Ruthenium(III) complexes with modified nucleobases: N6-Substituted adenines

Article abstract of DOI:10.1016/j.poly.2008.06.013

New chlorido-dimethylsulfoxide-ruthenium(III) complexes with different N⁶-substituted adenines have been prepared and characterized. Three ruthenium complexes have been structurally characterized by X-ray diffraction crystallography: [Ru^II

Full text of DOI:10.1016/j.poly.2008.06.013

Polyhedron 27 (2008) 2851–2858
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Polyhedron
journal homepage: www.elsevier.com/locate/poly
Ruthenium(III) complexes with modified nucleobases: N6-Substituted adenines
a,
a
a
a
Juan J. Fiol a, , Angel García-Raso , Francisca M. Albertí , Andrés Tasada , Miquel Barceló-Oliver ,
*
*
Angel Terrón a, María J. Prieto b, Virtudes Moreno b, Elies Molins c
a Departament de Química, Universitat de les Illes Balears, Campus UIB, 07122 Palma de Mallorca, Spain
b Departament de Química Inorgànica, Universitat de Barcelona, 08028 Barcelona, Spain
c Institut de Ciència de Materials de Barcelona (CSIC), Campus Universitat Autonòma de Barcelona, 08193 Bellaterra, Spain
a r t i c l e i n f o
a b s t r a c t
New chlorido-dimethylsulfoxide-ruthenium(III) complexes with different N6-substituted adenines have
been prepared and characterized. Three ruthenium complexes have been structurally characterized by
X-ray diffraction crystallography: [RuIIICl4(DMSO)[H-(N6-pentyladenine)]] (1), [RuIIICl4(DMSO)[H-(N6-
hexyladenine)]] (2) and [RuIIICl4(DMSO)[H-(N6,N6-dibutyladenine)]] (3). In all cases ruthenium ion show
octahedral geometry coordinated to four chlorido ligands and one S coordinated sulfoxide (DMSO). The
coordination sphere is completed by an adenine moiety coordinated to Ru(III) via N(9) and protonated
at N(3). Other similar complexes have been obtained with N6-propyladenine, [RuIIICl4(DMSO)[H-(N6-pro-
pyladenine)]] ꢀ 0.5EtOH (4) and N6-benzylaminopurine (BAP) [RuIIICl4(DMSO)[H-(BAP)]] ꢀ 0.5H2O (5)
which have been spectroscopically characterized. Otherwise, in different reaction conditions, we have
obtained an out sphere complex of Ru(II), [H-(BAP)][RuIICl3(DMSO)3] (6), with identical complex unit
than the structurally solved [H-(creat)][RuIICl3(DMSO)3] (7) which was included for comparison pur-
poses. Preliminary electrophoretic mobility and atomic force microscopy (AFM) studies of the interaction
between Ru(III) compounds and plasmidic DNA pBR322 have been performed. These results show differ-
ent morphological changes in plasmidic DNA forms.
Article history:
Received 5 February 2008
Accepted 13 June 2008
Available online 24 July 2008
Keywords:
Ruthenium complexes
X-ray structures
Adenine
AFM studies
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
covalent binding and strand cleavage of plasmid DNA have been
reported for several ruthenium(III) complexes [2].
Ruthenium(III) complexes have attracted large attention in the
last 25 years, as potential antitumor agents [1–2]. In particular sev-
eral Ru(III) compounds with halogens and nitrogenated ligands like
[IndH][trans-RuIIICl4(Ind)2] (KP 1019, Ind = indazole), recently
introduced into clinical trials, are active agents against colorectal
tumors [3]. Other Ru(III) complexes of the type [LH][trans-
RuIIICl4(DMSO)(L)] (L = nitrogenated ligand), like NAMI-A
[ImH][trans-RuIIICl4(DMSO)(Im)] (Im = imidazole) which has suc-
cessfully completed a phase I clinical trials show selective antimet-
astatic properties and lack of significant side effects [4–6]. The
chemical behavior of NAMI-A type complexes and their biological
activity in physiological aqueous solutions are related to the step-
wise hydrolysis of chlorido ligands and reduction to Ru(II) species
[4–7]. Therefore Ru(III) complexes are better handled as ‘‘pro-
drugs” which are converted in vivo into the more active species.
Although molecular biophysics studies have shown that com-
pounds like Na[trans-RuIIICl4(DMSO)(Im)] coordinate irreversibly
to DNA [8] it seems quite clear that ruthenium antitumor com-
plexes act in a different way than cisplatin. Activation by reduction,
On the other hand, mono and disubstituted N6-adenines are
especially important substrates owing to their possible cytokinin
activity. Natural cytokinins are adenine derivatives with a side
chain at the N6-position, and participate in conjunction with other
hormones in most aspects of plant growth and development [9].
Furthermore, natural cytokinins and synthetic analogs as well as
their metallic complexes present interesting biological properties
[10,11]. Due to the potential relevance of these products, several
Ru(III) complexes of the type [LH][trans-RuIIICl4(DMSO)(L)],
[trans-RuIIICl4(DMSO)(LH)] or related compounds (L = purine
nucleobase) have been structurally described [12–14]. In a previ-
ous paper, we have studied the synthesis and biological activity
of the [RuIIICl4(DMSO)[H-(N6-butyladenine)]] complex [15].
In order to study the scope and limitations of these synthetic
procedure, we have explored the synthesis of other Ru(III) zwitter-
ionic complexes as [RuCl4(DMSO)HL] by reaction of [trans-
RuIIICl4(DMSO)2]ꢁ with L in EtOH/HCl, where L is a N6-substituted
adenine (see Scheme 1). The structures of [RuIIICl4(DMSO)[H-(N6-
pentyladenine)]] (1), [RuIIICl4(DMSO)[H-(N6-hexyladenine)]] (2)
and [RuIIICl4(DMSO)[H-(N6-dibutyladenine)]] (3) have been deter-
mined by single-crystal X-ray diffraction analyses and the com-
plexes [RuIIICl4(DMSO)[H-(N6-propyladenine)]] ꢀ 0.5EtOH (4) and
* Corresponding authors.
E-mail address: dqujfa0@uib.es (J.J. Fiol).
0277-5387/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2008.06.013

2852
J.J. Fiol et al. / Polyhedron 27 (2008) 2851–2858
responding salt. Yields, elemental analyses, and 1H NMR data are
included in Table 1, and IR data of protonated ligands is discussed
in Table 4. A more complete spectroscopic characterization of these
ligands synthesized and their respective hydrochloride salts is in-
cluded as Supplementary data.
2.2.2. Synthesis of [RuIIICl4(DMSO)[H-(N6-pentyladenine)]] (1),
[RuIIICl4(DMSO)[H-(N6-hexyladenine)]] (2), [RuIIICl4(DMSO)-
[H-(N6-dibutyladenine)]] (3), [RuIIICl4(DMSO)[H-(N6-
propyladenine)]] ꢀ 0.5EtOH (4) and [RuIIICl4(DMSO)[H-
Scheme 1.
(BAP)]] ꢀ 0.5H2O (5)
A 0.05 mmol sample of [NH4][trans-RuCl4(DMSO)2] was dis-
solved in 5 ml of EtOH/HCl (0.1 M). The resulting solution was stir-
red for 5 min at room temperature and 0.1 mmol of the ligand
dissolved in 2 ml of EtOH/HCl (0.1 M) were added. The orange solu-
tion was stirred for 15 min until a deep orange solution was ob-
tained. Orange crystals appeared in the solution after 24 h. The
crystals were filtered off and dried in vacuum. Yield 40%.
[RuIIICl4(DMSO)[H-(BAP)]] ꢀ 0.5H2O (5) have been spectroscopically
characterized (BAP = N6-benzylaminopurine). Moreover, in an at-
tempt to obtain similar complexes from RuCl3 ꢀ 3H2O in DMSO/
HCl [16] or from cis-[RuCl2(DMSO)4] in EtOH/HCl we have obtained
a microcrystalline solid of an outer-sphere complex of Ru(II), [H-
(BAP)][RuIICl3(DMSO)3] (6). A similar crystalline Ru(II) complex
has been isolated with the creatinine bioligand, [H-(crea-
t)][RuIICl3(DMSO)3] (7) which has been structurally solved by
X-ray diffraction for comparison purposes.
2.2.2.1. [RuIIICl4(DMSO)[H-(N6-pentyladenine)]] (1). Anal. Calc. for
C
12H22N5OSCl4Ru: C, 27.33; H, 4.21; N, 13.28. Found: C, 27.86; H,
4.27; N, 13.03%. IR (cmꢁ1): 3485w,br, 1665vs, 1620m, 1579m,
1444m, 1404m, 1378w, 1340w, 1067s, 1019s, 428w. UV–Vis
2. Experimental
(methanol): k 280 (
e
1.1 ꢂ 04), 400 (1.94 ꢂ 103 Mꢁ1 cmꢁ1). KM
/
2.1. Materials, analysis and physical measurements
Xꢁ1 cm2 molꢁ1 (10ꢁ3 mol dmꢁ3 in DMSO, 25 °C) = 8.
All organic, including 6-benzylaminopurine (BAP) and creati-
nine, and inorganic (RuCl3 ꢀ xH2O) reagents were used without fur-
ther purification (Sigma and Aldrich). The starting complexes
[(DMSO)2H][trans-RuIIICl4(DMSO)2] and (NH4)[trans-RuIIICl4(DM-
SO)2] were synthesized according to the procedure of Alessio et
al. [16] and cis-[RuCl2(DMSO)4] to the method reported by Evans
et al. [17].
Tris–HCl, [tris(hydroxymethyl)aminomethane] hydrochloride,
and HEPES, [4-(hydroxyethyl)-1-piperazineethanesulfonic acid]
were obtained from ICN (Spain). pBR322 plasmid DNA and DTT
(1,4-dithio-DL-threitol) were from Boehringer Mannheim (Ger-
many). EDTA and ethydium bromide were from Sigma and ultra-
pure agarose was obtained from Pronadisa (Spain).
2.2.2.2. [RuIIICl4(DMSO)[H-(N6-hexyladenine)]] (2). Anal. Calc. for
C
13H24N5OSCl4Ru: C, 28.84; H, 4.47; N, 12.94. Found: C, 29.00; H,
4.40; N, 12.85%. IR (cmꢁ1): 3500w,br, 1663vs, 1620m, 1579m,
1441m, 1403m, 1377m, 1340w, 1066s, 1019s, 427w. UV–Vis
(methanol): k 277 (
X
e
1.57 ꢂ 104), 400 (1.58 ꢂ 103 Mꢁ1 cmꢁ1). KM
/
ꢁ1 cm2 molꢁ1 (10ꢁ3 mol dmꢁ3 in DMSO, 25 °C) = 7.
2.2.2.3. [RuIIICl4(DMSO)[H-(N6,N6-dibutyladenine)]] (3). Anal. Calc.
for C15H27N5OSCl4Ru: C, 31.70; H, 4.79; N, 12.32. Found: C, 31.59;
H, 4.76; N, 12.09%. IR (cmꢁ1): 3470w,br, 1635vs, 1607vs, 1562m,
1461s, 1402s, 1370m, 1340m, 1080s, 1023s, 691w, 427w. UV–Vis
(methanol): k 288 (
X
e
2.08 ꢂ 104), 399 (3.39 ꢂ 103 Mꢁ1 cmꢁ1). KM
/
ꢁ1 cm2 molꢁ1 (10ꢁ3 mol dmꢁ3 in DMSO, 25 °C) = 14.
Elemental analyses were carried out using Carlo-Erba models
1106 and 1108 and Thermo Finningan Flash 1112 microanalysers.
Infrared spectra (KBr pellets) were recorded on a Bruker IFS 66 and
on a Nicole Impact 400. UV–Vis spectra were recorded on a Varian
Cary 300 Bio UV–Vis spectrophotometer. 1H and 13C NMR spectra
were obtained with a Bruker AMX 300 spectrometer. Proton and
carbon chemical shifts in dimethylsulfoxide (DMSO-d6), chloro-
form (CDCl3) and deuterated water (D2O) solutions were refer-
enced itself to DMSO-d6 [1H NMR d(DMSO) = 2.47 ppm 13C NMR d
(DMSO) = 40.0 ppm], to CDCl3 [1H NMR d(CDCl3) = 7.26 ppm 13C
2.2.2.4. [RuIIICl4(DMSO)[H-(N6-propyladenine)]] ꢀ 0.5EtOH (4). Anal.
Calc. for C12H24N5O1.5SCl4Ru: C, 25.30; H, 4.05; N, 13.41. Found: C,
25.22; H, 3.87; N, 13.54%. IR (cmꢁ1): 3480w,br, 1658vs, 1614m,
1570m, 1445s, 1403m, 1335w, 1271w, 1114m, 1067s, 1018m,
430m. UV–Vis (methanol): k 275 (
e
1.08 ꢂ 104), 400 (1.82 ꢂ 103
Mꢁ1 cmꢁ1). KM ꢁ1 cm2 molꢁ1 (10ꢁ3 mol dmꢁ3 in DMSO, 25 °C) = 8.
/X
2.2.2.5. [RuIIICl4(DMSO)[H-(BAP)]] ꢀ 0.5H2O (5). Anal. Calc. for
C
14H19N5O1.5SCl4Ru: C, 30.23; H, 3.44; N, 12.59. Found: C, 30.35;
NMR d(CDCl3) = 77.0 ppm] and to D2O [1H NMR
d
H, 3.46; N, 12.29%. IR (cmꢁ1): 3445m,br, 1656s, 1573m, 1449m,
(D2O) = 4.79 ppm], respectively. Conductivity measurements were
carried out on a Crison 525 conductimeter at 25 °C.
1409m, 1375m, 1342m, 1065s, 1023m, 432w, UV–Vis (DMSO): k
282 (
e
6.3 ꢂ 103), 405 (1.35 ꢂ 103 Mꢁ1 cmꢁ1). KM
/X
ꢁ1 cm2 molꢁ1
(10ꢁ3 mol dmꢁ3 in DMSO, 25 °C) = 9.
2.2. Syntheses
2.2.3. Synthesis of [H-(BAP)][RuIICl3(DMSO)3] (6)
2.2.1. Synthesis of N6-substituted adenines
Attempts to prepare a similar product from the cis-[RuCl2(DM-
SO)4] in EtOH/HCl (0.1 M) yield the outer-sphere Ru(II) complex,
[H-(BAP)][RuIICl3(DMSO)3] (6). Anal. Calc. for C18H32N5O3S3Cl3Ru:
C, 32.26; H, 4.81; N, 10.45. Found: C, 32.54; H, 4.64; N, 10.11%. IR
(cmꢁ1): 3456w,br, 1652s, 1607m, 1571m, 1509m, 1487m,
1475m, 1453m, 1393m, 1347m, 1095s, 1019s, 424m, 1H NMR, d
(D2O): 8.45br s [1H, C(2)–H], 8.35s [1H, C(8)–H], 7.40m [5H,
C6H5], 4.92br s [2H, C(10)–H], 3.50s [6H, (CH3)3SO], 3.49s [6H,
(CH3)3SO], 3.39s [6H, (CH3)3SO]. 1H NMR, d (DMSO-d6): 10.09br s
[1H, N(6)–H], 8.62s [1H, C(2)–H], 8.56s [1H, C(8)–H], 7.30m [5H,
C6H5], 4.85br s [2H, C(10)–H], 2.29s [18H, (CH3)3SO]. UV–Vis
These ligands were obtained according to previously described
methods [18,19]: a suspension of 0.5 g (3.2 mmol) of 6-chloropu-
rine in 10 ml of n-butanol and 1.5 ml of triethylamine was refluxed
with the required amount (3.2 mmol) of the corresponding amine
during several hours. The resulting solution was evaporated in vac-
uum, yielding a syrup which was treated with concentrated
ammonium hydroxide and evaporated again. The resulting solids
were filtered off and washed with cold water and cold acetone to
remove the triethylammonium hydrochloride impurities. Dissolu-
tion of these compounds in HCl 2 M or in EtOH/HCl yields the cor-

J.J. Fiol et al. / Polyhedron 27 (2008) 2851–2858
2853
Table 1
Yield, elemental analyses, and 1H NMR data of prepared ligands
Ligand
Yield Elemental Analyses
1H NMR data (DMSO-d6)
R
(%)
Found/Calc.
6
N 7
5
4
1N
2
%C
%H
%N
8
9
N
N
H
3
BAP ꢀ HCl
70
54.7
55.1
4.5
4.6
26.7
26.8
10.36br t [1H, N(6)-H], 8.65s [1H, C(2)–H], 8.61s [1H, C(8)–H], 7.38br d [2H, o-C6H5,
Jest = 6.6 Hz], 7.32br t [2H, m-C6H5, Jest = 6.6 Hz], 7.28br t [1H, p-C6H5, Jest = 6.6 Hz], 4.85br d
[2H, C(10)–H, Jest = 5.7 Hz]
o-
10
m-
p-
NH
ipso
12
10
AdeC3
70
50
54.3
54.2
41.5
41.4
6.3
6.3
6.1
6.1
39.8
39.6
30.2
30.1
12.84s [1H, N(9)–H], 8.13s [1H, C(2)–H], 8.04s [1H, C(8)–H], 7.60br s [1H, N(6)–H], 3.40br s
[2H, C(10)–H], 1.57br hex [2H, C(11)–H, Jest = 7.2 Hz], 0.86t [3H, C(12)–H, Jest = 7.2 Hz]
9.95br t [1H, N(6)–H], 8.58s [1H, C(2)–H], 8.54s [1H, C(8)–H], 3.54br m [2H, C(10)–H], 1.57
hex [2H, C(11)–H, Jest = 7.2 Hz], 0.93t [3H, C(12)–H, Jest = 7.2 Hz]
NH
11
13
AdeC3HCl
12
10
14
AdeC5
60
57.7
57.3
7.4
7.5
33.4
33.4
12.74br s [1H, N(9)–H], 8.12s [1H, C(2)–H], 8.03s [1H, C(8)–H], 7.58br s [1H, N(6)–H], 3.42br s
[2H, C(10)–H], 1.56br m [2H, C(11)–H], 1.27br m [4H, C(12)–H/C(13)–H], 0.83br t [3H, C(14)–
H, Jest = 7.2 Hz]
9.619br s [1H, N(6)–H], 8.54s [1H, C(2)–H], 8.48s [1H, C(8)–H], 1.61br quint [2H, C(11)–H,
Jest = 6.9 Hz], 1.26br m [4H, C(12)–H/C(13)–H], 0.84br t [3H, C(14)–H, Jest = 6.9 Hz]
NH
10
11
AdeC5HCl
AdeC6
70
25
49.9
49.7
6.7
6.7
28.8
29.0
12
14
60.3
60.3
7.8
7.8
32.2
31.9
12.84br s [1H, N(9)–H], 8.12s [1H, C(2)–H], 8.02s [1H, C(8)–H], 7.58br s [1H, N(6)–H], 3.43br s
[2H, C(10)–H], 1.53br t [2H, C(11)–H], 1.25br s [6H, C(12)–H/C(13)–H/C(14)–H], 0.82br s [3H,
C(15)–H]
9.57br s [1H, N(6)–H], 8.53s [1H, C(2)–H], 8.47s [1H, C(8)–H], 1.61br quint [2H, C(11)–H],
1.31br m [2H, C(12)–H], 1.26br m [4H, C(13)–H/C(14)–H], 0.83br t [3H, C(15)–H, Jest = 6.9 Hz]
NH
15
13
11
13
11
AdeC6HCl
AdediC4
30
30
51.8
51.6
7.1
7.1
27.2
27.4
12
10'
10
12'
62.8
63.2
8.6
8.6
28.2
28.3
12.87br s [1H, N(9)–H], 8.12s [1H, C(2)–H], 8.04s [1H, C(8)–H], 3.91br s [4H, C(10)–H/C(100)–
H], 1.57br quint [4H, C(11)–H/C(110)–H, Jest = 7.2 Hz], 1.29br hex [4H, C(12)–H/C(120)–H,
Jest = 7.2 Hz], 0.88 t [6H, C(13)–H/C(130)–H, Jest = 7.2 Hz]
8.40s [1H, C(2)–H], 8.35s [1H, C(8)–H], 3.84br s [4H, C(10)–H/C(100)–H], 1.62br quint [4H,
C(11)–H/C(110)–H], 1.33br hex [4H, C(12)–H/C(120)–H, Jest = 7.5 Hz], 0.89t [6H, C(13)–H/
C(130)–H, Jest = 7.5 Hz]
13'
N
11'
AdediC4HCl
45
54.5
55.0
7.7
7.8
24.5
24.7
s = singlet; d = doblet; t = triplet; quint = quintuplet; hex = hexaplet; br = broad; Jest = estimated coupling constant.
(methanol):
k
358
(
e
319 ꢂ Mꢁ1 cmꢁ1). KM
/
X
ꢁ1 cm2 molꢁ1
nated DMSO present rotational disorder which has been modelled
assuming two fragments with complementary occupancies. Also,
the aliphatic chain of the adenines has been split in two (1) or four
(2) different positions to account for the observed disorder.
(10ꢁ3 mol dmꢁ3 in DMSO, 25°C) = 50.
Although complex (6) and the structurally solved [H-(crea-
t)][RuIICl3(DMSO)3] (7) present the same anion complex unit (see
Section 3), comparison of their powder X-ray diffraction patterns
revealed that both compounds do not have the same packing. De-
tails of the synthesis and description of the structure of the creat-
inine complex (7) are included in the Supplementary data
(Appendix B).
2.4. Preparation of adducts DNA–metal complexes
Fifteen nanograms of pBR322 DNA were incubated in an appro-
priate volume with the required complex concentration corre-
sponding to the molar ratio ri = 0.5. Ruthenium complexes were
dissolved in HEPES buffer (4 mM HEPES, 10 mM KCl and 2 mM
MgCl2, pH 7.4). The different solutions were passed through
0.2 nm FPO30/3 filters (Scheicher & Schuell, Germany). The incuba-
tion was run at 37 °C for 4 h.
2.3. X-ray crystallography
Suitable crystals of (1), (2), (3) and (7) were selected for X-ray
single crystal diffraction experiments and mounted at the tip of
glass fibres on an Enraf-Nonius CAD4 diffractometer producing
graphite monochromated Mo K
a
radiation (k = 0.71073 Å). In each
2.5. Atomic force microscopy (sample preparation and imaging)
case, after the random search of 25 reflections, the indexation pro-
cedure gave rise to the cell parameters (see Table 2 for a summary
Samples were prepared by placing a drop (3 ll) of DNA solution
of the crystal data). Intensity data were collected in the
mode and corrected for Lorenz and polarization effects. The
absorption correction was performed following the empirical
x
–2h scan
or DNA–metal solution onto freshly cleaved green mica (Ted Pella,
Inc., CA, US). After adsorption for 5 min at room temperature, the
sample was gently rinsed with MilliQ water and dried under a
stream of compressed argon gas. Imaging was performed using a
multimode atomic force microscope with a Nanoscope IIIa control-
ler (Veeco/Digital Instruments, Santa Barbara, CA, USA) operating
in air and at room temperature (t = 23 2 °C) and a relative humid-
ity (RH) always lower than 45%. Commercially available cantilevers
(NCH Pointprobe, Nanosensors, Norderfriedrichskoog, Germany)
were used for tapping mode scanning with a root mean square
amplitude of 0.7 V (ꢃ9 nm) and a drive frequency of ꢃ300 kHz.
Images were captured in height mode at a scan rate of ꢃ1 Hz in
a 512 ꢂ 512 pixel format.
W
-
scan [20] (7) and DIFABS [21] (1, 2 and 3) methods. The structural
resolution procedure was made using the WInGX package [22].
Solving for structure factor phases was performed by SIR2002
[23] (7) and SIR2004 [24] (1, 2 and 3), and the full matrix refine-
ment by SHELXL97 [25] for all of them. Non-H atoms were refined
anisotropically and H-atoms were introduced in calculated posi-
tions and refined riding on their parents atoms except for proton-
ation sites (1, 2 and 3). H-atoms of protonation [H(3)] were located
in Fourier maps and refined isotropically. A summary of refinement
parameters can also be seen in Table 2. In 1, 2 and 3, the coordi-

2854
J.J. Fiol et al. / Polyhedron 27 (2008) 2851–2858
Table 2
Selected crystallographic data for the compounds 7, 1, 2 and 3
Identification code
7
1
2
3
Empirical formula
Formula weight
C
10H26Cl3N3O4RuS3
C12H22Cl4N5ORuS
527.28
C13H24Cl4N5ORuS
541.30
C15H28Cl4N5ORuS
569.36
555.94
T (K)
293(2)
294(2)
294(2)
294(2)
0
Wavelength (ÅA)
Crystal system
Space group
0.71073
orthorhombic
Pnaa
0.71073
orthorhombic
P212121
0.71073
orthorhombic
P212121
0.71073
monoclinic
P21/c
a (Å)
b (Å)
c (Å)
14.107(3)
16.589(3)
17.594(2)
7.6917(15)
13.101(3)
20.008(5)
7.826(3)
13.311(4)
20.350(7)
13.105(3)
12.979(3)
14.771(3)
113.97(3)
2295.7(10)
4
1.647
1.255
1156
0.27 ꢂ 0.15 ꢂ 0.15
1.7–26.96
ꢁ16 6 h 6 15
0 6 k 6 16
0 6 l 6 18
5008
b (°)
V (Å3)
4117.4
8
1.794
1.475
2016.2(8)
4
1.737
1.422
1060
0.37 ꢂ 0.28 ꢂ 0.12
1.86–24.99
ꢁ9 6 h 6 9
0 6 k 6 15
0 6 l 6 23
3522
2119.9(13)
4
1.696
1.355
1092
0.45 ꢂ 0.06 ꢂ 0.03
1.83–24.98
ꢁ9 6 h 6 9
0 6 k 6 15
0 6 l 6 24
3704
Z
Dcalc (Mg/m3)
Absorption coefficient (mmꢁ1
F(000)
)
2256
Crystal size (mm3)
0.78 ꢂ 0.16 ꢂ 0.12
2.22–30.41
ꢁ20 6 h 6 0
ꢁ23 6 k 6 0
0 6 l 6 25
6223
h Range for data collection (°)
Index ranges
Reflections collected
Independent reflections
Completeness to final theta (%)
Absorption correction
Maximum and minimum transmission
Refinement method
6223
99.8
3522
99.8
empirical (DIFABS)
0.8479 and 0.6213
3704
100
5008
100
W
-scan
0.8429 and 0.7352
Full-matrix least-squares on F2
6223/0/224
0.9605 and 0.5808
0.8341 and 0.728
Data/restraints/parameters
3522/393/290
0.828
3704/553/400
0.896
5008/81/281
1.003
Goodness-of-fit on F2
1.018
Final R indices [I > 2
R indices (all data)
r
(I)]
R1 = 0.0340
wR2 = 0.0945
R1 = 0.0597
wR2 = 0.0993
R1 = 0.0729
wR2 = 0.1124
R1 = 0.215
wR2 = 0.1415
0.00 (TWIN refinement)
0.54 and ꢁ0.868
R1 = 0.0764
wR2 = 0.1108
R1 = 0.223
R1 = 0.0589
wR2 = 0.1387
R1 = 0.1054
wR2 = 0.1553
wR2 = 0.1398
ꢁ0.05(13)
Absolute structure parameter
Largest difference peak and hole (e Åꢁ3
)
1.369 and ꢁ0.577
0.471 and ꢁ0.673
0.772 and ꢁ0.576
2.6. Gel electrophoresis of drug-pBR322 complexes
pBR322 DNA aliquots (0.25 g/mL) were incubated in TE buffer
(10 mM Tris–HCl, 1 mM EDTA, pH 7.5) at molar ratio ri = 0.50 for
electrophoresis study. Incubation was carried out in the dark at
the site of coordination and there are only few exceptions that vio-
late these general guidelines [26].
l
All Ru(III) complexes show metal–nitrogen [2.139(12) for (1),
2.113(12) for (2) and 2.141(4) Å for (3)] and metal–sulfur bond
lengths [2.272(5) for (1), 2.264(5) for (2) and 2.2629(16) for (3)],
comparable to those of related complexes [13,15,27]. The Ru–Cl
bond distances [ranging from 2.325(4) to 2.359(4) Å for (1),
2.329(4) to 2.350(4) Å for (2) and 2.3439(18) to 2.3607(17) Å for
(3)] are in agreement with published values found in the related
structures above mentioned. The same can be mentioned with
the cis angles around the metal which vary between 86.7(3)° and
94.14(17)° for (1), 87.6(3)° and 94.49(18)° for (2) and 87.73(14)°
and 93.39(7)° for (3), while the trans angles are between
176.44(19)° and 178.5(4)° for (1), 177.80(18)° and 177.25(17)°
for (2) and 176.34 (15)° and 177.56(6)° for (3). On the other
hand, a comparison between the protonated adenines [(1), (2)
and (3)] and neutral adenine shows a more significant increment
of the C(2)–N(3)–C(4) angle which is in agreement with N(3) pro-
tonation [26]. Selected bond distances and angles are shown in
Table 3.
As observed previously [15], in the three complexes the proton-
ated adenine ligand is involved in an intramolecular hydrogen
bond with cis chlorido ligand: N(3)–HꢀꢀꢀCl = 2.68 for (1), 2.60 for
(2) and 2.54 for (3).
By comparison of powder X-ray diffraction patterns of complex
(6) and the structurally solved [H-(creat)][RuIICl3(DMSO)3] (7) it is
possible to deduce that both compounds do not have the same
packing. Detailed description of the structure of the outer-sphere
creatinine complex [H-(creat)][RuIICl3(DMSO)3] (7) is included in
the Supplementary data. The anion has a facial octahedral struc-
ture with three chlorido ligands and three DMSO (coordinated
37 °C for 24 h. 4
lL of charge marker were added to aliquots parts
of 20 L of the compound–DNA complex. The mixture was electro-
l
phoresed in agarose gel (1% in TBE buffer, Tris–Borate–EDTA) for
5 h at 1.5 V/cm. Afterwards, the DNA was dyed with ethydium bro-
mide solution (0.75 lg/mL in TBE) for 6 h. A sample of free DNA
was used as control. The experiment was carried out in an ECOGEN
horizontal tank connected to a PHARMACIA GPS 200/400 variable
potential power supply and the gel was photographed with an
image Master VDS, Pharmacia Biotech.
3. Results and discussion
3.1. Description of X-ray structures [RuIIICl4(DMSO)[H-(N6-
pentyladenine)]] (1), [RuIIICl4(DMSO)[H-(N6-hexyladenine)]] (2) and
[RuIIICl4(DMSO)[H-(N6,N6-dibutyladenine)]] (3)
The zwitterionic inner-sphere complexes (1), (2) and (3) (Figs.
1–3) present slightly distorted octahedral coordination around
Ru(III) ion with four chlorido ligands in the basal plane and the
two axial positions occupied by a S atom of a DMSO molecule
and the N(9) atom present in the corresponding purine ring. These
complexes show a similar disposition to that found in NAMI-A [4].
Previous crystallographic studies have demonstrated that the
most probable site of coordination on unsubstituted purines is
the imidazole N(9) nitrogen atom. When N(9) is blocked, N(7) is

J.J. Fiol et al. / Polyhedron 27 (2008) 2851–2858
2855
Fig. 1. ORTEP of [RuIIICl4(DMSO)[H-(N6-pentyladenine)]] (1). Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii.
Fig. 2. ORTEP of [RuIIICl4(DMSO)[H-(N6-hexyladenine)]] (2). Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii.
Fig. 3. ORTEP of [RuIIICl4(DMSO)[H-(N6-dibutyladenine)]] (3). Displacement ellipsoids are drawn at 50% probability level and H atoms are drawn as circles of arbitrary radii.
via S) molecules (Fig. 4). Selected bond distances and angles are
shown in Table 2 of Supplementary data.
changes in the complex bands are shown in Table 4. The most rel-
evant features are related to the binding between the Ru(III) and a
nitrogen atom of the purine ring [bond through the N(9) atom of
adenine and protonation of the N(3) atom]. These changes are:
(i) very small shifts on the bands related to [d(NHR)] and
[d(C@N–H)] of protonated N6-substituted adenine which indicate
the zwitterionic form of the complexes. The bands appearing at
1662–1668 cmꢁ1 and 1611–1615 cmꢁ1 show small shifts probably
as a consequence of a change in H-bonding (in complex 3, only one
band is observed at 1637 cmꢁ1); (ii) The 1513–1520 cmꢁ1 band
3.2. Infrared spectra
The IR spectra of inner-sphere complexes, [RuIIICl4(DMSO)[H-
(N6-pentyladenine)]] (1), [RuIIICl4(DMSO)[H-(N6-hexyladenine)]]
(2), [RuIIICl4(DMSO)[H-(N6,N6-dibutyladenine)]] (3), [RuIIICl4(DM-
SO)[H-(N6-propyladenine)]] ꢀ 0.5EtOH (4) and [RuIIICl4(DMSO)
[H-(BAP)]] ꢀ 0.5H2O (5) were compared with those of protonated
ligands. Tentative band assignments (cmꢁ1) for N6-substituted
adenines according to literature [28–30] and some characteristic
assignable to
m[C(4)–N(9)] + d[C(8)–H] + d[CH2] disappears in all
spectra of the complexes; iii) The band at ca. 1460 cmꢁ1 related

2856
J.J. Fiol et al. / Polyhedron 27 (2008) 2851–2858
ligand. Finally, strong bands at ca. 1070 cmꢁ1 assignable to
m
(S@O)
r(CH3)] as
(Ru–S)
Table 3
of the S-bonded DMSO molecules and ca. 1020 cmꢁ1
[q
Selected bond lengths (Å) and bond angles (°) for complexes 1–3
well as a weak intensity peak at ca. 430 cmꢁ1 related to
m
[RuIIICl4(DMSO)[H-(N6-pentyladenine)]] 1
Ru(1)–S(1)
Ru(1)–N(9)
S(1)–O(1S)
2.272(5)
2.139(12)
1.48(2)
Ru(1)–Cl(1)
Ru(1)–Cl(2)
Ru(1)–Cl(3)
Ru(1)–Cl(4)
2.325(4)
2.342(4)
2.328(5)
2.359(4)
modes, are observed in all the complexes.
The IR spectrum of the outer-sphere complex [H-(BA-
P)][RuIICl3(DMSO)3] (6) was compared with that of [H-(crea-
t)][RuIICl3(DMSO)3] (7) (See Supplementary data). Both spectra
are typical of fac-[RuIICl3(DMSO)3]ꢁ units in which two strong
bands are observed. The first one at 1095 cmꢁ1 with small shoulder
N(9)–Ru(1)–S(1)
S(1)–Ru(1)–Cl(1)
S(1)–Ru(1)–Cl(2)
S(1)–Ru(1)–Cl(3)
S(1)–Ru(1)–Cl(4)
Cl(1)–Ru(1)–Cl(2)
Cl(1)–Ru(1)–Cl(4)
Cl(2)–Ru(1)–Cl(4)
C(6)–N(1)–C(2)
178.5(4)
N(9)–Ru(1)–Cl(1)
N(9)–Ru(1)–Cl(2)
N(9)–Ru(1)–Cl(3)
N(9)–Ru(1)–Cl(4)
Cl(1)–Ru(1)–Cl(3)
Cl(3)–Ru(1)–Cl(2)
Cl(3)–Ru(1)–Cl(4)
C(2)–N(3)–C(4)
88.5(4)
86.7(3)
88.6(4)
92.77(17)
94.14(17)
90.09(17)
88.55(16)
88.47(18)
92.03(17)
177.24(17)
119.2(17)
90.6(3)
at ca. 1080 cmꢁ1 due to
and the second at 1019 cmꢁ1 corresponding to
due to (ring) exhibit essentially the same pattern of that observed
m
(S@O) of the S-bonded DMSO molecules
r(CH3). The bands
176.44(19)
89.21(17)
90.16(16)
118.4(17)
q
m
for the protonated ligand with important differences with respect
to the spectra of the inner-sphere complexes. The medium inten-
sity peak at 428 cmꢁ1 is related to
m(Ru–S).
[RuIIICl4(DMSO)[H-(N6-hexyladenine)]] 2
Ru(1)–S(1)
Ru(1)–N(9)
S(1)–O(1S)
2.264(5)
2.113(12)
1.561(19)
Ru(1)–Cl(1)
Ru(1)–Cl(2)
Ru(1)–Cl(3)
Ru(1)–Cl(4)
2.329(4)
2.350(4)
2.337(4)
2.346(4)
3.3. 1H NMR spectra of Ru(II) compounds
The 1H NMR spectrum of [H-(BAP)][RuIICl3(DMSO)3] (6) in D2O
shows three singlets between 3.37 and 3.27 ppm attributed to
the methyl protons of dimethylsulphoxide [31]. The presence of
more than one signal in D2O results from the formation of different
aquospecies as has been previously reported in the literature [16].
In a few days, the solution turns to greenish gray and the signals of
the spectrum show a progressive broadening and shifting which
are indicative of decomposition of the complex and presence of
paramagnetic Ru(III) species. On the other hand, the corresponding
spectrum in DMSO-d6 shows only one signal for the six equivalent
methyl groups of dimethylsulphoxide at 3.29 ppm, as it was ex-
pected. Similar results are obtained in the corresponding creatinine
complex [H-(creat)][RuIICl3(DMSO)3] (7).
N(9)–Ru(1)–S(1)
S(1)–Ru(1)–Cl(1)
S(1)–Ru(1)–Cl(2)
S(1)–Ru(1)–Cl(3)
S(1)–Ru(1)–Cl(4)
Cl(1)–Ru(1)–Cl(2)
Cl(1)–Ru(1)–Cl(4)
Cl(2)–Ru(1)–Cl(4)
C(6)–N(1)–C(2)
[RuIIICl4(DMSO)[H-(N6-dibutyladenine)]] 3
Ru(1)–S(1)
Ru(1)–N(9)
S(1)–O(1S)
177.6(4)
N(9)–Ru(1)–Cl(1)
N(9)–Ru(1)–Cl(2)
N(9)–Ru(1)–Cl(3)
N(9)–Ru(1)–Cl(4)
Cl(1)–Ru(1)–Cl(3)
Cl(3)–Ru(1)–Cl(2)
Cl(3)–Ru(1)–Cl(4)
C(2)–N(3)–C(4)
88.4(3)
89.8(3)
89.6(3)
90.43(16)
88.10(16)
91.62(16)
94.49(18)
89.43(16)
89.63(16)
177.25(17)
117.8(8)
87.6(3)
177.80(18)
91.42(16)
89.43(16)
118.9(8)
2.2629(16)
2.141(4)
1.515(10)
Ru(1)–Cl(1)
Ru(1)–Cl(2)
Ru(1)–Cl(3)
Ru(1)–Cl(4)
2.3439(18)
2.3607(17)
2.3465(18)
2.3511(17)
N(9)–Ru(1)–S(1)
S(1)–Ru(1)–Cl(1)
S(1)–Ru(1)–Cl(2)
S(1)–Ru(1)–Cl(3)
S(1)–Ru(1)–Cl(4)
Cl(1)–Ru(1)–Cl(2)
Cl(1)–Ru(1)–Cl(4)
Cl(2)–Ru(1)–Cl(4)
C(6)–N(1)–C(2)
176.34(15)
89.02(7)
91.40(6)
93.39(7)
90.84(6)
89.99(7)
91.00(7)
177.56(6)
121.0(5)
N(9)–Ru(1)–Cl(1)
N(9)–Ru(1)–Cl(2)
N(9)–Ru(1)–Cl(3)
N(9)–Ru(1)–Cl(4)
Cl(1)–Ru(1)–Cl(3)
Cl(3)–Ru(1)–Cl(2)
Cl(3)–Ru(1)–Cl(4)
C(2)–N(3)–C(4)
87.42(14)
87.73(14)
90.14(14)
90.10(14)
177.10(7)
88.34(7)
3.4. Electronic spectra
The electronic spectra of the 1–4 complexes were obtained in
methanol solution and are suggestive of octahedral geometry
around Ru(III). As observed in similar Ru(III) compounds a band
centred at 400 nm with charge-transfer character is observed
90.57(8)
117.4(6)
[(
e
= 1.94 ꢂ 103) for 1; (1.58 ꢂ 103) for 2; (3.39 ꢂ 103) for 3 and
(1.82 ꢂ 103) for 4]. The electronic spectrum of complex 5 was per-
formed in DMSO solution due to its low solubility in MeOH,
[405 nm (
e
= 1.35 ꢂ 103)]. Moreover, an important band corre-
*
sponding to the
p
?
p
transition of the protonated adenine ring,
is present [280 (1.1 ꢂ 104) for 1; 277 (1.57 ꢂ 104) for 2; 288
(2.08 ꢂ 104) for 3, 275 (1.08 ꢂ 104) for 4 and 282 (6.3 ꢂ 103) for
5]. A freshly solution was used in all our measurements in order
to avoid the known hydrolysis processes of these Ru(III) complexes
in methanol [16].
The electronic spectrum of the complex [H-(BAP)][RuIICl3(DM-
SO)3] (6) was obtained in a freshly prepared methanol solution
and is suggestive of octahedral geometry around Ru(II). The
observed band at 358 (e = 319) nm is assigned to the transition
1A1g ? T1g
.
1
3.5. Ruthenium complexes–plasmidic DNA interactions
Atomic force microscopy and electrophoretic mobility (Figs. 5
and 6, respectively) were used to verify the interactions of isolated
ruthenium complexes and DNA pBR322. Plasmidic DNA was incu-
bated for 4 h at 37 °C with the series of complexes 1–5 at identical
concentrations.
Fig. 4. ORTEP of [H-creat][RuIICl3(DMSO)3] (7). Displacement ellipsoids are drawn
at 50% probability level and H atoms are drawn as circles of arbitrary radii.
In Fig. 5a plasmid pBR322 DNA without previous treatment, in
mixed covalently closed circular (ccc) and open (oc) forms, was
AFM imaged. AFM images of the same DNA treated with the com-
plexes 1–5 are presented in Fig. 5b–f. There are not noticeable dif-
ferences in the images corresponding to the different complexes.
to m
[C(8)–N(9)] splits into a shoulder at ca. 1480 cmꢁ1 and a med-
ium intensity band between 1440 and 1460 cmꢁ1. These features
agree with the coordination of Ru to the N(9) atom of the adenine

J.J. Fiol et al. / Polyhedron 27 (2008) 2851–2858
2857
Table 4
Selected IR bands (cmꢁ1) for the complexes and tentative assignments
AdeC5 ꢀ HCl
(1)
AdeC6 ꢀ HCl
(2)
AdediC4 ꢀ HCl
(3)
AdeC3 ꢀ HCl
(4)
BAP ꢀ HC1
(5)
(6)
d(NHR)
d[C@N–H]
1668s
1665s
1620m
1579w
1665s
1663s
1620w
1579w
1635s
1607s
1562m
1668s
1659s
1618m
1576m
1662s
1656vs
1618sh
1573m
1652vs
1607m
1571m
1509w
m
(ring)
1615m
1578w
1519m
1614m
1578m
1518m
1637s
1580s
1615m
1582m
1519w
1611m
1574m
1513m
1520m
1483m
1467sh
1456m
1410m
1376m
1350m
*
ov.(sh)
ov.(sh)
ov.(sh)
1460m
1487s
ov.(sh)
1449m
**
m
(ring)
1463s
1470w
1437m
1395m
1385m
1345m
1457m
1426m
1399m
1377m
1340m
ov.(sh)
1066s
1017s
427m
1450m
1394m
1344m
1453m
1393m
1347m
1444m
1404m
1378w
1340w
1112m
1067s
1019s
428w
1456m
1395m
1374m
1345m
1441m
1403m
1377m
1340w
1111m
1066s
1019s
427w
1396m
1373w
1346w
1402m
1370m
1350m
1108sh
1080s
1409m
1375m
1342m
1117m
1065s
*
m
(S@0)
(DMSO)
r(CH3)
(Ru–S)
1095s
1019m
424m
q
1023m
427w
1023m
432w
m
*
[m
= stretching, d = bending, s = strong, m = medium, w = weak, br = broad, sh = shoulder, ov. = overlapping].
[C(4)–N(9)] + d[C(8)–H] + d[CH2]; 1450–1467 cmꢁ1: d[C(2)–H] +
m[C(8)–N(9)] + d[C(8)–H].
** m (ring bands) Refs. [28–30]: 1513–1520 cmꢁ1
:
m
Fig. 5. Plasmidic DNA pBR322 (a), incubated in presence of: [RuIIICl4(DMSO)[H-(N6-pentyladenine)]] (1), (b); [RuIIICl4(DMSO)[H-(N6-hexyladenine)]] (2) (c);
[RuIIICl4(DMSO)[H-(N6-dibutyladenine)]] (3) (d); [RuIIICl4(DMSO)[H-(N6-propyladenine)]]ꢀ0.5EtOH (4) (e). [RuIIICl4(DMSO)[H-(BAP)]] ꢀ 0.5H2O (5) (f). In all cases, Ru:DNA
base pairs relationship is 1:20 (each circular plasmid has 4361 base pairs).
Probably the type of interaction is identical for all the series and
the variation of the nature and length of the chain do not affect
it. However, in all of them, kinks can be observed confirming inter-
action with DNA in agreement with electrophoretic mobility re-
sults. Nuclease activity is not observed in the different complexes
and the modifications indicated confirm that these complexes do
not cleave the pBR322 plasmid DNA. They yield more coiled and/
or more associated plasmids which are in agreement with different
types of interactions between these ruthenium complexes and the
corresponding DNA: ruthenium covalent binding to the heterocy-
clic nitrogens, intercalation of the adenine ring and electrostatic
interaction of the protonated nitrogens and the phosphate groups
of other plasmidic units.
Fig. 6. Electrophoresis experiments: Plasmidic DNA pBR322 (DNA control),
The influence of the compounds on the tertiary structure of
incubated in presence of: [RuIIICl4(DMSO)[H-(N6-pentyladenine)]] (1), [RuIIICl4-
DNA was determined by its ability to modify the electrophoretic
mobility of the covalently closed circular (ccc) and open (oc)
forms of pBR322 plasmid DNA. Fig. 6 shows, from left to right,
(DMSO)[H-(N6-hexyladenine)]] (2), [RuIIICl4(DMSO)[H-(N6-dibutyladenine)]] (3),
[RuIII-Cl4(DMSO)[H-(N6-propyladenine)]] ꢀ 0.5EtOH (4), [RuIIICl4(DMSO)[H-(BAP)]] ꢀ
0.5H2O (5).

2858
J.J. Fiol et al. / Polyhedron 27 (2008) 2851–2858
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Topics in Biological Inorganic Chemistry, vol. 1, Springer, Berlin, 1999, pp. 143–
170.
[5] E. Alessio, G. Mestroni, A. Bergamo, G. Sava, in: A. Sigel, H. Sigel (Eds.), Metal
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the mobility of the native pBR322 plasmid DNA and the plasmid
DNA incubated with the compounds 1–5. The behavior of the gel
electrophoretic mobility of these two forms, ccc and oc, of
pBR322 plasmid and DNA ruthenium compounds adducts (Fig. 6)
presents differences in comparison to the DNA pattern. Incubation
with complexes (1) and (3) show that only the form oc of DNA is
present, while in case of the other compounds (2), (4) and (5) the
DNA pattern is modified showing a wide band with lower mobility
than ccc form of free plasmid control as it was observed previously
[15]. Probably, the insertion of the purine ligand in the double helix
origins opening of the DNA forms. We are aware that under phys-
iological conditions ruthenium compounds are prone to various
hydrolytic processes [2,17,22,57] but the exact study of such reac-
tions was out of the scope of this work.
[14] C. Price, M.R.J. Elsegood, W. Clegg, N.H. Rees, A. Houlton, Angew. Chem., Int. Ed.
Engl. 36 (1997) 1762.
Acknowledgements
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Bunic, A. Golobic, I. Turel, Inorg. Chem. Commun. 8 (2005) 800.
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Chem. 30 (1991) 609.
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We are grateful to Dirección General de Investigación Projects
CTQ2006-09339/BQU and CTQ2005-01834 for financial support.
FMA and MB-O acknowledge grants of Conselleria d’Economia, His-
enda i Innovació (Govern de les Illes Balears).
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