Drug delivery of lipophilic pyrenyl derivatives by encapsulation in a water soluble metalla-cage

Article abstract of DOI:10.1039/c0dt00436g

The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (p-PrⁱC₆H₄Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) bridges, in the presence of a functionalised pyrenyl derivative (pyrene-R), affords the triangular prismatic host-guest compounds [(pyrene-R) ? Ru ₆(p-PrⁱC₆H₄Me)₆(tpt) ₂(dobq)₃]⁶⁺ ([(pyrene-R) ? 1] ⁶⁺). The inclusion of eight mono-substituted pyrenyl derivatives including biologically relevant structures (a = 1-pyrenebutyric acid, b = 1-pyrenebutanol, c = 1-pyrenemethylamine, d = 1-pyrenemethylbutanoate, e = 1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene, f = N-hexadecylpyrene-1-sulfonamide, g = pyrenyl ethacrynic amide and h = 2-(pyren-1-ylmethylcarbamoyl) phenyl acetate), and a di-substituted pyrenyl derivative (i = 1,8-bis(3-methyl-butyn-1- yl-3-ol)pyrene), has been accomplished. The carceplex nature of these systems with the pyrenyl moiety being firmly encapsulated in the hydrophobic cavity of the cage with the functional groups pointing outwards was confirmed by NMR (¹H, 2D, DOSY) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). The cytotoxicities of these water-soluble compounds have been established using human ovarian A2780 cancer cells. All the host-guest systems are more cytotoxic than the empty cage itself [1][CF₃SO ₃]₆ (IC₅₀ = 23 μM), the most active carceplex [f ? 1][CF₃SO₃]₆ is an order of magnitude more cytotoxic.

Full text of DOI:10.1039/c0dt00436g

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PAPER
www.rsc.org/dalton | Dalton Transactions
Drug delivery of lipophilic pyrenyl derivatives by encapsulation in a water
soluble metalla-cage
Johan Mattsson,a Olivier Zava,b Anna K. Renfrew,b Yoshihisa Sei,c Kentaro Yamaguchi,c Paul J. Dysonb and
Bruno Therrien*a
Received 6th May 2010, Accepted 10th June 2010
First published as an Advance Article on the web 5th August 2010
DOI: 10.1039/c0dt00436g
The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene
(p-PriC6H4Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) bridges, in the
presence of a functionalised pyrenyl derivative (pyrene–R), affords the triangular prismatic host–guest
compounds [(pyrene–R) Ã Ru6(p-PriC6H4Me)6(tpt)2(dobq)3]6+ ([(pyrene–R) Ã 1]6+). The inclusion of
eight mono-substituted pyrenyl derivatives including biologically relevant structures (a =
1-pyrenebutyric acid, b = 1-pyrenebutanol, c = 1-pyrenemethylamine, d = 1-pyrenemethylbutanoate, e =
1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene, f = N-hexadecylpyrene-1-sulfonamide, g = pyrenyl ethacrynic
amide and h = 2-(pyren-1-ylmethylcarbamoyl) phenyl acetate), and a di-substituted pyrenyl derivative
(i = 1,8-bis(3-methyl-butyn-1-yl-3-ol)pyrene), has been accomplished. The carceplex nature of these
systems with the pyrenyl moiety being firmly encapsulated in the hydrophobic cavity of the cage with
the functional groups pointing outwards was confirmed by NMR (1H, 2D, DOSY) spectroscopy and
electrospray ionization mass spectrometry (ESI-MS). The cytotoxicities of these water-soluble
compounds have been established using human ovarian A2780 cancer cells. All the host–guest systems
are more cytotoxic than the empty cage itself [1][CF3SO3]6 (IC50 = 23 mM), the most active carceplex [f Ã
1][CF3SO3]6 is an order of magnitude more cytotoxic.
(KP1019, Im = imidazole)12 and [ImH][trans-Ru(DMSO)(Im)Cl4]
Introduction
(NAMI-A, Im = imidazole, DMSO = dimethylsulfoxide)13 as
Since the discovery of the antiproliferative properties of cisplatin
anticancer and antimetastatic agents has generated considerable
in the 1960s by Rosenberg,1 platinum compounds have become
interest. Recently, arene ruthenium complexes have started to
the most widely used drugs in the treatment of cancer.2 Although
attract a lot of attention and many show promising anticancer
activity.14 Arene ruthenium and other half sandwich complexes
have also been used as supramolecular building blocks,15 in
which three coordination sites are occupied by the arene ligand,
thus leaving only three open sites for further coordination.
Moreover, the relative inertness of the arene ligand and the
easy access to starting materials are appealing. When these
complexes are used as supramolecular building blocks, structures
with diverse functionalities and properties are obtained. Recently,
we combined these two areas, i.e. the medicinal properties of
arene ruthenium complexes and supramolecular arene ruthe-
nium chemistry, to afford a new hybrid drug delivery system.
The hexacationic prism [Ru6(p-iPrC6H4Me)6(tpt)2(dobq)3]6+ ([1]6+)
(tpt = 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine; dobq = 2,5-dioxydo-
1,4-benzoquinonato) was synthesized, which was capable of
encapsulating planar Pt and Pd acetylacetonate complexes,16 as
well as planar aromatic compounds of various sizes (Chart 1).17,18
In these systems the encapsulated guest is stable, with the physical
properties of the prism being retained following encapsulation.
The biological activity of some of these carceplexes has been
evaluated and encouraging results were obtained. The metalla-
prism itself exhibits some activity, which increases with the
encapsulation of a guest, suggesting transport and leaching of
the guest once inside the cell.16 The ability of [1]6+ to deliver
guest molecules to cells was confirmed by encapsulation of a
fluorescently labelled pyrene–R derivative (1-(4,6-dichloro-1,3,5-
triazin-2-yl)pyrene), and fluorescence spectroscopy was used to
effective, cisplatin has severe side effects including nephrotoxicity
and neurotoxicity due to low selectivity towards cancer cells.3
Increasing the selectivity of cisplatin is a major challenge that
has been addressed in numerous ways.4 In order to achieve
increased selectivity, i.e. increasing the amount of drug that
reaches the tumour relative to the healthy tissue, drugs may be
combined with a transport vector that accumulates in cancer
cells.5 In the case of platinum-based drugs, this strategy has been
attempted by incorporating them into various structures, including
carbon nanotubes,6 proteins,7 macrocycles8 and dendrimers.9
These macromolecular systems selectively accumulate in tumours
by targeting the enhanced permeability and retention (EPR)
effect.10 This effect arises from increased angiogenesis and perme-
ability mediator production combined with decreased lymphatic
drainage, thus allowing the accumulation of macromolecules in
cancer cells.
Ruthenium-based drugs have also been extensively explored
in the treatment of cancer.11 The potential clinical applica-
tions of ruthenium complexes, such as [ImH][trans-Ru(Im)2Cl4]
aInstitute of Chemistry, University of Neuchatel, 51 Ave de Bellevaux, CH-
2000, Neuchatel, Switzerland. E-mail: bruno.therrien@unine.ch; Fax: +41
32 7182511
bInstitut des Sciences et Inge´nierie Chimique, Ecole Polytechnique Fe´de´rale
de Lausanne (EPFL), CH-1015, Lausanne, Switzerland
cFaculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri
University, Shido, Sanuki-city, Kagawa, 769-2193, Japan
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Chart 1
monitor the uptake and release of the pyrene–R molecule in
amine, d = 1-pyrenemethylbutanoate, e = 1-(4,6-dichloro-1,3,5-
triazin-2-yl)pyrene and f = N-hexadecylpyrene-1-sulfonamide)
and two new derivatives (g = pyrenyl ethacrynic amide and
h = 2-(pyren-1-ylmethylcarbamoyl) phenyl acetate), see Chart
2, were encapsulated in the metalla-prism [1]6+. Most of the
pyrenyl compounds are known compounds, whereas g and h
are new compounds and were obtained from the reaction of
1-pyrenemethylamine and the corresponding acid chloride of
ethacrynic acid and aspirin, respectively, which, in turn, are
prepared, in situ from oxalyl chloride according to the literature
method (see Experimental).20 Three of the pyrenyl derivatives, f, g
and h, contain bioactive functionalities (see below).
cancer cells.19 We have also previously shown that encapsulation is
possible even with a pyrenyl derivative possessing pendant groups
that extend beyond the interior of the cage.17
Herein, we describe the synthesis and characterisation of a series
of pyrenyl derivatives possessing various functional groups, in-
cluding biologically-active functionalities, and their encapsulation
in the metalla-prism [Ru6(p-iPrC6H4Me)6(tpt)2(dobq)3]6+ ([1]6+).
The in vitro anticancer activity of these water soluble systems
was evaluated against human ovarian A2780 cancer cells and the
implication of the metalla-prism to deliver hydrophobic organic
drugs to cancer cells is discussed.
The encapsulation of the pyrenyl derivatives a–h in the
metalla-prism [1]6+ is achieved in a two step process, in which
the p-cymene ruthenium dobq (2,5-dioxydo-1,4-benzoquinonato)
bimetallic “molecular clip” is first reacted with silver triflate to
produce a reactive intermediate, which is then combined with
Results and discussion
A series of functionalised pyrenyl compounds, i.e. a = 1-
pyrenebutyric acid, b = 1-pyrenebutanol, c = 1-pyrenemethyl-
Chart 2
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Scheme 1 The synthesis of the metalla-prisms [a–h à 1][CF3SO3]6 encapsulating a functionalised pyrenyl derivative.
Fig. 1 The aromatic region of the 1H NMR spectra (acetone-d6) of [1]6+ (bottom), [pyrene à 1]6+ (middle) and [b à 1]6+ (top).
a 2 : 1 mixture of tpt (2,4,6-tris(pyridin-4-yl)-1,3,5-triazine) and
the functionalised pyrenyl derivative (Scheme 1), affording the
corresponding inclusion system [a–h à 1]6+. All the inclusion
complexes were isolated in good yield as their triflate salts.
whereas the rest of the signals associated to the side-chain remain
virtually unchanged. To further confirm the encapsulation of the
functionalised pyrenyl derivatives in the cavity of [1]6+, a series of
diffusion-ordered (DOSY) NMR spectra were recorded.
The encapsulation process may be monitored by 1H NMR
spectroscopy; in acetone-d6 a doublet corresponding to the Hb
protons of the tpt panels appears at d = 8.71 ppm in the
empty cage [1]6+,16 and both broadens and shifts upfield by
ca. 0.6 ppm upon encapsulation of the functionalised pyrenyl
derivative or even pyrene (Fig. 1). Similarly, the nine signals of
the pyrenyl group or the ten signals of pyrene are shifted upfield
following encapsulation, which is as expected since the pyrenyl
moiety is sandwiched between the two tpt panels via a p-stacking
arrangement. In contrast, the signals of the dobq protons are
shifted downfield in all systems and by as much as 0.4 ppm
in the case of [a à 1]6+. In general, the signals of the adjacent
methylene group of the pyrenyl side-chain are shifted downfield,
DOSY is a powerful tool for studying host–guest associations
in solution.21 The diffusion coefficient depends on the shape and
size of the molecules. Therefore, in a carceplex system in which
the guest is perfectly trapped in the cavity of the host, without
significantly affecting the size and shape of the host, the diffusion
coefficient of the guest à host adduct should be almost identical
to the diffusion coefficient of the host alone. DOSY measurements
of pyrenyl derivative g, the empty cage [1][CF3SO3]6, and the
inclusion system [g à 1][CF3SO3]6, are presented in Fig. 2. These
experiments show that in [g à 1]6+, both components possess
the same diffusion coefficient, which is almost identical to the
diffusion coefficient of the empty cage [1]6+, thus confirming the
encapsulation of g in [1]6+.
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Scheme 2 The synthesis of carceplex [i à 1][CF3SO3]6.
Fig. 3 Selected ESI-MS peaks of some carceplexes.
In the case of [h à 1]6+ the acetyl group of the aspirin moiety is
cleaved. These peaks were assigned unambiguously on the basis of
their characteristic isotope patterns. Moreover, a similar behaviour
was observed under ESI-MS conditions with planar aromatic
molecules encapsulated in [1]6+.17
The antiproliferative activity of [1]6+ and all the inclusion
systems [a–i à 1][CF3SO3]6 was evaluated against the human
ovarian A2780 cancer cell line using the MTT assay, which
measures mitochondrial dehydrogenase activity as an indication
of cell viability. The IC50 values are listed in Table 1 and are
reported together with that of cisplatin for comparison purposes.
As mentioned above, there is considerable on-going interest in the
anticancer properties of arene ruthenium complexes.14 It should
be noted that some pyrenyl derivatives have recently been shown
to interact with various DNA and RNA polynucleotides and
have been tentatively proposed to have potential applications
in the treatment of certain types of tumors.23 However, pyrene-
containing compounds are usually used as cellular probes due to
Fig. 2 The DOSY NMR spectra of g, [1]6+ and [g à 1]6+ in acetone-d6
(24 ◦C).
Cage [1]6+ can also encapsulate di-functionalised pyrenyl deriva-
tives, such as i. If one equivalent of 1,8-bis(3-methyl-butyn-1-yl-
3-ol)pyrene, prepared using a published procedure,22 is added to
the reaction mixture, the carceplex [i à 1]6+ is obtained in good
yield (Scheme 2). This structure is confirmed by 1H NMR in
which the characteristic broadening and shift of the Hb proton
signal of the tpt panels is observed. For [i à 1]6+, however, two
independent signals are observed for the dobq protons, which
is in accordance with the symmetry and the deshielding effect
produced by the proximity of the alkynyl bonds on four dobq
protons (d = 6.38 ppm), with the other two protons appearing
at d = 6.21 ppm. This carceplex system was further confirmed by
electrospray ionization mass spectroscopy (ESI-MS) with the mass
spectrum-containing peaks corresponding to [i à 1 + (CF3SO3)4]2+
at m/z = 1706.64 and to [i à 1 + (CF3SO3)3]3+ at m/z = 1088.84.
ESI-MS of all the carceplex systems corroborates their proposed
structures; see Fig. 3 for selected examples. The ESI mass spectra
of [a–g à 1][CF3SO3]6 show peaks corresponding to the cationic
carceplex system with the loss of 2, 3 or 4 triflate counter ions.
Table 1 The IC50 values determined on A2780 human ovarian cancer
cells
Compound
IC50/mM
Compound
IC50/mM
[1]6+
23
9
18 1.5
21
14
17
2
cisplatin
[e à 1]6+
[f à 1]6+
[g à 1]6+
[h à 1]6+
[i à 1]6+
1.6
[pyrene à 1]6+
[a à 1]6+
[b à 1]6+
[c à 1]6+
[d à 1]6+
2
6
2
3
5
5
1.5
0.6
1.1
0.4
0.8
2
2
1
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their favourable fluorescence properties.24 Here, however, due to
the encapsulation of the pyrene moiety into the water soluble
metalla-prism, the cytotoxic effect of even very hydrophobic
derivatives can be assessed.
concepts of supramolecular chemistry.16,19 Specifically, a series
of hexaruthenium carceplex systems encapsulating functionalised
pyrenyl derivatives have been prepared and characterized. The
compounds are stable and water soluble and were evaluated in
vitro for anticancer activity. The in vitro study reveals that the
nature of the pyrenyl derivative strongly influences the cytotoxicity
of the system, and consequently, by tuning the nature of the
functional group attached on the pyrenyl unit, highly cytotoxic
species can be produced, thus confirming that these metalla-
cages offer a strategy to deliver drugs to cancer cells at the same
time. The two most cytotoxic compounds contain a pyrenyl ring
functionalised with a possible carbonic anhydrase inhibitor and
a glutathione transferase inhibitor. Inhibition of both of these
enzymes is useful in certain types of cancer, but since these enzymes
are ubiquitous, selective delivery to the tumour environment is
important in order to avoid additional side effects. Therefore,
delivery within the supramolecular host molecule could prove
advantageous, although it should be noted that an in vivo study is
required to establish whether these systems do accumulate in the
tumour. However, prior to an in vivo study further optimisation
of the system is required in order to find the optimum system to
evaluate.
The empty cage, [1]6+, exhibits a moderate cytotoxicity of
23 mM, which is comparable to that of related supramolecular
arene ruthenium and arene osmium cages carrying relatively high
charges.16,17,25 It should be noted that highly charged complexes
cross cell membranes equally as well as neutral complexes, and in
some cases, their ability to enter cells is superior to that of neutral
compounds or compounds in a low charge state.26 Encapsulation
of the pyrenyl systems into the hexaruthenium cage has either a
negligible effect on the cytotoxicity (pyrenes a–d) or significantly
increases the cytotoxicity (pyrenes e–i), with [f à 1]6+ and [g Ã
1]6+ being an order of magnitude more cytotoxic than the empty
cage [1]6+. Indeed, the cytotoxicity of [f à 1]6+ and [g à 1]6+ is
comparable to cisplatin. These differences could be due to the
intrinsic cytotoxicities of the different pyrenyl derivatives, which,
due to the poor water solubility of these compounds, could not
be evaluated, or to differences in the uptake and/or further
intracellular release of these molecules.
The substituent tethered to the pyrenyl ring in [f à 1]6+, the
most active compound of the series, contains a group that is not
too dissimilar from an extensive range of sulfonamide-containing
inhibitors of carbonic anhydrase.27 Carbonic anhydrases represent
potential targets for anticancer drugs28 and therefore it is conceiv-
able that the high cytotoxicity of [f à 1]6+ corresponds, at least in
part, to the inhibition of this enzyme class.
The substituent tethered to the pyrenyl ring in [g à 1]6+,
which is also a very cytotoxic compound, is ethacrynic acid,
which is an excellent inhibitor of glutathione transferases and
has even been investigated as a potential anticancer drug in a
combination therapy with cisplatin.29 Indeed, arene ruthenium
compounds with tethered ethacrynic acid moieties are also good
glutathione transferase inhibitors and are moderately cytotoxic,30
and the crystal structure of an arene ruthenium compounds
containing ethacrynic acid embedded in the active site of the
human glutathione transferase P1-1 has been reported.20 Glu-
tathione transferases catalyze the nucleophilic attack by reduced
glutathione (GSH) on non-polar nucleophiles, acting on a range of
exogenous compounds, including anticancer agents, forming part
of a coordinated defence strategy to remove GSH conjugates from
the cell.31 Consequently, inhibition of this enzyme means that an
anticancer drug can function more effectively and it is possible that
[g à 1]6+ exerts its cytotoxicity by the ethacrynic acid derivative
inhibiting glutathione transferase within the cell resulting in a
sensitized cell that is more responsive to the empty cage, [1]6+.
Experimental
General details
All organic solvents were degassed and saturated with nitrogen
prior to use. [Ru2(p-PriC6H4Me)2(dobq)Cl2],16 diiodo-pyrene22 and
2,4,6-tris(4-pyridyl)-1,3,5-triazine (tpt)33 were prepared according
to published methods. All other reagents were commercially
1
available and used as received. The 1H, 13C{ H} and DOSY NMR
spectra were recorded on a Bruker AvanceII 400 spectrometer
using the residual protonated solvent as an internal standard.34
Infrared spectra were recorded as KBr pellets on a Perkin-
Elmer FTIR 1720X spectrometer. Electrospray ionization mass
spectrometry were recorded on a Bruker APEX II 9.4-tesla FT-
ICR-MS equipped with an Apollo II electrospray ion source;
sample conditions: 10–50 mmol l-1 in methanol at 30 ◦C, end plate
voltage 3500 V, and capillary voltage 4000 V. UV-visible absorption
spectra were recorded on a Uvikon 930 spectrophotometer using
precision cells made of quartz (1 cm).
Compound synthesis
Pyrenyl ethacrynic amide (g). Ethacrynic acid (0.23 g,
0.756 mmol) was suspended in oxalyl chloride (5 mL, 60 mmol)
and refluxed for 1 h. The unreacted oxalyl chloride was removed
under reduced pressure. A suspension of methylamine pyrene
(0.202 g, 0.756 mmol) and Et3N (0.75 mL, 5.3 mmol) in THF
(50 mL) was added drop-wise to the ethacrynic acid chloride. The
mixture was then stirred at 60 ◦C for 18 h. The solvent was removed
under reduced pressure and the product re-dissolved in CHCl3.
The solution was filtered and the filtrate was washed with NaHCO3
solution and thereafter brine, dried over MgSO4 and the solvent
evaporated to give an oil, which was purified on a silica gel column,
mobile phase: dichloromethane : acetone 3 : 1, to give the product
as a pale yellow powder. Yield: 163 mg (39%). nmax/cm-1 3427 (br),
3267(m), 1653(vs), 1586(m), 1564(m), 1466(m), 1382(w), 1251(m),
Conclusions
Targeting anticancer drugs to the tumour environment is an
important goal in medicinal chemistry, especially for anticancer
compounds that exert their antineoplastic effect via DNA but also
for drugs that act on other targets. In addition, platinum anticancer
drugs are usually administered in combination therapies with
organic drugs and it could be advantageous to ensure that
the drugs reach the tumour at the same time. Many different
drug targeting strategies have been assessed5b,32 and herein we
describe a nascent class of drug delivery vectors based on the
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1124(w), 1089(m), 998(w), 849(s), 841(m), 827(w), 797(w), 714(w);
H (400 MHz; CD2Cl2) 8.32 (1H, d, J 9.24, Hpy), 8.24 (2H, m, Hpy),
(12H, d, J 6.39, Ha), 8.07 (12H, br, Hb), 7.24 (1H, d, J 4.43, Hg),
7.11 (1H, m, Hg), 6.99 (1H, br, Hg), 6.91 (1H, br, Hg), 6.57 (1H, br,
Hg), 6.34 (1H, br, Hg), 6.22 (12H, d, J 6.24, Arp-cym), 6.18 (6H, s,
Hq), 6.13 (2H, br, Hg), 6.00 (12H, d, Arp-cym), 5.85 (1H, br, Hg), 2.98
(6H, septet, J 6.91, CHp-cym), 2.62 (2H, br, Hg), 2.50 (2H, br, Hg),
2.22 (18H, s, CH3 p-cym), 1.62 (2H, br, Hg), 1.39 (36H, d, CH3 p-cym);
dC (100 MHz; acetone-d6) 184.32, 167.90?, 154.00, 143.48, 124.32,
104.21, 102.08, 99.37, 83.96, 82.37, 31.29, 21.71, 17.31; m/z (ESI)
1062.42 [a à 1 + (CF3SO3)3]3+, 759.32 [a à 1 + (CF3SO3)2]4+.
[b à 1][CF3SO3]6. Yield: 78 mg (88%). lmax (MeOH)/nm
493 (e/dm3 mol-1 cm-1 45000), 342 (47000), 308 (81000) and
275 (64000); nmax/cm-11523(s), 1377(s), 1258(s), 1224(w), 1159(w),
1030(m), 811(w), 638(w); dH(400MHz; acetone-d6) 8.58 (12H, d, J
6.4, Ha), 8.06 (12H, br, Hb), 7.03 (1H, d, J 8.8, Hg), 6.95 (1H, d, J
6.8, Hg), 6.87 (1H, d, J 8.4, Hg), 6.52 (1H, d, J 8.8, Hg), 6.22 (12H,
d, J 6.4, Arp-cym), 6.18 (6H, s, Hq), 6.00 (12H, d, Arp-cym), 3.76 (2H,
d, J 5.2, Hg), 2.98 (6H, septet, J 6.8, CHp-cym), 2.52 (2H, t, J 7.2,
Hg), 2.22 (18H, s, CH3 p-cym), 1.63 (2H, m, Hg), 1.47 (2H, m, Hg),
1.39 (36H, d, J 7.2, CH3 p-cym); dC (100 MHz; acetone-d6) 185.109,
168.581, 154.772, 144.277, 137.478, 130.689, 130.107, 128.943,
128.444, 128.038, 127.640, 127.134, 126.639, 126.587, 125.683,
125.395, 125.366, 125.143, 124.007, 123.808, 123.745, 123.200,
120.804, 104.986, 102.866, 100.193, 84.779, 83.140, 62.257, 33.71,
33.21, 32.09, 22.50, 18.11; m/z (ESI) 1057.79 [b à 1 + (CF3SO3)3]3+,
756.09 [b à 1 + (CF3SO3)2]4+.
[c à 1][CF3SO3]6. Yield: 49 mg (56%). lmax (MeOH)/nm 494
(e/dm3 mol-1 cm-1 43000), 341 (54000), 309 (83000) and 275
(73000); nmax/cm-1 1524(s), 1377(s), 1259(s), 1225(w), 1161(w),
1031(m), 812(w), 639(w); dH(400 MHz; acetone-d6) 8.59 (12H, br,
Ha), 8.22 (12H, br, Hb), 6.20 (12H, d, J 6.21, Arp-cym), 6.14 (6H, s,
Hq), 5.99 (12H, d, Arp-cym), 2.98 (6H, septet, J 6.96, CHp-cym), 2.22
(18H, s, CH3 p-cym), 1.40 (36H, d, CH3 p-cym); dC (100 MHz; acetone-
d6) 185.23, 154.02, 124.40, 104.07, 101.90, 99.20, 83.83, 82.30,
31.36, 21.58, 17.27; m/z (ESI) 1043.41 [c à 1 + (CF3SO3)3]3+,
745.07 [c à 1 + (CF3SO3)2]4+.
[d à 1][CF3SO3]6. Yield: 64 mg (72%). lmax (MeOH)/nm
494 (e/dm3 mol-1 cm-1 46000) 342 (83800), 298 (113100), 275
(147200), 242 (260800) and 211 (274300); nmax/cm-1 1731(w),
1523(vs), 1376(s), 1258(s), 1159(w), 1057(w), 1030(m), 811(w),
638(m); dH(400 MHz; acetone-d6) 8.58 (12H, d, J 6.54, Ha), 8.10
(12H, br, Hb), 7.14 (d, 1H, J 9.11, Hg) 6.98 (1H, d, J 7.42, Hg), 6.92
(1H, d, J 8.88, Hg), 6.33 (1H, dd, J 7.41, Hg), 6.26 (1H, br, Hg),
6.22 (12H, d, J 6.31, Arp-cym), 6.19 (1H, m, Hg) 6.16 (6H, s, Hq),
6.08 (1H, d, J 7.56, Hg), 6.00 (12H, d, J 6.31, Arp-cym), 5.85 (1H, d,
J 7.53, Hg), 3.8 (3H, s, Hg), 2.98 (6H, septet, J 6.94, CHp-cym), 2.54
(4H, m, Hg), 2.23 (18H, s, CH3 p-cym), 1.67 (2H, m, Hg), 1.40 (36H,
d, J 6.94 Hz, CH3 p-cym); dC (100 MHz; acetone-d6) 185.19, 183.10,
168.83, 154.89, 144.39, 128.55, 127.87, 127.39, 126.73, 126.47,
125.89, 125.54, 125.25, 125.16, 124.11, 123.60, 123.18, 123.13,
120.91, 105.06, 102.93, 84.83, 83.30, 52.27, 34.26, 32.19, 26.89,
22.60, 18.22; m/z (ESI) 1067.10 [d à 1 + (CF3SO3)3]3+, 1674.70
[d à 1 + (CF3SO3)4]2+.
[e à 1][CF3SO3]6. Yield: 59 mg (65%). lmax (MeOH)/nm 491
(e/dm3 mol-1 cm-1 49000), 373 (51000), 300 (99000) and 271
(67000); nmax/cm-1 1523(s), 1377(s), 1258(s), 1224(w), 1159(w),
1030(m), 811(w), 638(w); dH(400 MHz; acetone-d6) 8.54 (12H,
br, Ha), 8.00 (12H, br, Hb), 6.20 (12H, d, J 6.02, Arp-cym), 6.18
(6H, s, Hq), 5.98 (12H, d, Arp-cym), 2.97 (6H, septet, J 6.68, CHp-cym),
2.21 (18H, s, CH3 p-cym), 1.39 (36H, d, CH3 p-cym); dC (100 MHz;
d
8.20 (d, 1H, J 2.24, Hpy), 8.18 (1H, s, Hpy), 8.07 (4H, m, Hpy), 7.18
(1H, s, NH), 7.12 (1H, d, J 8.52, HAr), 6.89 (d, 1H, J 8.55, HAr),
5.85 (1H, t, J 1.38, Hc = c), 5.42 (1H, s, Hc = c), 5.28 (2H, d,
J 5.80, Py–CH2–NH), 4.68 (2H, s, CO–CH2–O), 2.40 (2H, q,
J 7.41, C–CH2–CH3), 1.10 (3H, t, J 7.44, CH3); dC (100 MHz;
CD2Cl2) 206.50, 195.36, 166.47, 154.69, 150.18, 134.19, 131.40,
131.33, 131.00, 130.84, 128.93, 128.68, 128.27, 127.61, 127.44,
127.318, 126.88, 126.27, 125.56, 125.49, 125.04, 124.95, 124.73,
122.73, 111.34, 68.66, 41.36, 30.68, 23.43, 12.27; m/z (ESI) 553.6
[M (2 ¥ 35Cl) + K]+, 555.6 [M (35Cl, 37Cl) + K]+, 557.6 [M (2 ¥
37Cl) + K]+.
2-(Pyren-1-ylmethylcarbamoyl) phenyl acetate (h). Aspirin
(150 mg, 0.83 mmol) was suspended in thionyl chloride (20 mL)
and stirred for 4 h at room temperature. The thionyl chloride
was removed under reduced pressure and then a mixture of 1-
pyrenemethylamine (223 mg, 0.83 mmol) and Et3N (0.12 mL,
0.85 mmol) in THF (50 mL) was slowly added. The mixture
was stirred at 60 ◦C for 18 h. The solvent was removed under
reduced pressure and the product re-dissolved in chloroform.
The solution was filtered and the filtrate washed with NaHCO3
solution and thereafter brine, dried over MgSO4 and then the
solvent evaporated to give an oil, which was purified on a silica gel
column, mobile phase: dichloromethane : acetone 3 : 1, to give the
product as a pale yellow powder. Yield: 50 mg (15%). nmax/cm-1
3332(w), 1635 (m), 1583 (s), 1537(s), 1493(m), 1443(w), 1356(s),
1300(m), 1246(m), 1229(m), 1216(s), 1033(w), 847(s), 817(w),
758(m), 721(w), 704(w); dH (400 MHz; CD2Cl2) 8.33 (1H, d, J
9.25, Hpy), 8.21 (4H, m, Hpy), 8.06 (4H, m, Hpy), 7.38 (1H, ddd,
J 7.81 and 1.52, HAr), 7.32 (1H, dd, J 8.02 and 1.51, HAr), 6.97
(1H, dd, J 8.38 and 1.02, HAr), 6.78 (1H, ddd, J 7.62 and 1.17,
HAr), 6.75 (1H, br, NH), 5.35 (2H, d, J 5.37, Py–CH2–NH), 1.27
(3H, s, CH3); dC (100 MHz; CD2Cl2) 169.768, 161.849, 134.398,
131.502, 131.382, 130.847, 130.515, 129.200, 128.465, 127.747,
127.421, 127.311, 126.335, 125.623, 125.547, 125.079, 124.948,
124.698, 122.736, 118.695, 118.492, 114.235, 42.035, 29.796; m/z
(ESI) 350.3 [(M–CH2CO)–H]-.
Synthesis of [a–h
Ã
1][CF3SO3]6. [Ru2(p-PriC6H4Me)2-
(dobq)Cl2] (50 mg, 0.0736 mmol) and AgCF3SO3 (38 mg,
0.147 mmol) was stirred in methanol (30 mL) for 2 h,
thereafter the solution was filtered into a suspension of tpt
(15 mg, 0.049 mmol) and pyrenyl (1-pyrenebutanol 6.8 mg,
0.025 mmol; 1-pyrenemethyl butanoate 7.5 mg, 0.025 mmol; 1-
pyrenebutyric acid 7.1 mg, 0.025 mmol; 1-pyrenemethylamine
6.7 mg, 0.025 mmol; N-hexadecylpyrene-1-sulfonamide 12.6 mg,
0.025 mmol; 1-(4,6-dichloro-1,3,5-triazin-2yl)pyrene 8.8 mg,
0.025 mmol; pyrenyl ethacrynic amide 12.7 mg, 0.025 mmol; 2-
(pyren-1-ylmethylcarbamoyl) phenyl acetate 9.7 mg, 0.025 mmol)
in methanol (10 mL). The mixture was stirred at RT for 18 h.
The methanol was removed under reduced pressure and then the
product was re-dissolved in CH2Cl2 before being filtered. The
filtrate was reduced to about 5 ml and the product precipitated
with diethyl ether and collected by filtration as a red powder.
[a à 1][CF3SO3]6. Yield: 68 mg (77%). lmax (MeOH)/nm 495
(e/dm3 mol-1 cm-1 46000), 351 (42000), 304 (81000), 281 (57000)
and 271 (54000); nmax/cm-1 1524(s), 1377(s), 1258(s), 1224(w),
1159(w), 1030(m), 811(w), 638(w); dH(400 MHz; acetone-d6) 8.58
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The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 8248–8255 | 8253
©

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acetone-d6) 184.37, 154.07, 124.31, 104.25, 102.19, 99.34, 83.93,
82.37, 31.29, 21.69, 17.31; m/z (ESI-MS) 1081.40 [e à 1 +
(CF3SO3)3]3+, 773.81 [e à 1 + (CF3SO3)2]4+.
Hg), 6.79 (2H, br, Hg), 6.38 (4H, br, Hq), 6.21 (14H, m, Arp-cym, Hq),
6.06 (1H, br, Hg), 5.99 (12H, d, Ar p-cym), 5.80 (2H, br, Hg), 5.54
(1H, br, Hg), 5.06 (2H, br, Hg), 2.98 (6H, septet, J 6.89, CHp-cym),
2.21 (18H, s, CH3 p-cym), 1.74 (12H, s, CH3g), 1.38 (36H, d, CH3
p-cym); dC (100 MHz; acetone-d6) 185.03, 154.85, 125.15, 104.99,
100.23, 84.77, 83.04, 32.04, 22.48, 18.08; m/z (ESI) 1705.13 [i Ã
1 + (CF3SO3)4]2+, 1088.44 [i à 1 + (CF3SO3)3]3+.
[f à 1][CF3SO3]6. Yield: 61 mg (65%). lmax (MeOH)/nm 492
(e/dm3 mol-1 cm-1 39000), 351 (41000), 301 (76000) and 281
(66000); nmax/cm-1 1523(s), 1377(s), 1258(s), 1224(w), 1158(w),
1030(m), 811(w), 638(w); dH(400 MHz; acetone-d6) 8.63 (12H,
br, Ha), 8.42 (12H, br, Hb), 6.22 (12H, d, J 6.46, Arp-cym), 6.02
(6H, s, Hq), 6.01 (12H, d, Arp-cym), 2.99 (6H, septet, J 6.93, CHp-cym),
2.25 (18H, s, CH3 p-cym), 1.40 (36H, d, CH3 p-cym); dC (100 MHz;
acetone-d6) 184.32, 154.32, 124.81, 104.19, 101.96, 99.32, 83.94,
82.42, 31.44, 21.75, 17.53; m/z (ESI)1134.48 [f à 1 + (CF3SO3)3]3+,
813.63 [f à 1 + (CF3SO3)2]4+.
Cell culture and inhibition of cell growth
Human A2780 ovarian carcinoma cells were obtained from the
European Centre of Cell Cultures (ECACC, Salisbury, UK) and
maintained in culture as described by the provider. The cells
were routinely grown in RPMI 1640 medium with GlutaMAXTM
containing 5% foetal calf serum (FCS) and antibiotics (penicillin
and ciproxin) at 37 ◦C and 5% CO2. For the evaluation of growth
inhibition, the cells were seeded in 96-well plates (25 ¥ 103 cells per
well) and grown for 24 h in complete medium. Complexes were
made up to the required concentration and added to the cell culture
for 72 h incubation. Solutions of the compounds were applied
by diluting a freshly prepared stock solution of the correspond-
ing compound in aqueous RPMI medium with GlutaMAXTM
(20 mM). Following drug exposure, 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide (MTT) was added to the cells at
a final concentration of 0.25 mg ml-1 and incubated for 2 h, then the
culture medium was aspirated and the violet formazan (artificial
chromogenic precipitate of the reduction of tetrazolium salts by
dehydrogenases and reductases) dissolved in DMSO. The optical
density of each well (96-well plates) was quantified three times in
quadruplicates at 540 nm using a multiwell plate reader (iEMS
Reader MF, Labsystems, US), and the percentage of surviving
cells was calculated from the ratio of absorbance of treated
to untreated cells. The IC50 values for the inhibition of cell
growth were determined by fitting the plot of the logarithmic
percentage of surviving cells against the logarithm of the drug
concentration using a linear regression function. The median value
and the median absolute deviation were obtained from the ExcelTM
software (MicrosoftTM) and those values are reported in Table 1.
[g à 1][CF3SO3]6. Yield: 75 mg (78%). lmax (MeOH)/nm 492
(e/dm3 mol-1 cm-1 45000), 341 (56000), 309 (84000) and 275
(76000); nmax/cm-1 1524(s), 1377(s), 1259(s), 1225(w), 1159(w),
1031(m), 811(w), 638(w); dH(400 MHz; acetone-d6) 8.56 (12H,
br, Ha), 8.36 (2H, br, Hg), 8.00 (12H, br, Hb), 7.56 (2H, br, Hg),
7.23 (1H, br, Hg), 7.09 (1H, br, Hg), 6.80 (1H, br, Hg), 6.20 (12H,
d, J 6.08, Arp-cym), 6.18 (6H, s, Hq), 6.05 (2H, br, Hg), 5.99 (12H, d,
Arp-cym), 5.83 (2H, br, Hg), 5.79 (2H, br, Hg), 5.18 (2H, s, Hg), 4.52
(2H, br, Hg), 2.98 (6H, septet, J 6.93, CHp-cym), 2.53 (2H, q, J 7.07,
Hg), 2.23 (18H, s, CH3 p-cym), 1.39 (36H, d, CH3 p-cym), 1.21 (3H,
t, Hg); dC (100 MHz; acetone-d6) 184.27, 167.55, 153.96, 124.34,
104.21, 102.03, 99.24, 83.91, 82.45, 31.30, 21.71, 17.34. m/z (ESI)
1138.42 [g à 1 + (CF3SO3)3]3+, 816.32 [g à 1 + (CF3SO3)2]4+.
[h à 1][CF3SO3]6. Yield: 66 mg (72%). lmax (MeOH)/nm 495
(e/dm3 mol-1 cm-1 43000), 350 (46000), 342 (46000), 306 (81000),
281 (59000) and 276 (58000); nmax/cm-1 1524(s), 1377(s), 1258(s),
1224(w), 1158(w), 1030(m), 811(w), 637(w); dH(400 MHz; acetone-
d6) 9.12 (1H, br, Hg), 8.56 (12H, br, Ha), 7.97 (12H, br, Hb), 7.73
(2H, br, Hg), 7.39 (2H, br, Hg), 7.25 (1H, br, Hg), 6.95 (2H, br, Hg),
6.19 (19H, br, Arp-cym, Hq, Hg), 5.99 (13H, br, Arp-cym, Hg), 4.79 (2H,
br, Hg), 2.98 (6H, septet, J 6.64, CHp-cym), 2.26 (18H, s, CH3 p-cym),
1.41 (36H, d, CH3 p-cym); dC(100 MHz; acetone-d6) 184.23, 167.59,
153.91, 124.31, 104.12, 101.93, 83.91, 82.54, 65.31, 31.30, 21.69,
17.33, 14.81. m/z (ESI) 1083.46 [h à 1 - CH3CO + (CF3SO3)3]3+,
775.34 [h à 1 - CH3CO + (CF3SO3)2]4+.
1,8-Bis(3-methyl-butyn-1-yl-3-ol)pyrene. A Schlenk flask was
charged with a solution of 2-methyl-but-3-yn-2-ol (1 mL,
10.3 mmol) in freshly distilled diethylamine (60 mL). The solution
was freeze-pump-thaw degassed and transferred to a mixture of
1,6- and 1,8-diiodo pyrene (2.0 g, 4.4 mmol), Pd[PPh3]2Cl2 (68 mg),
and CuI (0.12 mmol) under nitrogen atmosphere. The reaction
mixture was heated to 50 ◦C under nitrogen for 20 h. The solvent
was removed under vacuum and the product was dissolved in
dichloromethane and filtered. The filtrate was then evaporated and
the crude product was purified by column chromatography, eluted
with dichloromethane–methanol (1% methanol). The product was
obtained as a yellow solid (0.1 g, Yield 6%). dH (400 MHz; CDCl3)
8.60 (2H, s), 8.10 (4H, s), 8.04 (2H, s), 1.81 (12H, s).
Acknowledgements
Financial support of this work by the Swiss National Science
Foundation and a generous loan of ruthenium(III) chloride
hydrate from the Johnson Matthey Research Centre are gratefully
acknowledged.
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