New 7-azaindole palladium and platinum complexes: Crystal structures and theoretical calculations. in vitro anticancer activity of the platinum compounds

Article abstract of DOI:10.1039/b920854b

A series of new 7-azaindolyl palladium and platinum complexes have been prepared. The X-ray structure determinations of [NBu₄][M(C ₆F₅)₂(Haza-N7)(aza-N1)]·Haza [M = Pd, Pt; aza = 7-azaindolate (lH-pyrrolo[2,3-b]pyridinate)] have established for the first time the coordination to the same metal centre of both neutral and anionic forms of the ligand. Theoretical calculations at the mPW1B95/aug6-31G* */StRSCecp level show that both kinetic and thermodynamic arguments support the observed coordination and H-bonding interaction of the pyrrolo and pyridine moieties of the neutral and deprotonated heterocyclic ligands. At 48 h incubation time the new platinum complex [Pt(dmba)(aza-N1)(DMSO)] (dmba = N,N-dimethylbenzylamine-κN,κC) shows sub-micromolar activity both in A2780 and T47D [IC₅₀ (μM) = 0.34 and 0.53, respectively]. The DNA adduct formation of the new platinum complexes was followed by circular dichroism and electrophoretic mobility. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b920854b

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www.rsc.org/dalton | Dalton Transactions
New 7-azaindole palladium and platinum complexes: crystal structures and
theoretical calculations. In vitro anticancer activity of the platinum
compounds†
Jose´ Ruiz,*a Venancio Rodr´ıguez,a Concepcio´n de Haro,a Arturo Espinosa,*b Jose´ Pe´rezc and Christoph Janiakd
Received 7th October 2009, Accepted 15th January 2010
First published as an Advance Article on the web 13th February 2010
DOI: 10.1039/b920854b
A series of new 7-azaindolyl palladium and platinum complexes have been prepared. The X-ray
structure determinations of [NBu4][M(C6F5)2(Haza-N7)(aza-N1)]·Haza [M = Pd, Pt; aza =
7-azaindolate (lH-pyrrolo[2,3-b]pyridinate)] have established for the first time the coordination to the
same metal centre of both neutral and anionic forms of the ligand. Theoretical calculations at the
mPW1B95/aug6-31G**/StRSCecp level show that both kinetic and thermodynamic arguments
support the observed coordination and H-bonding interaction of the pyrrolo and pyridine moieties of
the neutral and deprotonated heterocyclic ligands. At 48 h incubation time the new platinum complex
[Pt(dmba)(aza-N1)(DMSO)] (dmba = N,N-dimethylbenzylamine-kN,kC) shows sub-micromolar
activity both in A2780 and T47D [IC50 (mM) = 0.34 and 0.53, respectively]. The DNA adduct formation
of the new platinum complexes was followed by circular dichroism and electrophoretic mobility.
coordination chemistry.12–15 In the 7-aza ligand the donor atoms
are in rigid positions, although they have a large bite angle
Multidentate nitrogen-donor ligands are designed with the aim
(Chart 1).
Introduction
of preparing polynuclear compounds with an appropriate metal–
metal separation, which is very important in studies of functional
models for bimetallic biosites.1 Such ligands are also extensively
used for the assembly of cyclic supermolecules,2–7 the prepara-
tion and characterization of polynuclear metal complexes and
their potential use for the study of multi-centered catalysis.8
Chart 1
Recent reports by Reedijk et al. have shown that the azolate-
bridged dinuclear platinum(II) complexes, [{cis-Pt(NH3)2} (m-
OH)(m-pz)](NO3)2 (pz = pyrazolate) and [{cis-Pt(NH3)2}22(m-
In this article we describe the synthesis of 7-azaindolyl metal
complexes of the types [M(dmba)(aza-N1)(L)], [M(C6F5)2(Haza-
OH)(m-1,2,3-tz-N1,N2)](NO3)2 (1,2,3-tz = 1,2,3-triazolate), ex-
hibit remarkably high in vitro cytotoxicity on several human
tumour cell lines and largely circumvent the cross-resistance
to cisplatin.9–11 Metal 7-azaindolate (aza) complexes have also
attracted considerable interest in recent years due to their versatile
N7)2] and [NBu4][M(C6F5)2(Haza-N7)(aza-N1)]·Haza [M = Pd,
Pt; aza = 7-azaindolate (lH-pyrrolo[2,3-b]pyridinate); dmba =
N,N-dimethylbenzylamine-kN,kC], the latter exhibiting for the
first time the coordination to the same metal centre of both
neutral and anionic forms of the ligand according to a search
of the Cambridge Structure Database (CSD)16 and a survey
R
of recent literature in SciFinderꢀ Scholar. The azaindolate-
aDepartamento de Qu´ımica Inorga´nica, Facultad de Qu´ımica, Universidad de
Murcia, 30071, Murcia, Spain. E-mail: jruiz@um.es; Fax: +34 868 384148;
Tel: +34 868 887455
bridged dinuclear complexes [NBu4]2[{cis-M(C6F5)2}2(m-OH)(m-
aza-N1,N7)] (M = Pd, Pt) have also been prepared. Calculations
by means of DFT-based calculations at the BP86/def2TZVP level
have been undertaken. Values of IC50 were studied for the new
platinum complexes against a panel of human tumor cell lines
representative of ovarian (A2780 and A2780cisR), and breast
cancers (T47D, cisplatin resistant). The DNA adduct formation
of the new platinum complexes is also reported.
bDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad
de Murcia, 30071, Murcia, Spain. E-mail: artuesp@um.es; Fax: +34
868884149; Tel: +34 868 887489
Departamento de Ingenier´ıa Minera, Geolo´gica y Cartogra´fica (Area
c
´
de Qu´ımica Inorga´nica), Universidad Polite´cnica de Cartagena, 30203-,
Cartagena, Spain. E-mail: Jose.Pperez@upct.es; Fax: +34 968 325420;
Tel: +34 968 326420
dInstitut fu¨r Anorganische und Analytische Chemie, Universita¨t Freiburg,
Albertstr., 21, 79104, Freiburg, Germany. E-mail: janiak@uni-freiburg.de;
Fax: +49 761 2036147; Tel: +49 761 2036127
Results and discussion
† Electronic supplementary information (ESI) available: Figures illustrat-
ing the molecular structure of 1, the toluene disorder in 9, the TGA-DTA of
complexes 3 and 4 and other significant MO in 6calc. Cartesian coordinates
and energies for all calculated species and HSAB-derived parameters for
the reaction of 7 with aza. CCDC reference numbers 717464–717466
and 750363. For ESI and crystallographic data in CIF format see DOI:
10.1039/b920854b
Neutral bis(7-azaindolyl) complexes cis-[M(C6F5)2(Haza-N7)2]
The reaction of [M(C6F5)2(PhCN)2]17,18 (M = Pd, Pt) with Haza
in the molar ratio 1 : 2 gives the corresponding bis(7-azaindolyl)
complex of [M(C6F5)2(Haza-N7)2] 1–2 (Scheme 1). The reactions
3290 | Dalton Trans., 2010, 39, 3290–3301
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Fig. 1 The two possible atropisomers in square-planar metal complexes
containing two equal planar ligands occupying cis coordination positions.
about 100 ◦C where decomposition with loss of all the (H)aza
groups starts (ESI, Fig. S3 and S4).† The reaction of 1 or 2
with NBu4OH in the absence of additional Haza yielded only
a mixture of the starting material with 3 or 4, respectively. The
palladium compound 3, alternatively, can also be prepared from
the hydroxo palladium complex [NBu4]2[Pd(C6F5)2(m-OH)]218 and
Haza in a 1 : 8 molar ratio. The reaction of [NBu4]2[M(C6F5)2(m-
OH)]218,26 with Haza (in a 1 : 1 molar ratio for Pd, 1 : 2 molar ratio
for Pt) yields the corresponding azaindolate dinuclear complex
[NBu4]2[{M(C6F5)2}2(m-OH)(m-aza-N7,N1)] [M = Pd (5), Pt (6)].
The 1H NMR spectra of 3 and 4 in CD2Cl2 at room temperature
exhibit three different sets of resonances with relative intensities
1 : 1 : 1 for the three different 7-azaindolyl groups. The assignments
given in the Experimental for complexes 3 and 4 were supported
by the homonuclear (1H–1H) COSY spectra and, in the case of
complex 4, take into account that some resonances (H2 or H6 of
the coordinated azaindolyl ligands) are flanked by 195Pt satellites.
The 19F NMR patterns of 3 and 4 are consistent with the presence
of two non-equivalent C6F5 groups, one C6F5 trans to aza and one
C6F5 trans to Haza.
Scheme 1
take place without isomerization, and the reaction products are the
cis isomers. Their IR spectra show the characteristic absorptions
of the C6F5 group (1630 m, 1490 vs, 1050 s, and 950 vs cm-1)19
and a split band at ca. 800 cm-1 assigned to the cis-M(C6F5)2
moiety.20–24 The 19F NMR spectra of 1 and 2 show the expected
three signals for two equivalent C6F5 rings with relative intensities
of 2Fo:1Fp:2Fm. As expected, the ortho-F signals of complex 2 are
flanked by satellites due to coupling to 195Pt. The H spectrum
1
of complex 2 in CDCl3 at room temperature exhibits an unique
set of resonances for both heterocyclic ligands, no changes being
observable over the -50 to +50 ◦C range. The resonance at d
8.30 ppm for complex 2 should be assigned to 6-H because this
signal is flanked by 195Pt satellites in the spectrum. Furthermore,
the rest of assignments given in the Experimental for complexes 1
and 2 were also supported by the pertinent homonuclear (1H–1H)
COSY spectra.
The final confirmation of the nature of 1 was obtained by an
X-ray diffraction study. From the data available, the molecular
skeleton can be established (ESI, Fig. S1).†25 The two possible
dispositions H–H and H–T (Fig. 1) of the azaindole ligands create,
however, an inherent disorder problem.
The 1H NMR spectra in CDCl3 of 5 and 6 are consistent with the
bridging azaindolate ligand and only one set of signals is observed
for the protons of the heterocyclic moiety. The presence of the
OH group in complexes 5 and 6 is demonstrated by the high-field
1H resonance observed at d -1.34 and -0.12 ppm for 5 and 6,
respectively, as well as the n(OH) band observed at ca. 3600 cm-1.
Compounds [NBu4][M(C6F5)2(Haza-N7)(aza-N1)]·Haza and
[NBu4]2[{M(C6F5)2}2(l-OH)(l-aza-N7,N1)] (M = Pd, Pt)
Compounds [NBu4][M(C6F5)2(Haza-N7)(aza-N1)]·Haza [M = Pd
(3), Pt (4)] can be prepared from 1 or 2 and NBu4OH in the
presence of excess Haza (Scheme 2). They contain simultaneously
both the neutral Haza and the anionic aza ligands, and a Haza
molecule of crystallization. Compounds 3 and 4 are stable up to
Crystal structures of azaindole-azaindolate compounds 3 and 4
The structures of [NBu4][M(C6F5)2(Haza-N7)(aza-N1)]·Haza
(3, 4) were isomorphous, and both compounds crystallized in
a monoclinic unit cell, space group P21/c. The structure of the
Scheme 2
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Table 1 Selected bond lengths and angles for 3 and 4
anion of 3 is shown in Fig. 2. The coordination at palladium and
platinum is square-planar with interbond angles which deviate
little from 90◦ (Table 1). The neutral azaindole ligand (Haza) binds
through its pyridine nitrogen atom, the anionic azaindolate ligand
(aza) through its pyrrole nitrogen atom to the metal atom. In
the crystal, there is an intramolecular N–H ◊ ◊ ◊ N contact between
the two coordinated azaindolyl groups (Fig. 2), which is certainly
responsible for the orientation of the pyrrolo and the pyridine
moieties of the two ligands. The asymmetric intramolecular N–
H ◊ ◊ ◊ N contact observed in 3 and 4 contrasts with the symmetric
intramolecular interactions previously found in the related com-
plexes [NBu4][M(C6F5)2-(pyrazole)(pyrazolate)] (M = Pd, Pt),24
where the hydrogen atom was located in a symmetric position.
Two inversion-related free 7-azaindol molecules of crystallization
enter in intermolecular head-to-tail N–H ◊ ◊ ◊ N contacts with a
3
4
4calcda
M–C1
M–C7
M–N1
M–N3
2.012(2)
2.005(2)
2.116(2)
2.079(2)
0.87(3)
2.012(2)
2.005(2)
2.099(2)
2.071(2)
0.82(3)
2.022
2.005
2.133
2.119
1.053
1.846
2.838
90.98
179.35
88.84
87.75
177.24
92.41
155.46
N2–H2
H2 ◊ ◊ ◊ N4
N2 ◊ ◊ ◊ N4
C7–M–C1
C1–M–N3
C7–M–N3
C1–M–N1
C7–M–N1
N3–M–N1
N2–H2 ◊ ◊ ◊ N4
1.97(3)
2.05(3)
2.825(3)
86.28(8)
175.91(8)
90.83(7)
88.65(7)
174.47(7)
94.34(7)
166(2)
2.824(3)
87.65(9)
176.63(8)
90.26(8)
88.48(8)
175.76(8)
93.68(7)
158(3)
a 4calcd = [M(C6F5)2(Haza-N7)(aza-N1)]-·Haza.
2
R2 (8) motif, identical to the common complementary carboxylic
acid-carboxylic acid graph-set motif (Fig. 3 for 3).27–29 A p-stacking
interaction between one of the electron-poor C6F5 ligands and the
azaindole of crystallization is also observed (Fig. 3 for complex
3), showing a rather short centroid–centroid contact (Ct ◊ ◊ ◊ Ct <
˚
3.7◦A) between the slightly tilted ring planes (interplanar angle
30
˚
9.2 and centroid-to-plane separation 3.3 A for 3). Other inter-
molecular interaction contacts observed are of the type C–H ◊ ◊ ◊ F–
C.31–35 Thus, for example, there are intermolecular C–H ◊ ◊ ◊ F
hydrogen bonding between fluorine atoms of the fluorophenyl
+
groups and hydrogen atoms of NBu4 , with the five shortest
hydrogen bonds in complex 3 being F7 ◊ ◊ ◊ H41B F5 ◊ ◊ ◊ H33A,
F6 ◊ ◊ ◊ H36A, F8 ◊ ◊ ◊ H38C, and F3 ◊ ◊ ◊ H40B (2.45, 2.48, 2.51, 2.54
Fig. 3 p-Stacking interaction and intermolecular N–H ◊ ◊ ◊ N contacts in
3. Hydrogen bonding interaction (dashed line) [A, ◦] in 3: N6–H 0.91(3),
˚
˚
H ◊ ◊ ◊ N73 1.97(3), N6 ◊ ◊ ◊ N73 2.863(3), N6–H ◊ ◊ ◊ N73 166(2); corresponding
interaction in 4: 0.99(3), 1.89(3), 2.859(3), 167(2); symmetry relation 3 =
1 - x, -y, 2 - z.
and 2.54 A, respectively). Also short C–H ◊ ◊ ◊ p contacts between
+
NBu4 (H34B in complex 3) and one of the C6F5 rings (C5 in
complex 3) or C–H ◊ ◊ ◊ paza contacts have been found.23,36,37
The metal–C6F5 bond lengths are in the range found in the
literature for pentafluorophenyl metal complexes.15,21,31,37–39
can be considered as formally derived from a neutral unsaturated
[Pt(C6F5)2] species through coordination with neutral Haza and
anionic aza ligands (Scheme 3). The Haza ligand features only
one possible donor atom and therefore is bound to Pt through
the pyridine N7 atom, leading to the hypothetical still unsaturated
[Pt(C6F5)2(Haza-N7)] species 7 (Scheme 3). Finally, binding of
the azaindolate anion to the Pt atom in 7 could be achieved
through the pyrrole N1 or the pyridine N7 atom, thus leading
to 8 or the regioisomeric symmetric complex 8isom, respectively. A
simple analysis regarding the final model compounds points to the
expected complex 8 as the thermodynamically controlled product
(by only 2.09 kcal mol-1) in the potential energy surface at the
working level of theory.
Nevertheless, during the last two decades many important
concepts and parameters related to chemical reactivity have
been rationalized within the framework of DFT.40 The DFT
formulation41 of the Pearson’s hard–soft acid–base (HSAB)
principle42 states that the most favourable interaction occurs
when the reactants have equal softness, provided that the charge
reshuffling step can be neglected. The best suited local reactivity
index for studying regioselectivity43 is local softness s(r), easily
obtained from the Fukui function f (r), defined by Parr and Yang,44
and the global softness S = (∂N/∂m)v(r), which describes the ability
of the molecule to take or loose electrons in response to a change in
the chemical potential, m. Therefore s(r) describes both the charge
transfer between the reactants and how charge is redistributed
within the reactants themselves. A local HSAB principle can
Fig. 2 ORTEP representation (50% probability) of the complex anion of
3 (isostructural to 4). Hydrogen bonding interaction as dashed line (see
Table 1). Hydrogen atoms on carbon have been omitted for clarity.
Theoretical calculations on the platinate anion of 4
The two different binding modes exhibited by ligands Haza and
aza in the metallate complexes of 3 and 4 deserve a more detailed
analysis with the help of theoretical calculations. We have con-
ducted this study only on the platinum anion (later the p-stacked
Haza unit is included), [Pt(C6F5)2(Haza-N7)(aza-N1)]- (8)), that
3292 | Dalton Trans., 2010, 39, 3290–3301
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slightly favoured (DE = -1.02 kcal mol-1). Two sets of binding
forces holding together both units operate in almost orthogonal
directions and can be quantified separately. Parallel alignment of
the aromatic Haza unit to one C6F5 ligand (C1–C6 fragment in
Fig. 2) provides a first stabilization source through p,p-stacking
interaction (WBItotal 0.060). It is characterized by two BCPs
(bond critical points) within the framework of Bader’s atoms-in-
molecules (AIM) theory52 (r(rc)total = 1.38 ¥ 10-2 e/ao ), exhibiting
3
the typical large e values of diagnostic relevance for these type
of interactions (eaver = 0.84). On the other hand, two H atoms
in Haza lie close enough to another almost orthogonal C6F5
ligand (C7–C12 fragment in Fig. 2), thus allowing formation
of a comparatively weaker T-shaped H ◊ ◊ ◊ p stacking interaction
(WBItotal 0.037) for which only one BCP was found (r(rc) = 6.28 ¥
10-3 e/ao ; e = 0.22).
3
Crystal structure of 6·CHCl3
The structure of the diplatinate dianion in 6·CHCl3 is shown
in Fig. 4. The core of the anion comprises two platinum atoms
˚
3.177 A apart, bridged by an OH and an aza ligands. The bridging
azaindolate is disordered in an about 50 : 50 distribution. The
platinum ◊ ◊ ◊ platinum separation is shorter than the van der Waals
radii sum, the metal ◊ ◊ ◊ metal distance observed in the related dinu-
Scheme 3
53
˚
clear complex [NBu4][{Pt(C6F5)3}2(m-OH)(m-Pb)] being 3.494 A.
then be devised as follows: a regioisomer is favoured when the
new bond is formed between atoms of equal softness. In other
words, the preferred regioisomer in the reaction between atom
k in molecule A and molecule B will be formed on reaction at
atom l that minimizes the quadratic difference in local condensed-
to-atom softness function45 D(s2)kl = (sAk - sBl)2. An analogous
The steric constraints imposed by the bridging ligands in the
diplatinate complex of 6·CHCl3 also cause the coordination planes
of the platinum atoms to form an angle of 78.11◦. The platinum–
N distances are in good agreement with the values found in com-
pound 4. An almost face-to-face (rather than the typical slipped) p-
stacking interaction between two of the electron-poor C6F5 ligands
is also observed (Fig. 4), showing a rather short centroid–centroid
parameter D(w )kl = (wAk - wBl)2 has been proposed,46 based on
2
local philicities w(r) which, in turn, can be easily calculated—
◦
˚
contact (Ct ◊ ◊ ◊ Ct = 3.740(2) A, interplanar angle 12.4(2) and
via Fukui functions f (r)—from the global philicity47 w = m S,
2
30
˚
centroid-to-plane separation 3.72 A). C–H ◊ ◊ ◊ F intermolecular
measuring the stabilization in energy when the system acquires
an additional electronic charge, DN, from the environment. For
situations in which condensed local softness or philicity were found
inadequate to provide the correct intermolecular reactivity trends,
interactions are present, with the three shortest hydrogen bonds
being F19 ◊ ◊ ◊ H58B, F8 ◊ ◊ ◊ H59A, and F5 ◊ ◊ ◊ H57A (2.33, 2.41, and
˚
2.44 A, respectively). Other intermolecular interaction contacts
33,36,37
observed are of the type C–H ◊ ◊ ◊ paza
.
Fluorine atoms of
the group softness,48 (k)g, and group philicity,49
s w(k)g, descriptors
the C6F5 groups may function as intramolecular hydrogen-bond
acceptors for the bridging OH group (H ◊ ◊ ◊ F16 2.54(4), O1 ◊ ◊ ◊ F16
have been highlighted, which are obtained after summing the
condensed local property—softness or philicity—over all of the
n neighbouring atoms attached to the reactive site k. With this
aim we have computed both quadratic-difference parameters for
the nucleophilic attack of the two possible donor atoms N1 and
N7 in the anionic ligand 7-azaindolate, to the Pt(II) centre in the
tri-coordinated electrophilic species 750 using local properties and
natural charges (see the ESI).† Lower values are obtained for the
attack involving N1 as donor in comparison to the case of attack
through N7, for either D(s2)kl (0.07 and 0.38, respectively) and
D(w )kl (1.6 ¥ 10-2 and 2.5 ¥ 10-2, respectively), thus pointing to a
2
kinetically preferred binding of the 7-azaindolate ligand using its
pyrrole-like N1 atom,51 as experimentally observed.
Inclusion of a p-stacked Haza unit on the previously computed
geometry 8 affords the structure 4calcd that nicely agrees with the
experimentally obtained geometry for 4 (Table 1). Although small,
the most significant discrepancies deal with a slight overestimation
of the p-stacking of the free Haza unit in opening the C6F5–
Pt–C6F5 angle and, obviously, with the H atom position in
the N–H ◊ ◊ ◊ N hydrogen bond. According to our calculations
inclusion of the p-stacked Haza unit is expected to be only
Fig. 4 ORTEP representation (50% probability) of the anion of 6·CHCl3.
The disorder of the azaindolate ligand is explained in the text. See Table 2
for bond distances and angles.
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◦
calcda
˚
Table 2 Selected bond lengths (A) and angles ( ) for 6·CHCl3 and 6
6·CHCl3
6calcda
Pt1–C1, Pt2–C26
Pt1–C7, Pt2–C20
Pt1–O1, Pt2–O1
Pt1–N1, Pt2–N2
Pt1–Pt2
F1 ◊ ◊ ◊ F20
F10 ◊ ◊ ◊ F11
2.005(4), 2.009(4)
1.984(4), 1.989(4)
2.094(3), 2.078(3)
2.092(4), 2.072(3)
3.1773(2)
3.196
3.542
2.017, 2.018
2.004, 2.000
2.117, 2.120
2.120, 2.104
3.247
3.266
3.598
C1–Pt1–C7, C26–Pt2–C20
C1–Pt1–O1, C26–Pt2–O1
C7–Pt1–N1, C20–Pt2–N2
Pt1–O1–Pt2
90.69(15), 91.70(16)
90.55(13), 90.22(13)
92.97(13), 93.35(14)
99.19(11)
90.94, 91.22
92.46, 91.65
91.73, 92.44
100.06
Fig. 6 Calculated HOMO surface (iso-value 0.04) for 6calcd
.
a 6calcd = [Pt(C6F5)2(m-OH)(m-aza-N7,N1)]2-.
This optimized geometry for 6calcd also corroborates the anti
orientation of the hydroxo H atom with respect to the bridging
aza ligand. The OH ligand forms two moderately strong H ◊ ◊ ◊ F
hydrogen bonds with the nearest ortho-F atoms (dH ◊ ◊ ◊ F = 2.323
◦
˚
3.016(3) A, O1–H ◊ ◊ ◊ F16 125(4) and H ◊ ◊ ◊ F5 2.58(4), O1 ◊ ◊ ◊ F5
3.001(4), O1–H ◊ ◊ ◊ F5 120(4)).
Compound 6·CHCl3 crystallizes in the non-centrosymmetric
polar space group Cc. Accordingly, the molecules must show a
polar packing by having the same orientation along the polar c
axis: with their azaindolate ends, for example, the anions are all
pointing in the same direction (along the vertical polar c axis in
Fig. 5).
˚
and 2.550 A, WBI 0.008 and 0.003) with well defined BCP for
the former (r(rc) = 1.08 ¥ 10-2 e/ao ), as also observed in the X-
3
ray structure (see above). This H–F hydrogen bonding establishes
the difference with respect to the other possible conformer with
syn hydroxo orientation, that is 2.62 kcal mol-1 less stable in the
potential energy surface. It is worth to note that two ortho-F atoms
belonging to the other C6F5 groups lie very close to each other
-3
3
˚
(dF ◊ ◊ ◊ F = 3.267 A, WBI 0.001, r(rc) = 1.70 ¥ 10 e/ao ).
Neutral complexes [Pt(dmba)(aza-N1)(L)] [L = DMSO, PPh3]
The platinum complexes [Pt(dmba)(aza-N1)(L)] [L = DMSO
(9), PPh3 (10)] have been prepared from the corresponding
chloro platinum complex [Pt(dmba)(L)Cl] (L = DMSO or
PPh3)55 (Scheme 4). After precipitation of AgCl by addition of
AgClO4 in a 1 : 1 molar ratio in acetone, the solvent complexes
[Pt(dmba)(L)(Me2CO)]ClO4 generated in situ react with 1 equiv. of
both 7-azaindole and KOH/MeOH to give the neutral complexes
9 and 10. The structures were assigned also on the basis of
microanalytical, and 1H, 195Pt and 31P NMR data (for 10). The 1H
NMR spectra of complexes 9 and 10 show that both the N-methyl
groups and the methylene protons of the dmba are diastereotopic,
two separate singlets being observed for the former and two close
AB doublets for the later. Therefore, there is no plane of symmetry
in the metal coordination plane. The 1H resonances assigned to H2
of the aza ligand for 9 and 10 are flanked by 195Pt satellites, which
are also observed in several others resonances of complexes 9 and
10 (see the Experimental). In complex 10 the phosphine-trans-to-
NMe2 ligand arrangement in the starting material55 is preserved,
after chlorine abstraction and aza coordination, as can be inferred
Fig. 5 Projection of the unit cell packing of the anion and chloroform
solvate of 6·CHCl3 along a to illustrate the polar packing along the
vertical polar c axis (ammonium cations and chloroform disorder have
been removed for clarity).
Theoretical calculations on the dianion of compound 6
The calculated structure 6calcd = [{M(C6F5)2}2(m-OH)(m-aza-
N7,N1)]2-, although in very good general agreement with the
experimental one, slightly underestimates the Pt ◊ ◊ ◊ Pt interaction
(WBIPt ◊ ◊ ◊ Pt 0.038). Despite this obvious contact between the Pt
atoms, below the sum of their van der Waals radii, no BCP
was found. It could be tentatively interpreted in terms of a
difficult topological analysis of the electronic charge density r(rc)
in the complex region situated among the two Pt atoms and the
hydroxo ligand. Indeed the MO analysis reveals the existence
of a HOMO with antibonding character with respect to the
Pt ◊ ◊ ◊ Pt interaction (Fig. 6),54 as well as three other lower bonding
combinations (HOMO-5, HOMO-6 and HOMO-8) and two very
low lying HOMOs (i.e. HOMO-16 and HOMO-21) corresponding
to bonding zero-nodal combinations of the three-centre two-
electron interaction within a three-membered oxadiplatinirane
ring (see the ESI).† Also no BCP was observed between the almost
1
by H NMR from the small, but significant, coupling constant
˚
parallel C6F5 rings (dCt ◊ ◊ ◊ Ct = 4.069 A, sum of WBIAr ◊ ◊ ◊ Ar 0.011).
Scheme 4
3294 | Dalton Trans., 2010, 39, 3290–3301
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4JP–H (2.4–4.2 Hz) of the CH2N or the NMe2 protons of dmba
with the phosphorus atom.
Compound 9 crystallizes with half a molecule of crystal water
and a quarter molecule of toluene per molecular formula unit as
9·0.5H2O·0.25C7H8. The coordination at platinum in 9 is square-
planar with the DMSO ligand trans to the dmba nitrogen atom
¯
(Fig. 7). The center of inversion in P1 is occupied by the toluene
solvent molecule which shows its typical disorder around an
inversion center (ESI, Fig. S7).†
Fig. 8 Circular dichroism spectra of DNA and DNA incubated with
complex 4, complex 9 and complex 10 at different ri.
Fig. 7 ORTEP representation (50% probability) of the dimeric entity of
9·0.5H2O. The hydrogen atoms on O3 could not be found in this heavy atom
structure. Distances and angles in Table 3; hydrogen bonding interaction
as dashed line. Hydrogen atoms on carbon have been omitted for clarity.
The hydrogen-bonding action of the crystal water molecule to
the pyridine N atoms joins two molecules of 9 into a dimer (Fig. 7)
which then have to be symmetry independent (as the inversion
center is already taken by the toluene solvent. Except for the
solvent molecules this represents a Z¢ = 2 (Z¢ > 1) structure.31,56–58
Besides the noted hydrogen-bonding interactions, the packing in
9·0.5H2O·0.25C7H8 is solely controlled by C–H ◊ ◊ ◊ p interactions;
there is no p-stacking.30,36
Fig. 9 Electrophoretic mobility pattern of pBR322 plasmid DNA
incubated with Haza and their metal complexes: lane 1, pBR322; lane
2, Haza; lane 3, complex 4; lane 4 complex 9; lane 5, complex 10; lane 6,
CDDP.
and oc, coalescent form, was observed. A similar pattern has
been found previously in some others dmba phosphine platinum
complexes.21,23 On the other hand, complex 9 (lane 4) delayed the
mobility of the ccc form.
The behaviour observed for the electrophoretic mobility for the
platinum complexes 9 and 10 indicates that some conformational
changes occurred. This means that the degree of super helicity of
the DNA molecules has been altered.
Biological assays. Circular dichroism spectroscopy
The circular dichroism (CD) spectra of calf thymus DNA alone
and incubated with the new platinum(II) compounds 4, 9, and 10
at 37 ◦C for 24 h with several molar ratios were recorded.
The changes in ellipticity and wavelength caused by compounds
9 and 10 are significant (Fig. 8). These results suggest modifications
in the secondary structure of DNA caused by complexes 9 and
10.21–23,59–64 No important changes are observed for both the free
Haza and complex 4.
Cytotoxicity studies
To analyze the potential of the compounds as antitumour agents,
their cytotoxicity was evaluated towards the human breast cancer
(T47D, cisplatin resistant) and epithelial ovarian carcinoma cells
A2780 and A2780cisR (acquired resistance to cisplatin) and for
comparison purposes the cytotoxicity of cisplatin and the free
ligands was evaluated under the same experimental conditions.
Because of low aqueous solubility, the test compounds were
dissolved in DMSO first and then serially diluted in complete
culture medium such that the effective DMSO content did not
exceed 1%.
Gel electrophoresis of compound–pBR322 complexes
The influence of the compounds on the tertiary structure of DNA
was determined by their ability to modify the electrophoretic
mobility of the covalently closed circular (ccc) and open (oc)
forms of pBR322 plasmid DNA. The complexes 4, 9 and 10
were incubated at the molar ratio ri = 0.50 with pBR322 plasmid
DNA at 37 ◦C for 24 h. Representative gel obtained for the Pt
complexes 4, 9 and 10 are shown in Fig. 9. The behaviour of the
gel electrophoretic mobility of both forms, ccc and oc, of pBR322
plasmid and DNA:cisplatin adducts is consistent with previous
reports.64 When the pBR322 was incubated with the platinum
compound 10 (lane 5) a single footprinting for both forms, ccc
The primary in vitro antitumour screening of complexes 2, 4, 6,
9 and 10, Cisplatin and the free ligands at 100 mM concentration
(Table 4) shows that 4, 9 and 10 exhibit activity in the low-
micromolar range in all cell lines and values of IC50 were also
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◦
a
˚
resonances of complex 9. The stability of complex 4 in DMSO
solution was smaller, some changes being observed after 10 h in
solution.
Table 3 Selected bond lengths (A) and angles ( ) for 9·0.5H2O·0.25C7H8
Pt1
Pt2
Pt–C(dmba)
Pt–N(dmba)
Pt–N(aza)
Pt–S
O3 ◊ ◊ ◊ N(pyridine)
C–Pt–N(dmba)
C–Pt–N(pyridine)
N(dmba)–Pt–N(pyr)
C–Pt–S
N(dmba)–Pt–S
N(pyridine)–Pt–S
N3 ◊ ◊ ◊ O3 ◊ ◊ ◊ N6
2.013(10)
2.075(8)
2.083(8)
2.190(2)
2.86(1)
81.8(4)
172.0(3)
90.2(3)
1.991(9)
2.060(8)
2.084(7)
2.185(2)
2.80(1)
81.3(3)
171.9(3)
91.2(3)
95.5(3)
176.4(2)
92.2(2)
Conclusions
A series of new 7-azaindolyl palladium and platinum complexes
have been prepared. Among them we report the unprecedented
cases of mixed azaindole–azaindolate metal complexes where two
different binding modes of acid/base related ligands co-exist. The
structures of [NBu4][M(C6F5)2(Haza-N7)(aza-N1)]·Haza (M =
Pd, Pt) were isomorphous. Their X-ray structure determinations
have established the existence of an intramolecular N–H ◊ ◊ ◊ N
contact between the two coordinated azaindolyl groups and
intermolecular head-to-tail N–H ◊ ◊ ◊ N contacts between the free
7-azaindole molecules. Theoretical calculations show that both
kinetic and thermodynamical arguments support the observed
coordination and H-bonding interaction of the pyrrolo and the
pyridine moieties of the neutral and deprotonated heterociclic
ligands. At 48 h incubation time the new platinum complex 9 shows
sub-micromolar activity both in A2780 and T47D [IC50 (mM) =
0.34 and 0.53, respectively], and also very low resistance factors
against an A2780 cell line which has acquired resistance to cisplatin
(RF = 1.3). The DNA adduct formation of the new platinum
complexes 9 and 10 was followed by circular dichroism suggesting
modifications in the secondary structure of DNA. The behaviour
observed for the electrophoretic mobility for 9 and 10 indicates
alteration of the degree of super helicity of the DNA molecules.
95.9(3)
176.0(2)
92.1(2)
121.4(3)
a Two independent platinum molecules in the asymmetric unit.
Table 4 Percentage inhibition at 100 mM concentration for complexes
2, 4, 6, 9 and 10, cisplatin and the free ligands in the human breast and
ovarian carcinoma cell lines T47D, A2780 and A2780cisR
T47D
48 h
A2780
48 h
A2780cisR
48 h
Complex
2
15
70
45
78
82
70
38
2
4
3
3
2
1
3
4
48
83
80
91
91
91
20
3
4
1
2
1
2
1
5
35
89
83
85
91
87
13
2
5
2
3
1
2
2
4
4
6
9
10
Cisplatin
PPh3
7-Azaindole
Dmba
1
1
2
1
1
2
1
2
2
Experimental
Table 5 IC50 (mM) and resistance factors for cisplatin and complexes 5, 9
and 10
Instrumental measurements
T47D
48 h
A2780
48 h
A2780cisR
48 h (RF)a
The CHNS analyses were performed with a Carlo Erba model
EA 1108 microanalyzer. Decomposition temperatures were de-
termined with a SDT 2960 simultaneous DSC-TGA of TA
instruments at a heating rate of 5 ◦C min-1 and the solid samples
under nitrogen flow (100 mL min-1). The 1H, 19F and 195Pt NMR
spectra were recorded on a Bruker AC 300E, Bruker AC 400E
or Bruker AV 600 spectrometer, using SiMe4, H3PO4, CFCl3
and Na2[PtCl6] as standards. Infrared spectra were recorded
on a Perkin-Elmer 1430 spectrophotometer using Nujol mulls
between polyethylene sheets. Mass spectra (positive-ion FAB) were
recorded on a V. G. AutoSpecE spectrometer and measured using
3-nitrobenzyl alcohol as the dispersing matrix.
Complex
4
9
19
3
5.8 0.3
0.34 0.02
2.7 0.1
12 2 (2.1)
0.53 0.05
4.8 0.1
0.45 0.02 (1.3)
2.0 0.04 (0.7)
11 3 (12.6)
10
Cisplatin
37
4
0.87 0.03
a The numbers in parentheses are the resistance factors RF (IC50
resistant/IC50 sensitive).
calculated for them (Table 5). Noteworthy, at 48 h incubation time
the platinum complex 4 shows sub-micromolar activity both in
A2780 and T47D [IC50 (mM)= 0.34 and 0.53, respectively]. On
the other hand, A2780cisR encompasses all of the known major
mechanisms of resistance to cisplatin: reduced drug transport,65
enhanced DNA repair/tolerance66 and elevated GSH levels.67
The ability of complexes 4, 9 and 10 to circumvent cisplatin
acquired resistance was determined from the resistance factor
(RF), defined as the ratio of IC50 resistant line to IC50 parent line.
An RF of <2 was considered to denote non-cross resistance.68
Especially noteworthy are the very low resistance factors (RF) of
these new complexes at 48 h (RF = 0.7–2.1) indicating efficient
circumvention of cisplatin resistance (Table 5).
Materials
The starting complexes [M(C6F5)2(NCPh)2] (M = Pd, Pt),17,18
[NBu4]2[M(C6F5)2(m-OH)]2 (M = Pd, Pt)18,26 and [Pt(dmba)(L)Cl]
(L = DMSO or PPh3)55 were prepared by procedures described
elsewhere. Solvents were dried by the usual methods.
Preparation of [cis-bis(7-azaindole-jN7)bis(pentafluorophenyl)-
metall(II)] complexes, [M(C6F5)2(Haza)2] [M = Pd (1), Pt (2)]
The stability of the cytotoxic compounds 4, 9 and 10 have
been studied in DMSO by 1H NMR. Complexes 9 and 10
remained unaltered after six days in solution at room temperature,
although H/D exchange was observed for the coordinated DMSO
To a solution of [M(C6F5)2(NCPh)2] (0.155 mmol) in CH2Cl2
(15 mL) 7-azaindole (36.62 mg, 0.310 mmol) was added. The
resulting mixture was stirred at room temperature for 1 h, and then
the solvent was partially evaporated under vacuum and hexane
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added to precipitate a white solid, which was collected by filtration
and air-dried. 1: Yield: 74 mg (71%). Calcd for C26H12F10N4Pd: C
46.1◦4, H 1.79, N 8.28. Found: C 46.12, H, 1.65, N 8.26. Mp:
258 C (decomposition). IR (Nujol, cm-1): 3444 n(N–H), 800, 784
n(Pd–C6F5). 1H NMR (CDCl3): d 9.77 (br, 2 H, NH, Haza), 8.19
(dd, 2 H, H6, Haza, J(HH) = 5.4 Hz, J(HH) = 1.2 Hz), 7.86 (d,
2 H, H4, Haza, J(HH) = 7.8), 7.43 (dd, 2 H, H2, Haza, J(HH) =
3.6 Hz, J(HH) = 2.7 Hz), 6.92 (dd, 2 H, H5, Haza, J(HH) =
7.8 Hz, J(HH) = 5.4 Hz), 6.51 (dd, 2 H, H3, Haza, J(HH) =
3.6 Hz, J(HH) = 2.1 Hz). 19F NMR (CDCl3): d -116.7 (m, 4 Fo),
-160.1 (t, 2 Fp, J(FpFm) = 19.7 Hz), -162.5 (m, 4 Fm). 2: Yield:
79 mg (77%). Calcd for C26H12F10N4Pt: C 40.80, H 1.58, N 7.32.
Found: C 40.68, H 1.59, N 7.21. Mp: 311 ◦C (decomposition).
5.01, N 8.53. Mp: 211 ◦C (decomposition). IR (Nujol, cm-1): 802,
792 n(Pt–C6F5). H NMR (CD2Cl2): d 8.46 (dd, 1 H, H6, aza a,
1
J(HH) = 5.4 Hz, J(HH) = 0.8 Hz, Pt satellites are observed as
shoulders), 8.28 (m, 2 H, H6, Haza + H6 free Haza), 7.95 (dd, 1
H, H4, aza or free Haza, J(HH) = 7.8 Hz, J(HH) = 1.4 Hz), 7.80
(dd, 1 H, H4, Haza, J(HH) = 7.8 Hz, J(HH) = 1.0 Hz), 7.63 (m,
2 H, H2 of aza + H4 of aza or free Haza, satellites are observed as
shoulders), 7.36 (m, 2 H, H2, Haza + H2, free Haza), 7.08 (dd, 1
H, H5, aza or free Haza, JHH = 8.0 Hz, J(HH) = 4.8 Hz), 6.83 (dd,
1 H, H5, Haza, J(HH) = 7.6 Hz, J(HH) = 5.4 Hz), 6.70 (dd, 1
H, H5, aza or free Haza, JHH = 7.6 Hz, J(HH) = 4.8 Hz), 6.51 (d,
1 H, H3, Haza or free Haza, J(HH) = 3.6 Hz), 6.38 (d, 1 H, H3,
Haza or free Haza, J(HH) = 3.4), 6.16 (d, 1 H, H3, aza, J(HH) =
2.8). 19F NMR (CD2Cl2): d -117.1 (m, 2 Fo, J(PtFo) = 546.2 Hz),
-119.6 (m, 2 Fo, J(PtFo) = 498.8 Hz), -166.6 (m, 2 Fp + 4 Fm).
195Pt NMR (CD2Cl2): d -3495 (m).
1
IR (Nujol, cm-1): 3434 n(N–H), 812 n(Pt–C6F5), 800. H NMR
(CDCl3): d 10.01 (br, 2 H, NH, Haza), 8.30 (dd, 2 H, H6, Haza,
J(HH) = 5.2 Hz, J(HH) = 0.8 Hz, Pt satellites are observed as
shoulders), 7.89 (d, 1 H, H4, Haza, J(HH) = 7.6 Hz), 7.45 (dd,
1 H, H2, Haza, J(HH) = 3.6 Hz, J(HH) = 2.8 Hz), 6.95 (dd, 1
H, H5, Haza, J(HH) = 7.6 Hz, JHH = 5.2 Hz), 6.56 (dd, 1 H, H3,
Haza, JHH = 3.6 Hz, JHH = 2.0 Hz). 19F NMR (CDCl3): d -120.3
(m, 4 Fo, J(PtFo) = 492.7 Hz), -161.6 (t, 2 Fp, J(FpFm) = 19.7 Hz),
-163.7 (m, 4 Fm). 195Pt NMR (CDCl3): d -3625 (m).
Preparation of bis(tetra-n-butylammonium)-[cis(l-7-azaindolato-
jN1:N7)(l-hydroxo)-tetrakis(pentafluorophenyl)dipalladate(II)],
[NBu4]2[{Pd(C6F5)2}2(l-OH)(l-aza)] (5)
To a solution of [NBu4]2[Pd(C6F5)2(m-OH)]2 (100 mg, 0.071 mmol)
in CH2Cl2 (15 mL) was added 7-azaindole (8.4 mg, 0.071 mmol).
The resulting solution was stirred at room temperature for 1 h,
and then the solvent was partially evaporated under vacuum and
hexane added to precipitate a white solid, which was collected
by filtration and air-dried. 5: Yield: 87 mg (81%). Calcd for
C63H78F20N4OPd2: C 50.44, H 5.24, N 3.73. Found: C 50.12; H
5.45, N 3.78. Mp: 213 ◦C (decomposition). IR (Nujol, cm-1): 3606
Preparation of (tetra-n-butylammonium)[cis-(7-azaindolato-jN1)-
(7-azaindole-jN7)bis(pentafluorophenyl)metallate(II)]·7-azaindole
complexes, [NBu4][Pt(C6F5)2(Haza)(aza)]·Haza [M = Pd (3), Pt
(4)]
To a solution of [M(C6F5)2(Haza)2] (0.148 mmol) in acetone
(15 mL) 7-azaindole (17.48 mg, 0.148 mmol) and finally 20%
[NBu4]OH (aq) (194 mL, 0.148 mmol) were added. The mixture
was stirred at room temperature for 20 h and then solvent was
evaporated to dryness. The residue was treated with Et2O to give
a white solid, which was collected by filtration and air-dried.
1
n(O–H), 792, 778 n(Pd–C6F5). H NMR (CDCl3): d 7.65 (dd, 1
H, H4, aza, J(HH) = 7.5 Hz, J(HH) = 1.2 Hz), 7.45 (d, 1 H, H6,
aza, J(HH) = 5.4 Hz), 6.84 (d, 1 H, H2, aza, JHH = 2.4 Hz), 6.47
(dd, 1 H, H5, aza, J(HH) = 7.5 Hz, J(HH) = 5.4 Hz), 6.15 (d,
1 H, H3, aza, J(HH) = 2.7 Hz), -1.34 (s, 1 H, OH). 19F NMR
(CDCl3): d -112.7 (m, 2 Fo), -113.2 (m, 2 Fo), -113.4 (m, 2 Fo),
-113.8 (m, 2 Fo), -163.8 (t, 1 Fp, J(FpFm) = 19.7 Hz), -164.1 (t,
1 Fp, J(FpFm) = 19.7 Hz), -164.5 (t, 1 Fp, J(FpFm) = 19.7 Hz),
-165.3 (t, 1 Fp, J(FpFm) = 19.7 Hz), -165.6 (m, 6 Fm), -166.1 (m,
2 Fm).
Alternative method of preparation of complex 3. To a solution
of [NBu4]2[Pd(C6F5)2(m-OH)]2 (100 mg, 0.071 mmol) in CH2Cl2
(15 mL) was added 7-azaindole (67.5 mg, 0.571 mmol). The
resulting mixture was stirred for 20 h at room temperature and
then solvent was evaporated to dryness. The residue was treated
with Et2O to give a white solid, which was collected by filtration
and air-dried.
Preparation of bis(tetra-n-butylammonium)-[cis(l-7-azaindolato-
jN1:N7)(l-hydroxo)-tetrakis(pentafluorophenyl)diplatinate(II)],
[NBu4]2[{Pt(C6F5)2}2(l-OH)(l-aza)] (6)
3: Yield: 120 mg (78%), (112 mg, 75% for alternative method).
Calcd for C49H53F10N7Pd: C 56.79, H 5.15, N 9.46. Found: C 56.48,
◦
H 5.30, N 9.49. Mp: 174 C (decomposition). IR (Nujol, cm-1):
1
802, 792 n(Pd–C6F5). H NMR (CD2Cl2): d 8.44 (dd, 1 H, H6,
To a suspension of [NBu4]2[Pt(C6F5)2(m-OH)]2 (100 mg,
Haza, J(HH) = 5.4 Hz, J(HH) = 1.4 Hz), 8.33 (m, 2 H, H6, aza +
H6 of free Haza), 7.99 (dd, 1 H, H4, aza or free Haza, J(HH) =
7.8 Hz, J(HH) = 1.4 Hz), 7.82 (dd, 1 H, H4, Haza, J(HH) =
7.8 Hz, JHH = 1.4 Hz), 7.66 (m, 2 H, H2 of aza + H4 of aza or free
Haza), 7.41 (m, 2 H, H2, Haza + H2, free Haza), 7.11 (dd, 1 H,
H5, aza or free Haza, J(HH) = 7.8 Hz, J(HH) = 4.8 Hz), 6.88 (dd,
1 H, H5, Haza, J(HH) = 7.8 Hz, J(HH) = 5.4 Hz), 6.74 (dd, 1 H,
H5, aza or free Haza, J(HH) = 7.6 Hz, J(HH) = 4.6 Hz), 6.54 (d,
1 H, H3, Haza or free Haza, J(HH) = 3.6), 6.39 (d, 1 H, H3, Haza
or free Haza, JHH = 3.6), 6.22 (d, 1 H, H3, aza, J(HH) = 2.8).
19F NMR (CDCl3): d -114.8 (m, 2 Fo), -115.6 (m, 2 Fo), -164.3
(t, 1 Fp, J(FpFm) = 20.7 Hz), -164.9 (t, 1 Fp, J(FpFm) = 20.7 Hz),
-165.2 (m, 2 Fm), -165.8 (m, 2 Fm). 4: Yield: 114 mg (68%). Calcd
for C49H53F10N7Pt: C 52.31, H 4.75, N 8.71. Found: C 52.07, H
0.063 mmol) in toluene (15 mL) was added 7-azaindole (15.0 mg,
0.126 mmol). The resulting mixture was stirred under reflux for
7 h, filtered through a short pad of Celite and then the solvent
was evaporated to dryness. The residue was treated with Et2O to
give a white solid, which was collected by filtration and air-dried. 6:
Yield: 75 mg (70%). Calcd for C63H78F20N4OPt2: C 45.11, H 4.69, N
3.34. Found: C 44.82, H 4.81, N 3.45. Mp: 261 ◦C (decomposition).
1
IR (Nujol, cm-1): n(O–H) 3606, n(Pt–C6F5) 808, 798. H NMR
(CDCl3): d 7.76 (dd, 1 H, H4, aza, J(HH) = 7.5 Hz, J(HH) =
1.2 Hz), 7.60 (dd, 1 H, H6, aza, J(HH) = 5.4 Hz, J(HH) = 1.2 Hz,
Pt satellites are observed as shoulders), 6.93 (d, 1 H, H2, aza,
J(HH) = 2.7 Hz, Pt satellites are observed as shoulders), 6.46 (dd,
1 H, H5, aza, J(HH) = 7.5 Hz, J(HH) = 5.4 Hz), 6.21 (d, 1 H,
H3, aza, J(HH) = 2.7 Hz), -0.12 (s, 1 H, OH). 19F NMR (CDCl3):
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d -117.4 (m, 4 Fo), -118.3 (m, 2 Fo), -119.1 (m, 2 Fo), -165.6 (t,
1 Fp, J(FpFm) = 19.7 Hz), -166.1 (t, 1 Fp, J(FpFm) = 19.7 Hz),
-166.9 (m, 1 Fp + 6 Fm), -167.7 (m, 2 Fm), -166.1 (m, 2 Fm). 195Pt
NMR (CDCl3): d -3147 (m), -3190 (m).
those of 9·0.5H2O·0.25C7H8 from CH2Cl2–toluene–hexane. The
crystal and molecular structures of the compounds 3, 4, 6·CHCl3
and 9·0.5H2O·0.25C7H8 have been determined by X-ray diffrac-
tion studies (Table 6). The crystals were measured on a Bruker
Smart Apex diffractometer. Data were collected using monochro-
mated Mo Ka radiation in w scan mode. Absorption corrections
were applied on the basis of multi-scans. All structures were solved
by direct methods using SHELX-9769 and refined anisotropically
on F2. The NH hydrogen atoms were found and refined with
Preparation of (7-azaindolato-jN1)(N,N-dimethylbenzylamine-
jN,jC)-(dimethylsulfoxide-jS)/(triphenylphosphane)-
palladium(II) [Pt(dmba)(aza-N1)(L)] [L = DMSO (9), PPh3
(10)]
U
iso(H) = 1.2Ueq(N). Hydrogen atoms for aromatic CH, aliphatic
To
a
solution of [Pt(dmba)(Cl)(L)] (L
=
DMSO, PPh3)
CH, CH2 and methyl groups were positioned geometrically (C–
˚
˚
(0.24 mmol) in acetone (20 mL) AgClO4 (0.24 mmol) was added.
AgCl immediately formed. The resulting suspension was stirred
for 30 min in the darkness and then filtered through a short pad
of Celite. The filtrate was then evaporated to dryness and the
residue treated with a mixture of 7-azaindole (0.24 mmol) and
KOH (0.96 mmol) in methanol (20 mL). The mixture was stirred
at room temperature for 1 h and then evaporated to dryness. The
residue was treated with CH2Cl2 (20 mL) and filtered through a
short pad of Celite. The resulting solution was partially evaporated
under vacuum and hexane added to precipitate a white solid, which
was collected by filtration and air-dried. 9: Yield: 130 mg (73%).
Calcd for C18H23N3OSPt: C 41.22, H 4.42, N 8.01, S 6.11. Found:
C 41.09, H 4.51, N 7.98, S 6.08. Mp: 183 ◦C (decomposition). 1H
NMR (CDCl3): d(SiMe4) 8.22 (dd, 1 H, H6, aza, J(HH) = 4.8 Hz,
J(HH) = 1.5 Hz), 7.96 (m, 1 H, aromatic of dmba, Pt satellites are
observed as shoulders), 7.88 (dd, 1 H, H4, aza, J(HH) = 7.8 Hz,
J(HH) = 1.5 Hz), 7.38 (d, 1 H, H2, aza, J(HH) = 2.9 Hz, satellites
are observed as shoulders), 7.08 (m, 3 H, aromatics of dmba), 6.85
(dd, 1 H, H5, aza, J(HH) = 7.8 Hz, J(HH) = 4.8 Hz), 6.51 (d,
1 H, H3, aza, J(HH) = 2.9 Hz), 4.26 (d, 1 H, CH2N, J(HH) =
13.5 Hz, J(HPt) = 25.5 Hz), 3.84 (d, 1 H, CH2N, J(HH) = 13.5 Hz,
J(HPt) = 56.7 Hz), 3.39 (s, 3 H, DMSO, J(HPt) = 30.3 Hz), 2.57 (s,
3 H, N(CH3)2, J(HPt) = 37.2 Hz), 2.53 (s, 3 H, DMSO, J(HPt) =
19.2 Hz), 2.33 (s, 3 H, N(CH3)2, J(HPt) = 35.1 Hz). 195Pt NMR
(CDCl3): d(Na2[PtCl6]) -3645 (s). 10: Yield: 150 mg (83%). Calcd
for C34H32N3PPt: C 57.62, H 4.55, N 5.93. Found: C 57.34, H 4.43,
N 5.65. Mp: 298 ◦C (decomposition). 1H NMR (CDCl3): d(SiMe4)
7.98 (dd, 1 H, H6, aza, J(HH) = 4.4 Hz, J(HH) = 1.6 Hz), 7.57
(m, 6 H, PPh3), 7.51 (dd, 1 H, H4, aza, J(HH) = 7.6 Hz, J(HH) =
1.6 Hz), 7.22 (m, 3 H, PPh3), 7.10 (m, 6 H, PPh3 + 1 H, aromatic
of dmba), 6.99 (d, 1 H, H2, aza, J(HH) = 2.8 Hz, Pt satellites
are observed as shoulders), 6.87 (vtd, 1 H, aromatic of dmba,
J(HH) = 8.0 Hz, J(HP) = 0.8 Hz), 6.58 (m, 2 H, H5 of aza + H
of aromatic of dmba, Pt satellites are observed as shoulders), 6.43
(vtd, 1 H, aromatic of dmba, J(HH) = 8.0 Hz, J(HP) = 0.8 Hz),
6.03 (d, 1 H, H3, aza, J(HH) = 2.8 Hz), 4.43 (d, 1 H, CH2N,
J(HH) = 13.2 Hz, Pt satellites are observed as shoulders), 3.89 (dd,
1 H, CH2N, J(HH) = 13.2 Hz, J(HP) = 4.0 Hz, Pt satellites are
observed as shoulders), 2.64 (d, 3 H, N(CH3)2, J(HP) = 2.4 Hz,
J(HPt) = 28.5 Hz), 2.51 (d, 3 H, N(CH3)2, J(HP) = 3.2 Hz,
J(HPt) = 24.3 Hz). 31P NMR (CDCl3): d(H3PO4) 20.7 (s, J(PtP) =
4286 Hz). 195Pt NMR (CDCl3): d(Na2[PtCl6]) -3969 (d, J(PtP) =
4286 Hz).
H = 0.94 A for aromatic CH, C–H = 0.99 A for aliphatic CH,
˚
˚
C–H = 0.98 A for CH2, C–H = 0.97 A for CH3) and refined
using a riding model (AFIX 43 for aromatic CH, AFIX 13
for aliphatic CH, AFIX 23 for CH2, AFIX 137 for CH3), with
U
iso(H) = 1.2Ueq(CH, CH2) and Uiso(H) = 1.5Ueq(CH3). For
compound 6·CHCl3 the hydrogen atom on OH was found and
refined with Uiso(H) = 1.5Ueq(O). The azaindolate is disordered
in a 55 : 45 for A:B distribution. The chloroform crystal solvent is
disordered over various positions. More than two different CHCl3
positions are superimposed in the structure of 6·CHCl3 to give a
variation in occupancies of different chlorine atoms. Significant
residual electron densities in the near vicinity were added to
the chloroform solvent. The disorder of the chloroform solvent
cannot be satisfactorily solved, probably because of high mobility
concomitant with little constraining van der Waals interactions.
Thus, the chloroform atom positions should not be taken for any
structure discussions but are solely meant to include and add the
electron densities in a solvent accessible volume occupied by one
highly disordered CHCl3 molecule. In total there is one CHCl3
molecule per asymmetric unit. In 6·CHCl3 the twelve strongest
residual electron density peaks in the Fourier map are within
˚
1.0 A of either Pt1 or Pt2. In the structure of 9·0.5H2O·0.25C7H8
atoms C7 and C19 had to be refined isotropically because of
non-positive definite or very oblate character despite attempted
DELU restraints which were also applied to C1. The large residual
˚
electron density is within 1.0 A of the Pt1 atom.
Graphics of the X-ray diffraction determined structures were
drawn with DIAMOND (version 3.1f).71 Computations on the
supramolecular interactions were carried out with PLATON for
Windows.72 p-Stacking interactions can be viewed as medium
to weak if they exhibit rather long centroid-centroid distances
◦
˚
(Ct ◊ ◊ ◊ Ct > 4.0 A) together with large slip angles (b, g > 30 )
˚
and vertical displacements (d > 2.0 A). In comparison, strong p-
stacking show rather short centroid-centroid contacts (< 3.8 A),
˚
◦
˚
small slip angles (b, g < 25 ) and vertical displacements (d < 1.5 A)
which translate into a sizable overlap of the aromatic planes.30,73
Computational details
The reliably accurate description of weak interactions like those
between ligands and heavy metals generally requires a treatment
of electron correlation. Density functional theory (DFT)74 has
proved quite useful in this regard offering an electron correlation
correction frequently comparable to the second-order Møller–
Plesset theory (MP2) or in certain cases, and for certain purposes,
even superior to MP2, but at considerably lower computational
cost.75 Calculated geometries at the DFT level were fully optimized
in the gas-phase with tight convergence criteria using the Gaussian
X-Ray crystal structure analysis
Suitable crystals from 3 and 4 were grown from dichloromethane–
toluene–hexane. Crystals of 6·CHCl3 were grown from CHCl3,
3298 | Dalton Trans., 2010, 39, 3290–3301
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Table 6 Crystal structure determination details
d
Compound
3
4
6·CHCl3
9·0.5H2O·0.25C7H8
e
Empirical formula
FW/g mol-1
C49H53F10N7Pd
1036.38
C49H53F10N7Pt
1125.07
C64H79Cl3F20N4OPt2
1796.84
C39.5H52N6O3Pt2S2
1113.17
Crystal system
Monoclinic
11.0967(5)
18.6148(8)
22.5261(10)
90
93.2170(10)
90
4645.7(4)
100(2)
P21/c
4
1.482
0.483
Monoclinic
11.0665(5)
18.6258(8)
22.6090(10)
90
93.0130(10)
90
4653.8(4)
100(2)
P21/c
4
1.606
3.098
Monoclinic
11.3030(5)
37.3427(17)
16.9524(8)
90
107.53(10)
90
6823(5)
100(2)
Cc
4
1.749
4.312
3544
Triclinic
˚
a/A
8.6147(15)
10.4165(18)
21.917(4)
84.523(2)
87.574(2)
82.352(2)
1939.5(6)
100(2)
˚
b/A
˚
c/A
a/◦
b/◦
g /◦
V/A
T/K
3
˚
¯
Space group
Z
P1
2e
Dc/Mg m-3
1.906
7.359
1086
m/mm-1
F(000)
2128
2256
Crystal size/mm
2q range/◦
h, k, l (range)
0.40 ¥ 0.29 ¥ 0.17
3.62-56.56
-14 ≤ h ≤ 14
-23 ≤ k ≤ 23
-29 ≤ l ≤ 28
0.9224/0.8303
53617 (0.0257)
10 811
0.27 ¥ 0.20 ¥ 0.13
3.60-56.46
-12 ≤ h ≤ 14
-23 ≤ k ≤ 23
-28 ≤ l ≤ 28
0.6888/0.4884
28314 (0.0251)
10 375
0.21 ¥ 0.13 ¥ 0.08
3.94-54.70
-14 ≤ h ≤ 14
-48 ≤ k ≤ 47
-21 ≤ l ≤ 21
0.7242/0.4645
38715 (0.0257)
14 964
0.20 ¥ 0.08 ¥ 0.05
3.74-50.10
-10 ≤ h ≤ 10
-12 ≤ k ≤ 12
-26 ≤ l ≤ 26
0.7098/0.3207
19493 (0.0373)
6840
Max./min. transmission
Reflections collected (Rint
Independent reflections
)
Observed reflections [I > 2s(I)]
Restraints/parameters
Goodness-of-fit on F2a
R1, wR2 [I > 2s (I)]b
10 522
0/614
1.233
0.0369/0.0827
0.383/0.0835
0.583/-0.472
—
9241
1/614
1.056
0.0236/0.0583
0.0279/0.0600
1.232/-0.479
—
14 488
3/895
0.894
0.0226/0.0470
0.0239/0.0474
1.234/-0.520
0.008(3)
6373
2/469
1.230
0.0512/0.0955
0.0559/0.0971
4.843/-2.996
—
R1, wR2 (all reflections)b
-3c
˚
Max./min. Dr/e A
Absolute structure parameter
(Flack value)70
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2
2
2
a Goodness-of-fit = [ [w(Fo - Fc2)2]/(n - p)]1/2
.
b R1 = ꢀFo| - |Fcꢀ/ |Fo|, wR2 = [ [w(Fo - Fc2)2]/ w(Fo2)2]1/2; w = 1/[s (Fo2) + (aP)2 + bP],
where P = (2Fc + Fo2)/3 and a and b are constants set by the program. c Largest difference peak and hole. d Two symmetry independent platinum
molecules in the asymmetric unit; H atoms on the water of crystallization could not be found but were included in the empirical formula, calculation of
the molecular mass, density and F(000). e Checkcif suggests the doubled empirical formula with Z = 1.
2
03 package,76 and employing the Truhlar’s hybrid meta functional
mPW1B9577 that has been recommended for general purpose
applications and was developed in order to produce a better
performance where weak interactions are involved such as those
between ligands and heavy metals.78 The 6-31G** basis set was
used in the optimizations for all atoms and adding diffuse
functions on N and O atoms (denoted as aug6-31G**), as well as
the Stuttgart relativistic small-core basis set with effective core po-
tential (StRSCecp), for Pt. Ultrafine grids (99 radial shells and 590
angular points per shell) were employed for numerical integrations.
From these gas-phase optimized geometries all reported data were
obtained by means of single-point (SP) calculations at the same
level. Energy values are uncorrected for the zero-point vibrational
energy. Interaction energies were computed after correcting the
basis set superposition error (BSSE) by means of the Bq method.
Natural charges were obtained from the Natural Bond Orbital
(NBO) population analysis. Bond orders were characterized by the
Wiberg’s bond index (WBI)79 and calculated with the NBO method
as the sum of squares of the off-diagonal density matrix elements
between atoms. The topological analysis of the electronic charge
density was conducted by means of the Bader’s AIM methodology
using the AIM2000 software.80
Biological assays. Circular dichroism study
Spectra were recorded at room temperature on an Applied
Photophysics P*-180 spectrometer with a 75 W xenon lamp using
a computer for spectral subtraction and smooth reduction. The
platinum samples (ri = 0.1, 0.3, 0.5) were prepared by addition of
aliquots of each compound, from stock solutions (1 mg mL-1), to
a solution of calf thymus DNA (Sigma) in TE buffer (20 mg mL-1),
◦
and incubated for 24 h at 37 C. As a blank, a solution of each
compound in TE buffer (50 mM NaCl, 10 mM Tris-HCl, 0.1 mM
EDTA, pH 7.4) was used. Each sample was scanned twice in a
range of wavelengths between 220 and 330 nm. The drawn CD
spectra are the means of two independent scans. The ellipticity
values are given in millidegrees (mdeg).
Electrophoretic mobility study
pBR322 plasmid DNA of 0.25 mg/mL concentration was used for
the experiments. Four microlitres of charge maker (Lambda–pUC
Mix Marker, 4) were added to aliquot parts of 20 mL of the drug–
DNA complex. The platinum complexes were incubated at the
molar ratio ri = 0.50 with pBR322 plasmid DNA at 37 ◦C for
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24 h. The mixtures underwent electrophoresis in agarose gel 1%
in 1 ¥ TBE buffer (45 mM Tris-borate, 1 mM EDTA, pH 8.0)
for 5 h at 30 V. Gel was subsequently stained in the same buffer
containing ethidium bromide (1 mg mL-1) for 20 min. The DNA
bands were visualized with a The DNA bands were visualized with
an AlphaImager EC (Alpha Innotech).
Acknowledgements
This work was supported by the Ministerio de Educacion y
Ciencia of Spain and FEDER (project CTQ2008-02178/BQU)
and Fundacion Seneca-CARM (project 08666/PI/08). A. E.
wants to acknowledge the financial support from MICINN-Spain,
project CTQ2008-01402 and Fundacio´n Se´neca-CARM (project
04509/GERM/06).
Cell line and culture
The T-47D human mammary adenocarcinoma cell line used in this
study was grown in RPMI-1640 medium supplemented with 10%
(v/v) fetal bovine serum (FBS) and 0.2 unit/mL bovine insulin in
an atmosphere of 5% CO2 at 37 ◦C. The human ovarian carcinoma
cell lines (A2780 and A2780cisR) used in this study were grown
in RPMI 1640 medium supplemented with 10% (v/v) fetal bovine
serum (FBS) and 2 mM L-glutamine in an atmosphere of 5% CO2
at 37 ◦C.
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