TiIV complexes of branched diamine bis(phenolato) ligands: Hydrolysis and cytotoxicity

Article abstract of DOI:10.1002/ejic.201100725

Six Ti^IV complexes of branched diamine bis(phenolato) ligands that feature a pendant donor side arm with different aromatic and N-substitutions were synthesized and their hydrolytic stability and cytotoxicity were investigated as closely related analogues to the highly active and stable salan Ti^IV complexes [salan = N,Na′-bis(o-hydroxybenzyl)-1,2- diaminoethane]. Although the C_s-symmetrical complexes include binding of the side-arm N donor to the metal as analyzed crystallographically, thus making them highly similar in coordination features to the C₂- symmetrical salan complexes, they exhibit poor hydrolytic stability, presumably due to higher flexibility in binding of the side arm in solution. Complexes of alkyl aromatic substituents, both N-methylated and N-ethylated, with varying steric constraints demonstrated poor cytotoxicity. In contrast, ortho-halogenation, although it does not affect hydrolytic stability, substantially enhances the cytotoxicity towards colon HT-29 and ovarian OVCAR-1 cells. The cytotoxicity and hydrolysis of Ti^IV complexes of branched diamine bis(phenolato) ligands are reported. Alkylated complexes exhibit poor stability presumably due to weaker binding of the side arm, with negligible cytotoxicity. In contrast, ortho-halogenated complexes, although hydrolytically unstable, demonstrate marked cytotoxicity.

Full text of DOI:10.1002/ejic.201100725

FULL PAPER
DOI: 10.1002/ejic.201100725
TiIV Complexes of Branched Diamine Bis(phenolato) Ligands: Hydrolysis and
Cytotoxicity
Dani Peri,[a] Cesar M. Manna,[a] Michal Shavit,[a] and Edit Y. Tshuva*[a]
Keywords: Titanium / Antitumor agents / Cytotoxicity / Phenolato ligands / Hydrolysis
Six TiIV complexes of branched diamine bis(phenolato) li-
gands that feature a pendant donor side arm with different
dination features to the C2-symmetrical salan complexes,
they exhibit poor hydrolytic stability, presumably due to
aromatic and N-substitutions were synthesized and their hy- higher flexibility in binding of the side arm in solution. Com-
drolytic stability and cytotoxicity were investigated as closely
related analogues to the highly active and stable salan TiIV
complexes [salan = N,NЈ-bis(o-hydroxybenzyl)-1,2-diamino-
ethane]. Although the Cs-symmetrical complexes include
binding of the side-arm N donor to the metal as analyzed
crystallographically, thus making them highly similar in coor-
plexes of alkyl aromatic substituents, both N-methylated and
N-ethylated, with varying steric constraints demonstrated
poor cytotoxicity. In contrast, ortho-halogenation, although it
does not affect hydrolytic stability, substantially enhances the
cytotoxicity towards colon HT-29 and ovarian OVCAR-1
cells.
and general geometry (Scheme 2), but which differ in con-
nectivity, in which one of the N donors is located on a side
arm rather than being a part of the central ligand skeleton,
thus leading to [ONON]-type complexes of Cs-symmetry
rather than C2. Such group IV metal complexes are known
and have been previously investigated mainly in the field of
Introduction
Interesting cytotoxic activities have been recently re-
ported for complexes of transition metals other than plati-
num.[1] One such metal is TiIV, complexes of which –
namely, titanocene dichloride ([Cp2TiCl2], Scheme 1a), bu-
dotitane {[(bzac)2Ti(OEt)2], Scheme 1, b}, and their deriva-
tives – have shown promising activity towards cisplatin-sen-
sitive and resistant tumor cells with limited toxicity.[2] The
main drawback in TiIV complexes, however, is in their hy-
drolytic instability.[2d,2f,3] We have recently introduced a new
family of C2-symmetrical TiIV complexes of [ONNO]-type
diamine bis(phenolato) salan [salan
= N,NЈ-bis(o-hy-
droxybenzyl)-1,2-diaminoethane] ligands (Scheme 1, c) that
generally demonstrate higher activity towards ovarian OV-
CAR-1 and colon HT-29 cells than those of [Cp2TiCl2],
[(bzac)2Ti(OiPr)2], and cisplatin, and substantially higher
hydrolytic stability relative to that of known TiIV com-
plexes.[4] Herein we describe a new highly related family of
complexes with similar donor atoms, coordination number,
Scheme 1.
[a] Institute of Chemistry, The Hebrew University of Jerusalem,
91904, Jerusalem, Israel
Fax: +972-2-6584282
E-mail: tshuva@chem.ch.huji.ac.il
Scheme 2.
4896
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2011, 4896–4900

TiIV Complexes of Branched Diamine Bis(Phenolato) Ligands
catalysis.[5] The steric and electronic effects on hydrolysis
and cytotoxic activity of TiIV complexes of the [ONON]-
type ligands is hereby discussed.
Results and Discussion
Complexes [L1–6Ti(OiPr)2] 1–6 (Scheme 2), were cleanly
synthesized from the corresponding ligands H2L1–6, 1a–6a,
and titanium tetra(isopropoxide) similarly to known pro-
cedures[5b,5c] at room temperature and in THF solvent. The
ligands were prepared by a convenient Mannich condensa-
tion between the substituted phenol, formaldehyde, and
N,N-dimethylethylenediamine based on published pro-
cedures.[5] The complexes feature a Cs symmetry due to
binding of the phenolato O donors in a trans configuration,
where the side-arm binding forces a cis configuration of the
isopropoxo groups. This was evident by the NMR spectra
of the complexes, which feature a single set of aromatic sig-
nals and an AB system for the benzylic methylene protons.
Additional structural support was provided by the crystal-
lographic analysis of 4 and 6, for which an ORTEP drawing
is provided in Figures 1 and 2, respectively, with lists of se-
lected bond lengths and angles summarized in Tables 1 and
2, respectively. For the structure of 6, one CH2 unit of the
diaminoethylene bridge and the two methyl groups are dis-
ordered, with 85% occupancy for the main set of C(18)–
C(20), and full occupancy of the two depicted N atoms.
Figure 2. ORTEP drawing of [L6Ti(OiPr)2] (6) in 50% probability
ellipsoids. Hydrogen atoms and disorder in the dimethylethylenedi-
amine moiety were omitted for clarity to include only the C(18)–
C(20) of 85% occupancy.
Table 1. Selected bond lengths [Å] and angles [°] for 4.
O(1)–Ti
O(2)–Ti
O(3)–Ti
O(4)–Ti
1.912(2)
1.884(2)
1.830(2)
1.809(2)
N(1)–Ti
N(2)–Ti
2.327(2)
2.464(2)
O(1)–Ti–O(2) 163.69(9)
O(1)–Ti–N(1)
O(2)–Ti–N(1)
O(3)–Ti–N(1)
O(4)–Ti–N(1) 166.49(9)
O(1)–Ti–N(2)
O(2)–Ti–N(2)
84.20(8)
82.16(8)
88.65(8)
O(3)–Ti–O(1)
O(4)–Ti–O(1)
O(3)–Ti–O(2)
O(4)–Ti–O(2)
O(4)–Ti–O(3) 104.84(9)
N(1)–Ti–N(2) 75.60(8)
93.98(9)
94.06(9)
94.60(9)
97.11(9)
83.23(8)
84.75(8)
O(3)–Ti–N(2) 164.19(9)
O(4)–Ti–N(2) 90.89(8)
Table 2. Selected bond lengths [Å] and angles [°] for 6.
O(1)–Ti
O(2)–Ti
O(3)–Ti
O(4)–Ti
1.905(1)
1.916(1)
1.796(1)
1.833(1)
N(1)–Ti
N(2)–Ti
2.340(1)
2.384(2)
O(1)–Ti–O(2) 163.35(5)
O(1)–Ti–N(1)
O(2)–Ti–N(1)
O(3)–Ti–N(1) 163.21(6)
O(4)–Ti–N(1)
O(1)–Ti–N(2)
O(2)–Ti–N(2)
O(3)–Ti–N(2)
84.35(5)
82.29(5)
O(3)–Ti–O(1)
O(4)–Ti–O(1)
O(3)–Ti–O(2)
O(4)–Ti–O(2)
O(4)–Ti–O(3) 106.74(6)
N(1)–Ti–N(2) 74.57(5)
97.17(6)
91.73(6)
93.94(6)
94.18(6)
89.89(5)
85.09(5)
85.62(5)
88.86(6)
Figure 1. ORTEP drawing of [L4Ti(OiPr)2] (4) in 50% probability
ellipsoids. Hydrogen atoms were omitted for clarity.
O(4)–Ti–N(2) 164.37(2)
The X-ray structures of 4 and 6 reveal an approximate
Cs symmetry of the complexes in the solid state with two
cis isopropoxo groups, in which the phenolato ligands are result of the steric effects induced by the N-ethyl groups in
in a trans configuration, in accordance with the NMR spec- 4, as one methyl group points up with a 3.4 Å distance to
troscopic features (which indicate a Cs symmetry in solu- O(4) (Figure 1).
tion) and similar to other known compounds of this
Cytotoxicity of the complexes was measured on colon
class.[5b,5c] Binding of the side-arm donor to the metal is HT-29 and ovarian OVCAR-1 human tumor cells accord-
obvious in both structures, although for 6 the Ti–N bond ing to the methylthiazolyldiphenyltetrazolium bromide
to the side arm of 2.37 Å is rather similar to that to the (MTT) assay as described previously.[4a] The relative IC50
central N donor of 2.34 Å, whereas for [L4Ti(OiPr)2], the values obtained after 3 d incubation of the complexes with
metal bond to the side donor is substantially longer: 2.46 Å the cells are summarized in Table 3. Additionally, the hy-
relative to 2.33 Å for the central N donor. This might be a drolytic stability of the complexes was assessed by NMR
Eur. J. Inorg. Chem. 2011, 4896–4900
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4897

D. Peri, C. M. Manna, M. Shavit, E. Y. Tshuva
FULL PAPER
Figure 3. Dependence of HT-29 (left) and OVCAR-1 (right) cell viability after 3 d incubation period on administered concentration of
1, 5, and 6.
spectroscopy as described previously[4a,4b] by adding 10% are mostly lower than those obtained for cisplatin and the
D2O to a solution of the complexes in [D8]THF and moni- known TiIV complexes analyzed (Figure 3, Table 1). This
toring changes in the spectra.
implies that the pending donor arm is more important in
destabilizing the complexes in water environment, in which
the effect of halogenation on stability is less pronounced.
Nevertheless, it is clear that cytotoxicity may be improved
in an unrelated manner, even for unstable complexes.
Table 3. Relative IC50 and maximal inhibition values for the com-
plexes 1–6, cisplatin, [Cp2TiCl2], and [(bzac)2Ti(OiPr)2] towards
HT-29 and OVCAR-1 cell lines.
HT-29 [μm]
OVCAR-1 [μm]
(maximum inhibition, %) (maximum inhibition, %)
[L1–4Ti(OiPr)2] (1–4) negligible activity
negligible activity
6.3Ϯ0.3 (71)
3.3Ϯ0.3 (74)
701 Ϯ4 (90)
14.9Ϯ0.4 (90)
8.6Ϯ0.2 (90)
Conclusion
[L5Ti(OiPr)2] (5)
[L6Ti(OiPr)2] (6)
[Cp2TiCl2]
14Ϯ1 (56)
2.7Ϯ0.3 (60)
609Ϯ4 (90)
15.2Ϯ0.3 (90)
11.1Ϯ0.4 (88)
Herein we report a new family of potentially cytotoxic
TiIV complexes based on branched [ONON]-type tetraden-
tate diamine bis(phenolato) ligands. The alkyl-substituted
complexes are less hydrolytically stable than the analogous
salan complexes with ligands of the diamine bis(phenolato)
[ONNO]-type, presumably due to the different coordination
sphere that includes a pendant donor side arm, which is
probably related to their inactivity towards tumor colon
and ovarian cells. Nevertheless, the cytotoxicity of com-
plexes with pending donor arm, even relatively unstable
ones, may be restored by ortho substitution with Cl or Br,
an effect of cytotoxicity enhancement similar to the one ob-
served for the salan analogues.[4a] Thus, the halogenation
increased the cytotoxicity but not the hydrolytic stability.
An advantage of these complexes emerges from their Cs
symmetry, which offers evidence that chirality is not a pre-
requisite for cytotoxic activity of such complexes and abol-
ishes the need for chiral separation required for medicinal
utility.[6] Additional investigations to include halogenated,
methoxylated, and aminated derivatives are essential to fur-
ther identify structural parameters that may enhance both
the hydrolytic stability and cytotoxicity of these complexes,
and to make them of potential applicability.
[(bzac)2Ti(OiPr)2]
cisplatin
Complexes 1–4 vary in the steric effects caused by the
alkyl substituents on the aromatic rings and on the side N
donor. All four complexes demonstrate negligible cytotoxic
activity towards both cell lines analyzed, as well as poor
hydrolytic stability, as complete dissociation of the iso-
propoxo groups to give 2-propanol was observed within a
few minutes following D2O addition. These observations
are different than those of the analogous salan complexes,
especially those with identical aromatic substitutions to 1
and 2, which demonstrate high cytotoxicity and high hydro-
lytic stability with t1/2 of 5–31 h for isopropoxo dissociation
under similar conditions.[4b] As the coordination features of
the two families of complexes – that is, the [ONNO]- and
the [ONON]-type – are highly similar, we attribute the re-
duced hydrolytic stability of the latter, which might relate
to the resulting diminished cytotoxicity, to the flexibility of
the pending arm. The side-arm donor is probably able to
detach from the metal more easily upon interaction with
water, thus giving more rapidly inactive oxo-bridged cluster
1
as also evidenced by the H NMR spectra of the hydrolysis
products.
Experimental Section
ortho-Halogenation on the analogous salan [ONNO]-
type complexes has previously been reported to increase
both their hydrolytic stability and the cytotoxicity.[4a] There-
fore, 5 and 6, which feature ortho-Cl and ortho-Br substitu-
tions, were analyzed. Interestingly, although the hydrolytic
stability of these complexes remained poor, the cytotoxicity
General: Ligands H2L1–4 (1a–4a) and TiIV complexes [L1–3Ti-
(OiPr)2] (1–3) were synthesized as described previously.[5] Para-
formaldehyde (ca. 95%), N,N-dimethylethylenediamine (95%), and
substituted phenol compounds (Ͼ 95%) were purchased from Ald-
rich Chemical Company Inc. or Fluka Riedel-de Haën. Titanium
was markedly enhanced and gave relative IC50 values that tetra(isopropoxide) (97%) was purchased from Aldrich Chemical
4898 Eur. J. Inorg. Chem. 2011, 4896–4900
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

TiIV Complexes of Branched Diamine Bis(Phenolato) Ligands
Company, Inc. All solvents for complexes manipulation were dis-
tilled from K or K/benzophenone under nitrogen, or dried with
aluminum column with an M. Braun SPS-800 drying system. All
experiments that required a dry atmosphere were performed in an
M. Braun dry box or under nitrogen atmosphere using Schlenk line
techniques. NMR spectroscopic data were recorded with an AMX-
400 or 500 MHz Bruker spectrometer. X-ray diffraction data were
obtained with a Bruker Smart Apex diffractometer. Elemental
analyses were performed in the microanalytical laboratory of our
institute. Cytotoxicity was measured on HT-29 colon and OVCAR-
1 ovarian cells obtained from ATCC Inc. using the methylthiazolyl-
diphenyltetrazolium bromide (MTT) assay as described previous-
ly.[4a] Relative IC50 values were determined by a nonlinear re-
gression of a variable slope (four parameters) model. Kinetic stud-
ies by NMR spectroscopy were performed as described previous-
ly,[4a,4b] using 6 mm of the complex solution in [D8]THF and adding
Ͼ 1000 equiv. of D2O to give a final solution of 1:9 D2O/[D8]THF.
Ligand H2L5 (5a): This compound was synthesized by heating of
the following mixture to reflux (for about 10 h): 2-chloro-4-meth-
ylphenol (0.47 mL, 4.0 mmol), N,N-dimethylethylenediamine
(0.22 mL, 2.0 mmol), and paraformaldehyde (0.150 g, 5.0 mmol) in
methanol (20 mL). The crude product was cooled, filtered, and
washed with cold methanol (0.50 g, 63%). 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 7.14 (d, J = 1.4 Hz, 2 H, Ar–H), 6.71 (d, J =
1.4 Hz, 2 H, Ar–H), 3.64 (s, 4 H, CH2), 2.67 (m, 4 H, CH2), 2.31
(s, 6 H, CH3), 2.22 (s, 6 H, CH3) ppm. 13C NMR (500 MHz,
CDCl3, 30 °C): δ = 150.4, 130.2, 129.3, 128.8, 123.4, 121.3, 56.4,
55.9, 49.1, 45.1, 20.2 ppm. C20H26Cl2N2O2 (397.34): calcd. C 60.46,
H 6.60, N 7.05; found C 60.52, H 6.64, N 6.86.
from ethyl ether (0.075 g, 74%). 1H NMR (500 MHz, CDCl3,
25 °C): δ = 7.13 (s, 2 H, Ar–H), 6.76 (s, 2 H, Ar–H), 5.17 (sept, J
= 6.1 Hz, 1 H, CHCH3), 4.72 (m, J = 6.3 Hz, 1 H, CHCH3), 4.52
(d, J = 13.0 Hz, 2 H, CH2), 3.21 (d, J = 13.0 Hz, 2 H, CH2), 2.50
(t, J = 5.8 Hz, 2 H, CH2), 2.25 (s, 6 H, CH3), 2.23 (s, 6 H,CH3),
1.93 (t, J = 5.8 Hz, 2 H, CH2), 1.43 (d, J = 6.0 Hz, 2 H, CHCH3),
1.13 (d, J = 6.5 Hz, 2 H, CHCH3) ppm. 13C NMR (500 MHz,
CDCl3, 30 °C): δ = 156.3, 130.4, 128.6, 126.7, 125.5, 121.1, 78.9,
77.7, 64.6, 58.6, 50.9, 48.6, 25.9, 25.8, 20.3 ppm. C26H38Cl2N2O4Ti
(561.40): calcd. C 55.63, H 6.82, N 4.99; found C 55.80, H 6.57, N
4.69.
Complex [L6Ti(OiPr)2] (6): This compound was synthesized in
quantitative yield by treating Ti(OiPr)4 (0.050 g, 0.18 mmol) with
H2L6 (0.088 g, 0.18 mmol) in dry THF and could be recrystallized
from ethyl ether (0.055 g, 47%). 1H NMR (500 MHz, CDCl3,
25 °C): δ = 7.32 (s, 2 H, Ar–H), 6.88 (s, 2 H, Ar–H), 5.20 (sept, J
= 5.9 Hz, 1 H, CHCH3), 4.72 (sept, J = 6.1 Hz, 1 H, CHCH3),
4.52 (d, J = 13.0 Hz, 2 H, CH2), 3.21 (d, J = 13.0 Hz, 2 H, CH2),
2.52 (t, J = 5.8 Hz, 2 H, CH2), 2.29 (s, 6 H, CH3), 2.25 (s, 6 H,
CH3), 1.96 (t, J = 6.0 Hz, 2 H, CH2), 1.46 (d, J = 6.2 Hz, 2 H,
CHCH3), 1.14 (d, J = 6.3 Hz, 2 H, CHCH3) ppm. 13C NMR
(500 MHz, CDCl3, 30 °C): δ = 157.3, 133.3, 129.4, 127.2, 125.2,
111.5, 78.9, 77.7, 64.7, 58.5, 50.9, 48.9, 26.0, 25.4, 20.1 ppm.
C26H38Br2N2O4Ti (650.31): calcd. C 48.02, H 5.89, N 4.31; found
C 48.19, H 5.67, N 4.04.
Crystal Data for 6: C26H38Br2N2O4Ti, Mr = 650.30, monoclinic, a
= 9.2692(6) Å, b = 13.2687(9) Å, c = 23.550(2) Å, β = 98.926(1)°,
V = 2861.3(3) Å3, T = 173(1) K, space group P21/c, Z = 4, μ(Mo-
Kα) = 0.717 mm–1, 30973 reflections measured, 6232 unique (Rint
= 0.0214). R(F2o) for [IϾ2σ(I)] = 0.0262, Rw for [IϾ2σ(I)] =
0.0698.
Ligand H2L6 (6a): This compound was synthesized similar to 5a
from 2-bromo-4-methylphenol (0.48 mL, 4.0 mmol), N,N-dimethyl-
ethylenediamine (0.22 mL, 2.0 mmol) and paraformaldehyde
(0.18 g, 6.0 mmol) (0.76 g, 78%). 1H NMR (500 MHz, CDCl3,
25 °C): δ = 7.33 (d, J = 1.7 Hz, 2 H, Ar–H), 6.79 (d, J = 1.7 Hz, 2
H, Ar–H), 3.66 (s, 4 H, CH2), 2.64 (m, 4 H, CH2), 2.43 (s, 6 H,
CH3), 2.22 (s, 6 H, CH3) ppm. 13C NMR (500 MHz, CDCl3,
30 °C): δ = 151.3, 133.2, 130.0, 129.4, 123.2, 110.8, 56.4, 56.1, 49.1,
45.1, 20.1 ppm. C20H26Br2N2O2 (486.25): calcd. C 49.40, H 5.39,
N 5.76; found C 49.46, H 5.39, N 5.66.
CCDC-833128 (for 4) and -833129 (for 6) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
Complex [L4Ti(OiPr)2] (4): This compound was synthesized in
quantitative yield by treating Ti(OiPr)4 (0.18 g, 0.65 mmol) with
H2L4[5a] (0.23 g, 0.60 mmol) in dry THF and could be recrystallized
We thank Dr. Shmuel Cohen for solution of the X-ray structures.
This research received funding from the European Research Coun-
cil under the European Community’s Seventh Framework Pro-
gramme (FP7/2007-2013) and ERC Grant Agreement (239603).
The research was also partialy supported the Israel Science Foun-
dation (grant number 124/09).
1
from hexane (0.060 g, 18%). H NMR (400 MHz, CDCl3, 25 °C):
δ = 6.93 (d, J = 2.4 Hz, 2 H, Ar–H), 6.72 (d, J = 2.4 Hz, 2 H, Ar–
H), 5.07 (sept, J = 6.1 Hz, 1 H, CHCH3), 4.72 (sept, J = 6.1 Hz, 1
H, CHCH3), 4.54 (d, J = 13.1 Hz, 2 H, CH2), 3.19 (d, J = 13.1 Hz,
2 H, CH2), 2.59 (t, J = 5.6 Hz, 2 H, CH2), 2.27 (s, 3 H, CH3), 2.26
(s, 3 H, CH3), 2.05 (t, J = 5.6 Hz, 2 H, CH2), 1.41 (d, J = 6.1 Hz,
6 H, CHCH3), 1.13 (d, J = 6.1 Hz, 6 H, CHCH3), 0.99 (t, J =
7.2 Hz, 6 H, CH3) ppm. 13C NMR (400 MHz, CDCl3, 30 °C): δ =
158.9, 131.3, 127.4, 125.7, 124.5, 124.1, 65.2, 55.1, 46.8, 26.1, 25.9,
20.5, 16.5, 8.9 ppm. C30H48N2O4Ti (548.62): calcd. C 65.68, H
8.82, N 5.11; found C 65.61, H 8.78, N 5.61.
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0.1562.
Complex [L5Ti(OiPr)2] (5): This compound was synthesized in
quantitative yield by treating Ti(OiPr)4 (0.050 g, 0.18 mmol) with
H2L5 (0.072 g, 0.18 mmol) in dry THF and could be recrystallized
Eur. J. Inorg. Chem. 2011, 4896–4900
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Peri, C. M. Manna, M. Shavit, E. Y. Tshuva
FULL PAPER
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Received: July 13, 2011
Published Online: September 21, 2011
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