first maximum, observed at
1030 cmꢁ1, belongs to secondary aliphatic alcohol group, and the
second one, at 1110 cmꢁ1, belongs to hemiacetalic bond.22 The cor-
responding absorptions were found in spectra of the studied com-
the most significant changes in coordination chemical shifts (
where d is defined as dcomplex–dligand) should be anticipated for
C8–H signal in 1H NMR spectra. The experiments clearly supported
this presumption with d(C8–H) values of 0.32 ppm (for 1) and
Dd,
D
plexes in the ranges of 1035–1081 and 1074–1124 cmꢁ1
,
D
respectively. The spectra of all complexes (1–7) showed the very
0.39 ppm (for 2). The remaining interpretable chemical shifts
regarding any other proton signals observed in 1H NMR spectra
of the complexes did not differ significantly as compared to those
strong maximum at 382 cmꢁ1, which is clearly assignable to the
m
(Fe–Cl) vibration.23 The peak about 320 cmꢁ1 is hard to assign,
but we may assume that it can be connected with the m(Fe–N)
of free adenosine derivatives (e.g. maximal
for 1, maximal d(C2–H) = 0.02 ppm for 1,
D
d(N6–H) = 0.02 ppm
vibration, which is expected to be observed in this region.24,25
D
Dd for O17–H, O18–H
and O20–H is not greater then 0.07 ppm). These facts confirmed
our assumption that adenosine derivatives cannot be coordinated
through the ribose moiety to iron atom, and moreover, that the li-
gand cannot also be bonded to iron through N1, N3, and N6 atoms
of the adenosine moiety. The most important chemical shifts were
observed in 13C NMR spectra of some complexes, where the great-
est coordination shifts were determined for C8 and C5 atoms.
Unfortunately, the interpretation of majority of 13C NMR spectra
could not be unambiguous due to sample paramagnetism originat-
ing from iron cation. However, we can conclude that the coordina-
tion of the organic molecule to iron proceeds via N7 atom with
high probability.
ES+ mass spectra were carried out for all the complexes 1–7.
The spectra revealed only a few structurally important fragments.
Molecular peaks belonging to organic ligands Ln were observed in
the spectra of all the complexes (at 376 m/z for 1, 2; at 426 m/z
for 3, 4, 5; at 441 m/z for 6; and at 392 m/z for 7). The peaks ob-
served at 244 m/z (for 1 and 2), 294 m/z (for 3, 4 and 5), 309 (for
6) and 260 m/z (for 7) can be attributed to fragments belonging
to substituted 6-(benzylamino)purine moiety, that is to [Ln–
ribose]+.
3.5. Thermal analysis
TGA and DSC analyses were carried out for all the complexes 1–
7, and moreover, DTA analysis was performed for complex 6. The
thermal decomposition, which is very similar for all complexes,
proceeded in four main steps. Figure 5 represents TGA, DSC, and
DTA curves of complex 6. The first weight loss can be seen in the
temperature range of 45–112 °C and is connected with the elimi-
nation of one water molecule (found/calcd: 2.6%/2.9%). This step
is clearly supported by a broad endo-effect in the temperature
range of 33–106 °C and with the minimum on the DSC curve at
75 °C. The activation energy value connected with the thermal
effect,
D
H, is equal to 12.2 J gꢁ1 (ꢄ7.6 kJ molꢁ1, 1.8 kcal molꢁ1). It
has to be noted that the temperature interval in which the water
3.4. Infrared spectroscopy
The most important IR data are summarized in the Table 3. FT IR
spectra of all complexes showed peaks proving the presence of
adenosine derivatives as ligands in the complexes (1–7). The spec-
tra revealed that the maximum belonging to m(C@N) is typically
found at 1628 cmꢁ1 in the case of free adenosine derivatives, which
is significantly shifted to higher wave numbers in the case of the
complexes (ꢄ1655 cmꢁ1). This significant shift could be used as
an indirect proof of the coordination of the organic ligand via the
Figure 5. TGA, DTA and DSC curves of complex 6.
Table 3
Selected IR spectral data (cmꢁ1) of the complexes (1—7) and their assignements
Compound
m(C@N)
m
(C@C)ar
m
(Calif—O)
m(Car—F)
m(Fe—Cl)
m(Fe—N)
[Fe(L1)Cl3]ꢀH2O (1)
[Fe(L2)Cl3]ꢀH2O (2)
[Fe(L3)Cl3]ꢀH2O (3)
[Fe(L4)Cl3]ꢀH2O (4)
[Fe(L5)Cl3]ꢀH2O (5)
[Fe(L6)Cl3]ꢀH2O (6)
[Fe(L7)Cl3]ꢀH2O (7)
1655vs
1657vs
1645vs
1646vs
1657vs
1657vs
1656vs
1586m, 1455m
1604s, 1452s
1610s, 1454m
1614s, 1451m
1580s, 1451m
1616s, 1452m
1576m, 1448m
1035m/1093m
1040m/1081s
1038m/1117s
1074s/1124s
1066s/1123s
1081m/1106m
1041m/1089m
1229m
1221s
—
—
—
382s
382s
382s
382s
382s
383s
382s
320w
323w
322w
320w
322w
320m
320w
—
—

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Z. Trávnícek et al. / Bioorg. Med. Chem. 16 (2008) 8719–8728
8726
molecule is leaving the sample is rather broad. This phenomenon is
probably caused by the presence of unequal water molecules,
where a majority portion of these molecules probably exists in
the form of a crystalline water and a minority portion may be coor-
dinated to iron atom as a ligand (see Section 3.2). Thus, the temper-
ature interval broadening is detected as a consequence of the last-
mentioned possibility. The main thermal decay proceeds within
the interval of 157 and 430 °C. This weight loss is probably con-
nected with the combination of dissociation of ribose molecule,
and consequently, with thermal degradation of the remaining part
of the organic molecule. This degradation is accompanied by three
exo-effects on both DSC and DTA curves. The energy values con-
nected with the first two exo-effects were found to be: (i) in the
temperature range of 157–293 °C; maximum at 198 °C,
3.6. DFT calculations
Preliminary geometry optimizations were performed on the HF/
6-31* level. Then, geometries of Fe-complexes were fully opti-
mized on the B3LYP level using the 6-311+G* basis set. Harmonic
frequency analysis was used to verify the nature of founded sta-
tionary points as the minima. All calculations were performed
using the Gaussian03 program package.26 As a model compound,
the complex involving N6-(benzyl)adenosine moiety (L0) has been
chosen for the calculations. According to experimental observa-
tions, attributes of all possible geometric, oxidation, and spin states
have been investigated. Important structural parameters in the
vicinity of the iron atom are summarized in Table 4. Optimized
molecular structures are depicted in Figures 6 and 7.
The above-discussed Mössbauer and magnetic features clearly
confirmed the presence of geometric, valence, and spin states with-
in the Fe-complexes. As for the FeIII compounds, two possible
arrangements of the coordination sphere and compositions were
found by interpreting the results of DFT calculations: (i)
[FeIII(L0)Cl3] with the tetrahedral geometry and 5/2 spin state
(Fig. 6a, Table 4), (ii) [FeIII(L0)Cl3(H2O)] with the trigonal-bipyrami-
dal geometry and 3/2 spin state (Fig. 6b, Table 4). The calculated
Fe–Cl, Fe–N and Fe–O bond lengths correspond well to those found
for similar systems as determined by single crystal X-ray analysis
(see Table 4).15
D
H = ꢁ142 J gꢁ1 = ꢁ85.8 kJ molꢁ1 = ꢁ20.6 kcal molꢁ1
,
(ii) in the
temperature range of 299–360 °C; maximum at 350 °C,
D
H = ꢁ46.4 J gꢁ1 = ꢁ28.0 kJ molꢁ1 = ꢁ6.7 kcal molꢁ1
.
The maxi-
mum of the third exo-effect is lying at 415 °C as was determined
from DTA curve. The energy value connected with this
degradation step was estimated to be
D
H = ꢁ2664 J gꢁ1
=
ꢁ1609.1 kJ molꢁ1 = ꢁ385.9 kcal molꢁ1. The thermal decay is fin-
ished at ca. 600 °C. The product of the thermal decomposition
was identified by means of 57Fe Mössbauer spectroscopy as
a-
Fe2O3 (i.e. hematite, d = 0.37 mm sꢁ1
,
e
Q = ꢁ0.21 mm sꢁ1
.
BHF = 51.3 T) the total weight loss found/calcd: 87.7%/87.3%.
Table 4
Selected interatomic parameters (Å, °) of the studied complexes calculated on the B3LYP/6-311+G* level
FeIII
S = 5/2 (Td)
FeIII
S = 3/2 (TB)
FeII
S = 4/2 (Td)
FeII
S = 2/2 (TB)
FeIII
FeII
a
a
Fe—Cl1
Fe—Cl2
Fe—Cl3
Fe—N
2.195
2.207
2.196
2.081
—
112.48
113.97
114.31
104.72
105.52
104.62
—
2.270
2.242
2.298
1.955
1.997
123.45
121.91
113.72
90.56
93.37
95.80
85.34
91.46
83.81
174.87
2.298
2.367
2.269
2.237
—
107.61
128.97
120.57
94.61
95.24
96.68
—
2.376
2.372
2.361
2.007
2.023
114.35
124.11
121.04
90.49
92.46
93.95
86.32
92.61
84.47
174.79
2.259b, 2.310c
2.392b, 2.433c
2.106b, 2.194c
2.101c
2.182b, 2.234c
2.135c
Fe—O
Cl1—Fe—Cl2
Cl1—Fe—Cl3
Cl2—Fe—Cl3
N—Fe—Cl1
N—Fe—Cl2
N—Fe—Cl3
Cl1—Fe—O
Cl2—Fe—O
Cl3—Fe—O
N—Fe—O
—
—
—
—
—
—
a The values represent mean values which were determined from known X-ray structures of complexes bearing bFeCl3N or cFeCl3NO chromophore and are deposited within
the Cambridge Crystallographic Data Centre (CSD). Td, tetrahedron; TB, trigonal-bipyramid.
Figure 6. Geometries of [FeIII(L0)Cl3] (S = 5/2) and [FeIII(L0)Cl3(H2O)] (S = 3/2) complexes optimized on the B3LYP/6-311+G* level.

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Z. Trávnícek et al. / Bioorg. Med. Chem. 16 (2008) 8719–8728
8727
Figure 7. Geometries of [FeII(H+L0)Cl3] (S = 4/2) and [FeII(H+L0)Cl3(H2O)] (S = 2/2) complexes optimized on the B3LYP/6-311+G* level.
cytotoxicity has been found for the complex 6 on the MCF-7 cell
line. These values are quite comparable to those found for cisplatin
or oxaliplatin in the case of the same cell lines.27 All the remaining
complexes were found to be inactive within the evaluated concen-
Table 5
Selected IC50
(l
M) values assessed by a calcein AM assay
IC50
Compound
(lM)
G-361
HOS
K-562
MCF-7
tration interval, and their IC50 values are higher than 50 lM. In
conclusion, we may state that the complex formation had signifi-
cant impact on the cytotoxicity results in the case of the complexes
2 and 6, although the complexes have been characterized as mix-
tures from structural, valence, and spin-state point of view.
[Fe(L2)Cl3]ꢀH2O (2)
>50
>50
>50
>50
>200
8
9
16
>50
4
>50
>200
L2
>50
>50
>50
>200
>50
>50
>50
>200
[Fe(L6)Cl3]ꢀH2O (6)
L6
FeCl3 ꢀ6H2O
L2 = N6-(4-fluorobenzyl)adenosine; L6 = N6-(4-trifluoromethoxybenzyl)-adenosine.
The human cancer cell lines (G-361, malignant melanoma; HOS, osteogenic sar-
coma; K-562, chronic myelogenous leukemia; MCF-7, breast adenocarcinoma) were
Acknowledgments
Authors thank the Ministry of Education, Youth and Sports of
the Czech Republic for financial support (a Grant No.
MSM6198959218). Authors would also like to thank to Dr. Zdenek
treated with the solution of the tested compound in the 0.5–50
l
M range for 72 h,
M was used.
except for FeCl3 ꢀ6H2O, where the concentration range of 0.5–200
l
ˇ
ˇ
Šindelár for magnetic susceptibility measurements and Dita Parob-
Similarly as for FeIII complexes, two different geometries and
spin states were found in the case of FeII components: (i)
[FeII(H+L0)Cl3] – a deformed tetrahedral geometry with S = 4/2
(Fig. 7a, Table 4), (ii) [FeII(H+L0)Cl3(H2O)] – a trigonal-bipyramidal
geometry with S = 2/2 (Fig. 7b, Table 4). Besides, a protonation at
the N1 or N3 position may occur in the case of FeII species. This fact
can be connected with the oxidation of ribose simultaneously
releasing a proton, and moreover, with the tautomeric shift of such
a proton within the adenosine moiety. It has been found that the
system with the ligand protonized at the N1 position is more stable
as compared to the N3-protonized one. The calculated electronic
energies were found to be lower by 11.70 and 11.94 kcal molꢁ1
in favor of the N1-protonized tautomer for tetrahedral and trigo-
nal-bipyramidal arrangement, respectively. We may conclude that
FeII–donor atom bond lengths are elongated in most cases in com-
parison with those calculated for FeIII complexes, which is in good
agreement with X-ray data published recently for complexes
involving the same donor set (see Table 4).15
ková for in vitro cytotoxicity testing.
References and notes
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