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Synthesis and cytotoxicity studies of novel anion-exchanged Titanocene Y derivatives.

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Full Paper
Received: 4 February 2010
Accepted: 6 April 2010
Published online in Wiley Online Library: 28 June 2010
(wileyonlinelibrary.com) DOI 10.1002/aoc.1665
Synthesis and cytotoxicity studies of novel
anion-exchanged Titanocene Y derivatives
James Claffey, Anthony Deally, Brendan Gleeson, Siddappa Patil
and Matthias Tacke∗
Starting from the potential anticancer drug candidate Titanocene Y {bis-[(4-methoxybenzyl)cyclopentadienyl]titanium(IV)
dichloride}, anion exchange experiments were performed using silver malonate (1a) or silver cyclobutane-1,1malonate (1b) in order to yield bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV) malonate (2a) and bis-[(4-methoxybenzyl)cyclopentadienyl] titanium(IV) cyclobutane-1,1-malonate (2b). In addition, Titanocene Y was reacted with salicylic acid
(3a) or 3,5-dinitro-salicylic acid (3b) in the presence of diethylamine to synthesize bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV) salicylate (4a) or bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV) 3,5-dinitro-salicylate (4b). These titanocenes
had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in an
MTT-based assay in order to determine their IC50 values. Titanocenes 2a–b and 4a were found to have IC50 values of 74 (±13)
µM, 18 (±5) µM and 49 (±11) µM on the LLC-PK cell line, while compound 4b was found to have lost all its cytotoxic activity on
c 2010 John Wiley & Sons, Ltd.
this cell line. Copyright Supporting information may be found in the online version of this article.
Keywords: anticancer drugs; cisplatin; carboplatin; Titanocene Y; metal carboxylates; LLC-PK
Introduction
Appl. Organometal. Chem. 2010, 24, 675–679
∗
Correspondence to: Matthias Tacke, UCD School of Chemistry and Chemical
Biology, Conway Institute of Biomolecular and Biomedical Research, Centre for
Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4,
Ireland. E-mail: matthias.tacke@ucd.ie
Conway Institute of Biomolecular and Biomedical Research, The UCD School of
Chemistry and Chemical Biology, Centre for Synthesis and Chemical Biology,
University College Dublin, Belfield, Dublin 4, Ireland
c 2010 John Wiley & Sons, Ltd.
Copyright 675
Following the success of cisplatin and carboplatin in the clinic, the
search to find other transition metal-based complexes that show
promising anticancer activity began. Transition metal complexes
of gold, iron, ruthenium, tin, vanadium, molybdenum and titanium
have shown some promising antitumour activity in vitro and
in vivo testing, but only titanium has yet been introduced
into clinical trials. Budotitane{[cis-diethoxybis(1-phenylbutane1,3-dionato)titanium (IV)]} reached Phase I clinical trials[1] following
a promising early preclinical evaluation but did not progress any
further, despite the development of a Cremophor EL -based
formulation for it. Titanocene dichloride is the only metallocene
dichloride so far which has reached clinical trials. Cp2 TiCl2 shows
medium anti-proliferative activity in vitro and promising results
in vivo,[2,3] but its efficacy in phase II clinical trials in patients with
metastatic renal cell carcinoma[4] or metastatic breast cancer[5]
was too low to be pursued.
Titanocene dichlorides as anticancer reagents received renewed
interest when McGowan synthesized ring-substituted cationic
titanocene dichloride derivatives, which are water-soluble and
show significant activity against ovarian cancer.[6]
Through the use of Super Hydride, 6-anisyl fulvene can undergo
selective hydridolithiation to yield an isolable lithium cyclopentadienide. Following a transmetallation reaction of this lithium
cyclopentadienide with titanium tetrachloride, the promising
anticancer compound bis-[(p-methoxybenzyl)cyclopentadienyl]
titanium(IV) dichloride (Titanocene Y)[7] can be isolated (Fig. 1).
Titanocene Y has an IC50 value of 21 µM when tested on the
long-life epithelial pig kidney cell line LLC-PK. The anti-proliferative
activity of Titanocene Y has been studied in 36 human tumour
cell lines and also against explanted human tumours.[8] These
in vitro and ex vivo experiments showed that renal cell cancer
is the prime target for this compound, but it also has activity
against ovary, prostate, cervix, lung, colon and breast cancer.
Titanocenes have also been shown to give a positive immune
response by up-regulating the number of natural killer (NK) cells in
mice.[8] Animal studies reported the successful treatment of mice
bearing xenografted Caki-1, MCF-7[8] and A431[9] tumours with
Titanocene Y where reduction of tumour size was seen. Recently an
oxalate derivative of Titanocene Y (Oxali-Titanocene Y) has been
reported as having an IC50 of 1.6 µM on the LLC-PK cell line.[10]
This was also shown to have good anti-angiogenic properties
in a HUVEC anti-angiogenesis tests and in a mouse model was
shown to be cytostatic on xenografted Caki-1.[11] Following the
success of Titanocene Y and also Oxali-Titanocene Y in vivo and
in vitro, which showed very promising cytotoxic, anti-angiogenic
properties and probable different cytotoxic mechanism than
cisplatin, it was necessary to make further carboxylate anionsubstituted derivatives of Titanocene Y and to do some preliminary
in vitro biological testing. The syntheses of four carboxylate anionsubstituted derivatives of Titanocene Y are presented within this
paper.
J. Claffey et al.
Ph
OMe
O
Me
O
Me
Ti
O
OEt
Cl
Cl
Ti
OEt
Ti
Cl
Cl
O
OMe
Ph
Budotitane
Titanocene Dichloride
Titanocene Y
Figure 1. Structures of budotitane, titanocene dichloride and Titanocene Y.
Experimental
Synthesis of bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV)
cyclobutane-1,1-malonate, TiC32 O6 H32 (2b)
General Conditions
Malonic acid, salicylic acid and 3,5-dinitro-salicylic acid were
obtained from Aldrich Chemical Co. Silver nitrate and diethyl
cyclobutane-1,1-dicarboxylate were obtained from Fluka Chemical
Co. Pentane and THF were dried over Na/benzophenone and were
freshly distilled and collected under an atmosphere of nitrogen
prior to use. Diethylamine was distilled over KOH, stored over
KOH and under nitrogen prior to its use. Manipulations of airand moisture-sensitive compounds were done using standard
Schlenk techniques, under a nitrogen atmosphere. NMR spectra
were measured on a Varian 400 MHz spectrometer. Chemical shifts
are reported in ppm and are referenced to TMS. IR spectra were
recorded on a Perkin Elmer Paragon 1000 FT-IR Spectrometer
employing a KBr disk. UV–vis spectra were recorded on a Unicam
UV4 Spectrometer, while CHN analysis was done with an Exeter
Analytical CE-440 Elemental Analyser, while Cl was determined in
mercurimetric titrations.
Synthesis
Silver malonate 1a and silver cyclobutane-1,1-malonate 1b were
synthesized according to Ang et al.,[12] while Titanocene Y was
synthesized according to Sweeney et al.[7]
Synthesis of bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV)
malonate, TiC29 O6 H28 (2a)
676
Aliquots of 0.20 g (0.40 mmol) of bis-[(4-methoxy-benzyl)
cyclopentadienyl] titanium(IV) dichloride and 0.13 g (0.42 mmol)
of 1a were added to a Schlenk flask which was then evacuated.
The flask was shielded from the light. A 50 ml aliquot of dry THF
was added to the reaction flask. The reaction was left to stir for
7 days at room temperature. The reaction was allowed to stand for
1 h. The solution was filtered to leave a grey residue on the filter
paper and a brown filtrate. The solvent was removed in vacuo to
give 0.17 g (82.5% yield, 0.33 mmol) of a brown solid.
1 H NMR (δ ppm CDCl , 400 MHz): 3.28 [s, 2H, O C–CH –CO ],
3
2
2
2
3.71 [s, 4H, C5 H4 –CH2 ], 3.78 [s, 6H, C6 H3 –OCH3 ], 6.20 [m, 4H, C5 H4 ],
6.43 [m, 4H, C5 H4 ], 6.83 [d, 2H, J 8.4 Hz, C6 H4 –OCH3 ], 7.07 [d, 2H,
J 8.4 Hz, C6 H4 –OCH3 ]. 13 C NMR (δ ppm CDCl3 , 100 MHz, proton
decoupled): 33.9, 54.3, 67.0, 112.8, 113.1, 118.3, 128.7, 129.0, 129.1,
157.5, 170.1. IR (KBr, cm−1 ): 2958, 2940, 1870, 1853, 1762, 1650,
1631, 1546, 1263, 1088, 870, 660. UV–vis (CH2 Cl2 , nm): λ 216 (ε
21290), λ 232 (ε 50860). Analysis calculated for TiC29 O6 H28 : C,
66.93%; H, 5.42%; Cl, 0.00%; found: C, 66.21%; H, 5.71%; Cl, 0.11%.
wileyonlinelibrary.com/journal/aoc
Aliquots of 0.34 g (0.69 mmol) of Titanocene Y and 0.27 g
(0.75 mmol) of 1b were added to a Schlenk flask which was
then evacuated. The flask was shielded from the light. An 80 ml
aliquot of dry THF was added to the reaction flask. The reaction
was left to stir for 9 days at room temperature. The reaction was
allowed to stand for 1 h. The solution was filtered to leave a grey
residue on the filter paper and a brown filtrate. The solvent was
removed in vacuo to give 0.28 g (49.9% yield, 0.33 mmol) of a
black/brown solid.
1
H NMR (δ ppm CDCl3 , 400 MHz): 1.21 [2 H, t, J 7.0,
O2 C–CH–(CH2 )3 –CO2 ], 1.85 [2 H, t, J 6.4 O2 C–CH–(CH2 )3 –CO2 ],
2.23 [2 H, m, O2 C–CH–(CH2 )3 –CO2 ], 3.67 [2 H, s, C5 H4 –CH2 ], 3.77
[6 H, s, C6 H3 –OCH3 ], 6.13 [4 H, s, C5 H4 ], 6.38 [4 H, s, C5 H4 ], 6.81 [4
H, d, J 8.1, C6 H4 –OCH3 ], 7.06 [4 H, d, J 8.5, C6 H4 –OCH3 ]. IR (KBr,
cm−1 ): 2958, 2937, 2352, 2340, 2013, 1986, 1937, 1916, 1869, 1843,
1793, 1767, 1732, 1720, 1693, 1676, 1666, 1632, 1556, 1539, 1497,
1456, 1363, 1097, 879, 661. UV–vis (CH2 Cl2 , nm): λ 205 (ε 7600), λ
230 (ε 35000), λ 275 (ε 40000), λ 343 (ε 6700). Analysis calculated
for TiC32 O6 H32 : C, 68.57%; H, 5.75%; Cl, 0.00%; found: C, 67.23%; H,
5.01%; Cl, 0.00%.
Synthesis of bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV)
salicylate, TiC33 O5 H30 (4a)
Aliquots of 0.20 g (0.41 mmol) of Titanocene Y and 0.06 g
(0.41 mmol) of 3a were added to a Schlenk flask which was then
evacuated. A 100 ml aliquot of dry THF was added to the reaction
flask. A 0.09 ml (0.82 mmol) aliquot of distilled diethylamine was
added to the solution. The reaction was left to stir for 3 days at
room temperature, in which time a white precipitate formed. The
reaction was allowed to stand for 1 h. The solution was filtered
and the solvent was removed in vacuo to give 0.14 g (61.0% yield,
0.25 mmol) of a brown solid.
1
H NMR (δ ppm CDCl3 , 400 MHz): 7.89 [1 H, d, J 7.4, C7 H4 O3 ],
7.29 [1 H, t, J 7.3, C7 H4 O3 ], 7.01 [4 H, d, J 8.5, C6 H4 –OCH3 ], 6.84 [4
H, m, C6 H4 –OCH3 ], 6.79 [1 H, t, J 7.5, C7 H4 O3 ], 6.62 [1 H, d, J 7.5,
C7 H4 O3 ], 6.25 [8 H, m, C5 H4 ], 3.89 [4 H, s, C5 H4 –CH2 ], 3.78 [6 H, s,
C6 H4 –OCH3 ]. IR (KBr, cm−1 ): 2968, 2930, 1845, 1841, 1783, 1766,
1653, 1632, 1558, 1538, 1488, 1465, 1364, 1017, 878, 660. UV–vis
(CH2 Cl2 , nm): λ 211 (ε 15000), λ 230 (ε 37000), λ 268 (ε 21000),
λ 330 (ε 19000). Analysis calculated for TiC33 O5 H30 : C, 71.48%; H,
5.45%; Cl, 0.00%; Found: C, 70.21%; H, 5.75%; Cl, 0.00%.
Synthesis of bis-[(4-methoxy-benzyl)cyclopentadienyl] titanium(IV)
3,5-dinitro-salicylate, TiC33 O9 N2 H28 (4b)
Aliquots of 0.40 g (0.82 mmol) of Titanocene Y and 0.19 g
(0.82 mmol) of 3b were added to a Schlenk flask which was
c 2010 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2010, 24, 675–679
Novel anion-exchanged titanocene Y derivatives
then evacuated. 100 ml of dry THF was added to the reaction
flask. A 0.18 ml (164 mmol) aliquot of distilled diethylamine was
added to the solution. The reaction was left to stir for 3 days at
room temperature, in which time a white precipitate formed. The
solution was filtered and the solvent was removed in vacuo to give
0.42 g (79.3% yield, 0.65 mmol) of a black solid.
1 H NMR (δ ppm CDCl , 400 MHz): 8.97 [1 H, s, C N H O ], 8.40 [1
3
7 2 2 7
H, m, C7 N2 H2 O7 ], 7.01 [4 H, d, J 8.7, C6 H4 –OCH3 ], 6.83 [4 H, dd, J 8.0,
3.9, C6 H4 –OCH3 ], 6.24 [8 H, m, C5 H4 ], 3.90 [1 H, s, C5 H4 –CH2 ], 3.79
[6 H, s, C6 H4 –OCH3 ]. IR (KBr, cm−1 ): 2988, 2950, 1938, 1917, 1880,
1730, 1632, 1555, 1543, 1094, 1040, 881, 667. UV–vis (CH2 Cl2 , nm):
λ 221 (ε 14000), λ 230 (ε 76000), λ 239 (ε 24000), λ 263 (ε 15000), λ
308 (ε 9700), λ 354 (ε 7900). Analysis calculated for TiC33 O9 N2 H28 :
C, 61.50%; H, 4.38%; N, 4.35%; Cl, 0.00%; found: C, 61.21%; H, 4.94%;
N, 3.89%; Cl, 0.00%.
Cytotoxicity Studies
Preliminary in vitro cell tests were performed on the cell line
LLC-PK (long-lasting cells, pig kidney) in order to compare the
cytotoxicity of the compounds presented in this paper. This cell
line was chosen based on their regular and long-lasting growth
behaviour, which is similar to that shown in kidney carcinoma
cells. It was obtained from the ATCC (American Tissue Cell
Culture Collection) and maintained in Dulbecco’s modified Eagle
medium containing 10% (v/v) fetal calf serum, 1% (v/v) penicillin
streptomycin and 1% (v/v) L-glutamine. Cells were seeded in 96well plates containing 200 µl microtitre wells at a density of 5000
cells/200 µl of medium and were incubated at 37 ◦ C for 24 h to
allow for exponential growth. Compounds 2a–b and 4a–b were
dissolved in the minimal amount of DMSO (dimethylsulfoxide)
possible and diluted with medium to obtain stock solutions of
5 × 10−4 M in concentration and less than 0.7% DMSO. The cells
were then treated with varying concentrations of the compounds
and incubated for 48 h at 37 ◦ C. Then, the solutions were removed
from the wells and the cells were washed with phosphate buffer
solution, then fresh medium was added to the wells. Following a
recovery period of 24 h incubation at 37 ◦ C, individual wells were
treated with a 200 µl of a solution of MTT [3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide] in medium. The solution
consisted of 40 mg of MTT in 40 ml of medium. The cells were
incubated for 3 h at 37 ◦ C. The medium was then removed and
the purple formazan crystals were dissolved in 200 µl DMSO per
well. Absorbance was then measured at 540 nm using a Wallac
Victor (Multilabel HTS Counter) Plate Reader. Cell viability was
expressed as a percentage of the absorbance recorded for control
wells. The values used for the dose–response curves represent the
values obtained from four consistent MTT-based assays for each
compound tested.[13]
Results and Discussion
Synthesis
Titanocene Y was synthesized according to the literature method
by the hydridolithiation of 6-anisyl fulvene to give an isolable
lithium cyclopentadienide intermediate which could then be
transmetallated to TiCl4 [7] (Scheme 1).
A simple anion exchange reaction in THF employing silver
carboxylates eliminates insoluble silver chloride and produces
titanocenes 2a and 2b. This had already been shown to be an
effective way to achieve chloride substitution on titanocenes
during the synthesis of Oxali-Titanocene Y.[11] The coordination
of the malonato ligands is seen in the shift of the CO vibrations
of the malonato ligands from 1740/1717 cm−1 (malonic acid) to
1650/1631 cm−1 for complex 2a and going from a broad signal at
1720 cm−1 (cyclobutane-1,1-dicarboxylic acid) to 1666/1632 cm−1
for complex 2b (Scheme 2).
Diethylamine was used in the synthesis of the salicylate
substituted derivatives of Titanocene Y, 4a and 4b, instead of
triethylamine. The use of the secondary amine resulted in shorter
reaction times being required for the synthesis. Also it resulted
in higher yields and a higher degree of purity in the product.
This is probably due to the formation of the highly insoluble
diethyl ammonium chloride salt. This trend had also been seen in
previous literature examples.[14] (Scheme 3). Because of the lack of
solubility of titanocenes 2b, 4a and 4b, it was not possible to get a
satisfactory 13 C NMR. Compound 2a was the only titanocene that
this was achievable with.
R
H
R
2LiBEt3H
2
Et2O
-2BEt3
R
TiCl4
2
Cl
Ti
THF
-2LiCl(s)
H
H
Cl
R
Li
Scheme 1. Synthesis of benzyl-substituted titanocenes from fulvenes using the hydridolithiation reaction.
OMe
OMe
O
O
O
O
Cl
+
Ti
AgO
Cl
OAg
THF
R + 2AgCl
Ti
O
R
O
OMe
R= 1a H2
1b cyclobutane
R= 2a H2
2b cyclobutane
OMe
677
Scheme 2. Synthesis of malonate substituted titanocenes 2a and 2b.
Appl. Organometal. Chem. 2010, 24, 675–679
c 2010 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
J. Claffey et al.
OMe
Cl
OMe
O
O
R
HO
+
Ti
Cl
THF
2HNEt2
O
Ti
O
-2[H2NEt2]Cl
HO
R
R
OMe
R= 3a H
3b NO2
R= 4a H
4b NO2
R
OMe
Scheme 3. Synthesis of titanocene salicylates 4a and 4b.
MeO
Table 1. Selected bond lengths and angles from calculated structure
of titanocene 2a
Identification code
Bond lengths
Ti–C(1)
Ti–C(2)
Ti–C(3)
Ti–C(4)
Ti–C(5)
Ti–C(6)
Ti–C(7)
Ti–C(8)
Ti–C(9)
Ti–C(10)
Ti–O1
Ti–O2
Ti–Cent1
Ti–Cent2
C(1)–C(5)
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(4)–C(12)
C(6)–C(10)
C(6)–C(7)
C(7)–C(8)
C(7)–C(11)
C(8)–C(9)
C(9)–C(10)
Bond angles
O(1)–Ti–O(2)
O(1)–Ti–Cent1
O(1)–Ti–Cent2
O(2)–Ti–Cent1
O(2)–Ti–Cent2
Cent1–Ti–Cent2
4
2.41
2.41
2.40
2.47
2.42
2.39
2.45
2.45
2.44
2.36
1.89
1.89
2.09
2.09
1.42
1.43
1.43
1.43
1.42
1.51
1.44
1.42
1.43
1.51
1.42
1.43
86.3
109.6
103.1
105.4
108.4
133.8
Structural Discussion
678
Despite the efforts to crystallize titanocenes 2a, 2b, 4a and
4b, no crystal structures were obtained. This could possibly be
explained by the solubility problems encountered with these
isolated titanocenes. In order to acquire a structure density
functional theory calculations were carried out for titanocene
2a at the B3LYP level using the 6-31G∗∗ basis set.[15]
Selected bond lengths of the optimized structure of this
titanocene are listed in Table 1 and the atom numbering scheme
wileyonlinelibrary.com/journal/aoc
3
3d
12
O
1O
1
5
8
11
2
Ti
2
9O
7
6
O
10
MeO
Scheme 4. Numbering scheme of 2a for the structural density functional
theory discussion.
is seen in Scheme 4. The calculated structure of titanocene 2a is
presented in Fig. 2.
The lengths of the bonds between the titanium centre and
the carbon atoms of the cyclopentadienide rings are very similar
for both Titanocene Y and 2a. They vary from 2.34 to 2.41 Å
for Titanocene Y, while for 2a they vary from 2.36 to 2.47 Å.
The titanium–centroid distances are highly comparable as well
for 2a (2.09 Å) in comparison to Titanocene Y (2.06 Å). The
centroid–titanium–centroid bond angles are both 133.8◦ for
2a, which compares with 130.7◦ for the corresponding angle
in Titanocene Y. The widening of the centroid–titanium–centroid
bond angle has been seen before in other anion-exchanged
Titanocene Y derivatives.[11,16] The titanium–oxygen bond length
is 1.89 Å for 2a, while the oxygen–titanium–oxygen bond
angle is 86.3◦ for 2a. This angle compares favourably to the
previous literature crystallographic structure of Oxali-Titanocene
Y, which had an oxygen–titanium–oxygen bond angle of 86.8◦ [17]
(Scheme 3, Table 1).
Cytotoxicity Studies
The carboxylate anion-substituted derivatives of Titanocene Y
were tested on LLC-PK cells, which have been shown to be a
good in vitro model for kidney cancer, in order to determine their
cytotoxicity values. Titanocenes 2a–b and 4a show IC50 values
of 74 (±13), 18 (±5) and 49 (±11) µM, respectively, while 4b
shows no activity. Titanocenes 2a–b and 4a show significant
improvements in cytotoxicity in comparison to unsubstituted
titanocene dichloride, which has an IC50 value of 2000 µM on
the LLC-PK cell line.[18] Titanocene 4b was shown to have no
cytotoxic activity against this particular cell line. Titanocene Y
itself has been shown to have an IC50 value of 21 µM on the
LLC-PK cell line,[7] while cisplatin has been shown to have an IC50
of 3.3 µM on this particular cell line.[18] With the introduction of
c 2010 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2010, 24, 675–679
Novel anion-exchanged titanocene Y derivatives
Figure 2. Density functional theory calculated structure of 2a.
1.2
benzyl-substituted titanocenes of high purity, of which Titanocene
Y is a leading drug candidate. Titanocene Y can have the chlorides
removed and replaced to lead to the synthesis of compounds 2a–b
and 4a–b. In this respect, reaction time is crucial for the synthesis
of pure samples of the substituted derivatives of Titanocene Y. In
MTT-based assays, compounds 2a–b and 4a showed significant
improvement in cytotoxicities against LLC-PK cells compared with
unsubstituted titanocene dichloride, for which phase I/II clinical
trials have been performed. Compound 4b suprisingly lost all
cytotoxic behaviour against the LLC-PK cell line. Compounds 2a
and 4a showed a decrease in cytotoxic behaviour in comparison
to the parent compound Titanocene Y, whereas compound 2b has
highly comparable in vitro cytotoxicities with respect to Titanocene
Y. It is necessary to do further in vivo testing on 2b to fully evaluate
and realize the cytotoxic potential of it and to see whether the
exchange of chlorine vs the cyclobutane–malonate ligand, which
possibly leads slower hydrolysis, is beneficial in comparison to
Titanocene Y.
Normalised Cell Viability
1.0
Acknowledgements
0.8
The authors thank the Higher Education Authority, the Centre for
Synthesis and Chemical Biology, University College Dublin and
COST D39 for funding.
0.6
0.4
2a IC50: (74+/-13) E-6 M
2b IC50: (17+/-5) E-6 M
0.2
Supporting information
0.0
1E-10
1E-9
1E-8
1E-7
1E-6
1E-5
1E-4
1E-3
Supporting information may be found in the online version of this
article.
Log10 Drug Concentration (mol/L)
Figure 3. Cytotoxicity curves from typical MTT assays showing the effect
of compounds 2a and 2b on the viability of LLC-PK cells.
1.2
Normalised Cell Viability
1.0
0.8
0.6
0.4
4a: IC50: (49+/-11) E-6 M
4b: No activity
0.2
0.0
1E-10
1E-9
1E-8
1E-7
1E-6
1E-5
1E-4
1E-3
Log10 Drug Concentration (mol/L)
Figure 4. Cytotoxicity curves from typical MTT assays showing the effect
of compounds 4a and 4b on the viability of LLC-PK cells.
new anionic, bidentate and chelating ligands there has been no
apparent improvement in cytotoxic activity against this cell line.
These anionic ligands were chosen as they had previously shown
good activity in different metals cytotoxicity (Figs 3 and 4).
Conclusions and Outlook
Appl. Organometal. Chem. 2010, 24, 675–679
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c 2010 John Wiley & Sons, Ltd.
Copyright 679
The hydridolithiation of 6-aryl substituted fulvenes has been found
to be a very effective and reproducible way to produce cytotoxic
References
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exchanger, synthesis, anion, novem, titanocen, studies, cytotoxicity, derivatives
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