Major impact of N-methylation on cytotoxicity and hydrolysis of salan Ti(IV) complexes: Sterics and electronics are intertwined

Article abstract of DOI:10.1039/c1dt11108f

A series of Ti(IV) complexes containing diamino bis(phenolato) "salan" type ligands with NH coordination were prepared, and their hydrolysis and cytotoxicity were analyzed and compared to the N-methylated analogues. Substituting methyl groups on the coord

Full text of DOI:10.1039/c1dt11108f

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PAPER
Major impact of N-methylation on cytotoxicity and hydrolysis of salan Ti(IV)
complexes: sterics and electronics are intertwined†
Sigalit Meker, Cesar M. Manna, Dani Peri and Edit Y. Tshuva*
Received 13th June 2011, Accepted 3rd August 2011
DOI: 10.1039/c1dt11108f
A series of Ti(IV) complexes containing diamino bis(phenolato) “salan” type ligands with NH
coordination were prepared, and their hydrolysis and cytotoxicity were analyzed and compared to the
N-methylated analogues. Substituting methyl groups on the coordinative nitrogen donor of highly
active and stable Ti(IV) salan complexes with H atoms has two main consequences: the hydrolysis rate
increases and the cytotoxic activity diminishes. In addition, the small modification of a single
replacement of Me with H leads to a different major hydrolysis product, where a dinuclear Ti(IV)
complex with two bridging oxo ligands is obtained, as characterized by X-ray crystallography, rather
than a trinuclear cluster. A partial hydrolysis product containing a single oxo bridge was also
crystallographically analyzed. Investigation of a series of complexes with NH donors of different steric
and electronic effects revealed that cytotoxicity may be restored by fine tuning these parameters even for
complexes of low stability.
that possess activity towards ovarian OVCAR-1 and colon HT-29
cells that is higher than those of Cp2TiCl2, (bzac)2Ti(OiPr)2 and
Introduction
cisplatin, and their hydrolytic behavior has been investigated.22–26
It appears that the “salan” type ligands are particularly suitable
for stabilizing the active Ti(IV) species where the ligand remains
bound for the interaction with the biological target. Thus, we have
reported that various complexes with N–Me substitution such as
L1Ti(OiPr)2 (Scheme 2) are highly cytotoxic and highly water-
stable, where increasing the N-substituent to Et leads to rapid
hydrolysis and no cytotoxicity.23 Additionally, we observed that
steric effects at various locations on the aromatic rings also reduce
cytotoxicity, while activity and stability may be enhanced by intro-
ducing electronic effects, in particular, with Cl or Br substitutions
Meaningful cytotoxic activities have been reported for complexes
of transition metals other than platinum.1–10 One such metal
is Ti(IV), complexes of which, namely titanocene dichloride
(Cp2TiCl2, Scheme 1a), budotitane ((bzac)2Ti(OEt)2, Scheme 1b)
and their derivatives, have been studied for more than two decades
as they possess activity towards cisplatin sensitive and resistant
tumor cells with reduced toxicity.11–19 Their hydrolytic instability
and rapid formation of unidentified O-bridged aggregates upon
exposure to water, however, impeded their applicability and
mechanistic investigations.13,15,20,21 It therefore is as yet unclear
which the cellular target of these compounds is, what the structure
of the active species is and what role hydrolysis plays in its
formation.
Scheme 1
We have recently developed a new family of C2-symmetrical
Ti(IV) complexes of diamine bis(phenolato) ligands (Scheme 1c),
Institute of Chemistry, The Hebrew University of Jerusalem, 91904,
Jerusalem, Israel. E-mail: tshuva@chem.ch.huji.ac.il; Fax: +972 2 6584282
† CCDC reference numbers 829875–829877. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1dt11108f
Scheme 2
9802 | Dalton Trans., 2011, 40, 9802–9809
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◦
3
at the ortho positions.22 Considering these findings, and as the
well-identified salan-bound trinuclear hydrolysis product lacked
cytotoxicity, we proposed that stability is an essential feature,
although the involvement of the cluster was also proposed.22,23
In the current manuscript we report the hydrolytic behavior and
cytotoxicity of complexes bearing the NH coordination group in
comparison to their N-methylated analogues, while analyzing the
influence of steric and electronic parameters on the performance
of these complexes (Scheme 2).
˚
Table 1 Selected bond lengths (A) and angles ( ) for L Ti(OiPr)2
Atoms
Value
Atoms
Value
Lengths
O(1)–Ti
1.925(3)
1.917(3)
1.829(3)
1.806(3)
N(1)–Ti
N(2)–Ti
N(1)–H(1 N)
N(2)–H(2 N)
2.273(4)
2.260(4)
0.75(5)
0.71(5)
O(2)–Ti
O(3)–Ti
O(4)–Ti
Angles
O(4)–Ti–O(3)
O(4)–Ti–O(1)
O(3)–Ti–O(1)
O(4)–Ti–O(2)
O(3)–Ti–O(2)
O(1)–Ti–O(2)
N(1)–Ti–N(2)
107.0(2)
93.8(1)
96.5(1)
98.2(1)
92.1 (1)
162.5 (1)
74.7 (1)
O(4)–Ti–N(1)
O(3)–Ti–N(1)
O(1)–Ti–N(1)
O(2)–Ti–N(1)
O(4)–Ti–N(2)
O(3)–Ti–N(2)
O(1)–Ti–N(2)
O(2)–Ti–N(2)
163.8(2)
88.8(2)
80.5(1)
84.5(1)
90.0(2)
161.9(2)
88.4(1)
79.0(1)
Results and Discussion
Complexes Synthesis and Characterization
Whereas N-substituted salan ligands such as H2L1,9,11 (Scheme
2) can be easily prepared by a single-step Mannich condensation
between the diamine, formaldehyde and the substituted phenol,22,23
the ligands with secondary amines suffer from their tendency
to undergo an additional substitution with formaldehyde to
give undesired N–CH2–N or N–CH2–O methylene bridges.27,28
Thus, an alternative stepwise synthesis was employed, involving
condensation between the substituted hydroxylbenzaldehyde and
the diamine.29 Additionally, some of the ligands that do not
include para substitution of the aromatic rings require the stepwise
synthetic procedure also for the N-methylated derivatives in
order to avoid reaction of formaldehyde at this position.30 Thus,
although H2L3 was obtained with high yield by the Mannich
condensation, ligands H2L4,6,8,10,12 were prepared by the alternative
two-step procedure, where the synthesis of the N-methylated
analogues L5,7,13Ti(OiPr)2 was achieved by an additional methy-
lation reaction.31 H2L2 was prepared stepwise from the N-
methylethylenediamine starting material.
Fig. 1 ORTEP drawing of L3Ti(OiPr)2 with 50% probability ellipsoids.
H atoms were omitted for clarity.
of the H atom, corroborating that a coordinative bond formed
without deprotonation. No indications of hydrogen bonding could
be detected in the structure.
Hydrolysis
All complexes L1–13Ti(OiPr)2 were synthesized quantitatively as
we previously described for L1Ti(OiPr)2 and analogues,22,23 from
the ligand precursor and Ti(OiPr)4 at RT with THF as the solvent,
without addition of a base. The 1H NMR of all complexes except
for L2Ti(OiPr)2 is consistent with C2-symmetrical structures as
obtained for related compounds,31–34 with trans covalent binding
of the phenolato groups, two coordinative Ti–NH bonds and cis
binding of the two isopropoxo ligands, as characterized by a single
set of aromatic signals, four doublets of the methylene protons,
and a single septet and two doublets of the isopropoxo groups. In
contrast, L2Ti(OiPr)2 is derived from an asymmetric ligand, and
thus the complex should exhibit a C1-symmetry, as is also evident
from the eight doublets of the methylene units and four aromatic
signals in the 1H NMR. Nevertheless, for this particular complex,
the reduced symmetry prevents us determining unequivocally the
isomer that is formed, as a cis-phenolato compound cannot be
ruled out.
Single crystals suitable for X-ray crystallography were grown
from a solution of L3Ti(OiPr)2 in THF. Selected bond lengths and
angles are given in Table 1, and an ORTEP drawing of the structure
with 50% probability ellipsoids is presented in Fig. 1. The structure
is highly similar to those of known complexes of this family,22,23,31–34
with trans phenolato binding and cis isopropoxo ligands in
accordance with the NMR features. Particularly noteworthy are
1
Hydrolysis measurements were performed by H NMR in 1 : 9
D2O/THF-d8 solution as previously described.22,23 The values
obtained for t1 of the release of the labile isopropoxo ligands are
2
summarized in Table 2. These values are served as a comparative
tool between complexes, and do not presume to determine the
hydrolysis rate under physiological conditions.
When inspecting Table 2, it is obvious that complexes of NH
donors are less stable than their methylated analogues by at
least one order of magnitude. In particular, when comparing
L1–3Ti(OiPr)2, we observed the additive effect of the elimination
1
2
Table 2
t
(h) values of isopropoxo release of L1–13Ti(OiPr)2 at 1 : 9
D2O/THF-d8 solution at RT
1
2
complex
substitutions
t
(h)
parent
L1Ti(OiPr)2
2,4-di-Me; NMe
2,4-di-Me; NMe; NH
2,4-di-Me; NH
2-Cl; NH
5
L2Ti(OiPr)2
L3Ti(OiPr)2
L4Ti(OiPr)2
L5Ti(OiPr)2
L6Ti(OiPr)2
L7Ti(OiPr)2
L8Ti(OiPr)2
L9Ti(OiPr)2
L10Ti(OiPr)2
L11Ti(OiPr)2
L12Ti(OiPr)2
L13Ti(OiPr)2
0.5
0.2
0.5
50
0.5
150
1
110
0.2
2
electronic effects
2-Cl; NMe
2-Br; NH
2-Br; NMe
2,4-di-Cl; NH
2,4-di-Cl; NMe
4-Me; NH
steric effects
˚
˚
4-Me; NMe
H; NH
H; NMe
the Ti–NH distances of 2.26 A, relative to the 2.34 A value
obtained for L1Ti(OiPr)2.24 This shorter bond represents the strong
binding of the secondary amine and the reduced steric demands
0.2
2
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of the two N-methyl groups. As we previously observed that
larger steric effects on the N-donor substantially decrease the
hydrolytic stability,23 we attribute the effect of the NH groups to
electronic reasons. These may relate to hydrogen bonding to water
molecules, or to the possibility of deprotonation that may stabilize
positive intermediates upon release of anionic labile ligands and
therefore accelerate isopropoxo hydrolysis. When examining Table
2, it is apparent that although there are minimal steric effects
on the hydrolysis rate, some electronic stabilization occurs for
ortho-halogenated complexes as observed for the N-methylated
analogues;22 however, the effect is less pronounced, and thus the
stability difference for these halogenated complexes between NH
and NMe complexes, is up to two orders of magnitude.
We reported previously that the product of the hydrolytic
reaction measured for L1Ti(OiPr)2,23 as well as other N-methylated
complexes of this family,22 is a highly stable trinuclear compound,
where the isopropoxo groups were replaced with water molecules
giving oxo bridges, whilst each Ti(IV) center is bound to the
salan ligand (Fig. 2). Interestingly, L2Ti(OiPr)2, differing from
L1Ti(OiPr)2 by a single NH donor replacing an NMe group, yields
a different stable hydrolysis product. The X-ray structure of this
cluster is provided in Fig. 3 and Selected bond lengths and angles
are given in Table 3.
Fig. 3 ORTEP drawing of L2 Ti2(m-O)2, the hydrolysis product of
2
L2Ti(OiPr)2 with 50% probability ellipsoids shown from two angels. H
atoms and THF solvent were omitted for clarity.
The structure features a dinuclear complex, with two bridging
oxo atoms and a salan ligand bound to each metal center. The two
salan ligands bind with a different geometry relative to the starting
complex L2Ti(OiPr)2, with the phenolato oxygen atoms occupying
cis positions rather than trans. This is similar to the observations
with different complexes of this type that were obtained following
ligand replacement, supporting a similar associative mechanism
of this process.22,23,33 Nevertheless, despite the low C1-symmetry of
the original complex L2Ti(OiPr)2 resulting from the different N-
donors, a center of inversion in the cluster increases its symmetry
to Ci. The Ti–O–Ti and O–Ti–O angles of the bridging core
are 97.4◦ and 82.6◦, respectively, and the Ti–O–Ti–O moiety
is completely planar with a dihedral angle of 180.0◦. A short
Fig. 2 L1 Ti3(m-O)3, hydrolysis product of L1Ti(OiPr)2.23
3
˚
Ti . . . Ti distance of 2.81 A is observed, and the shortest NH–O
◦
2
˚
˚
Table 3 Selected bond lengths (A) and angles ( ) for L Ti2(m-O)2
2
distance obtained is 2.4 A which does not indicate any hydrogen
bonding.
Atoms
Value
Atoms
Value
Of particular interest is the comparison of the main hydrolysis
product of L2Ti(OiPr)2 (Fig. 2) with that of L1Ti(OiPr)2 (Fig.
3).23 Whereas L1Ti(OiPr)2 yielded a trinuclear complex with a
symmetry reduced to C1 due to two Ti(IV) centers of cis phenolato
binding and one of a trans binding, L2Ti(OiPr)2 gave rise to a
smaller cluster with higher symmetry, despite the relatively small
difference between the two precursor isopropoxo complexes that
appears to be rather distant from the metal center. Considering
that other N-methylated analogues, such as a complex featuring
ortho-Cl substituents that have significant steric and electronic
demands, give rise to similar trinuclear complexes as characterized
by X-ray crystallography,22 we assume that the difference in
structure of the hydrolysis product of L2Ti(OiPr)2 is due to the
Lengths
O(1)–Ti
1.7817(14)
1.9093(15)
1.8880(16)
1.9594(15)
N(1)–Ti
N(2)–Ti
N(1)–H(1 N)
Ti . . . Ti
2.223(2)
2.332(2)
0.87(3)
O(2)–Ti
O(3)–Ti
O(1)–Ti
Angles
O(1)–Ti–O(3)
O(2)–Ti–O(1)
O(3)–Ti–O(1)
O(1)–Ti–O(1)
O(3)–Ti–O(2)
O(1)–Ti–O(2)
N(1)–Ti–N(2)
2.8133(7)
95.42(7)
163.12(7)
101.82(7)
82.59(7)
99.48(7)
101.93(7)
77.48(7)
O(1)–Ti–N(1)
O(3)–Ti–N(1)
O(2)–Ti–N(1)
O(1)–Ti–N(1)
O(1)–Ti–N(2)
O(3)–Ti–N(2)
O(2)–Ti–N(2)
O(1)–Ti–N(2)
94.87(7)
162.33(7)
82.50(7)
80.91(7)
164.37(7)
84.92(7)
90.68(7)
82.75(6)
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4
Table 5 Absolute IC50 (mM) values of L1–13Ti(OiPr)2 and reference
compounds towards colon HT-29 and ovarian OVCAR-1 cells
˚
Table 4 Selected bond lengths (A) and angles ( ) for L Ti2(OiPr)2(m-O)
2
Atoms
Value
Atoms
Value
HT-29 OVCAR-1
complex
substitutions
(mM) (mM)
Lengths
N(1)–Ti(1)
N(2)–Ti(1)
N(3)–Ti(2)
N(4)–Ti(2)
O(1)–Ti(1)
O(1)–Ti(2)
2.221(2)
2.258(2)
2.217(2)
2.253(2)
1.8345(15)
1.8406(15)
O(2)–Ti(1)
O(3)–Ti(1)
O(4)–Ti(1)
O(5)–Ti(2)
O(6)–Ti(2)
O(7)–Ti(2)
Ti . . . Ti
1.9285(17)
1.8895(17)
1.8588(17)
1.9272(16)
1.8953(17)
1.8456(17)
3.56
parent
L1Ti(OiPr)2
L2Ti(OiPr)2
L3Ti(OiPr)2
L4Ti(OiPr)2
L5Ti(OiPr)2
L6Ti(OiPr)2
L7Ti(OiPr)2
L8Ti(OiPr)2
L9Ti(OiPr)2
2,4-di-Me; NMe
10
1
10
—
—
43
8
1
a
a
2,4-di-Me; NMe; NH —a
a
2,4-di-Me; NH
2-Cl; NH
2-Cl; NMe
2-Br; NH
2-Br; NMe
2,4-di-Cl; NH
2,4-di-Cl; NMe
4-Me; NH
4-Me; NMe
H; NH
—
21
4
50
12
—
—
15
7
electronic
effects
1
1
2
1
1
1
1
98
Angles
0.9 1.1
a
a
a
Ti(1)–O(1)–Ti(2)
O(1)–Ti(1)–O(4)
O(1)–Ti(1)–O(3)
O(4)–Ti(1)–O(3)
O(1)–Ti(1)–O(2)
O(4)–Ti(1)–O(2)
O(3)–Ti(1)–O(2)
O(1)–Ti(1)–N(1)
O(4)–Ti(1)–N(1)
O(3)–Ti(1)–N(1)
O(2)–Ti(1)–N(1)
O(1)–Ti(1)–N(2)
O(4)–Ti(1)–N(2)
O(3)–Ti(1)–N(2)
O(2)–Ti(1)–N(2)
N(1)–Ti(1)–N(2)
150.91(9)
93.37(7)
99.47(7)
103.87(8)
165.79(8)
93.13(7)
91.21(8)
85.14(7)
96.52(8)
158.73(8)
81.58(8)
84.66(7)
172.08(8)
84.04(7)
87.18(7)
75.68(8)
O(1)–Ti(2)–O(7)
O(1)–Ti(2)–O(6)
O(7)–Ti(2)–O(6)
O(1)–Ti(2)–O(5)
O(7)–Ti(2)–O(5)
O(6)–Ti(2)–O(5)
O(1)–Ti(2)–N(3)
O(7)–Ti(2)–N(3)
O(6)–Ti(2)–N(3)
O(5)–Ti(2)–N(3)
O(1)–Ti(2)–N(4)
O(7)–Ti(2)–N(4)
O(6)–Ti(2)–N(4)
O(5)–Ti(2)–N(4)
N(3)–Ti(2)–N(4)
92.46(7)
99.30(7)
104.89(8)
165.56(8)
94.37(7)
91.23(7)
84.36(7)
95.32(8)
159.22(8)
82.35(7)
85.38(7)
170.51(8)
84.59(8)
85.80(7)
75.29(8)
—
—
a
steric effects L10Ti(OiPr)2
L11Ti(OiPr)2
1
7
7
36
20
1
1
1
L12Ti(OiPr)2
14
17
1
1
1
1
1
L13Ti(OiPr)2
H; NMe
reference
Cp2TiCl2
(bzac)2Ti(OiPr)2
cisplatin
641 1 741
17
12
1
1
17
10
1
1
a Growth inhibition does not reach 50%.
Cytotoxicity
Cytotoxicity was measured on ovarian OVCAR-1 and colon HT-
29 cells based on the MTT assay following a three day incubation
period as previously described.22 The IC50 values are summarized
in Table 5.
electronic properties of the secondary amine coordination site.
Additionally, the reduced steric demand of the dinuclear complex
(nearest C(ortho) . . . C(ortho) distance of 7.9 A) relative to that
When inspecting the results for complexes L1–3Ti(OiPr)2 it
appears that, as we previously reported,22,23 the cytotoxic activity
is related to the hydrolytic stability (Fig. 5). Thus, increasing
the number of NH relative to NMe donors which decreases
not only the hydrolytic stability but the cytotoxicity as well.
Complex L3Ti(OiPr)2 is practically inactive, while L2Ti(OiPr)2
demonstrates a mild activity. Additionally, the dimeric hydrolysis
product L2 Ti2(m-O)2 is also completely inactive, further support-
ing the notion that the stability of the precursor complexes is of
importance for cytotoxicity.
Complexes L4–13Ti(OiPr)2 were analyzed in an attempt to elu-
cidate the relations between the parameters affecting cytotoxicity,
where steric and electronic effects known to enhance activity in
the N-methylated complexes were introduced to complexes of NH
donors.
As for electronic effects, the ortho chlorinated and ortho
brominated complexes of NH donors L4,6Ti(OiPr)2 showed some-
what enhanced cytotoxicity relative to the corresponsing non-
halogenated complexes22 (Fig. 6, Table 5), although their activity
is still markedly lower than those of the N-methylated analogues,
for which the halogenation effect is more pronounced giving
particularly active complexes. When inspecting the hydrolysis
rates, it might appear as though the increased stability might
be the reason for the enhanced activity, although the stability
enhancement for the ortho halogenated NH complexes is relatively
minor. Additionally, complex L8Ti(OiPr)2 of the highest stability
of this series demonstrated the lowest cytotoxicity, implying that
the relationship between these structural parameters is more
complex, where steric effects might play a particularly meaningful
role.23 Thus, sterics may account both for the reduced activity of
the ortho, para dichlorinated complex L8Ti(OiPr)2 and for the
reduced activity of the ortho brominated complex L6Ti(OiPr)2
relative to the ortho chlorinated one L4Ti(OiPr)2, a pattern
˚
of the trinuclear cluster (nearest C(ortho) . . . C(ortho) distance of
˚
3.7 A) may also account for the increased hydrolysis rate of NH
complexes and for the reduced effect of ortho substitutions.
Upon exposure to air, L4Ti(OiPr)2 underwent partial hydrolysis
as is obvious from the X-ray structure presented in Fig. 4 (Table
4).33,35 The structure features a dinuclear cluster, where each Ti(IV)
center is bound to the salan ligand and a single oxo ligand bridges
the two metal centers, leaving a single isopropoxo group bound
to each Ti(IV). In this structure, both phenolato ligands bind
2
in a cis configuration as observed for L2 Ti2(m-O)2 and related
2
structures of such LigTiOR–O–TiORLig (Lig: salan ligand)
moiety,33 supporting the main ligand rearrangement occurring
upon the first ligand replacement interaction. The symmetry of
the structure is reduced to C1 by the bend of the single oxo bridge,
˚
and the Ti . . . Ti distance is 3.56 A.
Fig. 4 ORTEP drawing of L4 Ti2(OiPr)2(m-O), the partial hydrolysis
2
product of L4Ti(OiPr)2 with 50% probability ellipsoids. H atoms and ether
solvent were omitted for clarity.
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Fig. 5 Dependence of HT-29 cell viability after a 3 day incubation period on administered concentration of L1–3Ti(OiPr)2 (a) and plot of integration of
bound isopropoxo signals in the 1H NMR of L1–3Ti(OiPr)2 vs. time following addition of D2O to the THF-d8 solution at RT (b).
Fig. 7 Dependence of HT-29 cell viability after a 3 day incubation period
on administered concentration of L10,12,13Ti(OiPr)2.
Fig. 6 Dependence of HT-29 cell viability after a 3 day incubation period
on administered concentration of L3,6,7Ti(OiPr)2.
efficient in enhancing the cytotoxic activity of complexes of NH
somewhat different than that observed for the N-methylated
analogues.22 It thus appears that steric effects are more pronounced
for complexes of NH donors, which urged us to further analyze
such effects for this series of complexes.
donors, giving complexes of activity similar to that of the corre-
sponding N-methylated compounds and higher activity than that
of their ortho halogenated NH analogues. Of particular interest
is the observation that complexes resulting from relatively rapid
hydrolysis may be highly cytotoxic if steric effects are eliminated.
It is therefore tempting to argue that rapidly hydrolyzed complexes
are more sensitive to structural modifications of a steric nature,
as these complexes may encounter kinetic obstacles that are size
dependent, and thus stable complexes, even if bulky, may overcome
them. Such obstacles may relate to cell penetration, interaction
with macromolecules via transport and reactivity, etc.
Another interesting point, when comparing complexes of NH
donors to the N-methylated ones, relates to the different hydrolysis
products. Whereas N-methylated complexes of different aromatic
substituents give trinuclear oxo-bridged clusters as the major
hydrolysis products,22,23 complexes of NH donors give dimeric
structures,36 which are higher in symmetry and smaller in size.
This may account for some of the differences observed in the
behavior of these complexes, since we have previously noticed a
correlation between the ability of a complex to form such salan-
bound clusters upon hydrolysis and its ability to induce cytotoxic
effects, suggesting involvement of the cluster in the activity.23
Nevertheless, both clusters were found to be inactive, raising the
possibility that a steric obstacle might relate to cell penetration
where their activity may possibly be pronounced if they are formed
in the cellular environment only (Scheme 3). Therefore, smaller
clusters of reduced steric demands may both account for the
increased hydrolysis rate and for the diminished dependence on
it. We are currently promoting this line of research in an attempt
Analyzing steric effects included eliminating first one
(L10Ti(OiPr)2) and then both (L12Ti(OiPr)2) of the two methyl
substitutions in each aromatic ring of L3Ti(OiPr)2, and comparing
the performance of the complexes to those of the N-methylated
analogues (L11,13Ti(OiPr)2 respectively). A major effect of steric
crowding is demonstrated, where the activity of the NH complexes
could be almost completely restored by eliminating the aromatic
methyl substitutions, despite their relatively rapid hydrolysis (Fig.
7). Thus, the activities of L10Ti(OiPr)2 and L12Ti(OiPr)2, which are
substantially higher than that of L3Ti(OiPr)2, are mostly similar
to that of L13Ti(OiPr)2, while no marked improvement is observed
for L11,13Ti(OiPr)2 relative to L1Ti(OiPr)2. It may therefore be
concluded that steric effects are more meaningful for complexes of
NH donors, in spite, or perhaps because of their reduced hydrolytic
stability.
Conclusion
In this paper we have compared a new series of salan Ti(IV) com-
plexes of NH donors to their N-methylated analogues. Whereas
marked stability and cytotoxicity enhancement is observed for
N-methylated complexes upon ortho halogenation, giving par-
ticularly active complexes with activity that mostly exceeds that
of cisplatin, this effect is relatively minor for complexes of NH
donors. In contrast, the elimination of steric groups is particularly
9806 | Dalton Trans., 2011, 40, 9802–9809
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1
20%). H NMR (400 MHz, CDCl3): d 6.71 (1 H, s, Ar), 6.69 (1
H, s, Ar), 6.63 (1 H, s, Ar), 6.57 (1 H, s, Ar), 3.93 (2 H, s, CH2),
3.64 (2 H, s, CH2), 2.95 (2 H, t, J = 6.4 Hz, CH2), 2.65 (2 H, t, J =
6.4 Hz, CH2), 2.28 (3 H, s, CH3), 2.19 (3 H, s, CH3), 2.18, (3 H,
s, CH3), 2.16 ppm (6 H, s, CH3); 13C NMR (100 MHz, CDCl3): d
155.3, 151.8, 136.2, 130.3, 128.7, 128.3, 127.1, 117.9, 117.3, 116.8,
82.4, 77.2, 59.7, 54.4, 49.9, 48.0, 41.2, 19.6, 19.5, 18.8, 18.7 ppm;
Found: C, 73.61; H, 8.37; N, 7.63. Calc. for C21H30N2O2: C, 73.65;
H, 8.83; N, 8.18%.
H2L3 was prepared by refluxing 3,4-dimethylphenol (3.67 g,
30 mmol), paraformaldehyde (0.30 g, 10 mmol), and ethylenedi-
amine (0.3 ml, 5 mmol) in methanol for 5 h. The solution was
cooled to -4 ◦C, and a colorless solid precipitated. The precipitate
was filtered and washed with methanol to yield H2L3 (0.9 g, 55%).
1H NMR (500 MHz, CDCl3): d 6.72 (2 H, s, Ar), 6.64 (2 H, s, Ar),
3.93 (4 H, s, CH2), 2.82 (4 H, s, CH2), 2.19 (6 H, s, CH3), 2.17 ppm
(6 H, s, CH3); 13C NMR (125 MHz, CDCl3): d 155.9, 137.2, 129.6,
127.0, 119.4, 117.8, 52.4, 48.0, 19.7 ppm; Found: C, 73.11; H, 8.57;
N, 8.40. Calc. for C20H28N2O2: C, 73.14; H, 8.59; N, 8.53%.
H2L4 was synthesized by slowly adding to a stirred solution of
3-chloro-2-hydroxybenzaldehyde (1.57 gr, 10 mmol) in 10 ml of
methanol a solution of ethylenediamine (0.3 ml, 5 mmol) in 30 ml
methanol. The solution was stirred for 3 h at RT during which a
color change to yellow was observed. NaBH4 (1.51 g, 40 mmol) was
added in small portions, and the reaction was stirred overnight.
The solution became colorless and a colorless solid precipitated.
100 ml of water were added, and the precipitate was collected by
vacuum filtration to yield H2L4 (0.4 g, 45%). 1H NMR (500 MHz,
CDCl3): d 7.26 (2 H, d, J = 7.6 Hz, Ar), 6.89 (2 H, d, J = 7.4 Hz,
Ar), 6.73 (2 H, t, J = 7.6 Hz, Ar) 4.01 (4 H, s, CH2), 2.85 ppm (4
H, s, CH2); 13C NMR (125 MHz, CDCl3): d 153.9, 129.5, 127.0,
123.6, 121.4, 119.8, 52.6, 47.9 ppm; Found: C, 56.10; H, 5.27; N,
7.89. Calc. for C16H18Cl2N2O2: C, 56.32; H, 5.32; N, 8.21%.
H2L5 was synthesized by dissolving H2L4 (0.98 g, 2.9 mmol) in
acetonitrile (110 ml) and acetic acid (15 ml). Formaldehyde was
added (5.5 ml, 70 mmol, 37–41% in water), and the mixture was
stirred for 45 min. NaBH4 was added (1.51 g, 40 mmol) and the
reaction was stirred for 12 h. The solvent was removed in vacuo.
The residue was hydrolyzed with 50 ml 2 M NaOH, leading to
precipitation of a colorless solid. The precipitate was collected by
vacuum filtration and was washed with methanol to yield H2L5
Scheme 3
to elucidate the active inner-cellular species, its penetration mode,
and its target.
Experimental Section
Ligands H2L1,9–13 and Ti(IV) complexes L1,9,11–13Ti(OiPr)2 were
synthesized as previously described.21,22,24,29,30 Paraformalde-
hyde (~95%), formaldehyde (37–41% in water), N,N¢-
dimethylethylenediamine (99%), N-methylethylenediamine (95%),
ethylenediamine (98%) and all substituted phenol compounds
(>97%) were purchased from Aldrich Chemical Company
Inc., Across Organics or Fluka Riedel-deHaen. Titanium
tetra(isopropoxide) (97%) was purchased from Aldrich Chem-
ical Company Inc. All solvents were distilled from K or
K/benzophenone under nitrogen, or dried over an aluminum
column on an M. Braun drying system SPS-800. All experiments
requiring a dry atmosphere were performed in an M. Braun
dry-box or under a nitrogen atmosphere using Schlenck line
techniques. NMR data were recorded using AMX-400 MHz or
AMX-500 MHz Bruker spectrometers. X-Ray diffraction data
were obtained with a Bruker SMART APEX CCD diffractometer,
running the SMART software package. After collection, the raw
data frames were integrated by the SAINT software package.
The structures were solved and refined using the SHELXTL
software package. Elemental analyses were performed in the
microanalytical laboratory in our institute. Accurare-Mass QTOF
LC/MS measurements were carried on an Agilent Technologies
6520 instrument. Cytotoxicity was measured on HT-29 colon
and OVCAR-1 ovarian cells obtained from ATCC Inc. using
the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay as
previously described.22 Absolute IC50 values were determined by a
non-linear regression of a variable slope (four parameters) model.
Kinetic studies by NMR were performed as previously described,
using 6 mM of the complex solution in THF-d8 and adding >1000
equiv. of D2O to give a final solution of 1 : 9 D2O/THF-d8. The t1
value is based on a pseudo first order fit for each compound. Th2e
results were verified by including p-dinitrobenzene as an internal
standard.
1
(0.8 g, 78%). H NMR (500 MHz, THF-d8): d 7.19 (2 H, d, J =
8.0 Hz, Ar), 6.93 (2 H, d, J = 7.5 Hz, Ar), 6.67 (2 H, t, J = 8.0 Hz,
Ar), 3.74 (4 H, s, CH2), 2.71 (4 H, s, CH2), 2.28 (6 H, s, CH3);
13C NMR (125 MHz, THF-d8): d 155.1, 130.0, 128.1, 125.0, 121.8,
120.0, 61.7, 55.0, 41.9 ppm; Found: C, 58.25; H, 5.81; N, 7.53.
Calc. for C18H22Cl2N2O2: C, 58.54; H, 6.00; N, 7.59%.
H2L6 was synthesized by slowly adding to a stirred solution of
3-bromo-2-hydroxybenzaldehyde (2.00 g, 10 mmol) in 10 ml of
methanol a solution of ethylenediamine (0.35 ml, 5.0 mmol) in
30 ml methanol. The solution was stirred for 10 h at RT during
which a color change to yellow was observed. NaBH4 (1.51 g,
40 mmol) was added in small portions, and the reaction was stirred
overnight. The solution became colorless and a colorless solid
precipitated. 100 ml of water was added, and the precipitate was
collected by vacuum filtration to yield H2L6 (0.6 g, 30%). 1H NMR
(500 MHz, THF-d8): d 7.43 (2 H, d, J = 8.0 Hz, Ar), 6.94 (2 H, d,
J = 7.5 Hz, Ar), 6.68 (2 H, t, J = 8.0 Hz, Ar), 4.00 (4 H, s, CH2),
2.85 ppm (4 H, s, CH2); 13C NMR (125 MHz, THF-d8): d 154.8,
H2L2 was synthesized by refluxing 3,4-dimethylphenol (2.44 g,
20.0 mmol) with paraformaldehyde (0.60 g, 20.0 mmol) and N-
methylethylenediamine (0.3 ml, 10.0 mmol) in methylene chloride
for 4 h. The solvent was removed by vacuum and the crude
product was dissolved in methanol : hexane 5 : 1 solution, which
was allowed to cool to -4 ◦C overnight. The colorless precipitate
was filtered and washed with cold methanol to yield H2L2 (0.7 g,
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132.5, 127.8, 123.5, 120.4, 110.7, 52.7, 47.9 ppm; Found: C, 44.14;
H, 4.15; N, 6.13. Calc. for C16H18Br2N2O2: C, 44.68; H, 4.22; N,
6.51%.
(6 H, d, J = 6.0 Hz, CHCH3); 13C NMR (125 MHz, CDCl3):
d 160.9, 137.0, 130.4, 125.2, 120.9, 118.9, 77.1, 53.3, 48.3, 26.0,
25.9, 19.7, 18.8 ppm; HRMS (C26H40N2O4Ti +H) Calc: 493.2546
Found: 493.2543. Single crystals of L3Ti(OiPr)2 were obtained
from a solution of hexane at -35 ◦C.
H2L7 was synthesized by dissolving H2L6 (0.64 g, 1.5 mmol) in
acetonitrile (110 ml) and acetic acid (15 ml). Formaldehyde was
added (5.5 ml, 70 mmol, 37–41% in water), and the mixture was
stirred for 10 min. NaBH4 was added (1.51 g, 40 mmol) and the
reaction was stirred for 12 h. The solvent was removed in vacuo.
The residue was hydrolyzed with 50 ml 2 M NaOH, leading to
precipitation of a white solid. The precipitate was collected by
vacuum filtration and was washed with methanol to yield H2L7
(0.4 g, 60%). 1H NMR (500 MHz, THF-d8): d 7.36 (2 H, dd, J =
6.5, 1.5 Hz, Ar), 6.96 (2 H, dd, J = 6.0, 1.5 Hz, Ar), 6.62 (2 H, t,
J = 8.0 Hz, Ar), 3.74(4 H, s, CH2), 2.72 ppm (4 H, s, CH2), 2.28
ppm (6 H, s, CH3); 13C NMR (125 MHz, THF-d8): d 156.2, 133.0,
128.8, 124.8, 120.6, 111.0, 62.0, 54.9, 41.9 ppm; Found: C, 46.88;
H, 4.62; N, 5.81. Calc. for C18H22Br2N2O2: C, 47.18; H, 4.84; N,
6.11%.
Crystal data for L3Ti(OiPr)2
˚
C26H40N2O4Ti, M = 492.50, Trigonal, a,b = 19.5096(9) A, c =
3
¯
˚
˚
12.402(1) A, V = 4088.1(5) A , T = 173(2) K, space group P3,
Z = 6, m(MoKa) = 0.345 mm-1, 42199 reflections measured, 5370
◦
2
unique (Rint = 0.0365), R(F ) for [I > 2s(I)] = 0.0973, Rw for [I
> 2s(I)] = 0.2425.
L4Ti(OiPr)2
1H NMR (500 MHz, THF-d8): d 7.15 (2 H, d, J = 7.5 Hz, Ar), 6.85
(2 H, d, J = 7.5 Hz, Ar), 6.51 (2 H, t, J = 7.5 Hz, Ar), 5.11 (2 H,
sept, J = 6.0 Hz, CHCH3), 4.75 (2 H, d, J = 12.0 Hz, CH2), 3.88
(2 H, s, NH), 3.73 (2 H, d, J = 14.0 Hz, CH2), 2.59 (2 H, m, CH2),
2.50 (2 H, m, CH2), 1.24 (6 H, d, J = 6.0 Hz, CHCH3), 1.20 ppm (6
H, d, J = 6.0 Hz, CHCH3); 13C NMR (125 MHz, THF-d8): 159.1,
129.5, 128.6, 125.9, 123.2, 117.6, 78.2, 54.2, 47.8, 26.5, 26.4 ppm;
HRMS (C22H30Cl2N2O4Ti +H) Calc: 505.1140 Found: 505.1138
H2L8 was synthesized by adding to a stirred solution of 3,5-
dichloro-2-hydroxybenzaldehyde (1.91 g, 10 mmol) in 10 ml of
methanol a solution of ethylenediamine (0.3 ml, 5 mmol) in 30 ml
methanol. The solution was stirred for 15 min at RT during which a
color change to yellow was observed. NaBH4 (1.51 g, 40 mmol) was
added in small portions, and the reaction was stirred overnight.
The solution became colorless and a colorless solid precipitated.
200 ml of water was added, and the precipitate was collected by
vacuum filtration to yield H2L8 (0.8 g, 40%). 1H NMR (500 MHz,
THF-d8): d 7.23 (2 H, d, J = 3.5 Hz, Ar), 6.99 (2 H, dt, J =
1.0, 2.5 Hz, Ar), 3.96 (4 H, s, CH2), 2.78 ppm (4 H, s, CH2); 13C
NMR (125 MHz, THF-d8): d 153.4, 127.8, 126.5, 126.0, 122.5,
121.2, 51.4, 47.4 ppm; Found: C, 46.93; H, 3.88; N, 6.77. Calc. for
C16H16Cl4N2O2: C, 46.86; H, 3.93; N, 6.83%.
L5Ti(OiPr)2
1H NMR (500 MHz, THF-d8): d 7.23 (2 H, dd, J = 8.0, 2.6 Hz, Ar),
6.90 (2 H, d, J = 7.0 Hz, Ar), 6.57 (2 H, t, J = 8.0 Hz, Ar), 5.26 (2
H, sept, J = 6.0 Hz, CHCH3), 4.67 (2 H, d, J = 13.5 Hz, CH2), 3.28
(2 H, d, J = 13.5 Hz, CH2), 2.94 (2 H, d, J = 9.5, Hz, CH2), 2.48 (6
H, s, CH3), 1.91 (2 H, d, J = 9.5 Hz, CH2), 1.30 (6 H, d, J = 6.0 Hz,
CHCH3), 1.22 ppm (6 H, d, J = 6.0 Hz, CHCH3); 13C NMR (125
MHz, THF-d8): d 158.7, 130.3, 129.0, 127.1, 122.7, 118.3, 79.2,
65.1, 52.7, 47.7, 26.8, 26.3 ppm; Anal. Calc. for C24H34Cl2N2O4Ti:
C, 54.05; H, 6.43; N, 5.25; found: C, 54.05; H, 6.26; N, 5.33.
L2–8,10Ti(OiPr)2 were synthesized as previously described by
reacting H2L2–8,10 (0.2 mmol) with Ti(OiPr)4 (0.05 g, 0.2 mmol)
in dry THF at RT for 2 h. Following removal of the solvent, the
products were obtained as yellow solids in quantitative yields.
L6Ti(OiPr)2
L2Ti(OiPr)2
1H NMR (500 MHz, THF-d8): d 7.34 (2 H, d, J = 7.5 Hz, Ar),
6.89 (2 H, d, J = 7.5 Hz, Ar), 6.45 (2 H, t, J = 7.5 Hz, Ar), 5.17
(2 H, sept, J = 6.0 Hz, CHCH3), 4.76 (2 H, d, J = 12.4 Hz, CH2),
3.84 (2 H, s, NH), 3.66 (2 H, d, J = 14.0 Hz, CH2), 2.60 (2 H,
m, CH2), 2.52 (2 H, m, CH2), 1.24 (6 H, d, J = 6.0 Hz, CHCH3),
1.20 ppm (6 H, d, J = 6.0 Hz, CHCH3); 13C NMR (100 MHz,
THF-d8): 160.0, 132.7, 129.4, 125.9, 118.2, 113.8, 78.2, 54.3, 47.8,
26.6, 26.5 ppm; HRMS (C22H30Br2N2O4Ti + Na) Calc: 616.9929
Found: 616.9924.
1H NMR (500 MHz, CDCl3): d 6.75 (1 H, s, Ar), 6.67 (1 H, s, Ar),
6.49 (1 H, s, Ar), 6.48 (1 H, s, Ar) 4.99 (1 H, sept, J = 6.0 Hz,
CHCH3), 4.95 (1 H, sept, J = 6.0 Hz, CHCH3), 4.54 (1 H, d, J =
13.2 Hz, CH2), 4.27 (1 H, d, J = 13.2 Hz, CH2), 3.83 (1 H, d, J =
13.6 Hz, CH2), 3.02 (1 H, d, J = 13.6 Hz, CH2), 2.91 (1 H, dt, J =
13.2, 3.6 Hz, CH2), 2.64 (1 H, dt, J = 13.2, 3.6 Hz, CH2), 2.52 (1 H,
dt, J = 13.2, 2.5 Hz, CH2), 2.48 (3 H, s, CH3), 2.20–2.10 (12 H, m,
CH3), 1.70 (1 H, dt, J = 13.2, 3.0 Hz, CH2), 1.28–1.17 ppm (12 H,
m, CHCH3); 13C NMR (100 MHz, CDCl3): d160.0, 159.8, 467.0,
136.9, 131.0, 130.4, 125.3, 125.2, 122.1, 121.8, 118.5, 118.4, 77.9,
71.6, 64.2, 56.3, 51.9, 47.6, 43.4, 26.0, 25.8, 22.2, 22.1, 19.6 ppm;
HRMS (C27H42N2O4Ti +H) Calc: 507.2702 Found: 507.2697.
L7Ti(OiPr)2
1H NMR (500 MHz, THF-d8): d 7.39 (2 H, d, J = 8.0, Hz, Ar),
6.93 (2 H, d, J = 7.5 Hz, Ar), 6.52 (2 H, t, J = 7.5 Hz, Ar), 5.32 (2
H, sept, J = 6.0 Hz, CHCH3), 4.67 (2 H, d, J = 13.5 Hz, CH2), 3.26
(2 H, d, J = 13.5 Hz, CH2), 2.94 (2 H, d, J = 9.5, Hz, CH2), 2.49 (6
H, s, CH3), 1.89 (2 H, d, J = 9.5 Hz, CH2), 1.30 (6 H, d, J = 6.0 Hz,
CHCH3), 1.22 ppm (6 H, d, J = 6.0 Hz, CHCH3); 13C NMR (100
MHz, CDCl3): d 158.3, 132.6, 128.7, 125.5, 118.0, 112.4, 78.8,
64.5, 51.6, 47.4, 26.1, 25.7 ppm; Anal. Calc. for C24H34Br2N2O4Ti:
C, 46.33; H, 5.51; N, 4.50; Found: C, 45.97; H, 5.22; N, 4.20.
L3Ti(OiPr)2
1H NMR (500 MHz, CDCl3): d 6.68 (2 H, s, Ar), 6.51 (2 H, s,
Ar), 4.90 (2 H, sept, J = 6.1 Hz, CHCH3), 4.62 (2 H, d, J =
13.0 Hz, CH2), 4.48 (2 H, d, J = 13.0 Hz, CH2), 2.90 (2 H, s,
NH), 2.56 (2 H, m, CH2), 2.49 (2 H, m, CH2), 2.17 (6 H, s, CH3),
2.13 (6 H, s, CH3), 1.26 (6 H, d, J = 6.1 Hz, CHCH3), 1.23 ppm
9808 | Dalton Trans., 2011, 40, 9802–9809
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L8Ti(OiPr)2
References
1H NMR (400 MHz, CDCl3): d 7.25 (2 H, s, Ar), 6.86 (2 H, s, Ar),
4.99 (2 H, sept, J = 6.1 Hz, CHCH3), 4.71 (2 H, d, J = 13.8 Hz,
CH2), 3.61 (2 H, d, J = 13.8 Hz, CH2), 2.92 (2 H, s, NH), 2.64 (2 H,
m, CH2), 2.52 (2 H, m, CH2), 1.26 (6 H, d, J = 6.1 Hz, CHCH3),
1.23 ppm (6 H, d, J = 6.0 Hz, CHCH3); 13C NMR (100 MHz,
CDCl3): 157.1, 128.9, 127.6, 125.2, 123.2, 121.1, 78.9, 53.2, 47.5,
25.7, 25.6 ppm; HRMS (C22H28Cl4N2O4Ti +H) Calc: 575.0332
Found: 575.0331.
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1H NMR (500 MHz, THF-d8): d 6.80 (2 H, d, J = 8.0 Hz, Ar),
6.70 (2 H, s, Ar), 6.40 (2 H, d, J = 8.0 Hz, Ar), 4.86 (2 H, sept, J =
6.0 Hz, CHCH3), 4.62 (2 H, d, J = 13.5 Hz, CH2), 3.80 (2 H, s,
NH), 3.50 (2 H, d, J = 12.5 Hz, CH2), 2.49 (4 H, m, CH2), 2.14 (6
H, s, CH3) 1.17 (6 H, d, J = 6.0 Hz, CHCH3), 1.17 ppm (6 H, d,
J = 6.0 Hz, CHCH3); 13C NMR (125 MHz, THF-d8): 161.8, 130.4,
129.5, 126.1, 124.3, 118.2, 77.3, 76.9, 54.3, 48.3, 26.6, 20.9 ppm;
HRMS (C24H36N2O4Ti +H) Calc: 465.2233 Found: 465.2230.
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Crystal data for L2 Ti2(l-O)2
2
C42H56N4O6Ti2·C4H8O (the structure contains a single THF
solvent molecule), M = 880.81, triclinic, a = 6.◦983(1), b = 12.7◦06(2),
◦
˚
c = 14.613(2) A, a = 66.685(2) , b = 84.776(3) , g = 83.530(3) , V =
3
¯
˚
1181.4(3) A , T = 293(2) K, space group P1, Z = 1, m(MoKa) = 0.389
mm-◦1, 13613 reflections measured, 5470 unique (Rint = 0.0193),
21 J. H. Toney and T. J. Marks, J. Am. Chem. Soc., 1985, 107, 947–953.
22 D. Peri, S. Meker, C. M. Manna and E. Y. Tshuva, Inorg. Chem., 2011,
50, 1030–1038.
2
R(F ) for [I > 2s(I)] = 0.0507, Rw for [I > 2s(I)] = 0.1548.
23 D. Peri, S. Meker, M. Shavit and E. Y. Tshuva, Chem.–Eur. J., 2009, 15,
2403–2415.
Crystal data for L4 Ti2(OiPr)2(l-O)
24 M. Shavit, D. Peri, C. M. Manna, J. S. Alexander and E. Y. Tshuva, J.
Am. Chem. Soc., 2007, 129, 12098–12099.
2
C38H45Cl4N4O7Ti2·0.5(C4H10O) (the structure contains 0.5 di-
ethylether solvent molecule), M = 944.44, Monoclinic, a =
25 E. Y. Tshuva and J. A. Ashenhurst, Eur. J. Inorg. Chem., 2009, 2203–
2218.
26 E. Y. Tshuva and D. Peri, Coord. Chem. Rev., 2009, 253, 2098–
2115.
◦
˚
˚
˚
13.059(1) A, b = 23.948(2) A, c = 15.351(2) A, b = 95.966(2) ,
3
˚
V = 4774.8(8) A , T = 173(1) K, space group P21/c, Z = 4,
27 C. M. Manna, M. Shavit and E. Y. Tshuva, J. Organomet. Chem., 2008,
m(MoKa) = 0.607 m◦m-1, 51349 reflections measured, 10419 unique
693, 3947–3950.
2
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Supporting information available
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2
L4 Ti2(OiPr)2(m-O).†
2
Acknowledgements
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2005, 2480–2485.
We thank Dr Shmuel Cohen for solution of the X-ray structures.
This research received funding from the European Research
Council under the European Community’s Seventh Framework
Programme (FP7/2007-2013)/ERC Grant agreement n◦ [239603].
The research was also partly supported the Israel Science Founda-
tion (grant No.124/09) and the Lower Saxony Ministry of Science.
34 A. Yeori, S. Groysman, I. Goldberg and M. Kol, Inorg. Chem., 2005,
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36 Unpublished results: additional complexes of NH donors investigated
in our laboratory also yielded dinuclear complexes as the main
hydrolysis products.
This journal is
The Royal Society of Chemistry 2011
Dalton Trans., 2011, 40, 9802–9809 | 9809
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