Palladium(II) and platinum(II) organometallic complexes with 4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine. Antitumor activity of the platinum compounds

Article abstract of DOI:10.1021/ic701873b

Palladium and platinum complexes with HmtpO (where HmtpO = 4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine, an analogue of the natural ocurring nucleobase hypoxanthine) of the types [M(dmba)(PPh ₃)(HmtpO)]ClO₄ [dmba = N,C-chelating 2- (dimethylaminomethyl)phenyl; M = Pd or Pt], [Pd(N-N)(C₆F ₅)(HmtpO)]ClO₄ [N-N = 2,2′-bipyridine (bpy), 4,4′-dimethyl-2,2′-bipyridine (Me₂bpy), or N,N,N′,N′-tetramethylethylenediamine (tmeda)] and cis-[M(C ₆F₅)₂(HmtpO)₂] (M = Pd or Pt) (head-to-head atropisomer in the solid state) have been obtained. Pd(II) and Pt(II) complexes with the anion of HmtpO of the types [Pd(tmeda)(C ₆F₅)(mtpO)], [Pd(dmba)(μ-mtpO)]₂, and [NBu₄]₂[M(C₆F₅)₂(μ- mtpO)]₂ (M = Pd or Pt) have been prepared starting from the corresponding hydroxometal complexes. Complexes containing simultaneously both the neutral HmtpO ligand and the anionic mtpO of the type [NBu ₄][M(C₆F₅)₂(HmtpO)(mtpO)] (M = Pd or Pt) have been also obtained. In these mtpO-HmtpO metal complexes, for the first time, prototropic exchange is observed between the two heterocyclic ligands. The crystal structures of [Pd(dmba)(PPh₃)(HmtpO)]⁺, cis-[Pt(C₆F₅)2(HmtpO)₂]·acetone, [Pd(C₆F₅)(tmeda)(mtpO)]·2H₂O, [Pd(dmba)(μ-mtpO)]₂, [NBu₄]₂[Pd(C ₆F₅)₂(μ-mtpO)]₂·CH ₂Cl₂·toluene, [NBu₄] ₂[Pt(C₆F₅)₂(μ-mtpO)] ₂·0.5(toluene), and [NBu₄][Pt(C₆F ₅)₂(mtpO)-(HmtpO)] have been established by X-ray diffraction. Values of IC₅₀ were calculated for the new platinum complexes cis-[Pt(C₆F₅)₂(HmtpO)₂] and [Pt(dmba)(PPh₃)(HmtpO)]ClO₄ against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR), lung (NCl-H460), and breast cancers (T47D). At 48 h incubation time, both complexes were about 8-fold more active than cisplatin in T47D and show very low resistance factors against an A2780 cell line, which has acquired resistance to cisplatin. The DNA adduct formation of cis-[Pt(C₆F₅) ₂(HmtpO)₂] and [Pt(dmba)(PPh₃)(HmtpO)]ClO ₄ was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by these platinum complexes on plasmid DNA pBR322 were also obtained.

Full text of DOI:10.1021/ic701873b

Inorg. Chem. 2008, 47, 4490-4505
Palladium(II) and Platinum(II) Organometallic Complexes with
4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimidine. Antitumor
Activity of the Platinum Compounds
Jose´ Ruiz,*,† Mar´ıa Dolores Villa,† Natalia Cutillas,† Gregorio Lo´pez,† Concepcio´n de Haro,†
Delia Bautista,‡ Virtudes Moreno,§ and Laura Valencia|
Departamento de Qu´ımica Inorga´nica, UniVersidad de Murcia, E-30071- Murcia, Spain, S.U.I.C.,
Edificio S.A.C.E., UniVersidad de Murcia, E-30071-Murcia, Spain, Department de Qu´ımica
Inorga`nica, UniVersitat de Barcelona, Mart´ı i Franque`s 1-11, E-08028 Barcelona, Spain, and
Departamento de Qu´ımica Inorga´nica, UniVersidad de Santiago de Compostela, AVda. de las
Ciencias s/n, E-15782 Santiago de Compostela, Spain
Received September 21, 2007
Palladium and platinum complexes with HmtpO (where HmtpO ) 4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-
a]pyrimidine, an analogue of the natural ocurring nucleobase hypoxanthine) of the types [M(dmba)(PPh3)(HmtpO)]ClO4
[dmba ) N,C-chelating 2-(dimethylaminomethyl)phenyl; M ) Pd or Pt], [Pd(N-N)(C6F5)(HmtpO)]ClO4 [N-N )
2,2′-bipyridine (bpy), 4,4′-dimethyl-2,2′-bipyridine (Me2bpy), or N,N,N′,N′-tetramethylethylenediamine (tmeda)] and
cis-[M(C6F5)2(HmtpO)2] (M ) Pd or Pt) (head-to-head atropisomer in the solid state) have been obtained. Pd(II)
and Pt(II) complexes with the anion of HmtpO of the types [Pd(tmeda)(C6F5)(mtpO)], [Pd(dmba)(µ-mtpO)]2, and
[NBu4]2[M(C6F5)2(µ-mtpO)]2 (M ) Pd or Pt) have been prepared starting from the corresponding hydroxometal
complexes. Complexes containing simultaneously both the neutral HmtpO ligand and the anionic mtpO of the type
[NBu4][M(C6F5)2(HmtpO)(mtpO)] (M ) Pd or Pt) have been also obtained. In these mtpO-HmtpO metal complexes,
for the first time, prototropic exchange is observed between the two heterocyclic ligands. The crystal structures of
[Pd(dmba)(PPh3)(HmtpO)]+, cis-[Pt(C6F5)2(HmtpO)2] · acetone, [Pd(C6F5)(tmeda)(mtpO)] · 2H2O, [Pd(dmba)(µ-mtpO)]2,
[NBu4]2[Pd(C6F5)2(µ-mtpO)]2 ·CH2Cl2 · toluene, [NBu4]2[Pt(C6F5)2(µ-mtpO)]2 · 0.5(toluene), and [NBu4][Pt(C6F5)2(mtpO)-
(HmtpO)] have been established by X-ray diffraction. Values of IC50 were calculated for the new platinum complexes
cis-[Pt(C6F5)2(HmtpO)2] and [Pt(dmba)(PPh3)(HmtpO)]ClO4 against a panel of human tumor cell lines representative
of ovarian (A2780 and A2780cisR), lung (NCI-H460), and breast cancers (T47D). At 48 h incubation time, both
complexes were about 8-fold more active than cisplatin in T47D and show very low resistance factors against an A2780
cell line, which has acquired resistance to cisplatin. The DNA adduct formation of cis-[Pt(C6F5)2(HmtpO)2] and
[Pt(dmba)(PPh3)(HmtpO)]ClO4 was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy
images of the modifications caused by these platinum complexes on plasmid DNA pBR322 were also obtained.
Introduction
complexes because they usually reproduce adequately the
binding of the platinum complexes but with faster kinetics.2
The HmtpO (4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-
a]pyrimidine) can be considered an analogue of the natural
ocurring nucleobase hypoxanthine (Chart 1). The synthesis
of the antitumor drug cisplatin analogue cis-[PtCl2(HmtpO)2]
Since the discovery of the antitumor activity of cisplatin
in 1969, studies into platinum-nucleobase interactions have
played an important role in the nucleobases as ligands.1 There
is also much interest in the study of palladium nucleobase
* To whom correspondence should be addressed. E-mail: jruiz@um.es.
Fax: +34 968 364148. Tel.: +34 968 367455.
†
Departamento de Qu´ımica Inorga´nica, Universidad de Murcia.
(1) Lippert, B. Coord. Chem. ReV. 2000, 200-202, 487–516, and
references cited therein.
‡
S.U.I.C., Edificio S.A.C.E., Universidad de Murcia.
Universitat de Barcelona.
§
(2) Barnham, K. J.; Bauer, C. J.; Djuran, M. I.; Mazid, M. A.; Rau, T.;
Sadler, P. J. Inorg. Chem. 1995, 34, 2826–2832.
|
Universidad de Santiago de Compostela.
4490 Inorganic Chemistry, Vol. 47, No. 11, 2008
10.1021/ic701873b CCC: $40.75  2008 American Chemical Society
Published on Web 04/30/2008

Pd(II) and Pt(II) Triazolopyrimidine Complexes
Chart 1
Scheme 1
has been reported by Salas et al.,3 and the anticancer activity
of this complex has been tested against the human cancer cell
lines MCF-7 breast carcinoma and A121 ovarian carcinoma.
A preliminary communication on new antitumor Pt(IV) HmtpO
complexes has just been reported.4 On the other hand, because
of the presence of an ionizable hydrogen at N(4), HmtpO is a
well suited ligand for the study of metal-metal interactions,
which give rise to homo- and heterodinuclear complexes of soft
atoms such as Pt(II) and Pd(II) with metal-metal separations
ranging from 2.744(2) to 3.337(1) Å.5,6
In the present study, our initial aim was to synthesize
mononuclear and dinuclear palladium and platinum orga-
nometallic complexes derived from the N,C-chelating 2-(di-
methylaminomethyl)phenyl (dmba) and pentafluorophenyl
C6F5 groups with both the HmtpO ligand and its anion,
mtpO-. To the best of our knowledge,7 the complexes herein
reported represent the first examples of palladium and
platinum complexes containing HmtpO and a σ-metal-carbon
bond. Seven complexes have been characterized by X-ray
diffraction, showing the different coordination modes of this
ligand. We have also studied the interactions of some of the
new platinum complexes with DNA by circular dichroism
and electrophoretic mobility. Atomic force microscopy
images of the modifications caused by the platinum com-
plexes on plasmid DNA pBR322 were also obtained. The
in vitro antiproliferative activity for the new platinum
complexes cis-[Pt(C6F5)2(HmtpO)2] and [Pt(dmba)(PPh3)-
(HmtpO)]ClO4 against a panel of human tumor cell lines
representative of ovarian (A2780 and A2780cisR), lung
(NCI-H460, nonsmall lung cancer cell), and breast cancers
(T47D, cisplatin resistant) has been studied. At 48 h
incubation time, both complexes were about 8-fold more
active than cisplatin in T47D (breast cancer) and show very
low resistance factors against an A2780 cell line that has
acquired resistance to cisplatin.
chlorometal complex [M(dmba)(PPh3)Cl] (M ) Pd or Pt).
After precipitation of AgCl by the addition of AgClO4 in a
1:1 molar ratio in acetone, the solvent complexes
[M(dmba)(PPh3)(Me2CO)]ClO4 (M ) Pd or Pt), generated
in situ, react with 1 equiv of HmtpO to give the cationic
complexes [M(dmba)(PPh3)(HmtpO)]ClO4 (1-2) (Scheme
1).
1 and 2 are white, air-stable solids that decompose on
heating above 230 °C in a dynamic N2 atmosphere. Their
acetone solutions show conductance values corresponding
to 1:1 electrolytes (ΛM in the range 135-150 S cm2 mol-1),8
which indicates the presence of the neutral ligand HmtpO
in these complexes. An IR band is observed at ca. 1095,
which is assigned to the ν3 mode of free perchlorate (Td
symmetry). The observation of an additional band at ca. 623
cm-1 for the ν4 mode confirms the presence of free
perchlorate.9 The IR spectra also show a very strong band
at ca. 1715 cm-1 assigned to the ν(CO) of the neutral HmtpO
1
(1680 cm-1 for the free ligand). The H NMR spectra of 1
and 2 show that both the N-methyl and the CH2 group of
the dmba are diastereotopic, two separate signals being
observed for the former and an AB quartet for the later (some
broadening being observed for 1). Therefore, there is no plane
of symmetry in the palladium coordination plane. In 1 and
2, the PPh3-trans-to-NMe2 ligand arrangement in the starting
products10,11 is preserved, after chlorine abstraction and
HmtpO coordination, as can be inferred from the small, but
4
significant, coupling constant JP-H (2.5 Hz) of one of the
two CH2N protons (resonance at δ 3.70 ppm) with the
phosphorus atom12,13 in 2. H NMR resonances in CDCl3
1
of H2, H6, and CH3 of coordinated HmtpO in 1 appear,
respectively, at 0.15, 0.23, and 0.11 ppm downfield-shifted
with respect to free HmtpO.
Crystal Structure of 1. The structure of 1 consists of
mononuclear [Pd(dmba)(PPh3)(HmtpO-N3)]+ cations and per-
Results and Discussion
(8) Geary, W. J. Coord. Chem. ReV. 1971, 7, 81–122.
(9) Nakamoto, K. Infrared and Raman Spectra of Inorganic and Coor-
dination Compounds, 5th ed.; Wiley-Interscience: New York, 1997;
p 199.
Complexes [M(dmba)(PPh3)(HmtpO)]ClO4. The dmba
complexes 1 and 2 have been prepared from the corresponding
(10) Deeming, A. J.; Rothwell, I. P.; Hursthouse, M. B.; New, L. J. Chem.
Soc., Dalton Trans. 1978, 1490–1496.
(3) Navarro, J. A. R.; Salas, J. M.; Romero, M. A.; Vilaplana, R.;
Gonza´lez-V´ılchez, F.; Faure, R. J. Med. Chem. 1998, 41, 332–338.
(4) Lakomska, I. J. Biol. Inorg. Chem. 2007, 12 (Suppl 1), S37-PO52.
(5) Navarro, J. A. R.; Romero, M. A.; Salas, J. M. J. Chem. Soc., Dalton
Trans. 1997, 1001–1005.
(11) Meijer, M. D.; Kleij, A. W.; Williams, B. S.; Ellis, D.; Lutz, M.; Spek,
A. L.; van Klink, G. P. M.; van Koten, G. Organometallics 2002, 21,
264–271.
(12) Braunstein, P.; Matt, D.; Dusausoy, Y.; Fischer, J.; Mitschler, A.;
Ricard, L. J. Am. Chem. Soc. 1981, 103, 5115–5125.
(13) Falvello, L. R.; Ferna´ndez, S.; Navarro, R.; Urriolabeitia, E. P. Inorg.
Chem. 1997, 36, 1136–1142.
(6) Salas, J. M.; Romero, M. A.; Sa´nchez, M. P.; Quiro´s, M. Coord. Chem.
ReV. 1999, 195, 1119–1142.
(7) CCDC CSD version 5.28, November 2006, update May 2007.
Inorganic Chemistry, Vol. 47, No. 11, 2008 4491

Ruiz et al.
Scheme 2
Å; C19 · · ·O1, 3.372 Å; C19 · · ·O4, 3.344 Å; C2 · · ·O4, 3.453
Å). Intermolecular aromatic CH/π interactions24 are found
and are also responsible for the formation of extensive
networks (distances H36 · · · C13, 2.776 Å; H36 · · · C14,
2.805 Å; H33 · · · C14, 2.678 Å; H42 · · · C23, 2.718 Å; and
H45 · · · C25, 2.743 Å).
Figure 1. ORTEP representation (50% probability) of 1. Selected bond
lengths (Å) and angles (deg): Pd(1)-C(11) ) 2.006(3), Pd(1)-N(5) )
2.135(3), Pd(1)-N(3) ) 2.141(3), Pd(1)-P(2) ) 2.2614(9), C(11)-Pd(1)-
N(5) ) 82.06(13), C(11)-Pd(1)-N(3) ) 170.22(13), N(5)-Pd(1)-N(3)
) 90.64(13), C(11)-Pd(1)-P(2) ) 93.85(10), N(5)-Pd(1)-P(2) )
174.91(10), N(3)-Pd(1)-P(2) ) 93.76(8).
Complexes [Pd(N-N)(C6F5)(HmtpO)]ClO4. In acetone,
the solvent complexes [Pd(N-N)(C6F5)(Me2CO)]ClO4 [N-N
)2,2′-bipyridine(bpy),4,4′-dimethyl-2,2′-bipyridine(Me2bipy),
or N,N,N′,N′-tetramethylethylenediamine (tmeda)] (prepared
by reaction of the corresponding chloride derivatives com-
plexes [Pd(N-N)(C6F5)Cl] with AgClO4 in 1:1 molar ratio
in acetone at room temperature) react with 1 equiv of HmtpO
to yield the corresponding cationic complexes [Pd(N-
N)(C6F5)(HmtpO)]ClO4 (3-5) (Scheme 2) in 55-72%
yields. The structures were assigned on the basis of mi-
chlorate anions. The cation of 1 is depicted in Figure 1.
Coordination at palladium is approximately square planar,
although the angles around palladium deviate from 90° due to
the bite of the cyclometallated ligand. The C(1)-Pd-N(5) angle
of 82.06(13)° is within the normal range for such com-
plexes.14,15 The PPh3 ligand is trans to the nitrogen donor due
to the difficulty of coordinating a phosphine trans to an aryl
ligand in palladium complexes (i.e., the destabilizing effect
known as transphobia).16 The Pd-N(3) distance (2.141(3) Å)
compares well with those found in the literature for palladium
complexes with similar heterocyclic ligands.17–21 The Pd-C
bond length is essentially the same as that reported in
[Pd(dmba)(PCy3)(TFA)].15 Furthermore, there is an intramo-
lecular interaction by phenyl-HmtpO π-stacking (centroid-
centroid distance, 3.611 Å).22,23 There are also intermolecular
N-H· · ·O, C-H· · ·N, and C-H· · ·O bond links (distances
N· · ·4-O3, 2.830 Å; C13 · · ·N1, 3.541 Å; C17 · · ·O1, 3.317
croanalytical, IR, and H and 19F NMR data. 3-5 are all
1
air-stable solids, and the thermal analysis shows that they
decompose above 236 °C in a dynamic N2 atmosphere. Their
acetone solutions show conductance values corresponding
to 1:1 electrolytes.8 The IR spectra show the characteristic
absorptions of the C6F5 group25 at 1630, 1490, 1450, 1050,
950, and a single band at ca. 800 cm-1 derived from the
so-called X-sensitive mode26 in C6F5X (X ) halogen)
molecules, which is characteristic of the presence of only
one C6F5 group in the coordination sphere of the palladium
atom and behaves like a ν(M-C) band.27 The characteristic
resonances of the chelate ligands are observed in the 1H NMR
spectra,27–32 and the assignments presented in the Experi-
mental Section are based on the atom numbering given in
Scheme 3. The 19F NMR spectra of 3-5 at room temperature
show hindered rotation of the C6F5 ring around the Pd-C
(14) Ruiz, J.; Cutillas, N.; Rodr´ıguez, V.; Sampedro, J.; Lo´pez, G.;
Chaloner, P. A.; Hitchcock, P. B. J. Chem. Soc., Dalton Trans. 1999,
2939–2946.
(15) Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton,
P. N.; Hursthouse, M. B.; Light, M. E. Organometallics 2003, 22,
987–999.
(16) Vicente, J.; Arcas, A.; Bautista, D.; Jones, P. G. Organometallics 1997,
16, 2127–2138.
(24) Nishio, M. CrystEngComm 2004, 6, 130–158.
(25) Long, D. A.; Steele, D. Spectrochim. Acta 1963, 19, 1955–1961.
(26) Maslowski, E. Vibrational Spectra of Organometallic Compounds;
Wiley: New York, 1977; 437.
(17) Ruiz, J.; Cutillas, N.; Vicente, C.; Villa, M. D.; Lo´pez, G.; Lorenzo,
J.; Avile´s, F. X.; Moreno, V.; Bautista, D. Inorg. Chem. 2005, 44,
7365–7376.
(18) Lakomska, I.; Szlyk, E.; Sitkowski, J.; Kozerski, L.; Wietrzyk, J.;
Pelczynska, M.; Nasulewicz, A.; Opolski, A. J. Inorg. Biochem. 2004,
98, 167–172.
(27) Ruiz, J.; Vicente, C.; Cutillas, N.; Pe´rez, J. Dalton Trans. 2005, 1999–
2006.
(28) Ruiz, J.; Mart´ınez, M. T.; Florenciano, F.; Rodr´ıguez, V.; Lo´pez, G.;
Pe´rez, J.; Chaloner, P. A.; Hitchcock, P. B. Inorg. Chem. 2003, 42,
3650–3661.
(19) Szlyk, E.; Grodzicki, A.; Pazderski, L.; Wojtczak, A.; Chatlas, J.;
Wrzeszcz, G.; Sitkowski, J.; Kamienski, B. J. Chem. Soc., Dalton
Trans. 2000, 867–872.
(29) Ruiz, J.; Mart´ınez, M. T.; Florenciano, F.; Rodr´ıguez, V.; Lo´pez, G.;
Pe´rez, J.; Chaloner, P. A.; Hitchcock, P. B. Dalton Trans. 2004, 929–
932.
(20) Szlyk, E.; Lakomska, I.; Surdykowski, A.; Glowiak, T.; Pazderski,
L.; Sitkowski, J.; Kozerski, L. Inorg. Chim. Acta 2002, 333, 93–99.
(21) Szlyk, E.; Pazderski, L.; Lakomska, I.; Surdykowski, A.; Glowiak,
T.; Sitkowski, J.; Kozerski, L. Polyhedron 2002, 21, 343–348.
(22) Ruiz, J.; Lorenzo, J.; Sanglas, L.; Cutillas, N.; Vicente, C.; Villa, M. D.;
Avile´s, F. X.; Lo´pez, G.; Moreno, V.; Pe´rez, J.; Bautista, D. Inorg.
Chem. 2006, 45, 6347–6360.
(30) Ruiz, J.; Mart´ınez, M. T.; Rodr´ıguez, V.; Lo´pez, G.; Pe´rez, J.; Chaloner,
P. A.; Hitchcock, P. B. Dalton Trans. 2004, 3521–3527.
(31) Uso´n, R.; Fornie´s, J.; Mart´ınez, F.; Toma´s, M. J. Chem. Soc., Dalton
Trans. 1980, 888–894.
(32) Uso´n, R.; Fornie´s, J.; Toma´s, M.; Menjo´n, B. Organometallics 1985,
4, 1912–1914.
(23) Janiak, C. J. Chem. Soc., Dalton Trans. 2000, 3885–3896.
4492 Inorganic Chemistry, Vol. 47, No. 11, 2008

Pd(II) and Pt(II) Triazolopyrimidine Complexes
Scheme 3
Figure 2. The two possible atropisomers in square-planar metal complexes
containing two equal planar ligands occupying cis coordination positions.
Scheme 4
Figure 3. ORTEP representation (50% probability) of 7·acetone. Selected
bond lengths (Å) and angles (deg): Pt(1)-C(11) ) 1.995(4), Pt(1)-C(1)
) 1.999(4), Pt(1)-N(4) ) 2.076(3), Pt(1)-N(1) ) 2.089(4), C(11)-Pt(1)-
C(1) ) 88.79(15), C(11)-Pt(1)-N(4) ) 177.80(14), C(1)-Pt(1)-N(4) )
91.41(14), C(11)-Pt(1)-N(1) ) 90.94(14), C(1)-Pt(1)-N(1) ) 179.44(13),
N(4)-Pt(1)-N(1) ) 88.84(13).
bond, and two separate signals are observed for the o-fluorine
atoms but only one for the p-fluorine atom.
energetic contributions such as those due to hydrogen
bonding or crystal packing may lead to the stabilization of
different atropisomers, with the energy difference between
them likewise being small.
Complexes cis-[M(C6F5)2(HmtpO)2] (M ) Pd or Pt).
The complexes cis-[NBu4]2[Pd2(C6F5)4(µ-Cl)2]31 and cis-
[Pt(C6F5)2(THF)2]32 are good precursors for the synthesis of
6 and 7, respectively (Scheme 4). The reactions 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)25 and a split band at ca. 800 cm-1 assigned to the
cis-M(C6F5)2 moiety.17,26 A split band at ca. 1700 cm-1 is
also observed for the ν(CO) of the HmtpO ligands. In any
metal complex containing two equal (or similar) planar
ligands occupying contiguous (cis) coordination positions,
we may expect that the steric repulsion between the ligands
is a minimum when the ligand planes are perpendicular to
the coordination plane. If the ligands are not symmetric, there
are two different situations that obey the previous condition:
one of them with the analogous portion of both ligands
pointing in the same direction and the other pointing to the
opposite direction. These two possibilities are usually referred
to as “head-head” (H-H) and “head-tail” (H-T), respec-
tively (Figure 2). If the rotation is hindered for some reason,
we can look at this situation as a special kind of isomerism,
the so-called rotation isomerism or atropisomerism.33 The
H-T cis-[Pt(NH3)2(HmtpO-N3)2](NO3)2 ·2H2O and the H-H
cis-[PtCl2(HmtpO-N3)2] · 2H2O platinum complexes have
been previously reported,4,33 which suggests that small
1
Both the H and 19F NMR spectra of 7 in acetone-d6 at
room temperature exhibit only one set of resonances over
the -60 to +60 °C range. A head-head orientation of 7
was revealed by X-ray diffraction (vide infra). On the other
1
hand, both the H and 19F NMR spectra of 6 in acetone-d6
at room temperature exhibit broad resonances, indicating
restricted rotation about the Pd-N bonds in solution. 1H and
19F NMR spectra of 6 become sharp at -50 °C, rendering a
unique set of resonances.
Crystal Structure of 7 ·acetone. Figure 3 shows the X-ray
structure of 7 · acetone. Platinum is located in an almost
square planar environment made up of two HmtpO ligands
bonded through N3 and two ipso carbon atoms of the
fluoroaryl groups. The PtN2C2 square has a cis configuration,
which is consistent with the preparation method. The most
interesting feature of this structure is the H-H orientation
(Figure 4) exhibited by the HmtpO moieties (dihedral angle
of 86.68°). Strong supramolecular interactions are present,
and the hydrogen bond interactions N(4)-H(04) · · ·O(2)#1
and N(8)-H(08) · · · O(2)#1 appear to be responsible for the
H-H conformation of the molecule (N(4)· · ·O(2)#1 contact
of 2.886(5) Å; N(8) · · ·O(2)#1 contact of 2.950(5) Å). There
is also a very short intermolecular contact F1 · · ·F8 (Figure
4). In fact, the structure reported here possesses the shortest.
(33) Haj, M. A.; Quiros, M.; Salas, J. M. J. Chem. Soc., Dalton Trans.
2002, 4740–4745.
Inorganic Chemistry, Vol. 47, No. 11, 2008 4493

Ruiz et al.
Scheme 5
Complex [Pd(tmeda)(C6F5)(mtpO)]. The reaction of the
hydroxopalladium complex28 [Pd(tmeda)(C6F5)(OH)] in metha-
nol with 1 equiv of HmtpO leads to the formation of
[Pd(tmeda)(C6F5)(mtpO)] (8) (Scheme 5). This reaction
implies proton abstraction from the HmtpO by the hydroxo
complex with the concomitant release of water. The structure
1
was assigned on the basis of microanalytical, IR, and H
and 19F NMR data. 8 is an air-stable solid, and the thermal
analysis shows that it decomposes above 240 °C in a dynamic
N2 atmosphere. The 19F NMR spectrum of the complex at
room temperature reveals the presence of a freely rotating
pentafluorophenyl ring, which gives three resonances (in the
ratio 2:2:1) at -121.65, -158.29, and -161.59 for the o-,
m-, and p-fluorine atoms, respectively.
Crystal Structure of 8 · 2H2O. A drawing of 8 · 2H2O is
shown in Figure 5. This is the first crystal structure of a
mononuclear palladium mtpO complex,7 although some
mononuclear copper mtpO complexes have been previously
reported.43,44 Coordination at palladium is approximately
square planar. The mtpO ligand is approximately perpen-
dicular to the coordination plane, with an angle between
planes of 76.66°. The anionic ligand is coordinated to the
palladium atom through the N(3) donor atom. The Pd-N
mtpO distance [Pd(1)-N(3): 2.022(2) Å] is shorter than that
observed in complex [Pd(tmeda)(C6F5)(1-methy)] [2.038(4)
Å], suggesting a very strong interaction between the metal
Figure 4. Intermolecular F· · ·F and C-F· · ·πF interactions in 7·acetone.
With regard to the Fortho · · · Fpara distance observed in
fluoroaryl transition metal complexes so far (2.653 Å, Figure
4), there were no cases where Fortho · · · Fpara distances shorter
than 2.7 Å have been previously reported.7 The influence of
these fluorine-based interactions seems to be a relevant,
noncasual phenomenon to be taken into account in crystal
engineering.35,36 F8 is also involved in intermolecular C-FπF
interactions (F8 · · · C2, 2.949 Å; F8 · · · C3, 3.089 Å, Figure
4).35,36 Other intermolecular interactions contacts observed
are of the type C-H · · · F-C36–40 (F4 · · · H21, 2.341 Å;
41
F4 · · ·H93B, 2.574 Å; F6 · · ·H31, 2.341 Å) and C-F·πHmtpO
(F1 · · · N6, 2.872 Å; F1 · · · N7, 2.867 Å; F1 · · · C33, 2.867 Å;
F3· · · C21, 2.856 Å; F7 · · · C35, 3.086 Å).
(34) Navarro, J. A. R.; Romero, M. A.; Salas, J. M.; Quiro´s, M. Inorg.
Chem. 1997, 36, 3277–3283.
(35) Reichenbacher, K; Suss, H. I.; Hulliger, J. Chem. Soc. ReV. 2005, 34,
22–30.
(36) Vangala, V. R.; Nangia, A.; Lynch, V. M. Chem. Commun. 2002,
1304–1305.
(37) Althoff, G.; Ruiz, J.; Rodr´ıguez, V.; Lo´pez, G.; Pe´rez, J.; Janiak, C.
CrystEngComm 2006, 8, 662–665.
(38) Babudri, F.; Farinola, G. M.; Naso, F.; Ragni, R. Chem. Commun.
2007, 1003–1022.
(39) Kasai, K.; Fujita, M. Chem.sEur. J. 2007, 13, 3089–3105.
(40) Ruiz, J.; Villa, M. D.; Rodr´ıguez, V.; Cutillas, N.; Vicente, C.; Lopez,
G.; Bautista, D. Inorg. Chem. 2007, 46, 5448–5449.
(41) Schottel, B. L.; Chifotides, H. T.; Shatruk, M.; Chouai, A.; Perez,
L. M.; Bacsa, J.; Dunbar, K. R. J. Am. Chem. Soc. 2006, 128, 5895–
5912.
Figure 5. ORTEP representation (50% probability) of 8·2H2O. Selected
bond lengths (Å) and angles (deg): Pd(1)-C(21) ) 2.013(2), Pd(1)-N(3)
) 2.022(2), Pd(1)-N(5) ) 2.082(2), Pd(1)-N(6) ) 2.120(2), C(21)-Pd(1)-
N(3) ) 86.75(9), C(21)-Pd(1)-N(5) ) 94.12(9), N(3)-Pd(1)-N(5) )
176.37(8), C(21)-Pd(1)-N(6) ) 173.04(9), N(3)-Pd(1)-N(6) ) 94.58(9),
N(5)-Pd(1)-N(6) ) 84.99(9).
(42) Navarro, J. A. R.; Romero, M. A.; Salas, J. M.; Quiros, M.; Tiekink,
E. R. T. Inorg. Chem. 1997, 36, 4988–4991.
4494 Inorganic Chemistry, Vol. 47, No. 11, 2008

Pd(II) and Pt(II) Triazolopyrimidine Complexes
Scheme 6
Scheme 7
and the nitrogen.22 The different Pd-N tmeda distances
(Pd(1)-N(5): 2.082(2) Å, Pd(1)-N(6): 2.120(2) Å) are in
agreement with the higher trans influence of the group C6F5
compared to the mtpO. The Pd-C6F5 bond length (2.013(2)
Å) is in the range found in the literature for pentafluorophe-
nyl-palladium complexes.22,27 The chelate angle N(5)-
Pd(1)-N(6) is 84.99(8). Intermolecular interactions contacts
C-H · · · F-C35–40 (F26 · · · H16C ) 2.452 Å; F26 · · · H10 )
2.545 Å; F22 · · · H8C ) 2.599 Å; F22 · · · H6 ) 2.599 Å;
F25 · · · H2 ) 2.548 Å), C-H · · · O-C (H13B · · · O1 ) 2.429
Å), C-O· · ·H-O (O1 · · ·O2 ) 2.788 Å), and H-O· · ·H-O
(O2 · · · O3 ) 2.770 Å; O3 · · · O3 ) 2.740 Å) are observed.
Complex [Pd(dmba)(PPh3)(mtpO)]. The reaction in
dichloromethane at room temperature of the hydroxopalla-
dium complex [Pd(dmba)(µ-OH)]214 with PPh3 and HmtpO
in the molar ratio 1:2:2 leads to the formation of the
mononuclear palladium complex [Pd(dmba)(PPh3)(mtpO)]
(8) (Scheme 6).
8 is a white, air-stable solid that decomposes on heating
above 246 °C in a dynamic N2 atmosphere. The structure
Scheme 8
1
was assigned on the basis of microanalytical, IR, and H
and 31P NMR data. The ν(CO) band of the IR spectrum of
8 is observed at 1660 cm-1, which is a significant difference
when comparing with the values (over 1700 cm-1) observed
for 1-7, containing the neutral HmtpO ligand. The 1H NMR
spectrum is temperature dependent, showing at 0 °C an AB
quartet at δ 4.1 ppm for the CH2N protons of the dmba,
which indicates that these are diastereotopic (broadening
being observed at room temperature, as it happens also in
1). Therefore, there is no plane of symmetry in the palladium
coordination plane.17
Dimeric Palladium Complexes [Pd(dmba)(µ-mtpO)]2.
The reaction of the hydroxopalladium complex14 [Pd-
(dmba)(µ-OH)]2 in dichloromethane with HmtpO (in a 1:2
ratio) leads to the formation of N(3),N(4)-bridged mtpO
dipalladium complexes of the type [Pd(dmba)(µ-mtpO)]2
(10a and 10b) (Scheme 7). This reaction implies proton
abstraction from the HmtpO ligand by the hydroxopalladium
complex with the concomitant release of water. On proto-
nation of the hydroxo complex, it is likely that an intermedi-
ate aqua complex is formed.45
of Scheme 8) and the other three with H-T arrangements (parts
Because both C6H4CH2NMe2 (dmba) and the mtpO anion
are unsymmetrical, there are five possible linkage isomers for
the dimeric complexes, two of them with H-H (parts d and e
a, b, and c of Scheme 8) of the bridging mtpO anionic ligands.
Accordingly, with the H NMR spectrum in CDCl3 at room
1
temperature, two linkage isomers (10a and 10b) are present in
1
a ratio 1:0.4. The H NMR spectrum is not temperature
(43) Dirks, E. J.; Haasnoot, J. G.; Kinneging, A. J.; Reedijk, J Inorg. Chem.
1987, 26, 1902–1906.
dependent in the -50 to +60 °C range. The H-H isomer 10a
was isolated pure by crystallization in CH2Cl2/toluene/hexane
of the mixture, whereas the H-L isomer 10b was isolated pure
by washing the mixture with ethanol.
(44) Navarro, J. A. R.; Romero, M. A.; Salas, J. M.; Molina, J.; Tiekink,
E. R. T. Inorg. Chim. Acta 1998, 274, 53–63.
(45) Ruiz, J.; Florenciano, F.; Vicente, C.; de Arellano, M. C. R.; Lo´pez,
G. Inorg. Chem. Commun. 2000, 3, 73–75.
Inorganic Chemistry, Vol. 47, No. 11, 2008 4495

Ruiz et al.
Scheme 9
Figure 6. ORTEP representation (50% probability) of 10a. Selected bond
lengths (Å) and angles (deg): Pd(1)-C(31) ) 1.989(4), Pd(1)-N(14) )
2.077(4), Pd(1)-N(5) ) 2.091(4), Pd(1)-N(4) ) 2.175(3), Pd(1)-Pd(2)
) 3.0885(5), Pd(2)-C(21) ) 1.996(4), Pd(2)-N(3) ) 2.043(3), Pd(2)-N(6)
) 2.080(4), Pd(2)-N(13) ) 2.143(4), C(31)-Pd(1)-N(14) ) 95.42(16),
C(31)-Pd(1)-N(5) ) 82.17(16), N(14)-Pd(1)-N(5) ) 175.11(14),
C(31)-Pd(1)-N(4) ) 175.90(16), N(14)-Pd(1)-N(4) ) 88.68(14),
N(5)-Pd(1)-N(4))93.76(14),C(21)-Pd(2)-N(3))94.57(17),C(21)-Pd(2)-
N(6) ) 82.13(17), N(3)-Pd(2)-N(6) ) 175.52(14), C(21)-Pd(2)-N(13)
) 176.75(17), N(3)-Pd(2)-N(13) ) 88.33(14), N(6)-Pd(2)-N(13) )
94.89(15).
palladium and carbon atoms, a feature which is quite
commonly observed in cyclometallated dmba complexes. The
two distances Pd-N triazolo are quite different (2.043 and
2.143 Å) due to the different trans influence of the ancillary
ligands (carbon and nitrogen donors). There are also C-H· · ·N
and C-H · · · O bond links (distances H2 · · · N11, 2.601 Å;
H18C · · · O1, 2.564 Å; H12 · · · O2, 2.397 Å; H27A · · ·O2,
It is well-known that the ligand dmba exerts very different
trans influences through its carbon and nitrogen atoms.46 On
the other hand, Quiro´s et al. have recently reported33 the
synthesis of the related complex [Pd2(µ-tpO)2(bpm)2]
(H5O2)(ClO4)3 ·3H2O(HtpO)4,7-dihydro-7-oxo[1,2,4]triazolo-
[1,5-a]pyrimidine; bpm ) bispyrimidine), where the H-H
and H-T isomers coexist even in the solid state.
2.561 Å). Other intermolecular interaction contacts observed
24,37
are of the type C-H · · · πHmtpO
(H24 · · · N8, 2.517 Å;
H14 · · ·C7, 2.740 Å; H14 · · ·N8, 2.744 Å; H38C · · ·C7, 2.688
Å; H29A· · · C16, 2.757 Å).
Dinuclear and Mononuclear Metal Complexes [NBu4]2-
[M(C6F5)2(µ-mtpO)]2 and [NBu4][M(C6F5)2(mtpO)(Hm-
tpO)] (M ) Pd or Pt). The di-µ-hydroxo palladium and
platinum complexes51,52 [NBu4]2[M(C6F5)2(µ-OH)]2 react
with HmtpO (in a 1:2 ratio) in acetone at room temperature
for 24 h to yield a mixture containing the corresponding
N(3),N(4)-bridgedmtpOdinuclearcomplex[NBu4]2[M(C6F5)2-
(µ-mtpO)]2 (11 or 12) and the mononuclear complex
[NBu4][M(C6F5)2(mtpO)(HmtpO)] (13 or 14) (Scheme 9) in
a molar ratio of approximately 1:0.4, together with starting
material. When the reaction of [NBu4]2[M(C6F5)2(µ-OH)]2
(M ) Pd or Pt) with HmtpO was done in a 1:4 ratio, again
a mixture of the new dinuclear and mononuclear metal
complexes was obtained (molar ratio of approximately 1:0.7).
The platinum complexes 12 and 14 were separated mechani-
cally after crystallization from dichloromethane/toluene/
hexane. In the case of palladium, only crystals of 11 could
be obtained.
The characteristic resonances of dmba were observed.47
The 1H-1H COSY and HSQC-DEPT spectra enabled us to
1
propose H assignments for 10a and 10b.
Crystal Structure of 10a. In the dinuclear molecule
(Figure 6), two mtpO moieties bridge the two palladium
centers with an anti structure, giving rise to a Pd · · · Pd
separation of 3.0885(5) Å, which is 0.3 Å shorter than the
van der Waals radii sum. This value is in the same range as
the distances found for other similar doubly bridged d8 metal
complexes14,22,34,48 where weak attractive metal-metal
interactions are present.49,50 An H-H arrangement of the
bridging mtpO anionic ligands is observed, as found previ-
ously in the heterodinuclear complex [(NH3)2Pt(µ-mtpO)2-
Pd(bipy)]2+.34 Coordination at palladium is approximately
square planar with the two coordination planes inclined at
30.89° to each other giving a basket-shaped 8-membered
ring. The cyclometallated rings are puckered with the
nitrogen atom significantly out of the plane defined by the
11 and 12 show no indication of dynamic behavior at room
1
temperature in the H NMR spectrum, a unique resonance
pattern for the H(2), H(6), and Me protons for the mtpO ligands
(46) Deeming, A. J.; Meah, M. N.; Bates, P. A.; Hursthouse, M. B. J. Chem.
Soc., Dalton Trans. 1988, 2193–2199.
(47) Ruiz, J.; Rodr´ıguez, V.; Cutillas, N.; Pardo, M.; Pe´rez, J.; Lo´pez, G.;
Chaloner, P.; Hitchcock, P. B. Organometallics 2001, 20, 1973–1982.
(48) Krumm, M.; Mutikainen, I.; Lippert, B. Inorg. Chem. 1991, 30, 884–
890.
(51) Lo´pez, G.; Ruiz, J.; Garc´ıa, G.; Vicente, C.; Casabo´, J.; Molins, E.;
Miravitlles, C. Inorg. Chem. 1991, 30, 2605–2610.
(52) Lo´pez, G.; Ruiz, J.; Garc´ıa, G.; Vicente, C.; Mart´ı, J. M.; Hermoso,
J. A.; Vegas, A.; Mart´ınez-Ripoll, M. J. Chem. Soc., Dalton Trans.
1992, 53–58.
(49) Novoa, J. J.; Aullo´n, G.; Alemany, P.; Alvarez, S. J. Am. Chem. Soc.
1995, 117, 7169–7171.
(53) Lo´pez, G.; Ruiz, J.; Vicente, C.; Mart´ı, J. M.; Garc´ıa, G.; Chaloner,
P. A.; Hitchcock, P. B.; Harrison, R. M. Organometallics 1992, 11,
4090–4096.
(50) Aullo´n, G.; Alemany, P.; Alvarez, S. Inorg. Chem. 1996, 35, 5061–
5067.
4496 Inorganic Chemistry, Vol. 47, No. 11, 2008

Pd(II) and Pt(II) Triazolopyrimidine Complexes
Figure 7. ORTEP representation (50% probability) of 11·CH2Cl2 ·toluene.
Selected bond lengths (Å) and angles (deg): Pd(1)-C(51) ) 2.009(3),
Pd(1)-C(41) ) 2.012(3), Pd(1)-N(3) ) 2.123(3), Pd(1)-N(14) ) 2.136(3),
Pd(2)-C(31) ) 2.012(3), Pd(2)-C(21) ) 2.014(3), Pd(2)-N(4) ) 2.117(3),
Pd(2)-N(13) ) 2.120(3), C(51)-Pd(1)-C(41) ) 86.02(13), C(51)-Pd(1)-
N(3) ) 91.51(11), C(41)-Pd(1)-N(3) ) 177.48(11), C(51)-Pd(1)-N(14)
) 170.80(12), C(41)-Pd(1)-N(14) ) 91.58(11), N(3)-Pd(1)-N(14) )
90.78(10), C(31)-Pd(2)-C(21) ) 86.58(14), C(31)-Pd(2)-N(4) )
Figure 8. ORTEP representation (50% probability) of 12 · 0.5(toluene).
Selected bond lengths (Å) and angles (deg): Pt(1)-C(21) ) 2.006(5),
Pt(1)-C(41) ) 2.007(5), Pt(1)-N(13) ) 2.094(4), Pt(1)-N(4) ) 2.122(4),
Pt(2)-C(51) ) 2.008(5), Pt(2)-C(31) ) 2.010(5), Pt(2)-N(3) ) 2.100(4),
Pt(2)-N(14) ) 2.105(4), C(21)-Pt(1)-C(41) ) 90.5(2), C(21)-Pt(1)-N(13)
) 177.92(17), C(41)-Pt(1)-N(13) ) 89.57(17), C(21)-Pt(1)-N(4) )
92.64(17), C(1)-Pt(1)-N(4) ) 169.95(17), N(13)-Pt(1)-N(4) ) 86.99(15),
C(51)-Pt(2)-C(31) ) 89.57(19), C(51)-Pt(2)-N(3) ) 174.81(17),
C(31)-Pt(2)-N(3) ) 92.74(18), C(51)-Pt(2)-N(14) ) 91.29(17),
C(31)-Pt(2)-N(14) ) 175.18(18), N(3)-Pt(2)-N(14) ) 86.02(16).
90.91(12), C(21)-Pd(2)-N(4)
) 171.84(12), C(31)-Pd(2)-N(13)
) 178.77(13), C(21)-Pd(2)-N(13) ) 93.11(12), N(4)-Pd(2)-N(13) )
89.24(11).
Table 1. Hydrogen Bonds for 11·CH2Cl2 ·Toluene (Angstroms and
Degrees)a
being observed, which suggests an H-T arrangement of the
bridging mtpO anionic ligands. The 19F NMR spectra of both
complexes reveal the presence of two different types of C6F5
groups resonances due to the asymmetric nature of mtpO. As
expected, the ortho-F signals of complex 12 are flanked by the
satellite due to coupling to 195Pt.
D-H· · ·A
d(D-H) d(H · · ·A) d(D· · ·A) <(DHA)
C(65)-H(65A)· · ·O(2)
C(81)-H(81A)· · ·O(1)
C(93)-H(93A)· · ·O(1)
C(85)-H(85B)· · ·F(2)#1
C(93)-H(93B)· · ·O(1)#2
C(73)-H(73A)· · ·F(12)#3
C(65)-H(65B)· · ·O(2)#4
a Symmetry transformations used to generate equivalent atoms: #1 -x
+ 1, -y + 2, -z + 1; #2 -x + 1, -y + 2, -z; #3 x + 1, y, z; #4 -x +
1, -y + 1, -z + 1.
0.99
0.99
0.99
0.99
0.99
0.99
0.99
2.34
2.48
2.37
2.35
2.36
2.45
2.51
3.243(4)
3.383(4)
3.276(5)
3.317(4)
3.351(5)
3.442(4)
3.485(5)
150.8
151.5
151.5
164.5
174.5
175.6
166.7
13 and 14 contain simultaneously both the neutral HmtpO
and the anionic mtpO ligands, and they are formulated as
1
[NBu4][Pt(C6F5)2(mtpO)(HmtpO)]. However, the H NMR
spectrum in CDCl3 over the -60 to +25 °C range of
temperature of both complexes suggests that both heterocy-
clic ligands are equivalent because only one set of proton
resonances for them is observed. The same conclusion is
inferred from the 19F NMR spectra of 13 and 14, only one
resonance being observed for the para-F of the two pen-
tafluorophenyl rings. This is the first time that prototropic
exchange is observed between the two heterocyclic ligands
for mtpO-HmtpO complexes, although exchange between
the two pyrazolyl rings of azole-azolate metal complexes
has been previously reported.53
Table 2. Hydrogen Bonds for 12·0.5(Toluene) (Angstroms and
Degrees)a
D-H· · ·A
d(D-H) d(H · · ·A) d(D· · ·A) <(DHA)
C(89)-H(89B)· · ·O(1)
C(81)-H(81A)· · ·O(1)
C(81)-H(81B)· · ·O(1)#1
C(85)-H(85A)· · ·F(18)#2
C(91)-H(91A)· · ·F(16)#3
C(66)-H(66B)· · ·F(2)#4
C(65)-H(65A)· · ·O(2)#5
0.99
0.99
0.99
0.99
0.99
0.99
0.99
2.54
2.45
2.27
2.40
2.55
2.41
2.14
3.436(7)
3.390(6)
3.211(6)
3.348(6)
3.504(7)
3.374(6)
3.075(6)
150.5
157.7
157.6
160.5
162.0
163.2
156.5
a Symmetry transformations used to generate equivalent atoms: #1 -x
+ 2, -y + 1, -z + 1; #2 x, y, z - 1; #3 -x + 1, -y + 1, -z + 1; #4 x
1
3
1
1
3
1
+ /2, -y + /2, z - /2; #5 x + /2, -y + /2, z + /2.
CrystalStructuresof11·CH2Cl2 ·tolueneand12·0.5(tolu-
ene). The structure of 11 · CH2Cl2 · toluene and 12 · 0.5(tolu-
ene) are dinuclear (Figures 7 and 8), with the two mtpO
ligands arranged in a H-T orientation bridging the two metal
centers. The metal · · · metal separation in these complexes is
very long (3.560 and 3.465 Å, for 11 · CH2Cl2 · toluene and
12 · 0.5(toluene), respectively) compared to that observed in
10a (3.0885 Å) and [Pd2(µ-mtpO)2(bipy)2][NO3] · 5H2O
[3.034(1) Å].5 The coordination planes of the two metal
atoms in 11 · CH2Cl2 · toluene and 12 · 0.5(toluene) form a
dihedral angle of 50.72 and 46.48°, respectively. The
metal-N distances are in good agreement with the values
found in 10a and in other dinuclear metal mtpO com-
plexes.5,34 C-HO and C-HF intermolecular interactions are
present in both complexes (Tables 1 and 2).
In 11 ·CH2Cl2 ·toluene also, intermolecular contacts F3-F8
(2.925 Å) are observed giving a centrosymmetric dimer-of-
dimers arrangement (Figure 9), whereas intermolecular
contacts F5-F9 (2.853 Å) in 12 · 0.5(toluene) lead to 1D
chains (Figure 10).
Crystal Structure of 14. The structure of the anion of 14
is shown in Figure 11. This complex is formulated as
[NBu4][Pt(C6F5)2(mtpO)(HmtpO)]. The coordination at plati-
num is square-planar with interbond angles that deviate little
from 90°. Two different distances Pt-N are observed
Inorganic Chemistry, Vol. 47, No. 11, 2008 4497

Ruiz et al.
N-donors of tmeda. Also, in 10a two quite different Pd-N3
distances (2.077 and 2.175 Å) are observed, the longer
corresponding to the mtpO ligand trans to the carbon donor
of dmba, which possesses a higher trans influence.
3. The metal · · ·metal separation in the dinuclear palladium
11 · CH2Cl2 · toluene (3.560 Å) is longer than that observed
in 10a (3.0885 Å). This could be due to the long Pd-N
distances observed in 11 · CH2Cl2 · toluene, where the C6F5
ancillary is present (which possesses a great trans influence).
Consequently, the dihedral angle of the coordination planes
of the two metal atoms in 11 · CH2Cl2 · toluene (50.72°) is
higher than that found in 10a (30.89°).
Biological Assays. Circular Dichroism Spectroscopy.
The circular dichroism (CD) spectra of calf thymus DNA
alone and incubated with the ligand HmtpO and its plati-
num(II) compounds 2 and 7 at 37 °C for 24 h with several
molar ratios were recorded.
Figure 9. Centrosymmetric dimer-of-dimers arrangement of 11·CH2Cl2 ·
toluene.
The free ligand HmtpO did not significantly modify either
the ellipticity of the bands or their position. In contrast, the
changes in ellipticity and wavelength caused by the new
platinum(II) compounds 2 and 7 are significant (Figure 13).
Both complexes reduce the ellipticity of the positive and
negative bands with increasing values of ri. An upshift in
the λmax (batochromic effect) is also observed. These results
suggest modifications in the secondary structure of DNA
caused by 2 and 7, clearly indicating the transformation from
DNA B form to DNA C form, with increasing winding of
the DNA helix by rotation of the bases.55–58
[(Pt(1)-N(1) ) 2.072(4) Å, Pt(1)-N(11) ) 2.096(4) Å].
The dihedral angle between the heterocyclic planar ligands
is 84.31°.
There are intermolecular π-π interactions between mtpO
ligands, so molecules of complex 14 are stacked to give
centrosymmetric pairs, as shown in Figure 12. The centroid-
centroid distance is 3.507 Å for the best overlapped rings,
which is at the low end of the range defined for this type of
interaction (3.4-3.8 Å).23 The interplanar distance is 3.313
Å. It is a slipped packing with a deviation of the center-center
line of the perpendicular of the plane of 20°.
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 elec-
trophoretic mobility of the covalently closed circular (ccc)
and open (oc) forms of pBR322 plasmid DNA. 2 and 7 and
the HmtpO ligand were incubated at the molar ratio ri )
0.50 with pBR322 plasmid DNA at 37 °C for 24 h.
Representative gel obtained for the platinum complexes 2
and 7 are shown in Figure 14. The behavior of the gel
electrophoretic mobility of both forms, ccc and oc, of
pBR322 plasmid and DNA-cisplatin adducts is consistent
with previous reports.59 No changes were observed in sample
incubated with the free ligand HmtpO. When the pBR322
was incubated with platinum compound 2 (lane 3), a single
footprinting for both forms, ccc and oc, coalescent form, was
observed. On the other hand, 7 (lane 4) accelerated the
mobility of the ccc form.
Intermolecular interactions contacts C-H · · · F-C, N-
H · · · O, C-H · · · O, C-H · · · πHmtpO, and N · · · πHmtpO are also
observed.23,24,37,54 Thus, for example, there is intermolecular
C-H · · · F hydrogen bonding between fluorine atoms of the
+
fluorophenyl groups and hydrogen atoms of NBu4 (F6 · · ·
H50B contact of 2.285 Å, F8 · · · H70B contact of 2.494 Å)
and the intermolecular hydrogen bond interaction N4-H4 · · ·
O11(N · · ·O11contactof2.724Å).TheH42 · · ·centroid(N2N3-
C5N1C1) and N14 · · ·centroid (N2N3C5N1C1) distances are
2.959 Å and 2.863 Å, respectively.
Comparison Among the New Crystal Structures. In the
Scheme 10 the metal-N3 bond distances of the seven new
structures reported in this article are collected, together with
the metal · · · metal distances of the dinuclear complexes.
The following observations can be found:
1.Inthedinuclearcomplexesofthetype[NBu4]2[M(C6F5)2(µ-
mtpO)]2 [M ) Pd (11 ·CH2Cl2 ·toluene) and Pt (12 ·0.5tolu-
ene)], the Pt-N3 distances are shorter than the Pd-N3. A
similar observation has been previously found in other related
systems, such as in [NBu4][M(C6F5)2(pz)(Hpz)] (M ) Pt,
Pd; Hpz ) pyrazole).53
2. The distance metal-N3 observed mainly depends on
the nature of the donor atom in the trans position, rather
than the neutral or anionic nature of the HmtpO/mtpO ligand,
as illustrated in 7·acetone and 14 (Scheme 10). On the other
hand, the shorter metal-N3 distance is observed for 8·2H2O
(2.022 Å), where the mtpO ligand is trans to one of the
The behavior observed for the electrophoretic mobility for
the platinum complexes indicates that some conformational
change occurred. This means that the degree of superhelicity
of the DNA molecules has been altered. In contrast, the free
ligand HmtpO does not seem to modify the tertiary structure
of DNA.
(55) Macquet, J. P.; Butour, J. L. Biochimie 1978, 60, 901–914.
(56) Brabec, V.; Kleinwa¨chter, V.; Butour, J.; Johnson, M. P. Biophys.
Chem. 1990, 35, 129–141.
(57) Cervantes, G.; Prieto, M. J.; Moreno, V. Metal Based Drugs 1997, 4, 9.
(58) Cervantes, G.; Marchal, S.; Prieto, M. J.; Pe´rez, J. M.; Gonza´lez, V. M.;
Alonso, C.; Moreno, V. J. Inorg. Biochem. 1999, 77, 197–203.
(59) Ushay, H. M.; Tullius, T. D.; Lippard, S. J. Biochemistry 1981, 20,
3744–3748.
(54) Hosmane, R. S.; Rossman, M. A.; Leonard, N. J. J. Am. Chem. Soc.
1982, 104, 5497–5499.
4498 Inorganic Chemistry, Vol. 47, No. 11, 2008

Pd(II) and Pt(II) Triazolopyrimidine Complexes
Figure 10. Schematic showing the chain formed by F5 · · ·F9 contact in 12·0.5(toluene).
Figure 11. ORTEP representation (50% probability) of 14. Selected bond
lengths (Å) and angles (deg): Pt(1)-C(20) ) 1.995(5), Pt(1)-C(30) )
2.005(4), Pt(1)-N(1) ) 2.072(4), Pt(1)-N(11) ) 2.096(4), C(20)-Pt(1)-
N(30) ) 87.87(18), C(20)-Pt(1)-N(1) ) 89.43(16), C(30)-Pt(1)-N(1)
) 176.50(16), C(20)-Pt(1)-N(11) ) 179.14(16), C(30)-Pt(1)-N(11) )
Figure 12. π-stacking interactions between nitrogen aromatic rings. One
molecule establishes π-stacking interactions with another related by
symmetry operation through -x, -y, -z + 2.
91.77(16), N(1)-Pt(1)-N(11) ) 90.95(14).
AFM Study of Compound-pBR322 Complexes. Con-
sequently to the behavior observed in the electrophoretic
mobility, the platinum complexes 2 and 7 modify the
morphology of the pBR322 DNA, and the ccc forms are
predominant in the pictures (Figure 15). In all cases, the
complexes seem to modify the morphology of the pBR322
DNA in similar mode as cisplatin does.17,57–61 The platinum
complexes attached to DNA cause kinks and cross-linking
in the plasmid forms. The background of part b of Figure
15 indicates the presence of a layer of water molecules from
the environment over the mica surface, which can be the
origin of the aggregation of the forms.
Cytotoxicity Studies. The in vitro growth inhibitory effect
of 2 and 7 and cisplatin was evaluated in a panel of human
tumor cell lines representative of ovarian (A2780 and
A2780cisR), lung (NCI-H460, nonsmall lung cancer cell),
and breast cancers (T47D, cisplatin resistant). A2780cisR
encompasses all of the known major mechanisms of resis-
tance to cisplatin: reduced drug transport,62 enhanced DNA
repair/tolerance,63 and elevated GSH levels.64 Table 2 shows
the IC50 values and the resistance factors (RF) of the new
platinum complexes. The ability of 2 and 7 to circumvent
cisplatin-acquired resistance was determined from the RF,
defined as the ratio of the IC50 resistant line to the IC50 parent
line. An RF of <2 was considered to denote noncross-
resistance.65 Especially noteworthy are the very low RFs of
both complexes at 48 h (RF ) 1.4 and 1.2, respectively),
indicating efficient circumvention of cisplatin resistance
(Table 3).
On the other hand, a 48 h incubation time for 2 and 7
were about 8-fold more active than cisplatin in T47D,
(62) Loh, S. Y.; Mistry, P.; Kelland, L. R.; Abel, G.; Harrap, K. R. Br. J.
Cancer 1992, 66, 1109–1115.
(63) Goddard, P. M; Orr, R. M.; Valenti, M. R.; Barnard, C. F.; Murrer,
B. A.; Kelland, L. R.; Harrap, K. R. Anticancer Res. 1996, 16, 33–8.
(64) Behrens, B. C.; Hamilton, T. C.; Masuda, H.; Grotzinger, K. R.;
Whang-Peng, J.; Louie, K. G.; Knutsen, T.; McKoy, W. M.; Young,
R. C.; Ozols, R. F. Cancer Res. 1987, 47, 414–418.
(60) Onoa, G. B.; Cervantes, G.; Moreno, V.; Prieto, M. J. Nucleic Acids
Res. 1998, 26, 1473–1480.
(65) Kelland, L. R.; Barnard, C. F. J.; Mellish, K. J.; Jones, M.; Goddard,
P. M.; Valenti, M.; Bryant, A.; Murrer, B. A.; Harrap, K. R. Cancer
Res. 1994, 54, 5618–5622.
(61) Onoa, G. B.; Moreno, V. Int. J. Pharm. 2002, 245, 55–65.
Inorganic Chemistry, Vol. 47, No. 11, 2008 4499

Ruiz et al.
and [NBu4]2[M2(C6F5)4(µ-OH)2] (M ) Pd or Pt)51,52 were prepared
by procedures described elsewhere. Solvents were dried by the usual
methods. 4,7-dihydro-5-methyl-7-oxo[1,2,4]triazolo[1,5-a]pyrimi-
dine (HmtpO), sodium salt of calf thymus DNA, EDTA (ethylene
diaminotetracetic acid), and Tris-HCl (tris-(hydroxymethyl)ami-
nomethane-hydrochloride) used in the circular dichroism (CD) study
were obtained from Sigma-Aldrich (Madrid, Spain), HEPES (N-
2-hydroxyethyl piperazyne-N′-2-ethanesulfonic acid) was obtained
from ICN (Madrid), and pBR322 plasmid DNA was obtained from
Boehringer-Mannheim (Mannheim, Germany).
Scheme 10
Warning! Perchlorate salts of metal complexes with organic
ligands are potentially explosiVe. Only small amounts of material
should be prepared, and these should be handled with great caution.
Preparation of [Pd(dmba)(PPh3)(HmtpO)]ClO4 1. To a solu-
tion of [Pd(dmba)(Cl)(PPh3)] (0.185 mmol, 100 mg) in CH2Cl2 (20
mL) was added AgClO4 (0.185 mmol, 38.5.0 mg). AgCl im-
mediately formed. The resulting suspension was stirred for 30 min
and then filtered through a short pad of Celite. To the filtrate was
then added HmtpO (0.185 mmol, 27.8 mg). The solution was stirred
for 5 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.
Data for 1. Yield: 65%. Anal. Calcd for C33H33ClN5O5PPd: C,
52.7; H, 4.4; N, 9.3. Found: C, 52.4; H, 4.4; N, 9.1. Mp: 230 °C
dec ΛM: 135 S cm2 mol-1. IR (Nujol, cm-1): ν(CO), 1716; ClO4,
1095, 623. 1H NMR (CDCl3): δ (SiMe4) 11.53 (s, 1H, NH of
HmtpO), 7.92 (s 1H, H2 of HmtpO), 7.68 (m, 6H, PPh3), 7.37 (m,
9H, PPh3), 7.03 (d, 1H, C6H4, JHH ) 7.6 Hz), 6.86 (false t, 1H,
C6H4, JHH ≈ JHH ) 8.2 Hz), 6.35 (m, 2H, C6H4), 5.69 (s, 1H, H6
of HmtpO), 5.29 (br, 1H, NCH2 of dmba), 3.46 (br, 1H, NCH2 of
dmba), 2.71 (br, 3H, NMe2 of dmba), 2.58 (br, 3H, NMe2 of dmba),
2.40 (s, 3H, Me of HmtpO). 31P NMR (CDCl3): δ (H3PO4) 41.78
(s).
Preparation of [Pt(dmba)(PPh3)(HmtpO)]ClO4 2. To a solu-
tion of [Pt(dmba)(PPh3)Cl] (0.159 mmol, 100 mg) in acetone (20
mL) was added AgClO4 (0.159 mmol, 33.1 mg). AgCl immediately
formed. The resulting suspension was stirred for 30 min and then
filtered through a short pad of Celite. To the filtrate was then added
HmtpO (0.159 mmol, 23.9 mg). The resulting solution was stirred
for 5 h, and then the solvent was partially evaporated under vacuum.
A white solid obtained which was collected by filtration and air-
dried.
Data for 2. Yield: 88%. Anal. Calcd for C33H33ClN5O5PPt: C,
47.1; H, 4.0; N, 8.3. Found: C, 47.3; H, 3.9; N, 8.4. Mp: 269 °C
dec ΛM: 150 S cm2 mol-1. IR (Nujol, cm-1): ν(CO), 1715; ClO4,
1095, 623. 1H NMR (CDCl3): δ (SiMe4) 11.63 (s, 1H, NH of
HmtpO), 7.92 (s 1H, H2 of HmtpO), 7.69 (m, 6H, PPh3), 7.33 (m,
9H, PPh3), 7.08 (d, 1H, C6H4, JHH ) 7.1 Hz), 6.88 (false t, 1H,
C6H4, JHH ≈ JHH ) 7.2), 6.38 (m, 2H, C6H4), 5.69 (s, 1H, H6 of
HmtpO), 5.17 (d, 1H, NCH2 of dmba, JHH ) 13.0 Hz), 3.70 (dd,
1H, NCH2 of dmba, JHH ) 13.2, JHP ) 2.5 Hz), 2.78 (s, 3H, NMe2
of dmba), 2.74 (s, 3H, NMe2 of dmba), 2.45 (s, 3H, Me of HmtpO).
31P NMR (CDCl3): δ (H3PO4) 19.30 (JPtP ) 4136 Hz).
Preparation of [Pd(N-N)(C6F5)(HmtpO)]ClO4 3-5. To a
solution of [Pd(N-N)(C6F5)(Cl)] (0.214 mmol) [N-N ) bpy (2,2′-
bipyridyl), Me2bpy (4,4′-dimethyl-2,2′-bipyridyl) or N,N,N′,N′-
tmeda (tetramethylethylenediamine)] in acetone (20 mL) was added
AgClO4 (0.214 mmol, 44.5 mg). AgCl immediately formed. The
resulting suspension was stirred for 30 min and then filtered through
a short pad of Celite. To the filtrate was then added HmtpO (0.214
mmol, 32.2 mg). The resulting solution was stirred for 5 h, and
then the solvent was partially evaporated under vacuum. A white
solid obtained, which was collected by filtration and air-dried.
whereas in NCI-H460 similar values of IC50 than cisplatin
were obtained.
Experimental Section
Instrumental Measurements. The carbon, hydrogen, and ni-
trogen analyses were performed with a Carlo Erba model EA 1108
microanalyzer. Decomposition temperatures were determined 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, 13C, 31P, and 19F NMR spectra were recorded
on a Bruker AC 200E or Bruker AC 300E spectrometer, using
SiMe4, H3PO4, and CFCl3 as standards. Infrared spectra were
recorded on a PerkinElmer 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.
Materials. The starting complexes [M(dmba)Cl(PPh3)] (M )
Pd or Pt),10,11 [Pd(N-N)(C6F5)Cl)] (N-N ) bpy, Me2bpy, or
tmeda),66 [NBu4]2[Pd2(C6F5)4(µ-Cl)2],31 cis-[Pt(C6F5)2(THF)2],32
[Pd(N-N) (C6F5)(OH)] (N-N ) tmeda),28 [Pd(dmba)(µ-OH)]2,14
4500 Inorganic Chemistry, Vol. 47, No. 11, 2008

Pd(II) and Pt(II) Triazolopyrimidine Complexes
Figure 13. Circular dichroism spectra of DNA and DNA incubated with free HmtpO, 2, and 7 at different ri.
tmeda), 2.55 (s, 3H, Me of HmtpO). 19F NMR (acetone-d6): δ
(CFCl3) -120.18 (m, 1Fo), -121.93 (m, 1Fo), -161.56 (t, 1Fp, JFpFm
18.8 Hz), -163.57 (m, 1Fm), -164.47 (m, 1Fm).
Preparation of cis-[Pd(C6F5)2(HmtpO)2] 6. To a solution of
[NBu4]2[Pd2(C6F5)4(µ-Cl)2] (100 mg, 0.070 mmol) in acetone (20
mL) was added AgClO4 (28.9 mg, 0.140 mmol). AgCl inmediately
formed. The resulting suspension was stirred for 30 min and then
filtered through a short pad of Celite. To the filtrate was then added
HmtpO (41.8 mg, 0.278 mmol). The solution was stirred for 24 h,
then the solvent was partially evaporated under vacuum, and hexane
was added to precipitate a white solid, which was collected by
filtration and air-dried.
Data for 6. Yield: 55%. Anal. Calcd for C24H12F10N8O2Pd: C,
38.9; H, 1.6; N, 15.1. Found: C, 38.8; H, 1.8; N, 15.2. Mp: 175 °C
dec IR (Nujol, cm-1): ν(CO), 1713, 1694; ν(Pd-C6F5), 798, 787.
1H NMR acetone-d6, -50 °C): δ (SiMe4) 13.0 (s, 2H, NH of
HmtpO), 8.65 (s, 2H, H2 of HmtpO), 5.96 (s, 2H, H6 of HmtpO),
2.42 (s, 6H, CMe of HmtpO). 19F NMR (acetone-d6): δ (CFCl3)
-115.90 (m, 4Fo), -162.69 (t, 2Fp, JFpFm 18.8 Hz), -165.04 (m,
4Fm).
Preparation of cis-[Pt(C6F5)2(HmtpO)2] 7. To a solution of cis-
[Pt(C6F5)2(THF)2] (145 mg, 0.215 mmol) in acetone (20 mL) was
added HmtpO (64.6 mg, 0.43 mmol). The solution was stirred for
20 h. The solvent was evaporated off under reduced pressure. The
residue was treated with diethyl ether to render a white solid, which
was collected by filtration and air-dried.
Data for 7. Yield: 55%. Anal. Calcd for C22H12F10N8O2Pt: C,
32.8; H, 1.5; N, 13.9. Found: C, 33.0; H, 1.5; N, 13.6. Mp: 250 °C
dec IR (Nujol, cm-1): ν(CO), 1713, 1682; ν(Pt-C6F5), 810, 801.
1H NMR (acetone-d6): δ (SiMe4) 12.37 (s, 2H, NH of HmtpO),
8.60 (s, 2H, H2 of HmtpO), 5.89 (s, 2H, H6 of HmtpO), 2.48 (s,
6H, Me of HmtpO). 19F NMR (acetone-d6): δ (CFCl3) -120.58
(m, 4Fo), -165.40 (t, 2Fp, JFpFm 16.9 Hz), -167.32 (m, 4Fm).
Preparation of [Pd(tmeda)(C6F5)(mtpO)] 8. To a solution of
[Pd(tmeda)(C6F5)(OH)] (100 mg, 0.245 mmol) in methanol (20 mL)
was added HmtpO (36.8 mg, 0.245 mmol). The resulting mixture
was stirred for 1 h at room temperature, during which time the
white mononuclear complex precipitated, and then the solvent was
partly evaporated under reduced pressure. The complex was filtered
off and air-dried.
Figure 14. Modification of the gel electrophoretic mobility of pBR322
plasmid incubated with HmtpO and their platinum compounds: lane 1, pBR;
lane 2, HmtpO; lane 3, 2; lane 4, 7; lane 5, pBR-cisplatin.
Data for 3. Yield: 65%. Anal. Calcd for C22H14ClF56O5Pd: C,
38.9; H, 2.1; N, 12.4. Found: C, 38.6; H, 2.2; N, 12.5. Mp: 251 °C
dec ΛM: 144 S cm2 mol-1. IR (Nujol, cm-1): ν(CO), 1710;
1
ν(Pd-C6F5), 772. H NMR (acetone-d6): δ(SiMe4) 12.81 (s, 1H,
NH of HmtpO), 8.74 (m, 2H, HR + HR′ of bpy), 8.45 (m, 2H, Hγ
+ Hγ′ of bpy), 8.46 (s, 1H, H2 of HmtpO), 8.34 (d, 1H, Hδ or Hδ′
of bpy, JHH ) 5.6 Hz), 8,18 (d, 1H, Hδ or Hδ′ of bpy, JHH ) 5.4
Hz), 7.70 (m, 2H, Hꢀ + Hꢀ′ of bpy), 6.07 (s, 1H, H6 of HmtpO),
2.83 (s, 3H, Me of HmtpO). 19F NMR (acetone-d6): δ(CFCl3)
-120.35 (m, 1Fo), -121.25 (m, 1Fo), -160.73 (t, 1Fp, JFpFm
)
18.8 Hz), -163.41 (m, 2Fm).
Data for 4. Yield: 72%. Anal. Calcd for C24H18ClF5N6O5Pd: C,
40.8; H, 2.6; N, 11.9. Found: C, 40.5; H, 2.6; N, 12.1. Mp: 260 °C
dec ΛM: 142 S cm2 mol-1. IR (Nujol, cm-1): ν(CO), 1720;
1
ν(Pd-C6F5), 796. H NMR (acetone-d6): δ (SiMe4) 12.59 (s, 1H,
NH of HmtpO), 8.04 (s, 1H, H2 of HmtpO), 7.95 (s, 2H, Hδ + Hδ′
of Me2bpy), 7.62 (d, 1H, HR of Me2bpy, JHRHꢀ ) 6.0 Hz), 7.41 (d,
1H, HR′ of Me2bpy, JHR′Hꢀ′ ) 5.7 Hz), 7.25 (d, 1H, Hꢀ of Me2bpy,
JHRHꢀ ) 6.0 Hz), 7.18 (d, 1H, Hꢀ′ of Me2bpy, JHR′Hꢀ′ ) 5.7 Hz),
5.99 (s, 1H, H6 of HmtpO), 2.58 (s, 3H, Me of HmtpO), 2,54 (s,
6H, Me of Me2bpy). 19F NMR (acetone-d6): δ (CFCl3) -118.29
(m, 1Fo), -120.50 (m, 1Fo), -155.96 (t, 1Fp, JFpFm 20.1 Hz),
-159.14 (m, 1Fm), -159.97 (m, 1Fm).
Data for 5. Yield: 55%. Anal. Calcd for C18H22ClF5N6O5Pd: C,
33.8; H, 3.5; N, 13.2. Found: C, 33.6; H, 3.8; N, 12.9. Mp: 236 °C
dec ΛM: 130 S cm2 mol-1. IR (Nujol, cm-1): ν(CO), 1730;
1
ν(Pd-C6F5), 790. H NMR (acetone-d6): δ (SiMe4) 11.85 (s, 1H,
NH of HmtpO), 8.37 (s, 1H, H2 of HmtpO), 5.96 (s, H, H6 of
HmtpO), 3.28 (m, 4H, CH2 of tmeda), 2.75 (m, 12H, NMe2 of
Data for 8. Yield: 60%. Anal. Calcd for C18H21F5N6OPd: C,
40.1; H, 3.9; N, 15.6. Found: C, 40.2; H, 3.9; N, 15.5. Mp: 240 °C
Inorganic Chemistry, Vol. 47, No. 11, 2008 4501

Ruiz et al.
Figure 15. TMAFM image corresponding to (a) pBR322, (b) pBR-2, and (c) pBR-7.
Table 3. IC50 (µM) and resistance factors for Cisplatin and Complexes
2 and 7
C6H4), 6.91 (m, 5H, C6H4), 6.68 (d, 1H, C6H4, JHH ) 6.8 Hz), 6.17
(s, 1H, H6 of mtpO), 5.91 (s, 1H, H6 of mtpO), 3.29 (d, 1H, NCH2,
JHH ) 13.0 Hz), 2.93 (d, 1H, NCH2, JHH ) 13.0 Hz), 2.92 (d, 1H,
NCH2, JHH ) 13.6 Hz), 3.16 (s, 3H, Me of mtpO), 2.99 (s, 3H,
NMe2), 2.96 (s, 3H, NMe2), 2.73 (d, 1H, NCH2, JHH ) 13.6 Hz),
2.67 (s, 3H, Me of mtpO), 1.817 (s, 3H, NMe2), 1.61 (s, 3H, NMe2).
Data for 10b. Yield: 17%. Anal. Calcd for C30H34N10O2Pd2: C,
46.2; H, 4.4; N, 18.0. Found: C, 46.0; H, 4.6; N, 17.8. Mp: 272 °C
T47D
NCI-H460
A2780
A2780cisR
complex 24 h 48 h 24 h 48 h 24 h 48 h 24 h (RF)a 48 h (RF)a
2
7
55.5 4.7 7.0 9.0
30.5 4.6 12.0 9.0
3.9 3.9
5.4 7.1
6.2 (1.6)
10 (1.9)
17 (1.7)
5.3 (1.4)
8.8 (1.2)
18 (18.4)
cisplatin 34.0 35.0 6.0 9.0 10.0 0.98
a The numbers in parentheses are the resistance factors RF (IC50 resistant/
IC50 sensitive).
1
dec H NMR (CDCl3): δ (SiMe4) 8.44 (s, 2H, H2 of mtpO), 7.07
(m, 2H, C6H4), 6.95 (m, 4H, C6H4), 6.84 (d, 2H, C6H4, JHH ) 7.4
Hz), 5.89 (s, 2H, H6 de mtpO), 2.83 (s, 4H, NCH2), 2.76 (s, 6H,
NMe2), 3.19 (s, 6H, Me of mtpO), 1.79 (s, 6H, NMe2).
1
dec IR (Nujol, cm-1): ν(CO), 1660; ν(Pd-C6F5), 770. H NMR
(CDCl3): δ (SiMe4) 7.75 (s, 1H, H2 of mtpO), 5.83 (s, 1H, H6 de
mtpO), 2.86 (br, 2H, CH2 of tmeda), 2.83 (br, 2H, CH2 of tmeda),
2.68 (s, 6H, NMe2 of tmeda), 2.62 (s, 6H, NMe2 of tmeda), 2.35
(s, 3H, Me of mtpO). 19F NMR (CDCl3): δ (CFCl3) -121.65 (m,
2Fo), -158.29 (t, 1Fp, JFpFm 28,8), -161.59 (m, 2Fm).
Preparation of [Pd(dmba)(PPh3)(mtpO)] 9. To a solution of
[Pd(dmba)(µ-OH)]2(100 mg, 0.195 mmol) in CH2Cl2 (20 mL) was
added PPh3 (102.3 mg, 0.390 mmol) and HmtpO (58.6 mg, 0.390
mmol). The resulting mixture was stirred for 1 h at room
temperature, and then the solvent was partially evaporated under
vacuum, and hexane was added to precipitate a white solid, which
was collected by filtration and air-dried.
Data for 9. Yield: 98%. Anal. Calcd for C33H32N5OPPd: C, 60.8;
H, 5.0; N, 10.7. Found: C, 60.6; H, 4.9; N, 10.9. Mp: 246 °C dec
IR (Nujol, cm-1): ν(CO), 1660. 1H NMR (CDCl3): δ (SiMe4) 7.61
(m, 7H, H2 of HmtpO + PPh3), 7.31(m, 9H, PPh3), 7.04 (d, 1H,
C6H4, JHH ) 7.4 Hz), 6.86 (false t, 1H, C6H4, JHH ≈ JH-H ) 8.2
Hz), 6.41 (m, 2H, C6H4), 5.58 (br, 1H, H6 of mtpO), 4.22 (br, 1H,
NCH2 of dmba), 4.07 (br, 1H, NCH2 of dmba), 2.64 (br, 6H, NMe2),
2.25 (s, 3H, Me of mtpO). 31P NMR (CDCl3): δ (H3PO4) 43.31
(s).
Preparation of Dimeric Palladium Complexes [Pd(dmba)(µ-
mtpO)]2 10a and 10b. To a solution of [Pd(dmba)(µ-OH)]2 (100
mg, 0.195 mmol) in methanol (15 mL) was added HmtpO (58.6
mg, 0.390 mmol). The resulting mixture was stirred for 20 min at
room temperature, and then the solvent was partially evaporated
under vacuum, and a suspension was obtained from which a white
solid was collected by filtration and air-dried. Accordingly, with
Preparation of [NBu4]2[M(C6F5)2(µ-mtpO)]2 (11 and 12)
and [NBu4][M(C6F5)2(mtpO)(HmtpO)] (13 and 14) (M ) Pd
or Pt). To a solution of [NBu4]2[M(C6F5)2(µ-OH)]2 (M ) Pd or
Pt) (0.071 mmol) in acetone (20 mL) was added HmtpO (21.4 mg,
0.142 mmol). The suspension was stirred for 24 h at room
temperature. The resulting solution was concentrated under vacuum
to dryness. Addition of ether yielded a white solid which was filtered
off and air-dried. The isolated solids were identified by NMR
spectroscopy as a mixture containing the corresponding [NBu4]2-
[M(C6F5)2(µ-mtpO)]2 (11 or 12) and [NBu4][M(C6F5)2(mtpO)-
(HmtpO)] (13 or 14) in a molar ratio of approximately 1:0.4,
together with starting material. The platinum complexes 12 and 14
were separated mechanically after crystallization from dichlo-
romethane/toluene/hexane. In the case of palladium, only crystals
of 11 could be obtained.
Data for 11. Yield: 16%. Anal. Calcd for C68H83F20N10O2Pd2:
1
C, 49.1; H, 5.0; N, 8.4. Found: C, 49.0; H, 4.8; N, 8.3. H NMR
(CDCl3): δ (SiMe4) 8.44 (s, 2H, H2 of mtpO), 5.43 (s, 2H, H6 of
mtpO), 3.44 (m, 16H, CH2N of NBu4), 2.87 (s, 6H, Me of mtpO),
2.04 (m, 16H, CH2 of NBu4), 1.40 (m, 16H, CH2 of NBu4), 0.93
(t, 24H, Me de NBu4, JHH 7.4), 19F NMR (CDCl3): δ (CFCl3)
-112.44 (m, 8Fo), -165.40 (t, 2Fp, JFpFm ) 20.7 Hz), -165.80 (t,
2Fp, JFpFm ) 20.7 Hz), -167.16 (m, 4Fm), -167.68 (m, 4Fm).
Data for 12. Yield: 14%. Anal. Calcd for C68H83F20N10O2Pt2:
1
C, 44.3; H, 4.5; N, 7.6. Found: C, 44.6; H, 4.3; N, 7.8. H NMR
(CDCl3): 8.67 (s, 2H, H2 of mtpO), 5.59 (s, 2H, H6 of mtpO),
3.09 (m, 16H, CH2N of NBu4), 2.80 (s, 6H, Me of mtpO), 1.40
(m, 16H, CH2 of NBu4), 1.25 (m, 16H, CH2 of NBu4), 0.86 (t,
24H, Me of NBu4), 19F NMR (CDCl3): δ (CFCl3) -117.14 (m,
8Fo, JPtFo ) 406 Hz), -165.62 (t, 2Fp, JFpFm ) 19.7 Hz), -165.97
(m, 2Fp, JFpFm ) 19.7 Hz), -167.30 (m, 4Fm), -168.14 (m, 4Fm).
Data for 13. 1H NMR (CDCl3): 7.94 (s, 2H, H2 of mtpO), 6.01
(s, 2H, H6 of mtpO), 3.44 (m, 8H, CH2N of NBu4), 2.41 (s, 6H,
Me of mtpO), 2.05 (m, 8H, CH2 of NBu4), 1.41 (m, 8H, CH2 of
NBu4), 0.95 (t, 12H, Me de NBu4, JHH 7.4), 19F NMR (CDCl3): δ
1
the H NMR in CDCl3 two linkage isomers (10a and 10b) are
present in a ratio (1:0.4). The H-H isomer 10a was isolated pure
by crystallization in CH2Cl2/toluene/hexane of the mixture, whereas
the H-L isomer 10b was isolated pure by washing the mixture
with ethanol.
Data for 10a. Yield: 35%. Anal. Calcd for C30H34N10O2Pd2: C,
46.2; H, 4.4; N, 18.0. Found: C, 46.1; H, 4.5; N, 17.9. Mp: 265 °C
dec IR (Nujol, cm-1): ν(CO), 1680. H NMR (CDCl3): δ (SiMe4)
1
8.41 (s, 1H, H2 of mtpO), 7.89 (s, 1H, H2 of mtpO), 7.05 (m, 2H,
4502 Inorganic Chemistry, Vol. 47, No. 11, 2008

Pd(II) and Pt(II) Triazolopyrimidine Complexes
Table 4. Crystal Structure Determination Details of 1, 7·acetone, 8·2H2O and 10a
params
1
7·acetone
8·2H2O
10a
empirical formula
fw
cryst syst
a (Å)
b (Å)
c (Å)
R (deg)
ꢀ (deg)
γ (deg)
V (Å3)
T (K)
C33H33ClN5O5PPd
752.46
monoclinic
11.7034(5)
36.114(2)
9.5959(6)
90
125.764(4)
90
3291.0(3)
173(2)
Cc
C27H18F10N8O3Pt
887.58
monoclinic
14.1739(6)
15.8664(6)
13.3379(5)
90
99.899(2)
90
2954.9(2)
100(2)
P21/c
C18H25F5N6O3Pd
574.84
C30H34N10O2Pd2
779.47
monoclinic
9.7961(8)
27.5078(18)
11.3078(8)
90
96.253(6)
90
3029.0(4)
173(2)
triclinic
9.2868(8)
10.5789(6)
12.4126(7)
82.845(4)
78.512(6)
69.745(6)
1119.08(13)
173(2)
P-1
2
0.903
7918
space group
Z
P21/n
4
1.234
6040
4
4
µ (mm-1
)
0.742
5783
5150
0.0237
0.0264
0.0676
2
4.859
33115
6830
reflns collected
independent reflns
R(int)
3938
0.0207
0.0242
0.0620
5333
0.0521
0.0366
0.0698
b
2
0.0280
0.0334
0.0760
R1 [I > 2σ (I) ]a
wR2 (all data)b
a R1 )∑|Fo| - |Fc|/∑|Fo|, wR2 ) [∑[w(Fo2 - Fc )2]/∑w(Fo ) ]0.5
.
w ) 1/[σ2(Fo ) + (aP)2 + bP], where P ) (2Fc2 + Fo )/3 and a and b are constants
2
2
2
set by the program.
Table 5. Crystal Structure Determination Details of 11·CH2Cl2 ·toluene, 12·0.5(toluene) and 14
params
11·CH2Cl2 ·toluene
12·0.5(toluene)
14
empirical formula
fw
cryst syst
a (Å)
b (Å)
c (Å)
R (deg)
ꢀ (deg)
γ (deg)
V(Å3)
C78H92Cl2F20N8O2Pd2
1837.30
triclinic
C
71.50H86F20N10O2Pt2
C40H47F10N9O2Pt
1070.96
monoclinic
10.4660(4)
20.5620(8)
21.5847(8)
90
93.0840(10)
90
4638.3(3)
100(2)
P21/n
4
3.109
50 823
9478
0.0538
0.0402
0.0972
1887.68
monoclinic
12.4458(5)
46.806(2)
14.2160(6)
90
113.605(2)
90
7588.4(6)
100(2)
P21/n
15.2953(7)
17.0706(8)
17.9758(8)
95.718(2)
108.812(2)
110.224(2)
4049.4(3)
100(2)
P-1
2
0.607
44 817
T (K)
space group
Z
4
µ (mm-1
)
5.182
reflns collected
independent reflns
R(int)
87 941
17 770
0.0640
0.0482
0.0922
16 452
0.0186
0.0463
0.1377
R1 [I > 2σ (I) ]a
wR2 (all data)b
b
a R1 )∑|Fo| - |Fc|/∑|Fo|, wR2 ) [∑[w(Fo2 - Fc )2]/∑w(Fo )2]0.5
.
w ) 1/[σ2(Fo ) + (aP)2 + bP], where P(2Fc2 + Fo )/3, and a and b are constants set
2
2
2
2
by the program.
(CFCl3) -115.16 (m, 2Fo), -115.79 (m, 2Fo), -164.2 (t, 2Fp, JFpFm
) 22.6), -166.4 (m, 4Fm).
Lorentz and polarization effects. Absorption corrections were
applied for 1, 8·2H2O, and 10a on the basis of Ψ-scans and for
7 · acetone, 11 · CH2Cl2 · toluene, 12 · 0.5(toluene), and 14, and
empirical absorption corrections were also applied.67
Data for 14. Yield: 10%. Anal. Calcd for C41H50F10N9O2Pt: C,
1
45.4; H, 4.6; N, 11.6. Found: C, 45.8; H, 4.3; N, 11.7. H NMR
(CDCl3): 8.06 (s, 2H, H2 of mtpO), 5.74 (s, 2H, H6 of mtpO),
3.15 (m, 8H, CH2N of NBu4), 2.38 (s, 6H, Me of mtpO), 1.66 (m,
8H, CH2 of NBu4), 1.28 (m, 8H, CH2 of NBu4), 0.86 (t, 12H, Me
of NBu4, JHH 7.4), 19F NMR (CDCl3): δ (CFCl3) -120.38 (m, 4Fo,
JPtFo ) 459), -165.62 (m, 2Fp, JFpFm 21.4), -164.77 (m, 4Fm).
X-ray Crystal Structure Analysis. Suitable crystals of 1 were
grown from dichloromethane/hexane. Crystals from 7·acetone were
grown from acetone/hexane. Crystals from 8 · 2H2O, 10a,
11·CH2Cl2 ·toluene, 12·0.5(toluene), and 14 were grown from
dichloromethane/toluene/hexane. The crystal and molecular struc-
tures of the 1, 7 · acetone, 8 · 2H2O, 10a, 11 · CH2Cl2 · toluene,
12·0.5(toluene), and 14 have been determined by X-ray diffraction
studies (Tables 4 and 5).
The structures of 7·acetone, 11·CH2Cl2 ·toluene, 12·0.5(tolu-
ene), and 14 were solved by direct methods using SHELX-97,68
which revealed the position of all non-hydrogen atoms, and the
structures of 1, 8·2H2O, and 10a were solved by the heavy method.
All the structures were refined on F2 by a full-matrix least-squares
procedure using anisotropic displacement parameters for all non-
hydrogen atoms. For 1 and 7·acetone, the hydrogen atom of the
amine group of the ligands were located on a difference Fourier
map and refined isotropically. The methyl groups were refined using
a rigid groups, and the other hydrogens were refined using a riding
mode for 1, 7·acetone, 8·2H2O, 10a, 11 ·CH2Cl2 ·toluene, and
12·0.5(toluene).
1, 8·2H2O, and 10a were measured on a Siemens P4/LT2
machine and 7·acetone, 11·CH2Cl2 ·toluene, 12·1/2toluene, and
14 were measured on a Bruker Smart Apex CCD machine. Graphite
monochromated Mo KR was used. All data were corrected by
(66) Uso´n, R.; Fornie´s, J.; Mart´ınez, F. J. Organomet. Chem. 1976, 112,
105–110.
(67) Sheldrick, G. M. (1996). SADABS. Program for Empirical Absoption
Correction of Area Detector Data. University of Go¨tingen, Germany.
Inorganic Chemistry, Vol. 47, No. 11, 2008 4503

Ruiz et al.
Special features:
As a blank was used a solution of each compound in TE
buffer (50 mM NaCl, 10 mM Tris-HCl, 0.1 mM EDTA, pH
7.4). Each sample was scanned twice in a range of wave-
lengths 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 µg/µL of concentration was used for the experiments.
Four microlitres of charge maker were added to aliquot parts
of 20 µL of the complex/DNA compound containing 0.7 µg
of DNA previously incubated at 37 °C for 24 h. The mixtures
underwent electrophoresis in a 1% agarose gel in 1x TBE
buffer (45 mM Tris-borate, 1 mM EDTA, pH 8.0) for 5 h at
30 V. The gel was subsequently stained in the same buffer
containing ethidium bromide (1 µg/mL) for 20 min. The
DNA bands were visualized with a Typhoon 9410 Variable
Mode Imager (Amersham Biosciences).
Atomic Force Microscopy. Preparation of adducts of
DNA-metal complexes. pBR322 DNA (25 µg/µL), previ-
ously heated at 60 °C, was incubated in an appropriate
volume with the required platinum concentration correspond-
ing to the molar ratio ri ) 0.005. The complexes were
dissolved in HEPES buffer (40 mM HEPES pH 7.4, and 10
mM MgCl2). The different solutions as well as Milli-Q water
were passed through 0.2 nm FP030/3 filters (Schleicher &
Schuell GmbH, Germany) and centrifuged at 4000g several
times to avoid salt deposits and provide a clear background
when they were imaged by AFM. The reactions were run at
37 °C for 24 h in the dark.
Sample Preparation for Atomic Force Microscopy.
Samples were prepared by placing a drop (3 µL) of DNA
solution or DNA-metal complex solution onto green mica
(Ashville-Schoonmaker Mica Co., Newport New, VA). After
adsorption for 5 min at room temperature, the samples were
rinsed for 10 s in a jet of deionized water of 18 MΩ cm-1
from a Milli-Q water purification system directed onto the
surface with a squeeze bottle. They were then placed into
ethanol-water mixture (1:1) five times, plunged three times
each in ethanol (100%). The samples were blow dried with
compressed argon over silica gel and then imaged in the
AFM.
For 1: The perchlorate anion is disordered over two sites.
For 8 · 2H2O: The structure contains two solvent residues
that were tentatively identified as water. Their hydrogens
were not included in the refinement.
For 11 ·CH2Cl2 ·toluene: One butyl of a NBu4 is disordered
over two positions, ca. 54:46. Its hydrogens were not
included in the refinement. The structure contains two solvent
residues: the dichloromethane is well-ordered but with a peak
of 1.78 eA3 at 1.79 Å from Cl1, whereas the other region
was tentatively identified as toluene with the highest peak
of 3.20 eÅ3 at 2.13 Å from one of its carbon atoms. The
additional peaks suggest some solvent disorder. Solvent
carbons were refined isotropically. Toluene methyl hydrogens
were not included in the refinement.
For 12: Two methyls of NBu4 are disordered over two
sites. The toluene of solvation is disordered over an inversion
center.
For 14: The hydrogen atoms of the carbons were located
in their calculated positions and refined using a riding model.
The hydrogen atom of the amine group of one ligand was
located on a difference Fourier map and refined isotropically.
Molecular graphics were generated using CAMERON and
ORTEP-3.69
The unit cell contains two potential solvent-accessible
symmetry-related cavities located on the crystallographic
inversion centers at (0, 0, /2) and (1/2, /2, 0), filled with
disordered solvent, probably dichloromethane. The volume
of each cavity is 241 Å3. Attempts to model dichloromethane
molecules into the solvent density did not result in an
acceptable model. As an alternative strategy, the SQUEEZE70
function of PLATON71 was used to eliminate the contribution
of the electron density in the solvent region from the intensity
data. The use of this strategy and the subsequent solvent-
free model produced slightly better refinement results than
the attempt to model the solvent atoms. Therefore, the
solvent-free model and intensity data were used for the final
results reported here. A total of 88 e was found in each
cavity, corresponding to approximately two dichloromethane
molecules per cavity. Where relevant, the crystal data
reported earlier in this article are given without the contribu-
tion of the disordered solvent.
1
1
Imaging by Atomic Force Microscopy. The samples
were imaged in a Nanoscope III Multimode AFM (Digital
Instrumentals Inc., Santa Barbara, CA) operating in tapping
mode in air at a scan rate of 1-3 Hz. The AFM probe was
a 125 mm long monocrystalline silicon cantilever with
integrated conical shaped silicon tips (Nanosensors GmbH
Germany) with an average resonance frequency fo ) 330
kHz and spring constant K ) 50 N/m. The cantilever is
rectangular and the tip radius given by the supplier is 10
nm, with a cone angle of 35° and a high aspect ratio. In
general, the images were obtained at room temperature (T
) 23 ( 2 °C) and the relative humidity (RH) was typically
lower than 40%.
Biological Assays
Circular Dichroism Study. Spectra were recorded at
room temperature on an Applied Photophysics Π*-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,
2% in DMSO), to a solution of Calf Thymus DNA (Sigma)
in TE buffer (20 µg/mL), and incubated for 24 h at 37 °C.
(68) Sheldrick, G. M. SHELX-97, An Integrated System for SolVing and
Refining Crystal Structures from Diffraction Data; University of
Go¨ttingen: Go¨ttingen, Germany, 1997.
(69) ORTEP-3 Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
(70) Sluis, P. van der; Spek, A. L. Acta Crystallogr. 1990, A46, 194–201.
(71) Spek, A. L.; PLATON. University of Utrecht, The Netherlands, 2001.
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
4504 Inorganic Chemistry, Vol. 47, No. 11, 2008

Pd(II) and Pt(II) Triazolopyrimidine Complexes
bovine serum (FBS) and 0.2 unit/mL bovine insulin in an
atmosphere of 5% CO2 at 37 °C.
Conclusions
The first organometallic Pd(II) and Pt(II) complexes with
the HmtpO ligand and its anion mtpO- have been prepared,
showing the different coordination modes of this ligand. The
structure of [NBu4][Pt(C6F5)2(mtpO)(HmtpO)] 14 is the first
crystal structure of a metal complex containing simulta-
neously both the neutral HmtpO and the anionic mtpO. In
the mtpO-HmtpO metal complexes (13 and 14), for the first
time, prototropic exchange is observed between the two
heterocyclic ligands. The distance metal-N3 observed in the
new complexes mainly depends on the nature of the donor
atom in the trans position, rather than the neutral or anionic
nature of the HmtpO/mtpO ligand. The value of the
metal · · · metal separation in the new dinuclear complexes
(10a, 11 · CH2Cl2 · toluene, and 12 · 0.5(toluene)) is also a
consequence of the trans influence of the ancillary ligands.
cis-[Pt(C6F5)2(HmtpO)2] · acetone (7 · acetone) exhibits an
H-H orientation of the HmtpO moieties. Strong supramo-
lecular interactions are present in all of the structures.
7 · acetone possesses the shortest distances Fortho · · ·Fpara
observed in fluoroaryl transition metal complexes so far.
Circular dichroism, electrophoretic mobility, and atomic force
microscopy studies indicate interaction of the new platinum
complexes with DNA. Values of IC50 were calculated for 2
and 7 against the human tumor cell lines A2780, A2780cisR,
NCI-H460, and T47D. At 48 h incubation time, both
complexes were about 8-fold more active than cisplatin in
T47D and show very low resistance factors against an A2780
cell line, which has acquired resistance to cisplatin.
Cytotoxicity Assay. Cell proliferation was evaluated by
a crystal violet assay. T-47D cells were plated in 96 well
sterile plates at a density of 5 × 103 cells/well with 100 µL
of medium and were then incubated for 48 h. After
attachment to the culture surface, the cells were incubated
with various concentrations of the compounds tested freshly
dissolved in DMSO and diluted in the culture medium
(DMSO final concentration 1%) for 48 h at 37 °C. The cells
were fixed by adding 10 µL of 11% glutaraldehyde. The
plates were stirred for 15 min at room temperature and then
washed 3 to 4 times with distilled water. The cells were
stained with 100 µL 1% crystal violet. The plate were stirred
for 15 min and then washed 3 to 4 times with distilled water
and dried. Acetic acid (100 µL, 10%) were added and the
mixture was stirred for 15 min at room temperature.
Absorbance was measured at 595 nm in a Tecan Ultra
Evolution spectrophotometer.
The effects of complexes were expressed as corrected
pertentage inhibition values according to the following
equation,
% inhibition ) [1 - (T/C)] × 100
where T is the mean absorbance of the treated cells and C
the mean absorbance in the controls.
The inhibitory potential of compounds was measured by
calculating concentration-percentage inhibition curves, these
curves were adjusted to the following equation,
Acknowledgment. This work was supported by the
Direccio´n General de Investigacio´n del Ministerio de Ciencia
y Tecnolog´ıa (Project CTQ2005-09231-C02-01/BQU), Spain,
and the Fundacio´n Se´neca de la Comunidad Auto´noma de
la Regio´n de Murcia (Project 00448/PI/04), Spain. We thank
Dr. M. J. Prieto for AFM facilities (Universitat de Barcelona),
the Screening Unit of the Institute for Industrial Pharmacy
of the Universidad de Santiago de Compostela (Spain) for
the in vitro studies, and Prof. J. M. Salas (University of
Granada, Spain) for helpful discussions.
E ) Emax ⁄ [1 + (IC50) ⁄ C)n]
where E is the percentage inhibition observed, Emax is the
maximal effects, IC50 is the concentration that inhibits 50%
of maximal growth, C is the concentration of compounds
tested, and n is the slope of the semilogarithmic dose-response
sigmoid curves. This nonlinear fitting was performed using
GraphPad Prism 2.01, 1996 software (GraphPad Software
Inc.).
For comparison purposes, the cytotoxicity of cisplatin was
evaluated under the same experimental conditions. All
compounds were tested in two independent studies with
triplicate points. The in vitro studies were performed at the
USEF platform of the University of Santiago de Compostela
(Spain).
Supporting Information Available: X-ray crystallography data
in CIF format for 1, 8·2H2O, 10a, 7·acetone, 11·CH2Cl2 ·toluene,
12·1/2toluene, and 14. This material is available free of charge
via the Internet at http://pubs.acs.org.
IC701873B
Inorganic Chemistry, Vol. 47, No. 11, 2008 4505