Cytotoxicity of ruthenium-arene complexes containing β-ketoamine ligands

Article abstract of DOI:10.1021/om301115e

New ruthenium(II) arene derivatives (arene = p-cymene, benzene, hexamethylbenzene) containing β-ketoamine ligands L′ (HL′ in general; in detail, HL^ph,ph = (4Z)-3-methyl-4-((phenylamino)(phenyl) methylene)-1-phenyl-1H-pyrazol-5(4H)-one, HLⁿ

Full text of DOI:10.1021/om301115e

Article
pubs.acs.org/Organometallics
Cytotoxicity of Ruthenium−Arene Complexes Containing
β‑Ketoamine Ligands
Riccardo Pettinari,*,† Claudio Pettinari,† Fabio Marchetti,‡ Catherine M. Clavel,§ Rosario Scopelliti,§
and Paul J. Dyson*,§
†School of Pharmacy and ‡School of Science and Technology, University of Camerino, via S. Agostino 1, 62032 Camerino MC, Italy
§Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: New ruthenium(II) arene derivatives (arene = p-cymene,
benzene, hexamethylbenzene) containing β-ketoamine ligands L′ (HL′ in
general; in detail, HLph,ph = (4Z)-3-methyl-4-((phenylamino)(phenyl)-
methylene)-1-phenyl-1H-pyrazol-5(4H)-one, HLnaph,ph = (4Z)-3-methyl-4-
((phenyamino)(naphthalen-2-yl)methylene)-1-phenyl-1H-pyrazol-5(4H)-
one, HLet,ph = (4Z)-3-methyl-4-(1-(phenylamino)propylidene)-1-phenyl-1H-
pyrazol-5(4H)-one) have been synthesized and characterized by spectroscopy
1
(IR, ESI-MS, H and 13C NMR) and elemental analysis. The ligands in the
anionic form coordinate ruthenium in a chelating κ2N,O-bidentate fashion,
affording 1:1 derivatives of the formula [Ru(arene)(L′)Cl]. Further reaction
of [Ru(p-cymene)(L′)Cl] with AgPF6 or PTA (PTA = 1,3,5-triaza-7-
phosphaadamantane) in methanol affords [Ru(p-cymene)(L′)(CH3OH)]-
[PF6] and [Ru(p-cymene)(L′)(PTA)]Cl, respectively. The solid-state
structures of the ligand HLet,ph and complexes [Ru(p-cymene)(Lph,ph)Cl] (1), [Ru(p-cymene)(Lnaph,ph)Cl] (4), and [Ru(p-
cymene)(Let,ph)Cl] (7) have been determined by single-crystal X-ray diffraction. The antitumor activity of both the ligands and
complexes has been evaluated against the human ovarian carcinoma cell line A2780 and its cisplatin-resistant equivalent A2780R,
some of the complexes showing significant cytotoxicity toward the cisplatin-resistant cell line.
a hard donor able to stabilize a higher oxidation state of the
ruthenium atom, whereas the nitrogen atom is less hard and,
accordingly, is suitable to better stabilize the lower oxidation
state of the ruthenium atom. On coordination, both atoms
could help a metal to form stable direct (coordination) bonds
with potential biomolecular targets. We have previously
reported an extensive study10 on the coordination chemistry
of ruthenium arene fragments with 4-acyl-5-pyrazolone ligands,
unsymmetrical β-diketones containing a pyrazole ring fused to
the chelating moiety, and in this paper, we report the
preparation and characterization of some ruthenium arene
complexes containing some β-ketoamine bases derived from
the same 4-acyl-5-pyrazolones. The effect on cytotoxicity of β-
ketoamine, arene, and ancillary ligands coordinated to
ruthenium has been widely investigated against human ovarian
carcinoma cells sensitive to (A2780) and resistant to (A2780R)
cisplatin.
INTRODUCTION
■
Organometallic compounds play a unique role in medicinal
chemistry because of their physicochemical properties that
include chemical stability and structural diversity combined
with relevant photo- and electrochemical properties.1 Among
the various classes of metal complexes developed as anticancer
agents, ruthenium arene based organometallics have recently
attracted considerable interest, especially the RAPTA family2
and ethylene-1,2-diamine complexes,3 which have undergone
extensive in vivo evaluation. It is interesting to note that
RAPTA complexes have a low cytotoxicity in vitro but a high
antimetastatic activity in vivo as well as an intrinsic
antiangiogenic activity and the ability to reduce growth of
certain primary tumors.4 In contrast, ruthenium arene
complexes containing ethylenediamine chelating ligands show
very high cytotoxicities and in vivo reduce tumor growth.5 In
addition to these families of compounds a number of different
types of auxiliary supporting ligands have been used in
conjugation with the ruthenium arene fragment, including
acetylacetones,6 pyridines,7 bipyridines,8 and N,O-chelating
ligands such as glycine, alanines, and phenylalanines.9
EXPERIMENTAL SECTION
■
Materials and Methods. The dimers [Ru(η6-arene)Cl2]2 (arene =
p-cymene, benzene, hexamethylbenzene) were purchased from Aldrich
and TCI Europe and were used as received. The acylpyrazolone
ligands HQph (3-methyl-1-phenyl-4-benzoyl-5-pyrazolone), HQnaph (3-
β-Ketoamine ligands are an interesting class of N,O-bidentate
ligands that can be readily modified to fine tune the steric and
electronic environment around a ruthenium ion. Interestingly,
the two donor atoms of these β-ketoamine ligands, i.e. the N
and O atoms, exhibit two opposing features: the oxygen atom is
Received: November 20, 2012
Published: December 18, 2012
© 2012 American Chemical Society
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Article
methyl-1-phenyl-4-(1-naphthoyl)-5-pyrazolone), and HQet (3-methyl-
1-phenyl-4-propionyl-5-pyrazolone) were synthesized using literature
methods.11 All other materials (products) were obtained from
commercial sources and were used as received. IR spectra were
recorded from 4000 to 600 cm−1 on a Perkin-Elmer Spectrum 100 FT-
IR instrument. 1H, 13C, and 31P NMR spectra were recorded on a 400
Mercury Plus Varian instrument operating at room temperature (400
MHz for 1H, 100 MHz for 13C, and 161 MHz for 31P). Referencing is
relative to TMS (1H and 13C) and 85% H3PO4 (31P). Positive and
negative ion electrospray mass spectra were obtained with an HP
Series 1100 MSI detector spectrometer, using an acetonitrile mobile
phase. Solutions (3 mg/mL) for electrospray ionization mass
spectrometry (ESI-MS) were prepared using reagent-grade acetoni-
trile. Mass and intensities were compared to those calculated using
IsoPro Isotopic Abundance Simulator, version 2.1.28. Melting points
are uncorrected and were taken on an STMP3 Stuart scientific
instrument and on a capillary apparatus. Samples for microanalysis
were dried in vacuo to constant weight (20 °C, ca. 0.1 Torr), and
analyses were performed on a Fisons Instruments 1108 CHNS-O
elemental analyzer. Electrical conductivity measurements (ΛM,
reported as S cm2 mol−1) of acetonitrile and dichloromethane
solutions of the complexes were recorded using a Crison CDTM
522 conductimeter at room temperature.
CH3CN (m/z, relative intensity %): 305 [100] [H2Let,ph]+. ESI-MS
(−) CH3CN (m/z, relative intensity %): 305 [100] [Let,ph]−.
Synthesis of the Ruthenium Complexes. [Ru(η6-cymene)-
(Lph,ph)Cl] (1). To the proligand HLph,ph (230.8 mg, 0.653 mmol)
dissolved in methanol (20 mL) was added KOH (36.6 mg, 0.653
mmol). The mixture was stirred for 1 h at room temperature, and then
[Ru(η6-p-cymene)Cl2]2 (200.0 mg, 0.326 mmol) was added. The
resulting solution was refluxed with stirring for 24 h. The solvent was
removed under reduced pressure, and dichloromethane (10 mL) was
added. The mixture was filtered to remove sodium chloride. The
solution was concentrated to ca. 2 mL and stored at 4 °C. The red
crystals obtained and collected (366.3 mg, 0.587 mmol, yield 91%)
were soluble in diethyl ether, alcohols, acetone, acetonitrile, DMSO,
and chlorinated solvents and sparingly soluble in water. Mp: 248−250
°C. Anal. Calcd for C33H32N3RuClO: C, 63.61; H, 5.18; N, 6.74.
Found: C, 63.51; H, 5.19; N, 6.66. IR (cm−1): 3050 w, 3123 w, 1589 s,
1570 s, 1525 m, 1499 s ν(CC; CN). 1H NMR (CDCl3, 298 K): δ
1.19 (s, 3H, C3-CH3), 1.23 (d, 3H, 3J = 6.9 Hz, CH3C6H4CH(CH3)2),
1.30 (d, 3H, 3J = 6.9 Hz, CH3C6H4CH(CH3)2), 2.06 (s, 3H,
CH3 C6 H4 CH(CH3 )2 ), 2.74 (sept, 1H, 3 J
= 6.9 Hz,
CH3C6H4CH(CH3)2), 3.50 (d, 1H, 3J = 5.6 Hz, CH3C6H4CH-
(CH3)2), 5.14 (d, 1H, 3J = 5.6 Hz, CH3C6H4CH(CH3)2), 5.16 (d, 1H,
3J = 6.4 Hz, CH3C6H4CH(CH3)2), 5.36 (d, 1H, 3J = 6.4 Hz,
CH3C6H4CH(CH3)2), 6.79−7.97 (m, 15H). 13C NMR (CDCl3, 298
K): δ 15.5 (s, C3-CH3), 18.6 (s, CH3C6H4CH(CH3)2), 21.1 and 23.7
(s, CH3C6H4CH(CH3)2), 30.8 (s, CH3C6H4CH(CH3)2), 80.2, 83.6,
84.2, 86.8, 96.5, 101.4 (s, CH3C6H4CH(CH3)2), 102.3 (s, C4), 120.6,
124.7, 124.9, 125.1, 127.3, 127.4, 128.1, 128.3 128.4, 128.6, 129.0,
136.0, 139.5, 149.4, 156.1, 160.3, 168.5 (s, ligand Lph,ph). ESI-MS (+)
CH3OH (m/z, relative intensity %): 588 [100] [Ru(η6-cym)(Lph,ph)]+.
ESI-MS (−) CH3OH (m/z, relative intensity %): 659 [100] [Ru(η6-
cym)(Lph,ph)Cl2]‑.
Synthesis of the Proligands HL′. HLph,ph. To a solution of HQph
(1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, 5.00 g, 18 mmol) in
ethanol (75 mL) was added dropwise a solution of aniline (1.70 g,
18 mmol). The solution was stirred under reflux for 24 h. The solvent
was removed under reduced pressure, and dichloromethane (10 mL)
was added. The mixture was filtered, and n-hexane (20 mL) was added
to the solution to form a diphase that was stored at 4 °C. Yellow
crystals were obtained and collected (4.70 g, 13 mmol, yield 94%).
The compound is soluble in diethyl ether, alcohols, acetone,
acetonitrile, DMSO, and chlorinated solvents. Anal. Calcd for
C23H19N3O: C, 78.16; H, 5.42; N, 11.89. Found: C, 78.07; H, 5.42;
N, 11.70. IR (cm−1): 3350−3070 br ν(N−H···O), 1609 s ν(CO),
[Ru(η6-benzene)(Lph,ph)Cl] (2). The synthesis was performed as for 1
using [Ru(η6-benzene)Cl2]2 (163.3 mg, 0.326 mmol). 2 is soluble in
alcohols, acetone, acetonitrile, DMSO, and chlorinated solvents and
sparingly soluble in water. Mp: 278−280 °C. Anal. Calcd for
C29H24N3ORuCl: C, 60.53; H, 4.36; N, 7.57. Found: C, 60.40;
H,4.26; N, 7.44. IR (cm−1): 3058 w, 1602 s, 1591 s, 1567 s, 1531 s
ν(CC; CN). 1H NMR (CDCl3, 298 K): δ 1.20 (s, 3H, C3-CH3),
5.20 (s, 6H, C6H5), 6.80−7.94 (m, 15H). 13C NMR (CDCl3, 298 K):
δ 15.4 (s, C3-CH3), 84.7s (s, C6H6), 102.8 (s, C4), 120.8, 125.0, 125.1,
125.3, 127.4, 127.5, 127.6, 128.2, 128.3, 128.8, 129.1, 135.8, 139.4,
149.5, 156.3, 160.5s, 168.7 (s, ligand Lph,ph). ESI-MS (+) CH3OH (m/
z, relative intensity %): 532 [100] [Ru(η6-benz)(Lph,ph)]+.
1
1583 s, 1574 s, 1534 w, 1499 s ν(CC; CN). H NMR (CDCl3,
298 K): δ 1.61 (s, 3H, C3-CH3), 6.82 (d, 2H), 7.04−7.52 (m, 11H),
8.02 (s, 2H), 13.03 (sbr, 1H, −NH). 13C NMR (CDCl3, 298 K): δ
16.3 (s, C3-CH3), 101.6 (s, C4), 119.5, 124.0, 126.2, 128.7, 129.23,
130.7, 131.7, 137.7, 139.1, 148.3, 162.4, 165.9 (s, ligand). ESI-MS (+)
CH3OH (m/z, relative intensity %): 354 [100] [H2Lph,ph]+. ESI-MS
(−) CH3OH (m/z, relative intensity %): 352 [100] [Lph,ph]−.
The synthesis was performed as for HLnaph,ph using 1-phenyl-3-
methyl-4-naphthoyl-5-pyrazolone (5.90 g, 18 mmol) and aniline (1.70
g, 18 mmol). The compound is soluble in diethyl ether, alcohols,
acetone, acetonitrile, DMSO, and chlorinated solvents. Mp: 162−163
°C. Anal. Calcd for C27H21N3O: C, 80.37; H, 5.25; N, 10.41. Found:
C, 79.97; H, 5.25; N, 10.37. IR (cm−1): 3400−3050 br ν(N−H....O),
1614 s ν(CO), 1589 sh, 1578 s, 1539 s ν(CC; CN). 1H NMR
(CDCl3, 298 K): δ 1.57 (s, 3H, C3-CH3), 6.85 (d, 2H), 7.04−7.91 (m,
13H), 8.03 (d, 2H), 13.19 (sbr, 1H, -NH). 13C NMR (CDCl3, 298 K):
δ 16.4 (s, C3-CH3), 101.9 (s, C4), 119.5, 123.9, 124.7, 125.2, 126.1,
127.5, 128.0, 128.3, 128.6, 128.9, 129.0, 129.2, 132.7, 133.9, 137.7,
139.1, 148.3, 162.2, 165.9 (s, ligand). ESI-MS (+) CH3OH (m/z,
relative intensity %): 829 [100] [(HLnaph,ph)2Na]+; 404 [50]
[H2Lnaph,ph]+. ESI-MS (−) CH3OH (m/z, relative intensity %): 827
[100] [(Lnaph,ph)(HLnaph,ph)Na]−; 402 [50] [Lnaph,ph]−.
[Ru(η6-hexamethylbenzene)(Lph,ph)Cl] (3). The synthesis was
performed as for 1 using [Ru(η6-hexamethylbenzene)Cl2]2 (218.3
mg, 0.326 mmol). 3 is soluble in alcohols, acetone, acetonitrile,
DMSO, and chlorinated solvents and sparingly soluble in water. Mp:
131−132 °C. Anal. Calcd for C35H36N3ClORu: C, 64.55; H, 5.57; N,
6.64. Found: C, 64.2; H, 5.46; N, 6.41. IR (cm−1): 3062 w, 1602 s,
1
1588 s, 1572 s, 1523 m, 1500 w ν(CC; CN). H NMR (CDCl3,
298 K): δ 1.15 (s, 3H, C3-CH3), 1.77 (s, 18H, C6(CH3)6), 6.67−8.03
(m, 15H). 13C NMR (CDCl3, 298 K): δ 15.2 (s, C6(CH3)6), 15.8 (s,
C3-CH3), 92.0 (s, C6(CH3)6), 102.2 (s, C4), 119.5, 122.0, 124.7,
124.8, 124.9, 126.9, 127.8, 128.3, 128.4, 128.7, 129.0, 129.1, 129.2,
137.1, 139.4, 149.5, 154.5, 160.3, 169.3 (s, ligand Hph,ph). ESI-MS (+)
CH3OH (m/z, relative intensity %): 616 [100][Ru(η6-hmb)(Lph,ph)]+.
[Ru(η6-cymene)(Lnaph,ph)Cl] (4). The synthesis was performed as for
1 using HLnaph,ph (263.3 mg, 0.653 mmol). 4 is soluble in alcohols,
acetone, acetonitrile, DMSO, and chlorinated solvents and sparingly
soluble in water. Mp: 260−262 °C. Anal. Calcd for C37H34ClN3ORu:
C, 66.01; H, 5.09; N, 6.24. Found: C, 65.96; H, 5.13; N, 6.16. IR
HLet,ph. The synthesis was performed as for HLph,ph using 1-phenyl-
3-methyl-4-propionyl-5-pyrazolone (4.14 g, 18 mmol) and aniline
(1.70 g, 18 mmol). The compound is soluble in diethyl ether, alcohols,
acetone, acetonitrile, DMSO and chlorinated solvents. Anal. Calcd for
C19H19N3O: C, 74.73; H, 6.26; N, 13.76. Found: C, 74.36; H, 6,10; N,
13.53. IR (cm−1): 3400−3050br ν(N−H···O), 1616 ν(CO), 1580 s,
1
(cm−1): 3048 w, 1589 s, 1570 s, 1530 s ν(CC; CN). H NMR
(DMSO, 273 K): δ 0.9 (s, 6H, C3-CH3), 1.25t and 1.34 (dd, 12H,
CH3C6H4CH(CH3)2), 1.95 (d, 6H, CH3C6H4CH(CH3)2), 2.68 (m,
1
1537 s, 1500 w ν(CC; CN). H NMR (CDCl3, 298 K): 1.20 (t,
3
2H, CH3C6H4CH(CH3)2), 3.60 (d, 1H, J = 6.3 Hz, CH3C6H4CH-
3H, CH2CH3), 2.46 (s, 3H, C3-CH3), 2.71 (q, 2H, CH2CH3), 7.14−
7.46 (m, 8H), 8.03 (d, 2H), 13.06 (sbr, 1H, −NH). 13C NMR
(CDCl3, 298 K): δ 13.8 (s, CH2CH3), 17.1 (s, C3-CH3), 22.4 (s,
CH2CH3), 99.1 (s, C4), 119.5 s, 124.6 s, 126.4 s, 128.1 s, 128.9 s,
129.8, 136.9, 139.2, 146.9, 166.4, 169.5 (s, ligand). ESI-MS (+)
(CH3)2), 3.65 (d, 1H, 3J = 6.3 Hz, CH3C6H4CH(CH3)2), 5.26 (d, 1H,
3J = 6.3 Hz, CH3C6H4CH(CH3)2), 5.31 (d, 1H, 3J = 6.3 Hz,
CH3C6H4CH(CH3)2), 5.40 (d, 1H, 3J = 5.8 Hz, CH3C6H4CH-
(CH3)2), 5.43 (d, 1H, 3J = 5.8 Hz, CH3C6H4CH(CH3)2), 5.55 (d, 2H,
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3J = 6.3 Hz, CH3C6H4CH(CH3)2), 6.80−7.90 (m, 30H), 7.98 (d, 4H).
1H NMR (DMSO, 363 K): δ 0.9 (s, 3H, C3-CH3), 1.21 and 1.29 (sbr,
6H, CH3C6H4CH(CH3)2), 1.99 (s, 3H, CH3C6H4CH(CH3)2), 2.72
(m, 1H, CH3C6H4CH(CH3)2), 3.90 (sbr, 1H, CH3C6H4CH(CH3)2),
5.19 (sbr, 1H, CH3C6H4CH(CH3)2), 5.37 (sbr, 1H, CH3C6H4CH-
(CH3)2), 5.47 (sbr, 1H, CH3C6H4CH(CH3)2), 6.80−7.86 (m, 15H),
7.99 (d, 2H). 13C NMR (CDCl3, 298 K): δ 15.6 (s, C3-CH3), 15.8 (s,
C3-CH3), 18.7 (s, CH3C6H4CH(CH3)2), 21.2, 21.3, 23.8 (s,
CH3C6H4CH(CH3)2), 30.8s (CH3C6H4CH(CH3)2), 80.2, 80.3, 83.8,
84.3, 84.4, 86.9, 96.5, 101.5, 101.6 (CH3C6H4CH(CH3)2), 102.5,
102.7 (s, C4), 120.7, 120.8, 124.5, 124.8, 125.1, 125.3, 126.1, 126.3,
126.6, 126.7, 126.7, 126.8, 127.1, 127.2, 127.3, 127.4, 127.5, 127.7,
127.8, 120.0, 128.1, 128.3, 128.6, 128.7, 132.2, 132.4, 132.6, 132.7,
133.5, 133.6, 139.5, 149.4, 149.5, 156.1, 156.2, 160.3, 160.5, 168.3,
168.6 (s, ligand Lnaph,ph). ESI-MS (+) CH3OH (m/z, relative intensity
%): 638 [100] [Ru(η6-cym)(Lnaph,ph)]+. ESI-MS (−) CH3OH (m/z,
relative intensity %): 710 [100] [Ru(η6-cym)(Lnaph,ph)Cl2]−.
cymene)(Lph,ph)Cl] (1; 200.0 mg, 0.320 mmol) in methanol. The
reaction mixture was refluxed for 24 h and then cooled to room
temperature. The solvent was removed under reduced pressure, and
chloroform (15 mL) was added. The mixture was filtered to remove
AgCl, the solution was dried under vacuum, and the red residue was
identified as 8 (159.6 mg, 208.6 mmol, 65% yield), which is soluble in
alcohols, acetone, acetonitrile, and DMSO and sparingly soluble in
water and chlorinated solvents. Mp: 143−145 °C. Anal. Calcd for
C34H36F6N3O2PRu: C, 53.40; H, 4.75; N, 5.49. Found: C, 53.03; H,
4.43; N, 5.44. Λm (MeCN, 298 K, 10−4 mol/L): 136 S cm2 mol−1. IR
(cm−1): 3500 br ν(H2O), 3060 w, 1589 s, 1567 s, 1524 s ν(CC;
1
CN), 827 s ν(PF6). H NMR ((CD3)2CO, 298 K): δ 1.19 (s, 3H,
C3-CH3), 1.22 (d, 6H, CH3C6H4CH(CH3)2), 2.04 (s, 3H,
CH3C6H4CH(CH3)2), 2.70 (sept, 1H, CH3C6H4CH(CH3)2), 3.10
(s, 3H, CH3OH), 5.25 and 5.64 (sbr, 4H, CH3C6H4CH(CH3)2),
7.06−7.59 (m, 13H), 8.19 (d, 2H). 13C NMR ((CD3)2CO, 298 K): δ
15.3 (s, C3-CH3), 18.4 (s, CH3C6H4CH(CH3)2), 22.5 (s,
CH3C6H4CH(CH3)2), 32.3 (s, CH3C6H4CH(CH3)2), 85.5, 98.0 (s,
CH3C6H4CH(CH3)2), 102.6 (s, C4), 121.8, 122.1, 127.1, 129.3, 129.5,
129.9, 130.1, 130.3, 136.1, 137.8, 138.5, 140.2, 142.0, 156.5, 158.5,
160.1 (s, ligand Lph,ph). ESI-MS (+) CH3OH (m/z, relative intensity
%): 588 [100][Ru(η6-cym)(Lph,ph)]+.
[Ru(η6-benzene)(Lnaph,ph)Cl] (5). The synthesis was performed as for
1 using HLnaph,ph (263.3 mg, 0.653 mmol) and [Ru(η6-benzene)Cl2]2
(163.3 mg, 0.326 mmol). 5 is soluble in alcohols, acetone, acetonitrile,
DMSO, and chlorinated solvents and sparingly soluble in water. Mp:
350 °C dec. Anal. Calcd for C33H26ClN3ORu: C, 64.23; H, 4.25; N,
6.81. Found: C, 64.56; H, 4,13; N, 6.56. IR (cm−1): 3053 w, 1589 s,
1568 s, 1523 s ν(CC; CN). 1H NMR (CDCl3, 298 K): δ 1.08 (s,
3H, C3-CH3), 5.22 (d, 6H, C6H6), 6.80−7.80 (m, 15H), 7.94 (d, 2H).
13C NMR (CDCl3, 298 K): δ 15.6 (s, C3-CH3), 84.8s (s, C6H6), 102.9
(s, C4), 120.6, 124.8, 125.0, 125.4, 127.6, 127.7, 127.8, 128.4, 128.5,
128.9, 129.1, 135.7, 139.6, 149.6, 156.5, 160.7, 168.9 (s, ligand
[Ru(η6-cymene)(Lph,ph)(PTA)]Cl (9). PTA (PTA = 1,3,5-triaza-7-
phosphaadamantane, 50.4 mg, 0.320 mmol) was added to a solution of
[Ru(η6-cymene)(Lph,ph)Cl] (1; 200.0 mg, 0.320 mmol) in methanol.
The reaction mixture was refluxed for 2 h and then cooled to room
temperature. The solution was concentrated to ca. 2 mL, and diethyl
ether (25 mL) was added. The mixture was left at 277 K until an
orange precipitate formed. The orange crystalline powder that was
recovered by filtration and air-dried (162 mg, 0.208 mmol, 65%) was
identified as 9, which is soluble in alcohols, acetonitrile, DMSO,and
acetone, sparingly soluble in water, and poorly soluble in chlorinated
solvents. Mp: 170−172 °C. Anal. Calcd for C39H44N6ClOPRu: C,
62.89; H, 5.95; N, 11.28. Found: C, 62.95; H, 6.07; N, 11.11. Λm
(MeCN, 298 K, 10−4 mol/L): 145 S cm2 mol−1. IR (cm−1): 3159 br,
3050 w, 1560 s, 1521 s ν(CC; CN). 1H NMR (CDCl3, 298 K): δ
L
naph,ph). ESI-MS (+) CH3OH (m/z, relative intensity %): 582 [100]
[Ru(η6-benz)(Lnaph,ph)]+.
[Ru(η6-hexamethylbenzene)(Lnaph,ph)Cl] (6). The synthesis was
performed as for 1 using HLnaph,ph (263.3 mg, 0.653 mmol) and
[Ru(η6-hexamethylbenzene)Cl2]2 (218.3 mg, 0.326 mmol). 6 is
soluble in alcohols, acetone, acetonitrile, DMSO, and chlorinated
solvents and sparingly soluble in water. Mp: 233−235 °C. Anal. Calcd
for C39H38ClN3ORu: C, 66.80; H, 5.46; N, 5.99. Found: C, 66.56; H,
5,33; N, 5.76. IR (cm−1): 3047 w, 1601 s, 1589 s, 1567 s, 1528 s
ν(CC; CN). 1H NMR (CDCl3, 298 K): δ 1.03 (d, 3H, C3-CH3),
1.78 (s, 18H, C6(CH3)6), 6.67−8.00 (m, 17H). 13C NMR (CDCl3,
298 K): δ 15.2 (s, C6(CH3)6), 16.1, 16.2 (s, C3-CH3), 89.8, 92.0 (s,
C6(CH3)6), 101.94 (s, C4), 119.6, 122.0, 124.0, 124.7, 125.0, 126.2,
126.4, 126.5, 127.8, 127.9, 128.2, 128.3, 128.6, 129.1, 131.9, 132.7,
132.8, 133.9, 134.5, 134.7, 139.1, 139.3, 148.3, 149.4, 149.5, 154.4,
154.6, 162.3, 169.3, 169.7 (s, ligand Lnaph,ph). ESI-MS (+) CH3OH (m/
z, relative intensity %): 666 [100] [Ru(η6-hmb)(Lnaph,ph)]+.
3
3
1.12 (d, 3H, J = 7.2 Hz, CH3C6H4CH(CH3)2), 1.14 (d, 3H, J = 7.2
Hz, CH3C6H4CH(CH3)2), 1.25 (s, 3H, C3-CH3), 1.59 (s, 3H,
CH3 C6 H4 CH(CH3 )2 ), 2.37 (sept, 1H, 3 J
= 6.9 Hz,
CH3C6H4CH(CH3)2), 4.04 (d, 1H, 3J = 6.4 Hz, CH3C6H4CH-
(CH3)2), 4.54 and 4.62 (d, 6H, JAB = 13 Hz, PCHAHBN, PTA), 4.78
and 4.90 (d, 6H, JAB = 14 Hz, NCHAHBN, PTA), 5.27 (d, 1H, 3J = 6.0
3
Hz, CH3C6H4CH(CH3)2), 6.12 (d, 1H, J = 6.0 Hz, CH3C6H4CH-
3
(CH3)2), 6.69 (d, 1H, J = 7.6 Hz, CH3C6H4CH(CH3)2), 6.93−7.83
(m, 15H). 13C NMR (CDCl3, 298 K): δ 15.6 (s, C3-CH3), 17.8 (s,
CH3C6H4CH(CH3)2), 20.5 and 23.0 (s, CH3C6H4CH(CH3)2), 30.9
(s, CH3C6H4CH(CH3)2), 52.4 (d, PCH2N, PTA), 73.1 (d, NCH2N,
PTA), 82.2, 86.8, 86.9, 90.1, 95.0, 96.9 (s, CH3C6H4CH(CH3)2), 104.5
(s, C4), 120.2, 121.7, 124.2, 126.0, 126.3, 127.8, 128.2, 128.8, 129.2,
129.4, 135.2, 138.4, 149.6, 155.6, 159.4, 170.8 (s, ligand Lph,ph). 31P
NMR (CDCl3, 298 K): δ −29.31. ESI-MS (+) CH3OH (m/z, relative
intensity %): 745 [100][Ru(η6-cym)(Lph,ph)(PTA)]+, 588 [60][Ru(η6-
cym)(Lph,ph)]+.
[Ru(η6-cymene)(Let,ph)Cl] (7). The synthesis was performed as for 1
using HLet,ph (199.3 mg, 0.653 mmol). 7 is soluble in alcohols, acetone,
acetonitrile, DMSO, and chlorinated solvents and sparingly soluble in
water. Mp: 221−222 °C dec. Anal. Calcd for C29H32ClN3ORu: C,
60.56; H, 5.61; N, 7.31. Found: C, 60.37; H, 5.49; N, 7.16. IR (cm−1):
1
3061 w, 1603 s, 1592 s, 1577 s, 1519 w ν(CC; CN). H NMR
3
(CDCl3, 298 K): 0.99 (t, 3H, CH2CH3), 1.15 (d, 3H, J = 6.8 Hz,
CH3C6H4CH(CH3)2), 1.19 (d, 3H, 3J = 6.9 Hz, CH3C6H4CH-
(CH3)2), 1.99 (s, 3H, CH3C6H4CH(CH3)2), 2.34 (s, 3H, C3-CH3),
[Ru(η6-cymene)(Lnaph,ph)(CH3OH)][PF6] (10). The synthesis was
performed as for 8 using 4 (216.0 mg, 0.320 mmol). 10 is soluble
in alcohols, acetone, acetonitrile, and DMSO and sparingly soluble in
water and chlorinated solvents. Mp: 142−144 °C. Anal. Calcd for
C38H38F6N3O2PRu: C, 56.02; H, 4.70; N, 5.16. Found: C, 56.17; H,
4.54; N, 5.22. Λm (MeCN, 298 K, 10−4 mol/L): 122 S cm2 mol−1. IR
(cm−1): 3554 br ν(H2O), 3060 w, 1591 s, 1571 s, 1525 s ν(CC;
2.45 (q, 2H, CH2CH3), 2.66 (sept, 1H, 3J
= 6.8 Hz,
CH3C6H4CH(CH3)2), 3.43 (d, 1H, 3J = 5.6 Hz, CH3C6H4CH-
(CH3)2), 5.02 (d, 1H, 3J = 6.4 Hz, CH3C6H4CH(CH3)2), 5.12 (d, 1H,
3J = 5.6 Hz, CH3C6H4CH(CH3)2), 5.30 (d, 1H, 3J = 6.4 Hz,
CH3C6H4CH(CH3)2), 7.13−7.46 (m, 7H), 7.73 (d, 1H), 7.96 (d,
2H). 13C NMR (CDCl3, 298 K): δ 14.0 (s, C3-CH3), 17.6 (s,
CH2CH3), 18.5 (s, CH3C6H4CH(CH3)2), 21.1 and 23.6 (s,
CH3C6H4CH(CH3)2), 24.9 (s, CH2CH3), 30.7 (s, CH3C6H4CH-
(CH3)2), 79.6, 83.9, 84.8, 86.5, 95.9, 101.56 (s, CH3C6H4CH(CH3)2),
100.6 (s, C4), 119.5, 120.7, 123.2, 124.6, 124.7, 125.9, 126.2, 126.4,
128.0, 128.6, 128.9, 129.7, 129.8, 139.6, 147.3, 156.0, 160.9, 172.0 (s,
ligand Let,ph). ESI-MS (+) CH3OH (m/z, relative intensity %): 540
[100] [Ru(η6-cym)(Let,ph)]+.
1
CN), 831 ν(PF6). H NMR ((CD3)2CO, 298 K): δ 1.05 (3H, C3-
CH3), 1.26 (d, 6H, CH3C6H4CH(CH3)2), 2.05 (s, 3H, CH3C6H4CH-
(CH3)2), 2.77 (m, 1H, CH3C6H4CH(CH3)2), 3.24 (s, 3H, CH3OH),
5.18 (sbr, 1H, CH3C6H4CH(CH3)2), 5.27 (sbr, 1H, CH3C6H4CH-
(CH3)2), 5.81 (sbr, 2H, CH3C6H4CH(CH3)2), 6.98−7.85 (m, 13H),
8.19 (d, 2H). 13C NMR ((CD3)2CO, 298 K): δ 15.6 (s, C3-CH3), 18.3
(s, CH3C6H4CH(CH3)2), 22.3, 22.4 (s, CH3C6H4CH(CH3)2), 31.9 (s,
CH3C6H4CH(CH3)2), 83.8, 84.2, 85.1, 85.3, 97.5, 100.2
(CH3C6H4CH(CH3)2), 102.4 (s, C4), 119.1, 120.3, 125.9, 126.7,
128.6, 129.0, 129.4, 129.8, 133.3, 133.6, 133.8, 140.1, 149.5, 156.4,
[Ru(η6-cymene)(Lph,ph)(CH3OH)][PF6] (8). Silver hexafluorophos-
phate (81.1 mg, 0.320 mmol) was added to a solution of [Ru(η6-
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160.5, 170.5. ESI-MS (+) CH3OH (m/z, relative intensity %): 638
[100] [Ru(η6-cym)Ru(Lnaph,ph)]+.
Chart 1
[Ru(η6-cymene)(Lnaph,ph)(PTA)]Cl (11). The synthesis was per-
formed as for 9 using 4 (216.0 mg, 0.320 mmol). 11 is soluble in
alcohols, acetonitrile, DMSO, and acetone, sparingly soluble in water,
and poorly soluble in chlorinated solvents. Mp: 154−156 °C. Anal.
Calcd for C43H46ClN6OPRu: C, 62.20; H, 5.58; N, 10.12. Found: C,
62.04; H, 5.38; N, 9.96. Λm (MeCN, 298 K, 10−4 mol/L): 129 S cm2
1
mol−1. IR (cm−1): 1590 s, 1571 s, 1524 s ν(CC; CN). H NMR
(CDCl3, 298 K): δ 1.13−1.21 (m, 3H, C3-CH3 and 6H,
CH3C6H4CH(CH3)2), 1.61 (s, 3H, CH3C6H4CH(CH3)2), 2.40 (m,
3
1H, CH3C6H4CH(CH3)2), 4.02 (d, 1H, J = 6.0 Hz, CH3C6H4CH-
3
(CH3)2), 4.05 (d, 1H, J = 6.0 Hz, CH3C6H4CH(CH3)2), 4.56 and
4.63 (d, 6H, JAB = 13 Hz, PCHAHBN, PTA), 4.83 and 4.90 (d, 6H, JAB
3
= 14 Hz, NCHAHBN, PTA), 5.29 (d, 1H, J = 6.4 Hz, CH3C6H4CH-
(CH3)2), 6.13 (m, 1H, CH3C6H4CH(CH3)2), 6.80−7.80 (m, 17H).
13C NMR (CDCl3, 298 K): δ 15.6, 15.9 (s, C3-CH3), 17.9 (s, CH3−
C6H4−CH(CH3)2), 20.5, 23.0, 24.3 (s, CH3−C6H4−CH(CH3)2), 30.9
(s, CH3−C6H4-CH(CH3)2), 52.6 (d, PCH2N, PTA), 73.2 (d, NCH2N,
PTA), 82.2, 86.9, 87.1, 90.1, 95.1, 97.1 (s, CH3C6H4CH(CH3)2),
104.6, 104.9 (s, C4), 120.2, 120.6, 121.7, 121.9, 122.3, 124.6, 126.0,
126.3, 127.2, 127.6, 127.9, 128.1, 128.6. 128.9, 129.1, 129.4, 132.2,
132.5, 132.7, 132.8, 138.4, 149.5, 149.6, 155.6, 155.7, 159.5, 159.6,
170.6, 170.7 (s, ligand Lnaph,ph). 31P NMR (CDCl3, 298 K): δ −31.35,
−31.30. ESI-MS (+) CH3OH (m/z, relative intensity %): 638 [60]
[Ru(η6-cym)(Lnaph,ph)]+, 795 [100] [Ru(η6-cym)(PTA)(Lnaph,ph)]+.
Single Crystal X-ray Diffraction Analysis. The diffraction data
of the proligand HLet,ph and of complexes 1 and 7 were measured at
low temperature (100(2) or 170(2) K) using Mo Kα radiation on a
Bruker APEX II CCD diffractometer equipped with a κ geometry
goniometer. The data sets were reduced by EvalCCD12 and then
corrected for absorption.13 The data collection of compound 4 was
carried out at room temperature using Mo Kα radiation on an Agilent
Technologies SuperNova dual system in combination with an Atlas
CCD detector. The data reduction was performed using Crysalis
PRO,14 and the solutions and refinements were performed with
SHELX.15 The crystal structures were refined using full-matrix least
squares based on F2 with all non-hydrogen atoms anisotropically
defined. Hydrogen atoms were placed in calculated positions by means
of the “riding” model.
The novel ruthenium arene complexes 1−7 were prepared in
high yield from the reaction of the appropriate dimer, [Ru(η6-
arene)Cl2]2, with the appropriate proligand and KOH in
methanol (Chart 2). The complexes are air stable in solution
Chart 2
Cell Culture and Evaluation of the Anticancer Activity. The
human A2780 and A2780R ovarian carcinoma cells were obtained
from the European Collection of Cell Cultures (Salisbury, U.K.). Cells
were grown routinely in RPMI-1640 medium with 10% fetal calf serum
(FCS) and antibiotics at 37 °C and 5% CO2. Cytotoxicity was
determined using the MTT assay (MTT = 3(4,5-dimethyl-2-
thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide). Cells were seeded
in 96-well plates as monolayers with 100 μL of cell solution
(approximately 20000 cells) per well and preincubated for 24 h in
medium supplemented with 10% FCS. Compounds were prepared as
DMSO solutions and then dissolved in the culture medium and serially
diluted to the appropriate concentration, to give a final DMSO
concentration of 0.5%. A 100 μL portion of the drug solution was
added to each well, and the plates were incubated for another 72 h.
Subsequently, MTT (5 mg/mL solution) was added to the cells and
the plates were incubated for a further 2 h. The culture medium was
aspirated, and the purple formazan crystals formed by the
mitochondrial dehydrogenase activity of vital cells were dissolved in
DMSO. The optical density, directly proportional to the number of
surviving cells, was quantified at 590 nm using a multiwell plate reader,
and the fraction of surviving cells was calculated from the absorbance
of untreated control cells. Evaluation is based on means from two
independent experiments, each comprising three microcultures per
concentration level.
and in the solid state and are highly soluble in most organic
solvents and sparingly soluble in water. Conductivity measure-
ments indicate a slight dissociation of the chloride in DMSO at
room temperature; however, ionization increases with temper-
ature and at 353 K it is almost complete (see the Supporting
Information).
RESULTS AND DISCUSSION
■
The proligands (HL′) were obtained in high yields via the
condensation of 4-acyl-5-pyrazolones (HQ′) with aniline
(Chart 1).
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Figure 1. Proposed conformers of 4, which differ in the orientation of the naphthyl group.
The IR spectra of 1−7 show the typical shift of the ν(CO)
vibrations to lower frequency upon coordination of the β-
ketoamine proligands to the metal ion.16 In the positive ESI
mass spectra of 1−7 peaks due to the cationic fragment
[Ru(arene)(L′)]+, generated from loss of Cl−, are observed as
the predominant species.
2H), while the methyl groups of the isopropyl moiety give rise
to two partially superimposed doublets. However, at higher
temperature (343 K) all the peaks of the p-cymene ring protons
broaden and at 363 K they coalesce into four broad resonances,
due to rapid isomerization between the two forms on the NMR
time scale. The 13C NMR spectra of 4−6 further confirm the
presence of two conformational isomers in solutioneight
different p-cymene ring carbons being observed in the range
80.2−86.9 ppm (four for each isomer), together with the
presence of four different resonances in the range 20.5−23.7
ppm for the methyl groups of the isopropyl moiety.
The chloride ligand in 1 and 4 can be easily removed by
reaction with AgPF6 in methanol, to afford [Ru(η6-cymene)-
(Lph,ph)(CH3OH)][PF6] (8) and [Ru(η6-cymene)(Lnaph,ph)-
(CH3OH)][PF6] (10), in which one methanol molecule
takes the place of the chloride in the Ru coordination sphere.
The chloride of 1 and 4 can also be replaced by the water-
soluble phosphine 1,3,5-triaza-7-phosphaadamantane (PTA),
affording the complexes [Ru(η6-cymene)(Lph,ph)(PTA)]Cl (9)
and [Ru(η6-cymene)(Lnaph,ph)(PTA)]Cl (11), as depicted in
Scheme 1.
1
The H NMR spectra of 1−7 display a distinct shift of
resonances of the β-ketoamine protons in comparison with the
equivalent protons in the free proligands. The asymmetry (C1)
1
of the complexes induces significant modifications to the H
and 13C NMR signals of the p-cymene moiety in 1, 4, and 7;
1
the H NMR spectra of 1 and 7 in CDCl3 show a doublet for
each of the four p-cymene ring protons and two doublets for
the methyl groups of the isopropyl moiety. Surprisingly, one of
the four proton resonances attributable to the p-cymene ring is
strongly shifted to higher fields, in the range 3.43−3.50 ppm,
whereas the other three doublets are in the range 5.02−5.36
ppm, which is typical of ruthenium arene systems.6
The aforementioned high-field shift of one of the aromatic
protons is likely due to the close vicinity of the phenyl group in
the ammine moiety of the coordinated ligand, as confirmed by
X-ray diffraction studies (see below). Also in the 13C NMR
spectra of 1 and 7 four different p-cymene ring carbons are
observed in the range 79.6−86.5 ppm, together with two
different methyl groups of the isopropyl moiety in the range
20.5−23.7 ppm.
Complexes 8−11 are soluble in alcohols, acetonitrile,
DMSO, and acetone, sparingly soluble in water, and poorly
soluble in chlorinated solvents. In acetonitrile 8−11 display
conductivity values within the range typical of 1:1 electro-
lytes.18 In the IR spectra of 8 and 10 a strong sharp absorption
A similar pattern has been observed in the 1H and 13C NMR
of 4, where, however, two sets of signals are observed. They are
likely due to the presence in solution of two conformers
differing in the orientation of the naphthyl group in the ligand
(Figure 1).17
−
is observed at 827 and 831 cm−1 due to the PF6
counteranion.19
1
The H NMR spectra of 9 and 11 show all the expected
signals due to the coordinated p-cymene ring, β-ketoamine, and
PTA. A doublet for each of the four p-cymene ring protons and
two doublets for the methyl groups of the isopropyl moiety are
observed. Moreover, the four doublets are shifted to lower field
with respect to those observed in the spectra of 1 and 4, in
accordance with a stronger donor interaction between the arene
The presence of two conformers (1:1 ratio) has been
observed also in the NMR spectra of the other complexes
containing the Lnaph,ph ligand (5 and 6). A variable-temperature
1H NMR study of 4 in the range 273−323 K, carried out in
CDCl3, reveals unchanged spectra. In contrast, the same study
performed in DMSO-d6 shows the coalescence of the two sets
of resonances at higher temperatures (Figure 2). In detail, at
273 K the aromatic protons of p-cymene show six separate
doublets (integrating to 1H each) and a doublet (integration
1
moiety and the cationic ruthenium(II) center. The H NMR
spectra of 9 and 11 show two types of methylene protons in the
coordinated PTA ligand, both displaying AB spin systems
centered respectively at 4.58 (JAB = 13 Hz) and 4.84 ppm (JAB
=
14 Hz).20 The 31P NMR spectrum of 9 contains a singlet at
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Scheme 1
fragment [Ru(η6-cymene)(L′)]+, due to dissociation of the
PTA ligand.
The solid state structures of HLet,ph, 1, 4, and 7 were
established by X-ray crystallography (see Table 1S in the
Supporting Information and also see the Experimental Section
for details of the crystals, data collection, and structure
refinement). The crystal structure of the proligand HLet,ph
(Figure 3) shows two independent molecules within the
Figure 3. X-ray structure of the proligand HLet,ph Key bond length (Å)
for HLet,ph: N2−N3 = 1.408(1) Å.
asymmetric unit. The molecules are mostly planar, except for
the ethyl and the −NHPh substituents (mostly due to steric
hindrance). A strong intramolecular H bond occurs between
the −NH and the O of the pyrazolone moiety (N−H···O:
2.706(2), 2.671(2) Å; 143(2), 145(2)°).
Complexes 1, 4, and 7 (Figure 4) show the usual piano-stool
geometry about the ruthenium center. The bond distances
around the Ru atom vary over a small range (Ru−O =
2.066(2)−2.098(2) Å; Ru−N = 2.113(4)−2.127(2) Å; Ru−Cl
= 2.429(2)−2.440(1) Å) and are comparable to those of similar
compounds.22
All the compounds were tested using the MTT assay (see
Experimental Section for details) for their in vitro anticancer
activity against two human ovarian carcinoma cell lines, A2780
and A2780R, the latter having acquired resistance to cisplatin
(Table 1).
1
Figure 2. H NMR spectra of 4 in DMSO-d6 in the range 3.5−5.5
ppm at different temperatures.
−29.31 ppm, which is in the region typical for related
complexes, in accordance with the existence of only one
species in solution.21 However, in the 31P NMR spectrum of 11
a doublet centered at δ −32.3 ppm is observed, confirming the
presence of two different conformers in solution.
The ESI mass spectra of 9 and 11 show the presence of two
peaks, the most intense corresponding to [Ru(η6-cymene)-
(L′)(PTA)]+ species and the less intense peak assignable to the
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Table 1. IC50 Values of HLnaph,ph, HLph,ph, HLet,ph, and
Complexes 1−11 in Ovarian Carcinoma Cell Lines A2780
and A2780R (Cisplatin-Resistant)
compd
IC50 in A2780 (μM)
IC50 in A2780R (μM)
HLnaph,ph
14.4 1.6
275 76
116 2.4
7.6 1.1
10.2 0.7
>500
14.0 1.7
271 70
204 17
14.0 1.7
7.7 1.0
51.4 4.5
10.1 0.2
21.4 2.0
80.3 2.9
>500
HLph,ph
HLet,ph
1
2
3
4
9.1 0.5
19.1 0.4
35.6 2.4
>500
5
6
7
8
9.6 0.7
18.9 0.8
5.9 0.2
6.0 0.5
1.0 0.2
10.5 0.6
19.5 0.3
7.2 0.4
6.1 0.5
25.0 0.2
9
10
11
a
cisplatin
a
Cisplatin is used as a reference compound and has been tested before.
The HLnaph,ph ligand is quite cytotoxic against the ovarian
carcinomas, whereas HLph,ph and HLet,ph are much less active,
HLph,ph being the least active of the ligands with an IC50 value
around 270 μM in both cell lines. In comparison, the complexes
bearing the HLph,ph ligand, i.e. 1 and 2, are more active than
their HLnaph,ph analogues 4 and 5. The complexes with the p-
cymene ligand are the most active of the series, with 1 and 4
followed by the benzene complexes 2 and 5 and finally
hexamethylbenzene complexes 3 and 6. Notably, rather small
changes to the β-ketoamine ligand lead to very large differences
in cytotoxicity, with 7 being inactive in both cell lines (IC50
>
500 μM) in comparison to IC50 values of <10 μM for 1 and 2.
Replacing chloride by an aqua ligand in 1 gives 8, which has a
lower activity, whereas the aqua complex 10 is more active than
its precursor 4, with an IC50 value in the low micromolar range.
Switching to the PTA ligand further decreases the activity of
compound 9, but not that of 11, which, to within experimental
errors, is the most active compound in both cell lines. It is
noteworthy that most ruthenium arene complexes with a PTA
ligand display limited cytotoxicities unless functionalized with a
biologically active group,2b indicating the important biological
role of the β-ketoamine ligands in these complexes.
None of the compounds are as cytotoxic as cisplatin in the
A2780 cell line, whereas a number of them are substantially
more active in A2780R cells, indicating that they operate via a
mechanism of action different from that of cisplatin.
CONCLUSIONS
■
Organometallic compounds are attracting considerable interest
in medicinal chemistryespecially in imaging and as putative
anticancer compounds.23 Many different classes of organo-
metallic compounds have been evaluated, from the pioneering
studies on titanocene dichloride that underwent extensive
testing in the clinic,24 to rationally designed ferrocifens,25 to the
current situation in which a large range of main-group and
transition metals and essentially all the classic ligands
encountered in organometallic chemistry have been explored.1
Of particular current interest are ruthenium arene compounds
which have been extensively modified to give compounds with
various therapeutic effects.2,3 Herein we have shown that
ruthenium arene compounds with β-ketoamine ligands have
Figure 4. X-ray structures of (top) 1, (middle) 4, and (bottom) 7. Key
bond lengths (Å) and angles (deg) for 1: Ru−O = 2.098(2) Å, Ru−N1
= 2.120(2), Ru−Cl = 2.439(6), N2−N3 = 1.398(4); O−Ru−N1 =
87.60(8), O−Ru−Cl = 84.91(6), N1−Ru−Cl: 83.85(7). Key bond
lengths (Å) and angles (deg) for 4: Ru−O = 2.081(4), Ru−N1 =
2.113(4), Ru−Cl = 2.429(2), N2−N3 = 1.410(7); O−Ru−N1 =
88.84(2), O−Ru−Cl = 85.16(1), N1−Ru−Cl = 84.84(1). Key bond
lengths (Å) and angles (deg) for 7: Ru−O = 2.066(2) Å, Ru−N1 =
2.127(2), Ru−Cl = 2.437(6), N2−N3 = 1.393(3); O−Ru−N1 =
88.46(7), O−Ru−Cl = 83.88(5), N1−Ru−Cl = 82.96(5).
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Parkin, A.; Parsons, S.; Brabec, V.; Sadler, P. J. Inorg. Chem. 2008, 47,
11470.
relevant anticancer properties in vitro: for example, displaying
significant cytotoxicity on resistant human ovarian cancer cells.
Minor changes to the β-ketoamine ligand, such as changing an
ethyl group for a phenyl group, result in considerable changes
to their cytotoxicity. Consequently, these ligands represent an
interesting class for further study in order to fine tune the
anticancer properties of the ruthenium arene unit.
́
(9) Habtemariam, A.; Melchart, M.; Fernandez, R.; Parsons, S.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
Text giving 1H NMR and conductivity data for complex 4 and a
table and CIF files giving crystallographic data for HLet,ph, 1, 4,
and 7. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*R.P.: e-mail, riccardo.pettinari@unicam.it; tel, +39
0737402338; fax, +39 0737 402338.
■
Author Contributions
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The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Swiss National Science Foundation (CMM) and
the University of Camerino for financial support.
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