Acetylcholine-like and trimethylglycine-like PTA (1,3,5-Triaza-7- phosphaadamantane) derivatives for the development of innovative Ru- and Pt-based therapeutic agents

Article abstract of DOI:10.1021/ic402953s

The PTA N-alkyl derivatives (PTAC₂H₄OCOMe)X (1X: 1a, X = Br; 1b, X = I; 1c, X = PF₆; 1d, X = BPh₄), (PTACH ₂COOEt)X (2X: 2a, X = Br; 2b, X = Cl; 2c, X = PF₆), and (PTACH₂CH₂COOEt)X (3X: 3a, X = Br; 3c, X = PF ₆), presenting all the functional groups of the natural cationic compounds acetylcholine or trimethylglycine combined with a P-donor site suitable for metal ion coordination, were prepared and characterized by NMR, ESI-MS, and elemental analysis. The X-ray crystal structures of 1d and 2c were determined. Ligands 1c, 2b, and 3c were coordinated to Pt(II) and Ru(II) to give the cationic complexes cis-[PtCl₂(L)₂]X₂ and [RuCpCl(PPh₃)(L)]X (L = 1, 2, 3, X = Cl or PF₆) designed with a structure targeted for anticancer activity. The X-ray crystal structure of [CpRu(PPh₃)(PTAC₂H₄OCOMe)Cl]PF₆ (1cRu) was determined. The antiproliferative activity of the ligands and the complexes was evaluated on three human cancer cell lines.

Full text of DOI:10.1021/ic402953s

Article
pubs.acs.org/IC
Acetylcholine-like and Trimethylglycine-like PTA (1,3,5-Triaza-7-
phosphaadamantane) Derivatives for the Development of Innovative
Ru- and Pt-Based Therapeutic Agents
Valeria Ferretti,† Marco Fogagnolo,† Andrea Marchi,† Lorenza Marvelli,† Fabio Sforza,‡
and Paola Bergamini*,†
†Dipartimento di Scienze Chimiche e Farmaceutiche, Universita
̀
degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy
‡Dipartimento di Biochimica e Biologia Molecolare, Sezione di Biologia Molecolare, Universita
Mortara 74, 44121 Ferrara, Italy
̀
degli Studi di Ferrara, Via Fossato di
S
* Supporting Information
ABSTRACT: The PTA N-alkyl derivatives (PTAC2H4OCOMe)X (1X:
1a, X = Br; 1b, X = I; 1c, X = PF6; 1d, X = BPh4), (PTACH2COOEt)X
(2X: 2a, X = Br; 2b, X = Cl; 2c, X = PF6), and (PTACH2CH2COOEt)X
(3X: 3a, X = Br; 3c, X = PF6), presenting all the functional groups of the
natural cationic compounds acetylcholine or trimethylglycine combined
with a P-donor site suitable for metal ion coordination, were prepared and
characterized by NMR, ESI-MS, and elemental analysis. The X-ray crystal
structures of 1d and 2c were determined. Ligands 1c, 2b, and 3c were
coordinated to Pt(II) and Ru(II) to give the cationic complexes cis-
[PtCl2(L)2]X2 and [RuCpCl(PPh3)(L)]X (L = 1, 2, 3, X = Cl or PF6)
designed with a structure targeted for anticancer activity. The X-ray crystal
structure of [CpRu(PPh3)(PTAC2H4OCOMe)Cl]PF6 (1cRu) was deter-
mined. The antiproliferative activity of the ligands and the complexes was
evaluated on three human cancer cell lines.
attracted by molecules bearing a quaternary ammonium group,
for the following reasons:
INTRODUCTION
■
There is still a great interest in medical applications of metal
complexes. The present challenges of inorganic medicinal
chemistry are (a) to improve the therapeutic performance of
classic platinum anticancer drugs, based on over 30 years of
research and successful clinical use,1 and (b) to open a new
scenario by investigating the potential activity of metal drugs
for the diagnosis and therapy of other pathologies, mainly
neurodegenerative diseases, where an aberrant biochemistry of
endogenous metals seems to have a relevant role.2 The design
and synthesis of metal compounds capable of reaching the
central nervous system (CNS), overcoming the physiological
protecting barriers, meet both purposes. In fact traditional
platinum-containing anticancer drugs do not reach therapeutic
concentrations in the CNS and therefore cannot be used
against brain cancer;3 for the same reason the possibility of a
positive interference of exogenous metal complexes with
biochemical mechanisms causing neurodegenerative diseases
has just started to get attention.4
• When inserted in a metal complex, they should favor the
antiproliferative effect on cancer cells because of the
electrostatic attraction between N+ and the polyanionic
DNA.
• They could exploit OCTs (organic cation transporters)
expressed in the brain−blood barrier (BBB) to pass from
the blood to CNS, thus acting as Trojan horses for metal
ions.6
We describe here our work on synthetic analogues of two
model molecules containing a quaternary ammonium group,
acetylcholine and trimethylglycine. We designed a structural
modification of their structure in order to synthesize derivatives
preserving all the functional groups of the natural molecule,
associated with a suitable coordination site for metals.
The work previously reported by us and others7 about N-
alkylation of PTA (1,3,5-triaza-7-phosphaadamantane) sug-
gested that 1X, 2X, and 3X could represent appropriate, readily
available candidates for our purposes. In Scheme 1 the
structural analogies with the natural molecules are highlighted.
Following the consolidated idea that endogenous molecules
with appropriate character could bind therapeutics and drag
them into specific biological cycles,5 we looked for natural
molecules suited to be introduced as ligands in Pt and Ru
complexes, hopefully improving their performance related to
the above-described aims. Our attention has been recently
Received: December 3, 2013
Published: May 6, 2014
© 2014 American Chemical Society
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Inorganic Chemistry
Article
N+CH2P), 56.0 (1C, N+CH2CH2CO), 60.0 (1C, N+CH2CH2CO),
70.5 (1C, NCH2N), 79.1 (2C, NCH2N+), 169.9 (1C, CO). ESI-MS:
observed m/z 244, calculated 244 for C10H19N3O2P [M − Br]+. S25 °C
(H2O): 700 g L−1.
Scheme 1
Synthesis of (PTAC2H4OCOMe)I, 1b. Step (i): Synthesis of
IC2H4OCOMe. IC2H4OCOCH3 was obtained as a pale yellow oil
through the same procedure above-described for BrC2H4OCOMe,
using 2-iodoethanol (1.0 g, 5.8 × 10−3 mol) and acetic anhydride (1.2
1
g, 1.2 × 10−2 mol, 2 equiv). H NMR (400 MHz, CDCl3) δ (ppm):
3
3
2.09 (s, 3H, CH3), 3.30 (t, JHH = 6.0 Hz, 2H, ICH2), 4.33 (t, JHH
6.0 Hz, 2H, −CH2OCOMe) ppm.
=
Step (ii): PTA Alkylation with IC2H4OCOMe. PTA (0.062 g, 4 ×
10−4 mol) was dissolved in acetone (30 mL), and the mixture was
gently warmed; an excess of IC2H4OCOMe (0.17 g, 8 × 10−4 mol)
was then added to the solution, and the mixture was refluxed for 15
min. The pale yellow solid (PTAC2H4OCOCH3)I was filtered off,
washed with diethyl ether, and dried under vacuum. (0.06 g, 2.47 ×
10−4 mol, yield 62%). Anal. Calcd for C10H19I N3O2P (MW 371): C
32.4, H 5.2, N 11.3. Found: C 32.5, H 5.4, N 11.1. IR: CO 1746 cm−1.
PTA and its derivatives are attracting increasing attention for
medicinal applications because of their favorable properties
such as stability to oxidation, small dimensions, and solubility in
water.8 A group of Ru-PTA complexes called RAPTA type are
particularly promising species, mainly because of their peculiar
antimetastatic activity, never observed before in other metal
anticancer drugs.9
1
31P{1H} NMR (121.5 MHz, d6-dmso) δ (ppm): −83.67. H NMR
(300 MHz, d6-dmso) δ (ppm): 2.05 (s, 3H, OCOCH3), 3.15 (m, 2H,
N+CH2CH2OCOCH3), 3.85 (m, 4H, NCH2P), 4.40 (m, 2H, PCH2N+
+ 2H, CH2OCOCH3), δ 4.47 (d, 2H, CH2, NCH2N), 4.90 (m, 2H,
CH2, NCH2N+), 5.10 (m, 2H, N+CH2N). S25 °C (H2O): 270 g L−1.
Synthesis of (PTAC2H4OCOMe)PF6, 1c. A methanolic solution of
KPF6 (0.17 g, 0.93 × 10−3 mol, 1.5 equiv) in 1 mL of MeOH was
EXPERIMENTAL SECTION
■
General Procedures. All the reactions were routinely performed
under a dry nitrogen atmosphere. The compound PTA10 and the
metal complex precursors cis-[PtBr2(PTA)2],11 [CpRu(PPh3)2Cl], and
[CpRu(PPh3)(PTA)Cl]12 were prepared as described in the literature.
All chemicals and solvents were used as purchased (reagent grade).
NMR spectra were recorded at 25 °C on a Varian Gemini 300 MHz
spectrometer (1H at 300 MHz, 13C at 75.43 MHz, 31P at 121.50 MHz)
and a Varian 400 MHz (1H at 400 MHz, 13C at 100.57 MHz, 31P at
161.92 MHz). The 13C and 31P spectra were run with proton
decoupling, and 31P spectra are reported in ppm relative to an external
85% H3PO4 standard, with positive shifts downfield. 13C NMR spectra
are reported in ppm relative to external tetramethylsilane (TMS), with
positive shifts downfield. The ESI mass spectra were acquired with a
Micromass LCQDuo Finningan. Elemental analyses (C, H, N) were
performed using a Carlo Erba instrument model EA1110. FT-IR
spectra were recorded on a Bruker Vertex 70 FT-IR instrument
(4000−400 cm−1).
added dropwise to a solution of (PTAC2H4OCOMe)Br (0.2 g, 0.62 ×
−3
10
mol) in the same solvent (40 mL). The solvent was slowly
−
evaporated in a stream of nitrogen, and microcrystals of the PF6 salt
were filtered off, rapidly washed with methanol, and finally dried under
vacuum (1.43 g, 0.37 × 10−3 mol, yield 60%). Anal. Calcd for
C10H19F6N3O2P2 (MW 389): C 30.8, H 4.9, N 10.8. Found: C 30.5, H
5.2, N 10.5. IR: CO 1746 cm−1. 31P{1H} NMR (121.5 MHz, D2O) δ
1
1
(ppm): −83.33 (s), −142.7 (sept, JFP = 707 Hz). H NMR (300
MHz, D2O) δ (ppm): 1.99 (s, 3H, OCOCH3), 3.18 (m, 2H,
N+CH2CH2OCOCH3), 3.80 (m, 4H, NCH2P), 4.40 (m, 2H NCH2N
+2H N+CH2P + 2H N+CH2CH2OCOCH3), 4.98 (m, 4H, N+CH2N).
13C{1H} NMR (100.57 MHz, d6-dmso) δ (ppm): 21.1 (CH3), 45.2 (d,
1JPC = 20 Hz, 2C, NCH2P), 51.8 (d, JPC = 32.0 Hz, 1C, N+CH2P),
1
56.0 (1C, N+CH2CH2CO), 60.1 (1C, N+CH2CH2CO), 70.7 (1C,
NCH2N), 79.0 (2C, NCH2N+), 170.0 (1C, CO). S25 °C (H2O): 0.74 g
L−1.
Synthesis of (PTAC2H4OCOMe)Br, 1a. Step (i): Synthesis of
BrC2H4OCOMe. A flask containing acetic anhydride (1.6 g, 1.5 × 10−2
mol) and a drop of 98% H2SO4 was cooled in an ice-bath; previously
precooled 2-bromoethanol (1.0 g, 8 × 10−3 mol) was added in the
same flask at 0 °C. The mixture was left at room temperature for 20 h
and subsequently transferred into a separating funnel with 30 mL of
diethyl ether. The organic phase was treated with a saturated aqueous
solution of NaHCO3 and a saturated aqueous solution of NaCl and
finally was dried over anhydrous sodium sulfate. The final solution was
concentrated under vacuum to a small volume, and the product was
Synthesis of (PTAC2H4OCOMe)BPh4, 1d. A solution of NaBPh4
(0.3 g, 3.3 × 10−4 mol, 1.1 equiv) in MeOH (3 mL) was added to a
solution of (PTAC2H4OCOMe)Br (0.1 g, 3 × 10−4 mol) in 20 mL of
MeOH. 1d precipitated as white microcrystals, which were filtered off
and washed with diethyl ether (0.09 g, 1.52 × 10−4 mol, yield 51%).
The crude product was recrystallized at room temperature from
acetone and diethyl ether, giving crystals suitable for X-ray analysis
(see Figure 1 and Table 2). 31P{1H} NMR (121.5 MHz, d6-dmso) δ
1
(ppm): −84.66 (s). H NMR (300 MHz, d6-dmso) δ (ppm): 2.00 (s,
isolated as a pale yellow oil (1.2 g, 7.2 × 10−3 mol, yield 90%). H
3H, OCOCH3), 3.21 (m, 2H, N+CH2CH2OCOCH3), 3.79 (m, 4H,
NCH2P), 4.40 (m, 2H, NCH2N + 2H, N+CH2P + 2H,
N+CH2CH2OCOCH3), 5.00 (m, 4H, N+CH2N) ppm, 6.5−7.5 (m,
20H, Ph). S25 °C (H2O): 1.6 × 10−2 g L−1.
1
NMR (400 MHz, CDCl3) δ (ppm): 2.09 (s, 3H, CH3), 3.50 (t, 2H,
3
3JHH = 6.2 Hz, BrCH2‑), 4.37 (t, 2H, JHH = 6.2 Hz,−CH2OCOMe).
Step (ii): PTA Alkylation with BrC2H4OCOMe. PTA (0.3 g, 1.91 ×
10−3 mol) was dissolved in acetone (30 mL), and the mixture was
gently warmed; an excess of BrC2H4OCOMe (1.59 g, 5 equiv) was
added to the solution, and the mixture was stirred under reflux for 3 h.
1a precipitated as an off-white solid. The warm mixture was filtered,
and the isolated solid product was dried under vacuum (0.48 g, 1.48 ×
10−3 mol, yield 78%). Anal. Calcd for C10H19BrN3O2P (MW 324): C
37.0, H 5.9, N 13.0. Found: C 37.1, H 5.9, N 12.7. IR: CO 1746 cm−1.
31P{1H} NMR (121.5 MHz, d6-dmso) δ (ppm): −84.77 (s). 1H NMR
(300 MHz, d6-dmso) δ (ppm): 2.05 (s, 3H, OCOCH3), 3.20 (m, 2H,
N+CH2CH2OCOCH3), 3.91 (m, 4H, NCH2P), 4.41 (m, 2H,
N+CH2CH2OCOCH3), 4.49 (m, 2H, NCH2N), 4.74 (m, 2H,
N+CH2P), 4.98 (m, 2H, N+CH2N), 5.10 (m, 2H, N+CH2N).
13C{1H} NMR (100.57 MHz, d6-dmso) δ (ppm): 20.8 (CH3), 45.2
Synthesis of cis-[(PTAC2H4OCOMe)2PtCl2](PF6)2, 1cPt. A
solution of (PTAC2H4OCOMe)PF6 (0.11 g, 2.83 × 10−4 mol) in
H2O (10 mL) was added to an aqueous solution of K2PtCl4 (0.058 g,
1.4 × 10−4 mol; 1 mL of H2O) under stirring. An off-white solid
immediately started to precipitate. After 4 h, the cream-white solid was
collected on a sintered glass-frit, washed with water, and dried over
P2O5 (0.06 g, 5.7 × 10−5 mol, yield 40%). Anal. Calcd for
C20H38Cl2F12N6O4P4Pt (MW 1044): C 23.0, H 3.7, N 8.0. Found:
C 22.5, H 3.8, N 7.8. IR: CO 1745 cm−1. 31P{1H} NMR (121.5 MHz,
−
d6-dmso) δ (ppm): −41.74 (s, 1JPtP 3495 Hz), −142.7 (sept, PF6 , 1JFP
1
= 707 Hz). H NMR (300 MHz, d6-dmso) δ (ppm): 2.0 (s, 3H,
OCOCH3), 2.7 (m, 2H, −N+CH2CH2OCOMe), 4.5 (bm, 10H), 5.0−
5.2 (m, 4H, N+CH2N). ESI-MS: observed m/z 377, calculated 377 for
C20H38Cl2N6O4P2Pt [M − 2PF6]2+. S25 °C (H2O): 0.01 g L−1.
1
1
(d, JPC = 19.9 Hz, 2C, NCH2P), 52.1 (d, JPC = 32.1 Hz, 1C,
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Inorganic Chemistry
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Table 2. Selected Bond Distances and Angles and
Geometrical Parameters for C−H···O and C−H···π
Intermolecular Interactions in 1d (Å, deg)
bond distances
bond angles
97.9(2)
P1−C3
1.695(6)
1.698(6)
1.708(5)
1.443(6)
1.338(6)
1.176(6)
C3−P1−C5
C3−P1−C6
C5−P1−C6
P1−C5
P1−C6
O1−C8
O1−C9
O2−C9
97.5(3)
100.9(3)
a
intermolecular interactions
D−H D···A
H···A
D−H···A
C2−H2A···O2i
0.97
0.97
3.370(6)
3.23
2.46
2.92
154
162
C5−H5A···(C29−C34)i
a
Centroid; symmetry code (i): x+1/2, 3/2−y, −z.
Figure 1. ORTEP view and atom-numbering scheme for 1d. Thermal
ellipsoids are drawn at the 40% probability level.
13C{1H} NMR (100.57 MHz, d6-dmso) δ (ppm): 20.7 (CH3), 49.5 (d,
1JPC 19.9 Hz, 2C, NCH2P), 51.6 (d, 1JPC 32.1 Hz, 1C, N+CH2P), 56.1
(1C, N+CH2CH2CO), 59.9 (1C, N+CH2CH2CO), 64.5 (1C,
NCH2N), 79.4 (5C, Cp), 80.9 (2C, NCH2N+), 128−138 (18C, Ph),
169.9 (1C, CO). ESI-MS: observed m/z 708, calculated 708 for
C33H39ClN3O2P2Ru (M − PF6)+. S25 °C (H2O): 0.05 g L−1.
Synthesis of [CpRu(PPh3)(PTAC2H4OCOMe)Cl]Br, 1aRu. To a
solution of [CpRu(PPh3)(PTA)Cl] (0.1 g, 1.6 × 10−4 mol) in 25 mL
of acetone was added dropwise a large excess of 2-bromoethyl acetate
(10 equiv). After 24 h under stirring, 1aRu was recovered as a yellow
solid, filtered off, and washed with ethyl ether (0.04 g, 4.8 × 10−4 mol,
yield 30%). 31P{1H} NMR (121.5 MHz, d6-dmso) δ (ppm): 46.45 (d,
Synthesis of (PTACH2COOEt)Br, 2a. A solution of PTA (0.220 g,
1.4 × 10−3 mol) in 30 mL of acetone was treated with ethyl
bromoacetate (0.37 g, 2.2 × 10−3 mol, 1.6 equiv) and stirred at room
temperature for 3 h. The white precipitate was filtered off and washed
with acetone (0.354 g, 1.1 × 10−3 mol, yield 78%).31P{1H} NMR
(121.5 MHz, d6-dmso) δ (ppm): −84.05 (s). 1H NMR (300 MHz, d6-
2
2
1
PPh3, JPP = 43.7 Hz), −14.32 (d, JPP = 43.7 Hz). H NMR (300
MHz, d6-dmso) δ (ppm): 2.07 (s, 3H, OCOCH3), 2.70 (m, 2H,
−N+CH2CH2OCOMe), 3.21 (m, 4H, NCH2P), 3.45 (m, 2H,
−N+CH2CH2OCOMe), 4.42 (m, 4H, NCH2N + N+CH2P), 4.56 (s,
Cp, 5H), 4.7−5.0 (m, 4H, N+CH2N), 7.35−7.50 (15H, PPh3).
Synthesis of [CpRu(PPh3)(PTAC2H4OCOMe)Cl]PF6, 1cRu. A
slight excess of solid 1c (0.08 g, 0.2 × 10−3 mol, 1.5 equiv) was added
under stirring to a solution of [CpRu(PPh3)2Cl], (0.1 g, 0.14 × 10−3
mol) in acetone (30 mL). The mixture was refluxed for 3 h. The
evaporation of the solvent to a small volume and the slow addition of
diethyl ether gave a light yellow precipitate, which was filtered off and
dried in air (0.095 g, 0.11 × 10−3 mol, yield 80%). Anal. Calcd for
C33H39ClF6N3O2P3Ru (MW 853): C 46.5, H 4.6, N 4.9. Found: C
46.1, H 4.9, N 4.5. IR: CO 1748 cm−1. 31P{1H} NMR (121.5 MHz, d6-
3
dmso) δ (ppm): 1.20 (t, JHH = 5 Hz, 3H, CH2CH3), 3.92 (m, 2H,
3
N+CH2COOEt + 4H, NCH2P), 4.22 (q, JHH = 5 Hz, 2H, CH2CH3),
2
4.41 (d, JHH = 10 Hz, 1H, NCH2N), 4.52 (m, 1H, NCH2N + 2H,
N+CH2P), 4.90 (d, 2JHH = 9 Hz, 2H, N+CH2N), 5.20 (d, 2JHH = 9 Hz,
2H, N+CH2N). S25 °C (H2O): 625 g L−1.
Synthesis of (PTACH2COOEt)Cl, 2b. PTA (0.4 g, 2.6 0.10−3 mol)
was dissolved in warm acetone (50 mL), and the solution was treated
with 800 μL of ethyl chloroacetate (0.932 g, 7.6 × 10−3 mol, 3 equiv);
the mixture was stirred at room temperature for 18 h. An off-white
solid was then filtered off and washed with acetone and diethyl ether
(0.44 g, 1.6 × 10−3 mol, yield 61%). Anal. Calcd for C10H19ClN3O2P
(MW 280): C 42.9, H 6.8, N 15.0. Found: C 43.0, H 7.1, N 14.8. IR:
CO 1745 cm−1. 31P{1H} NMR (121.5 MHz, CD3OD) δ (ppm):
−81.03 (s). 1H NMR (300 MHz, CD3OD) δ (ppm): 1.32 (t, 3JHH = 5
Hz, 3H, CH2CH3), 3.95 (m, 4H, NCH2P + 2H N+CH2CO), 4.32 (q,
dmso) δ (ppm): 46.50 (d, PPh3, 2JPP = 43.7 Hz), −14.49 (d, 1c, 2JPP
=
−
1
1
43.7 Hz), −143.25 (PF6 , JFP = 707 Hz). H NMR (300 MHz, d6-
dmso) δ (ppm): 2.05 (s, 3H, OCOCH3), 2.72 (m, 2H,
−N+CH2CH2OCOMe), 3.21 (m, 4H, NCH2P), 3.43 (m, 2H,
−N+CH2CH2OCOMe), 4.40 (m, 4H, NCH2N + N+CH2P), 4.56 (s,
Cp, 5H), 4.8−5.0 (m, 4H, N+CH2N), 7.35−7.50 (15H, PPh3).
2
3JHH = 5 Hz, 2H, CH2CH3), 4.50 (d, JHH = 11 Hz, 1 H, NCH2N),
Table 1. Crystal Data and Details of Data Collection for 1d, 1cRu, and 2c
1d
1cRu
2c
chemical formula
(C10H19N3O2P)+(C24H20B)−
(C33H39ClN3O2P2Ru)+(PF6)−
(C10H19N3O2P)+(PF6)−
Mr
563.46
853.10
389.22
cryst syst, space group
a, b, c (Å)
α, β, γ (deg)
V (Å3)
orthorhombic, P212121
triclinic, P1
monoclinic, P21/n
̅
9.8011(1), 10.2689(1), 29.9161(5) 9.3552(3), 14.1403(5), 14.8980(6) 9.4394(2), 10.9595(2), 16.1133(3)
68.377(2), 75.999(1), 75.979(3)
103.1990(7)
3010.95(7)
1751.87(11)
1622.88(5)
Z
4
2
4
μ (mm−1
)
0.13
0.73
0.34
cryst size (mm)
0.39 × 0.26 × 0.15
0.19 × 0.12 × 0.04
0.44 × 0.29 × 0.19
no. of measd, indep, and obsd [I > 2σ(I)] reflns 5839, 5839, 4189
12 060, 6386, 5030
6654, 3511, 2979
Rint
0.040
0.037
0.013
R[F2 > 2σ(F2)], wR(F2), S
0.074, 0.245, 0.99
0.051, 0.154, 1.06
0.076, 0.248, 1.13
no. of reflns
5839
6386
3511
no. of params
no. of restraints
Δρmax, Δρmin (e Å−3
370
443
208
6
0
0
)
0.35, −0.59
0.91, −0.80
0.64, −0.47
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Inorganic Chemistry
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2
2
4.65 (d, JHH = 11 Hz, 1H, NCH2N), 4.67 (d, 2H, JHP = 7 Hz,
N+CH2P), 5.10 (d, 2H, 2JHH = 9 Hz, N+CH2N), 5.39 (d, 2H, 2JHH = 9
Hz, N+CH2N). 13C{1H} NMR (100.57 MHz, d6-dmso) δ (ppm): 13.8
(CH3), 45.4 (d, 1JPC = 20.1 Hz, 2C, NCH2P), 52.7 (d, 1JPC = 33.7 Hz,
1C, N+CH2P), 59.2 (1C, N+CH2CO), 62.1 (1C, CH2CH3), 69.1 (1C,
NCH2N), 79.6 (2C, NCH2N+), 162.2 (1C, COOEt). S25 °C (H2O):
910 g L−1.
Table 3. Selected Bond Distances and Angles and
Geometrical Parameters for C−H···Halide Intermolecular
Interactions in 1cRu (Å, deg)
bond distances
bond angles
Ru1−C1
Ru1−P1
Ru1−P2
2.455(2) Cl1−Ru1−P1
2.269(1) Cl1−Ru1−P2
2.309(1) P1−Ru1−P2
89.63(4)
91.56(4)
98.20(4)
Synthesis of (PTACH2COOEt)PF6, 2c. (PTACH2COOEt)PF6
was obtained by adding a solution of KPF6 (0.2 g, 1.4 × 10−3 mol,
2 equiv) in 1 mL of methanol to a solution of 2a (0.23 g, 7.2 × 10−4
mol) in 20 mL of methanol.
The solution was stirred at room temperature for 10 min and then
slowly concentrated under nitrogen (over about 20 h) to give white
microcrystals, which were filtered off and washed with methanol (0.17
g, 4.3 × 10−4 mol, yield 60%). The crude product 2c, recrystallized at
room temperature from MeOH and Et2O, gave crystals suitable for X-
ray analysis (Figure 3, Table 4). Anal. Calcd for C10H19F6N3O2P2
Ru1−Cp(centroid) 1.856
Cl1−Ru−Cp(centroid) 122.7
Ru−C (mean)
P1−C (mean)
P2−C (mean)
2.20(2)
P1−Ru−Cp(centroid)
1.846(5) P2−Ry−Cp(centroid)
1.832(7)
121.3
124.7
a
intermolecular interactions
D−H
D···A
3.51(1)
H···A
D−H···A
C3−H···F4
C5−H···F1
C10−H···F6i
C5−H···F1ii
C6−H···F1ii
C6−H
0.97
0.97
0.96
0.97
0.97
0.97
0.97
2.62
2.45
2.45
2.53
2.55
2.78
2.92
152
152
141
150
150
159
152
3.33(1)
3.25(2)
3.41(1)
3.424(8)
3.708(6)
3.805(5)
C1−H···Cl1iii
a
Symmetry code: (i) 1−x, −y, 2−z, (ii) 2−x, −y, 2−z, (iii) 1−x, 1−y,
2−z.
Table 4. Selected Bond Distances and Angles and
Geometrical Parameters for C−H···X Intermolecular
Interactions in 2c (Å, deg)
bond distances
bond angles
95.6(1)
P1−C1
1.835(3)
1.821(4)
1.834(5)
1.180(4)
1.327(4)
1.464(6)
C1−P1−C4
C1−P1−C6
C4−P1−C6
P1−C4
P1−C6
O1−C8
O2−C8
O2−C9
96.8(2)
97.4(2)
Figure 2. ORTEP view and atom-numbering scheme for 1cRu.
Thermal ellipsoids are drawn at the 40% probability level. The PF6
anion has been omitted for clarity.
a
intermolecular interactions
D−H
D···A
H···A
D-H···A
C1−H···F3
C3−H···F2
C6−H···F4
C2−H···O1i
C3−H···F1ii
C6−H···F1iii
C5−H···F3iii
C4−H···F5iv
0.97
0.97
0.97
0.97
0.97
0.97
0.97
0.97
3.429(5)
3.598(6)
3.569(6)
3.233(5)
3.146(4)
3.438(5)
3.524(7)
3.515(5)
2.50
2.65
2.66
2.44
2.33
2.57
2.57
2.56
160
164
156
138
141
148
169
167
a
Symmetry code: (i) 1−x, −y, 1−z., (ii) −x, 1−y, 1−z, (iii) x+1/2, 1/
2−y, z+1/2, (iv) −x, −y, 1−z.
(CH3), 47.5 (d, 1JPC = 20.6 Hz, 2C, NCH2P), 55.2 (d, 1JPC = 34.4 Hz,
1C, N+CH2P), 60.7 (1C, N+CH2CO), 63.8 (1C, CH2CH3), 71.3 (1C,
NCH2N), 82.1 (2C, NCH2N+), 165.4 (1C, COOEt). ESI-MS:
observed m/z 244, calculated 244 per C10H19N3O2P [M − PF6]+.
S25 °C (H2O): 1.9 g L−1.
Figure 3. ORTEP view and atom-numbering scheme for 2c. Thermal
ellipsoids are drawn at the 40% probability level.
Synthesis of cis-[(PTACH2COOEt)2PtBr2]Br2, 2aPt. cis-
[PtBr2(PTA)2] (0.15 g, 2.24 × 10−4 mol) was suspended in MeOH
(30 mL), and a large excess of BrCH2COOEt (500 μL = 0.75 g, 4.48 ×
10−3 mol, 20 equiv) was added. The mixture was stirred overnight at
room temperature and then taken to dryness, leaving a white residue,
which was washed with MeOH (0.119 g, 1.43 × 10−4 mol, yield 64%).
31P{1H}NMR (121.5 MHz, CD3OD): δ −42.12 ppm (br s, 1JPtP 3364
(MW 389): C 30.8, H 4.9, N 10.8. Found: C 30.8, H 4.6, N 11.0. IR:
CO 1745 cm−1. 31P{1H} NMR (121.5 MHz, d6-dmso) δ (ppm):
−83.46 s, −142.7 sept (1JFP 707 Hz). 1H NMR (300 MHz, CD3OD) δ
3
(ppm): 1.32 (t, JHH = 5 Hz, 3H, CH3), 3.9 (m, 4H, NCH2P+ 2H,
3
2
N+CH2CO), 4.35 (q, JHH = 5 Hz, 2H, CH2), 4.50 (d, JHH = 11 Hz,
2
1
3
1H, NCH2N), 4.60 (d, 1H, NCH2N), 4.67 (d, JHP = 4 Hz, 2H,
Hz). H NMR (300 MHz, CD3OD) δ (ppm): 1.35 (t, JHH = 5 Hz,
3
N+CH2P), 5.05 (d, 2JHH = 9 Hz, 2H, N+CH2N), 5.35 (d, 2JHH = 9 Hz,
2H, N+CH2N). 13C{1H} NMR (100.57 MHz, CD3OD) δ (ppm): 14.2
3H, CH2CH3), 4.20 (s, 2H, N+CH2CO), 4.32 (q, JHH = 5 Hz, 2H,
CH2), 4.50 (d, 2JHH = 11 Hz, 1H, NCH2N), 4.67 (d, 2JHH = 11 Hz, 1H,
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Inorganic Chemistry
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2
NCH2N), 4.80−5.00 (m, 4H, N+CH2P + NCH2P), 5.15 (d, 2H, JHH
(1JFP 707 Hz). 1H NMR (300 MHz, d6-dmso) δ (ppm): 1.20 (t, 3JHH
=
2
= 9 Hz) 5.45 (d, 2H, JHH = 9 Hz, N+CH2N).
9 Hz, 3H, CH3), 2.90 (t, 2H, N+CH2CH2CO), 3.07 (t, 2H,
3
N+CH2CH2CO), 3.82 (m, 4H, NCH2P), 4.10 (q, JHH = 9 Hz, 2H,
Synthesis of cis-[(PTACH2COOEt)2PtCl2]Cl2, 2bPt. The ligand
(PTACH2COOEt)Cl (0.112 g, 4 × 10−4 mol, 2 equiv) was dissolved
in 1.5 mL of water, and this solution was added to a second one
obtained by dissolving K2PtCl4 (0.083 g, 2 × 10−4 mol, 1 equiv) in 0.7
mL of water. A white precipitate was formed immediately. After 30
min under stirring, the solid was separated by centrifugation, washed
with water (2 × 2 mL), and dried under vacuum over P2O5 (0.135 g,
1.6. 10−4 mol, yield 80%). Anal. Calcd for C20H38Cl4N6O4P2Pt (MW
825): C 29.1, H 4.6, N 10.2. Found: C 28.7, H 4.9, N 9.7. IR: CO
1746 cm−1. 31P{1H} NMR (121.5 MHz, d6-dmso) δ (ppm): −38.87
(s, JPtP 3489 Hz). H NMR (300 MHz, d6-dmso) δ (ppm): 1.22 (t,
3JHH = 5 Hz, 3H, −CH2CH3), 4.20 (m, 4H, NCH2P + 2H N+CH2CO),
4.32 (q, 3JHH = 5 Hz, 2H, −CH2CH3), 4.40−4.70 (m, 4H), 5.00−5.30
(m, 4H). S25 °C (H2O): 0.7 g L−1. The aqueous supernatant was
examined by 31P{1H} NMR, and the singlet with satellites of Pt
2
Et) 4.31 (m, 2H, N+CH2P + 1 H, NCH2N), 4.48 (d, JHH = 11 Hz,
2
2
1H, NCH2N), 4.80 (d, JHH = 11 Hz, 2H, N+CH2N), 4.95 (d, JHH
=
11 Hz, 2H, N+CH2N). 13C{1H} NMR (100.57 MHz, CD3OD) δ
(ppm): 14.4 (CH3), 26.1 (CH2CH2N+), 47.4 (d, JPC 21.4 Hz, 2C,
1
NCH2P), 54.1 (d, JPC 34.5 Hz, 1C, N+CH2P), 58.6 (1C,
1
CH2CH2CO), 62.5 (1C, CH2CH3), 71.2 (1C, NCH2N), 82.2 (2C,
NCH2N+), 171.3 (1C, COOEt). ESI-MS: observed m/z 258,
calculated 258 for C11H21N3O2P [M − PF6]+. S25 °C (H2O): 1.6 g L−1.
Synthesis of cis-[(PTACH2CH2COOEt)2PtCl2](PF6)2, 3cPt. The
ligand (PTACH2CH2COOEt)PF6, 3c (0.080 g, 2. 10−4 mol, 2 equiv),
was dissolved in 2 mL of water, and this solution was added to a
second one obtained by dissolving K2PtCl4 (0.041 g, 1 × 10−4 mol, 1
equiv) in 1 mL of water. The milky suspension was stirred for 18 h,
and then a white solid was separated by centrifugation, washed with
water (2 × 2 mL), and dried under vacuum over P2O5 (0.061 g, 0.5 ×
10−4 mol, yield 57%). Anal. Calcd for C22H42Cl2F12N6O4P4Pt.H2O
(MW 1090): C 24.6, H 3.9, N 7.8. Found: C 24.2, H 4.0, N 7.7. IR:
CO 1748 cm−1. 31P{1H} NMR (121.5 MHz, d6-dmso) δ (ppm):
1
1
1
complex (−38.9 s, JPtP = 3511 Hz) was the only observed signal.
Synthesis of [CpRu(PPh3)(PTACH2COOEt)Cl]Cl, 2bRu. Method
1. To a solution of [CpRu(PPh3)(PTA)Cl] (0.1 g, 0.16 × 10−3 mol)
in 20 mL of acetone was added dropwise a 5-fold excess of ethyl
chloroacetate (0.099 g, 0.8 × 10−3 mol). The complete conversion into
the final product required 20 h at room temperature. The volume was
reduced to 1 mL, and the addition of diethyl ether gave a yellow
precipitate of 2bRu, which was filtered and washed with ether (0.1 g,
0.13 × 10−3 mol, yield 81%).
−
−41.69 (s, 1JPtP = 3425 Hz), −143.25 (PF6 , 1JFP = 707 Hz). 1H NMR
3
(300 MHz, d6-dmso) δ (ppm): 1.20 (t, JHH = 9 Hz, 3H, CH3), 2.95
(m, 2H, N+CH2CH2CO), 3.4 (m, 6H, NCH2P + N+CH2CH2CO),
4.10 (q, 3JHH = 9 Hz, 2H, CH2CH3), 4.5 (m, 4H, N+CH2P + NCH2N),
5.0 (m, 4H, N+CH2N). S25 °C (H2O): 0.02 g L−1.
Method 2. A slight excess of solid (PTACH2COOEt)Cl (2b) (0.06
g, 0.2 × 10−3 mol, 1.5 equiv) was added under stirring to a solution of
[CpRu(PPh3)2Cl] (0.1 g, 0.14 × 10−3 mol) in 30 mL of acetone. The
mixture was refluxed for 6 h. The evaporation of the solvent to a small
volume and the slow addition of diethyl ether gave a yellow precipitate
of 2bRu, which was filtered and dried in air (0.05 g, 0.75 × 10−3 mol,
yield 54%). Anal. Calcd for C33H39Cl2N3O2P3Ru (MW 743): C 53.3,
H 5.3, N 5.6. Found: C 54.3, H 4.9, N 5.0. IR: CO 1750 cm−1. 31P{1H}
NMR (121.5 MHz, CDCl3) δ (ppm): 46.32 (d, PPh3, 2JPP = 43.7 Hz),
−14.38 (d, 2, 2JPP2 = 43.7 Hz). 1H NMR (300 MHz, d6-dmso): 1.35 (t,
3H, OCH2CH3, JHH = 11 Hz), 2.70 (m, 2H, −NCH2COOEt), 3.2−
4.0 (br m, 4H, cage), 4.18 (q, 2H, OCH2CH3, 2JHH = 11 Hz), 4.35 (m,
4H, cage), 4.56 (s, 5H, Cp), 4.8−5.0 (m, 4H, N+CH2N), 7.35−7.45
(15H, PPh3). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 14.1 (s,
CH3), 49.5 (d, NCH2P, 1JPC = 20.1 Hz), 51.6 (d, N+CH2P, 1JPC = 32.0
Hz), 57.2 (s N+CH2COOEt), 60.0 (s OCH2CH3), 65.5 (s, NCH2N),
79.4 (s, Cp), 79.8 (s, N+CH2N), 137−128 (18H, aromatic), 169.0 (s,
1C, CO). ESI-MS: observed m/z 708, calculated 708 for
C33H39ClN3O2P2Ru [M − Cl]+. S25 °C (H2O): 21.5 g L−1.
Synthesis of [CpRu(PPh3)(PTACH2CH2COOEt)Cl]PF6, 3cRu. A
slight excess of solid 3c (0.061 g, 0.15 × 10−3 mol, 1.1 equiv) was
added under stirring to a solution of [CpRu(PPh3)2Cl], (0.10 g, 0.14
× 10−3 mol) in acetone (25 mL), and the mixture was refluxed for 4 h.
The solvent was then removed in vacuo, leaving an orange solid, which
was washed with diethyl ether, then filtered and dried in air (0.11 g,
0.12 × 10−3 mol, yield 88%). Anal. Calcd for C34H41ClF6N3O2P3Ru
(MW 866.7): C 47.1, H 4.8, N 4.9. Found: C 45.1, H 4.6, N 4.9. IR:
CO 1750 cm−1. 31P{1H} NMR (121.5 MHz, CD3OD) δ (ppm): 45.55
2
2
(d, PPh3, JPP = 43.7 Hz), −14.55 (d, 3c, JPP = 43.7 Hz), −143.25
−
1
1
(PF6 3, JFP = 707 Hz). H NMR (300 MHz, CD3OD) δ (ppm): 1.29
(t, JHH
= 11 Hz, 3H, OCH2CH3), 2.63 (br s, 2H,
N+CH2CH2COOEt), 3.2−4.0 (br m, 6H), 4.18 (q, JHH = 11 Hz,
2H, OCH2CH3), 4.35 (m, 4H), 4.55 (s, Cp, 5H), 4.6−4.8 (m, 4H,
N+CH2N), 7.35−7.50 (15H, PPh3). 13C{1H} NMR (300 MHz,
CD3OD) δ (ppm): 14.0 (s, OCH2CH3), 42.5 (d, NCH2P, 1JPC = 20.0
3
Hz), 52.0 (d, N+CH2P, JPC = 32.0 Hz), 56.1 (s, N+CH2CH2CO2Et),
1
59.9 (s, N+CH2CH2CO2Et), 60.6 (s, OCH2CH3), 64.5 (s, NCH2N),
80.1 (s, Cp), 80.8 (s, N+CH2N), 137−127 (aromatics), 170.03 (s,
CO). ESI-MS: observed m/z 722, calculated 722 for
C34H41ClN3O2P2Ru [M − PF6]+.
Synthesis of (PTACH2CH2COOEt)Br, 3a. A solution of PTA
(0.200 g, 1.3 ·10−3 mol) in 30 mL of acetone was treated with ethyl 3-
bromopropionate (400 μL, 0.56 g, 3.1 × 10−3 mol, 2.4 equiv) and
stirred at room temperature for 48 h. The white precipitate was filtered
off and washed with acetone (2 × 2 mL) (0.27 g, 8 × 10−4 mol, 63%).
Anal. Calcd for C11H21BrN3O2P (MW 338): C 39.1, H 6.2, N 12.4.
Found: C 40.3, H 6.2, N 11.9. 31P{1H} NMR (121.5 MHz, CD3OD) δ
Crystallography. The crystallographic data for 1d, 1cRu, and 2c
were collected on a Nonius Kappa CCD diffractometer at room
temperature using graphite-monochromated Mo Kα radiation (λ =
0.71073 Å). Data sets were corrected for Lorentz−polarization effects;
data for 1cRu were corrected also for absorption effects.13 The crystal
parameters and other experimental details of the data collections are
summarized in Table 1.
1
(ppm): −82.67 (s). H NMR (300 MHz, CD3OD) δ (ppm): 1.25 (t,
3JHH = 8 Hz, 3H, CH3), 2.95 (t, 2H, N+CH2CH2CO), 3.22 (t, 2H,
N+CH2CH2CO), 3.9 (m, 4H, NCH2P), 4.2 (q, 3JHH = 8 Hz, 2H, Et +
d, 3JHP = 5.6 Hz 2H, N+CH2P), 4.45 (d, 2JHH = 12 Hz 1 H, NCH2N),
The structures were solved by direct methods (SIR97)14 and
refined by full-matrix least-squares methods with all non-hydrogen
atoms anisotropic. Hydrogens were included on calculated positions,
riding on their carrier atoms. In 1d, a case of substitutional disorder,
i.e., a situation in which the same site in two unit cells is occupied by
different types of atoms, was present, involving atoms P1 and N3. The
positions of the two atoms were assigned on the basis of the highest
SOF.
2
2
4.6 (d, JHH = 12 Hz, 1H, NCH2N), 4.90 (d, JHH = 11 Hz, 2H,
N+CH2N), 5.10 (d, JHH = 11 Hz, 2H, N+CH2N). ESI-MS: observed
2
m/z 258, calculated 258 for C11H21N3O2P [M − Br]+. S25 °C (H2O):
173 g L−1.
S y n t h e s i s o f ( P T A C H 2 C H 2 C O O E t ) P F 6 , 3 c .
(PTACH2CH2COOEt)PF6 was obtained by adding a solution of
KPF6 (0.28 g, 1.5 × 10−3 mol) in 1 mL of methanol to a solution of
(PTACH2CH2COOEt)Br (0.52 g, 1.5 × 10−3 mol) in 20 mL of
methanol. The solution was stirred at room temperature for 10 min
and then slowly concentrated under nitrogen, giving a white solid,
which was filtered off and washed with methanol (0.27 g, 7 × 10−4
mol, yield 47%). Anal. Calcd for C11H21F6N3O2P2 (MW 403): C 32.8,
H 5.2, N 10.4. Found: C 33.2, H 5.4, N 10.2. IR: CO 1746 cm−1.
31P{1H} NMR (121.5 MHz, d6-dmso) δ (ppm): −85.08 s, −143.2 sept
All calculations were performed using SHELXL-9715 implemented
in the WINGX system of programs.16 Selected bond distances and
angles and geometrical parameters for C−H···X and C−H···π
interactions for 1d, 1cRu, and 2c are given in Tables 2, 3, and 4.
We have considered only contacts where C−H···X angles are greater
than 130° and H···X distances are shorter than the sum of the van der
Waals radii.
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Inorganic Chemistry
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ORTEP III17 views of 1d, 1cRu, and 2c are given in Figures 1, 2,
and 3.
ppm (1b), close to the values previously reported for other N-
alkylPTA derivatives.19−21 In 1H NMR, the conversion of PTA
into an alkyl derivative is typically characterized by an increased
number of signals due to the loss of symmetry of the
phosphaadamantane cage. Some signals of 1a and 1b appear
complicated by the geminal coupling between the two
diastereotopic protons of each CH2 group and, for P-bonded
CH2, also by the coupling to that nucleus.
Growth Inhibition Assays. Cell growth inhibition assays were
carried out using the leukemia cell line K562 and two human ovarian
cancer cell lines, A2780 and SKOV3; A2780 cells are cisplatin-
sensitive, and SKOV3 cells are cisplatin-resistant. Cell lines were
obtained from ATCC (Manassas, VA, USA) and maintained in RPMI
1640, supplemented with 10% fetal bovine serum (FBS), penicillin
(100 U mL−1), streptomycin (100 U mL−1), and glutamine (2 mM);
the pH of the medium was 7.2 and incubation was performed at 37 °C
in a 5% CO2 atmosphere. Cells were routinely passaged every 3 days at
70% confluence; for the adherent cell lines, 0.05% trypsin-EDTA
(Lonza) was used. The antiproliferative activity of compounds was
tested with the MTT assay. The cells were seeded in triplicate in 96-
well trays at a density of 5 × 103 in 50 μL of complete medium. Stock
solutions (20 mM) of each compound were made in dmso and diluted
in complete medium to give final concentrations of 0.1, 1, 10, 50, and
100 μM. Cisplatin was employed as a control for the cisplatin-sensitive
A2780 cell line and for the cisplatin-resistant SKOV3. Untreated cells
were placed in every plate as a negative control. The cells were
exposed to the compounds, in 100 μL total volume, for 72 h, and then
25 μL of a 12 mM solution of 3-(4,5-dimethylthiozol-2-yl)-2,5-
diphenyltetrazolium bromide solution (MTT) was added. After 2 h of
incubation, 100 μL of lysing buffer (50% DMF + 20% SDS, pH 4.7)
was added to convert the MTT solution into a violet-colored
formazan. After an additional 18 h the solution absorbance,
proportional to the number of live cells, was measured by
spectrophotometer at 570 nm and converted into % of growth
inhibition.18
The [M − Br]+ peak of 1a is observed by ESI-MS at the
expected value of 244.
In view of the coordination of ligand 1X to metal ions,
noncoordinating anions are preferred in order to avoid
exchange with metal ligands (e.g., metal-bonded chloride), so
−
−
the bromide of 1a was exchanged with PF6 and with BPh4 ,
giving 1c and 1d, respectively.
The solubility in water at 25 °C, remarkable for 1a (700 g/
L), decreases with the increase in the anion size (1a = 700 g/L
and 1b = 270 g/L, 1c = 0.74 g/L and 1d = 1.56 × 10−2 g/L).
The tetraphenylborate 1d, recrystallized with acetone and
diethyl ether, gave crystals suitable for X-ray determination of
crystal structure (Figure 1 and Table 2).
The asymmetric unit of 1d consists of PTAC2H4OCOMe+
−
and BPh4 ions; the substitutional disorder, described in the
experimental paragraph, makes the P1−C distances abnormally
short (Table 2) and the N3−C quite long (N−C mean distance
= 1.59[6] Å). Besides electrostatic forces between anions and
cations, in this structure, given the absence of “good” proton
donors, the different units interact with each other through
weak C−H···O hydrogen bonds and through C−H··· π
interactions (see Table 2).
RESULTS AND DISCUSSION
■
The new ligands, as halides salts 1X (1a, X = Br and 1b, X = I),
2X (2a, X = Br and 2b, X = Cl), and 3X (3a, X = Br), can be
easily prepared in a pure form because the N-alkylation of PTA
is a selective process giving exclusively monoalkylated cationic
derivatives, as previously reported for many PTA derivatives
including MePTA19 and larger and more functionalized
products.20 In general, the N-alkylation of PTA can be
performed with either alkyl bromides or alkyl iodides, but the
reaction is faster with iodide. When the alkylating agent bears
the halide on an activated carbon atom (benzylic, allylic, or α to
a carbonylic group), the reaction is faster and takes place also
with chloro derivatives.21 The alkylation of PTA is generally
carried out in acetone and occurs with product precipitation,
which probably drives the process nearly to completeness
giving fairly pure products.
The reaction of 1c with K2PtCl4 (molar ratio 2:1) in water
( S c h e m e 3 ) g a v e
a
s i n g l e c o m p l e x , c i s -
Scheme 3
Synthesis and Characterization of 1a−d and Coordi-
nation to Pt(II) and Ru(II). The ligand 1a was obtained in two
steps starting from 2-bromoethanol, which was first acetylated
with acetic anhydride, and the resulting bromoester was then
used as an alkylating agent for PTA. The iodide 1b was
obtained in the same way from 2-iodoethanol (Scheme 2). The
alkylation step is faster with the alkyl iodide, but the 31P NMR
observation of the solution shows the formation of P-oxidated
impurities, which reduce the yield of 1b.
[PtCl2(PTAC2H4OCOMe)2](PF6)2 (1cPt), as a precipitate
with low solubility in water (S25 °C(H2O) = 0.01 g L−1). It was
identified by 31P NMR (−41.74 broad singlet, 1JPtP 3495 Hz, in
dmso), where the observed shift of the Pt complex signal at
−41.74 ppm is about 40 ppm downfield with respect to the free
ligand 1c (−83.33 ppm) and about 10 ppm downfield with
respect to the neutral PTA complex cis-[PtCl2(PTA)2] (31P
1
−51.85 ppm JPtP 3285 Hz). These data comply with those
The 31P NMR signal, observed at −100 ppm for free PTA in
dmso, in the products is shifted to −84.77 ppm (1a) or −83.67
found for other Pt complexes of N-alkylPTA ligands, e.g., cis-
[PtCl2(MePTA)2](PF6)2 (31P −43.51 ppm, JPtP 3384 Hz)7b
1
compared with MePTAPF6 (31P −84.2 ppm).
The broadness observed for the 31P NMR signal of 1cPt has
been reported in many cases for metal complexes of PTA or
PTA derivatives by us7b and others.7c−e,8a We did some
additional NMR experiments on 1cPt in DMSO, and we found
that the line broadening is not effected by concentration (the
line width does not change by reducing the concentration to 1/
10) or temperature (from 25 to 120 °C). Also, on replacing
DMSO with DMF the signal does not become sharp.
Scheme 2
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Scheme 4
The signal broadening in complex 1cPt (and analogues)
could be the consequence of a restricted conformational
freedom around P−Pt bonds due to the presence of two ligands
bearing two positive charges, which tend to keep as far as
possible one from each other in order to minimize the
electrostatic repulsion. The steric hindrance of the alkyl
substituents on two spatially close nitrogen atoms could also
limit the rotation.
ature led to several unidentified side products. In particular, the
MePTA complex [RuCpCl(MePTA)(PPh3)]PF6 (d, 16.06, d,
2
46.31, JPP = 43.7 Hz in dmso) was occasionally observed as a
side-product when reaction mixtures were refluxed, probably
due to the presence of traces of water. It was previously
observed that MePTA is formed by Cα−Cβ bond breaking of
N-alkylPTA derivatives in the presence of water.7c
We attempted to prepare also Pt complexes of 1a and 1b by
alkylation of Pt-coordinated PTA, but the product signal was
not observed by 31P NMR over 3 days. After prolonged
reaction time, signals of P-containing oxidative degradation
products started to appear in the 31P NMR.
To support this hypothesis, it is useful to verify if in the 31P
NMR of a Pt complex bearing only one 1c ligand the signal is
sharp; so we did the following NMR experiment: the known
complex [terpyPt(H2O)]2+ was dissolved in DMSO and 1
equiv of ligand 1c was added to give [terpyPt(1c)]2+. After 18 h
the observed 31P NMR spectrum was indeed a sharp singlet
The 31P NMR spectrum of [RuCpCl(PTAC2H4OCOMe)-
(PPh3)]X (1cRu, X = PF6; 1aRu, X = Br) shows two doublets
at about 46.5 ppm (Ru-coordinated PPh3) and −14.5 ppm (Ru-
coordinated ligand 1) reciprocally coupled with 2JPP = 43.7 Hz.
These signals are clearly distinguishable from the corresponding
ones of the reagent complexes [RuCpCl(PPh3)2] for route (i)
(38.8 ppm)26 and [RuCpCl(PTA)(PPh3)]12 for route (ii)
1
with satellites at −50.8 with JPtP = 3599 Hz.
The isotopic pattern for the [M − 2PF6]2+ ion of 1cPt,
observed by ESI-MS at 377 m/z, compared with the calculated
one, confirmed the composition of the Pt complex, while the
value of the PtP coupling constant (3495 Hz) indicates the cis
geometry.
2
(48.16 and −34.96 ppm, JPP = 34.7 Hz).
The Ru(II) coordination of ligand 1c was also successfully
achieved. This result is particularly relevant because the
development of Ru-based drugs is one of the most promising
frontiers of research in inorganic medicinal chemistry.1a,22 For
example, the peculiar pharmacological activity of [RuCl2(η6-
arene)(PTA)] (arene = p-cymene, toluene, benzene, benzo-15-
crown-5, 1-ethylbenzene-2,3-dimethylimidazolium tetrafluoro-
borate, ethyl benzoate, hexamethylbenzene) complexes, abbre-
viated RAPTA, was evaluated in mice, and it was observed that
they can reduce the growth of lung metastases without action
on the primary tumor growth.23
The solubility in water of 1c (S25 °C 0.74 g L−1) decreases
upon coordination to Pt (1cPt, S25 °C 0.01 g L−1) and to Ru
(1cRu, S25 °C 0.05 g L−1).
Complex 1cRu was separated in a pure form by
recrystallization with acetone and Et2O, which gave crystals
suitable for X-ray diffraction (Figure 2, Table 3).
The asymmetric unit is formed by one Ru complex and one
PF6 anion (not shown in Figure 2). The ruthenium atom is in
an octahedral environment since it is bound to a cyclo-
pentadienyl ring (formally three fac positions), two phosphorus
atoms, one from a triphenylphosphine and one from ligand 1,
and a chloride ion. The coordination geometry of the complex
is that of a three-legged “piano stool”. For comparative reasons,
five structures27,12 strictly related to the present Ru complex, in
which the metal ion is surrounded by PTA, Cl, TriP, and Cp
ligands, were retrieved from the Cambridge Crystallographic
Database.28 In these structures the Ru−P(PTA), Ru−P(TriP),
Ru-Cp(centroid), and Ru−Cl distances vary in the ranges
2.280−2.314, 2.270−2.309, 1.837−1.890, and 2.449−2.466 Å,
respectively, perfectly in line with the structural parameters
listed in Table 3.
In the crystal anions and cations are linked not only via
electrostatic forces but also by a number of weak C−H···Halide
interactions, listed in Table 3.
Synthesis and Characterization of 2a−c and Coordi-
nation to Pt(II) and Ru(II). Ligand 2 was prepared as the ethyl
esters 2X (2a, X = Br and 2b, X = Cl) by treating PTA with
commercial XCH2COOEt in acetone. A similar synthesis for
the methyl esters (PTACH2COOMe)X (X = Br and X = Cl)
has been reported by Laguna.21,29
Since in our previous work on Ru-containing complexes we
found that the combination of PTA and PPh3 in the same
complex seems to improve the antiproliferative activity with
respect to single-phosphine analogues,24 the mixed phosphine
complexes [RuCpCl(PTAC2H4OCOMe)(PPh3)]X (X = Br,
−
1aRu; X = PF6 , 1cRu) looked like the best candidates for
achieving anticancer activity.
Complex 1cRu was prepared by replacing one PPh3 of
[RuCpCl(PPh3)2] with ligand 1c (Scheme 4, route (i)), while
the bromide 1aRu was obtained by alkylation of the Ru-
coordinated PTA in [RuCpCl(PTA)(PPh3)]25 (Scheme 4,
route (ii)).
The first route gives the pure product 1cRu as a yellow
precipitate with a good yield (80%) after 3 h of reflux in
acetone. The second requires 24 h at room temperature, and
the yield is low (ca. 30%).
In general, the alkylation of metal-bonded PTA seems to
occur as a slow process (24 h) when PTA is coordinated to Ru.
Attempts to accelerate the reaction by increasing the temper-
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series of molecules where the distance between the carbonyl
carbon and the quaternary nitrogen N+ is four bonds (1X),
three bonds (3X), and two bonds (2X) (Scheme 7). The
availability of the three compounds will be useful for
investigating the interactions of ligands and their metal
complexes with acetylcholine receptors or cation transporters
and establishing a structure−activity relationship. In fact it has
been proposed that the affinity of a chemical species with
acetylcholine receptors is related to its length.30
Scheme 5
The reaction between 3-bromoethylpropionate and PTA in
acetone produced 3a, which was collected as a white solid after
20 h. The NMR in CD3OD confirmed the structure, showing a
By exchange with KPF6 in methanol, the bromide 2a was
converted in the PF6− salt 2c, whose X-ray crystal structure was
determined (Figure 3, Table 4). The crystal structures of the
analogue methyl ester bromide21 and triflate29 were previously
reported.
1
31P signal at −82.67 ppm and, in H NMR, two signals at 2.95
and 3.22 ppm due to the alkyl chain CH2 groups besides the
typical signals of the alkylated PTA cage.
In 2c the asymmetric unit contains the PTA derivative and its
counterion; the different units interact with each other through
weak C−H···O/F hydrogen bonds.
−
The PF6 salt 3c was obtained from the bromide by anion
exchange with KPF6 in methanol (Scheme 8).
The reaction of the chloride 2b with K2PtCl4 in water gave
the Pt complex cis-[PtCl2(PTACH2COOEt)2]Cl2, 2bPt,
characterized by a 31P NMR single signal at −38.87 ppm
Scheme 8
1
with JPtP = 3489 Hz, confirming the cis geometry.
The bromide analogue of this complex, cis-
[PtBr2(PTACH2COOEt)2]Br2, 2aPt, can be obtained by
alkylation of Pt-coordinated PTA in cis-[PtBr2(PTA)2] with
BrCH2COOEt (Scheme 6). The alkylation of PTA bonded to
Pt has not been observed before, and it does not occur with the
corresponding chloride ClCH2COOEt.
The reaction of 3c with K2PtCl4 in water gave the complex
cis-[PtCl2(PTACH2CH2COOEt)2](PF6)2, 3cPt, characterized
in 31P NMR data by a singlet at −41.69 ppm with a 1JPtP = 3425
Hz.
Scheme 6
The Ru complex 3cRu was also obtained with a good yield
from the reaction of [CpRu(PPh3)2Cl] with a slight excess of
solid 3c in refluxing acetone. Its 31P NMR in CD3OD shows
two doublets at 45.55 ppm due to coordinated PPh3 and
−14.55 ppm due to Ru-bonded 3c, reciprocally coupled with
2JPP= 43.7 Hz.
Antiproliferative Activity of 1c, 2b, 2c, 3c, 1cPt, 1cRu,
2bPt, 2cRu, and 3cPt. The antiproliferative activity of ligands
1c, 2b, 2c, and 3c and complexes 1cPt, 1cRu, 2bPt, 2cRu, and
3cPt was tested on two human ovarian cancer cell lines, A2780
and SKOV3, and on the leukemic line K562, in comparison
with cisplatin, and the results are reported in Table 5.
The complexes to test were designed and chosen in order to
get the highest activity on the basis of previously reported
characteristics, e.g., cis geometry for Pt complexes, Ru state of
oxidation = 2, and chloride as metal-bonded halide (rather than
bromide and iodide). Moreover all complexes tested have Cl−
The ruthenium complex [CpRu(PPh3)(PTACH2COOEt)-
Cl]Cl, 2bRu, was prepared either by alkylation of Ru-
coordinated PTA in [CpRu(PPh3)(PTA)Cl] or by substitution
of PPh3 with 2b in [CpRu(PPh3)2Cl], as above-mentioned for
the Ru complexes of ligand 1a and 1c.
As previously observed for ligand 1X, the water solubility of
−
2X changes with the anion X and the trend is Cl− > Br− > PF6 :
2b (S25 °C 910 g L−1) > 2a (S25 °C 625g L−1) >2c (S25 °C 1.9 g
L−1). Although in general we found that the water solubility of
these ligands greatly decreases upon coordination, complexes
2bPt (S25 °C 0.7 g L−1) and 2bRu (S25 °C 21.5 g L−1), where X =
Cl−, maintain some aqueous solubility.
or PF6 as counterions so as to avoid ligand exchanges.
−
These figures indicated that the organic free ligands 1c, 2b,
2c, and 3c do not show appreciable activity on all three lines,
while their metal complexes do in some cases.
The platinum complexes 1cPt, 2bPt, and 3cPt show low
activity on cisplatin-resistant SKOV3 and an appreciable activity
on cisplatin-sensitive A2780. These data allow us to
hypothesize a cisplatin-like action for Pt complexes.
Synthesis and Characterization of 3a and 3c and
Coordination to Pt(II) and Ru(II). Ligand 3X, the superior
homologue of 2X, was also prepared, in order to complete a
Scheme 7
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Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi
Biologici) for support.
Table 5. Estimated IC50 (μM) of 1c, 2b, 2c, 3c, 1cPt, 1cRu,
2bPt, 2cRu, and 3cPt on A2780, SKOV3, and K562 Cell
a
Lines
REFERENCES
compound
A2780
SKOV3
>100
K562
>100
■
(1) (a) Barry, N. P. E.; Sadler, P. J. Chem. Commun. 2013, 49, 5106−
5131. (b) Harper, B. W.; Krause-Heuer, A. M.; Grant, M. P.; Manohar,
M.; Garbutcheon-Singh, K. B.; Aldrich-Wright, J. R. Chem.Eur. J.
2010, 16, 7064−7077. (c) Wheate, N. J.; Walker, S.; Craig, G. E.; Oun,
R. Dalton Trans. 2010, 39, 8113−8127.
(2) Breydo, L.; Uversky, V. N. Metallomics 2011, 3 (11), 1163−1180.
(3) (a) Jacobs, S.; McCully, C. L.; Murphy, R. F.; Bacher, J.; Balis, E.
F. M.; Fox, E. E. Cancer Chemother. Pharmacol. 2010, 65, 817−824.
(b) Bernocchi, G.; Bottone, M. G.; Piccolini, V. M.; Dal Bo, V.; Santin,
G.; De Pascali, S. A.; Migoni, D.; Fanizzi, F. P. Chemother. Res. Pract.
2011, 1−14.
1c
49
1
3
5
4
3
1
4
2b
46
47
56
18
4.7
36
>100
>100
>100
>100
>100
>100
40
2c
3c
1cPt
1cRu
2bPt
2bRu
3cPt
cisplatin
42 11
6.0 0.5
47
8.3 0.8
2
5.1 0.3
66
5.5 0.2
2
3
5.8 0.5
17
0.91 0.08
4
63
2
3
59
2
1
7.9
7.4
a
(4) (a) Valensin, D.; Gabbiani, C.; Messori, L. Coord. Chem. Rev.
2012, 256, 2357−2366. (b) Kenche, V. B.; Hung, L. W.; Perez, K.;
Volitakes, I.; Ciccotosto, G.; Kwok, J.; Critch, N.; Sherratt, N.; Cortes,
M.; Lal, V.; Masters, C. L.; Murakami, K.; Cappai, R.; Adlard, P. A.;
Barnham, K. J. Angew. Chem., Int. Ed. 2013, 52, 3374−3378. (c) Collin,
F.; Sasaki, I.; Eury, H.; Faller, P.; Hureau, C. Chem. Commun. 2013, 49,
2130−2132.
(5) (a) Pardridge, W. M. Curr. Opin. Pharmacol. 2006, 6, 494−500.
(b) Pavan, B.; Dalpiaz, A. Curr. Pharm. Des. 2011, 17, 3560−3576.
(c) Manfredini, S.; Pavan, B.; Vertuani, S.; Scaglianti, M.;
Compagnone, D.; Biondi, C.; Scatturin, A.; Manganelli, S.; Ferraro,
L.; Prasad, P.; Dalpiaz, A. J. Med. Chem. 2002, 45, 559−562.
(d) Napolitano, C.; Scaglianti, M.; Scalambra, E.; Manfredini, S.;
Ferraro, L.; Beggiato, S.; Vertuani, S. Molecules 2009, 14, 3268−3274.
(6) Koepsell, H.; Schmitt, B. M.; Gorboulev, V. Rev. Physiol. Biochem.
Pharmacol. 2003, 150, 36−90.
Results are presented as a mean
experiments performed in triplicates.
SD of three independent
The Ru complexes of 1c and 2c have a remarkable activity on
all three cell lines. In particular, complex 1cRu was found very
active on all three tested cell lines. This observation is relevant
as, in many cases, Ru complexes were found inactive against
primary tumors.
CONCLUSION
■
Three PTA derivatives (1X, 2X, and 3X), designed as ligands
for Pt and Ru therapeutics, as well as their Pt(II) and Ru(II)
complexes, were prepared and characterized.
All ligands and their Pt and Ru complexes, as chloride or
(7) (a) Bergamini, P.; Marvelli, L.; Marchi, A.; Bertolasi, V.;
Fogagnolo, M.; Formaglio, P.; Sforza, F. Inorg. Chim. Acta 2013, 398,
11−18. (b) Bergamini, P.; Marvelli, L.; Marchi, A.; Vassanelli, F.;
Fogagnolo, M.; Formaglio, P.; Bernardi, T.; Gavioli, R.; Sforza, F.
Inorg. Chim. Acta 2012, 391, 162−170. (c) Kirillov, A. M.; Smolensky,
P.; Haukka, M.; Guedes da Silva, M. F. C.; Pombeiro, A. J. L.
Organometallics 2009, 28, 1683−1687. (d) Romerosa, A.; Saoud, M.;
Campos-Malpartida, T.; Lidrissi, C.; Serrano-Ruiz, M.; Peruzzini, M.;
Garrido, J. A.; García-Maroto, F. Eur. J. Inorg. Chem. 2007, 2803−2812.
(e) Porchia, M.; Benettolo, F.; Refosco, F.; Tisato, F.; Marzano, C.;
Gandin, V. J. Inorg. Biochem. 2009, 103, 1644−1651.
−
PF6 salts, were tested for antiproliferative activity on three
human cancer cell lines, and the best performance was obtained
by Ru complexes. The X-ray crystal structure of complex 1cRu
was determined.
These results encourage us to investigate the behavior of all
these compounds as neuroactive species: the nontoxic salts 1c,
2c, 3c, and 2b could interfere with the cholinergic cascade
involved in Alzheimer disease, while, after appropriate
coordination, they could act as carriers for metal ions through
the blood−brain barrier, allowing them to act as metal-
lotherapeutics in the central nervous system.
(8) (a) Phillips, A. D.; Gonsalvi, L.; Romerosa, A.; Vizza, F.;
Peruzzini, M. Coord. Chem. Rev. 2004, 248, 955−993. (b) Bravo, J.;
Bolano, S.; Gonsalvi, L.; Peruzzini, M. Coord. Chem. Rev. 2010, 254,
̃
ASSOCIATED CONTENT
■
555−607. (c) Guerrero, E.; Miranda, S.; Luttenberg, S.; Frohlich, N.;
̈
̈
S
* Supporting Information
Koenen, J.; Mohr, F.; Cerrada, E.; Laguna, M.; Mendía, A. Inorg. Chem.
2013, 52, 6635−6647. (d) Serrano-Ruiz, M.; Aguilera-Saez, L. M.;
Lorenzo-Luis, P.; Padron, J. M.; Romerosa, A. Dalton Trans. 2013, 42,
11212−11219.
Crystallographic data in cif format. This material is available
free of charge via the Internet at http://pubs.acs.org.
Crystallographic data for the structural analysis of 1d, 2c, and
1cRu have been deposited at the Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge, CB2 1EZ, UK, and
are available free of charge from the Director on request
quoting the deposition number CCDC 960858, 960859, and
960860 for 1d, 2c, and 1cRu, respectively.
́
́
(9) (a) Dyson, P. J.; Sava, G. Dalton Trans. 2006, 1929−1933.
(b) Renfrew, A. K.; Juillerat-Jeanneret, L.; Dyson, P. J. J. Organomet.
Chem. 2011, 696, 772−779. (c) Kilpin, K. J.; Cammack, S. M.; Clavel,
C. M.; Dyson, P. J. Dalton Trans. 2013, 42, 2008−2014. (d) Nazarov,
A. A.; Hartinger, C. G.; Dyson, P. J. J. Organomet. Chem. 2014, 751,
251−260. (e) Pettinari, R.; Pettinari, C.; Marchetti, F.; Clavel, C. M.;
Scopelliti, R.; Dyson, P. J. Organometallics 2013, 32, 309−316.
(10) Daigle, D. J.; Decuir, T. J.; Robertson, J. B.; Darensbourg, D. J.
Inorg. Synth. 1998, 32, 40.
(11) Krogstad, D. A.; Cho, J.; DeBoer, A. J.; Klitzke, J. A.; Sanow, W.
R.; Williams, H. A.; Halfen, J. A. Inorg. Chim. Acta 2006, 359, 136−
148.
(12) (a) Bruce, M. I.; Wong, F. S.; Skelton, B. W.; White, A. H. J.
Chem. Soc., Dalton Trans. 198113981405.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: p.bergamini@unife.it. Tel: +39 0532 455129. Fax: +39
0532 455167.
Notes
The authors declare no competing financial interest.
(13) Blessing, R. H. Acta Crystallogr. 1995, A51, 33−38.
(14) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115−119.
ACKNOWLEDGMENTS
We thank Dr. T. Bernardi, Dr. E. Bianchini, and Mr. P.
Formaglio for technical assistance and CIRCMSB (Consorzio
■
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Inorganic Chemistry
Article
(15) Sheldrick, G. M. SHELXL97, Program for Crystal Structure
Refinement; University of Gottingen: Gottingen, Germany, 1997.
̈
̈
(16) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837−838.
(17) Burnett, M.N.; Johnson, C.K. ORTEP-III: Oak Ridge Thermal
Ellipsoid Plot Program for Crystal Structure Illustrations; Report ORNL-
6895; Oak Ridge National Laboratory: Oak Ridge, TN, 1996.
(18) Hansen, M. B.; Nielsen, S. E.; Berg, K. J. J. Immunol. Methods
1989, 119, 203−210.
(19) Daigle, D. J.; Pepperman, A. B., Jr. J. Heterocycl. Chem. 1975, 12,
579−580.
(20) (a) Krogstad, D. A.; Ellis, G. S.; Gunderson, A. K.; Hammrich,
A. J.; Rudolf, J. W.; Halfen, J. A. Polyhedron 2007, 26, 4093.
(b) Krogstad, D. A.; Gohmann, K. E.; Sunderland, T. L.; Geis, A. L.;
Bergamini, P.; Marvelli, L.; Young, V. G., Jr. Inorg. Chim. Acta 2009,
362, 3049−3055.
(21) García-Moreno, E.; Cerrada, E.; Bolsa, M. J.; Luquin, A.;
Laguna, M. Eur. J. Inorg. Chem. 2013, 2020−2030.
(22) Alessio, E.; Mestroni, G.; Bergamo, A.; Sava, G. Curr. Top. Med.
Chem. 2004, 4, 1525−1535.
(23) Scolaro, C.; Bergamo, A.; Bresciani, L.; Brescacin, L.; Delfino,
R.; Cocchietto, M.; Laurenczy, G.; Geldbach, T. J.; Sava, G.; Dyson, P.
J. J. Med. Chem. 2005, 48, 4161−4171.
(24) Hajji, L.; Saraiba-Bello, C.; Romerosa, A.; Segovia-Torrente, G.;
Serrano-Ruiz, M.; Bergamini, P.; Canella, A. Inorg. Chem. 2011, 50,
873−882.
́
(25) García-Fernandez, A.; Díez, J.; Gamasa, M. P.; Lastra, E. Inorg.
Chem. 2009, 48, 2471−2481.
(26) Consiglio, G.; Morandini, F.; Bangerter, F. Inorg. Chem. 1982,
21, 455−457.
(27) (a) Romerosa, A.; Campos-Malpartida, T.; Lidrissi, C.; Saoud,
M.; Serrano-Ruiz, M.; Peruzzini, M.; Garrido-Cardenas, J. A.; Garcia-
Maroto, F. Inorg. Chem. 2006, 45, 1289−1298. (b) Nair, R. P.; Kim, T.
H.; Frost, B. J. Organometallics 2009, 28, 4681−4688.
(28) Allen, F. H. Acta Crystallogr. 2002, B58, 380−388.
(29) Schafer, S.; Frey, W.; Hashmi, A. S. K.; Cmrecki, V.; Luquin, A.;
̈
Laguna, M. Polyhedron 2010, 29, 1925−1932.
(30) Ing, H. R. Science 1949, 109, 264−266.
4890
dx.doi.org/10.1021/ic402953s | Inorg. Chem. 2014, 53, 4881−4890