Titanium isopropoxide complexes supported by pyrrolyl Schiff base ligands: syntheses, structures, and antitumor activity

Abstract

The syntheses, structures and antitumor activity of four titanium isopropoxide complexes supported by pyrrolyl Schiff base ligands are reported. Treatment of Ti(OⁱPr)₄ with 2 equivalents of HL1 (HL1 = N-(1H-pyrrol-2-ylmethylene)(2-pyridinyl)methanimine), HL2 (HL2 = 2-pyrrolecarbaldmethylimine), HL3 (HL3 = N-((1H-pyrrol-2-yl)methylene)(phenyl)methanimine) and HL4 (HL4 = N-((1H-pyrrol-2-yl)methylene)-2-phenylethanimine), respectively, results in the formation of Ti(OⁱPr)₂(L1)₂ (1), Ti(OⁱPr)₂(L2)₂ (2), Ti(OⁱPr)₂(L3)₂ (3) and Ti(OⁱPr)₂(L4)₂ (4). All complexes have been characterized by elemental analyses and NMR studies. The solid-state structures of complexes 1 and 3 have been further established by single X-ray crystallography. The cytotoxicity activities of 1–4 towards the tumor cells HCT-116, PC3 and MCF-7 were measured. Complexes 1, 2 and 3 showed good antitumor properties.

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Introduction

The identification of novel cytotoxic non-platinum metal complexes as alternatives to conventional cisplatin is currently attracting considerable attention,¹ due to the disadvantage of high toxicity and limited activity range of cisplatin.² Among them, Ti(IV) complexes based on cyclopentadienide and diketonato type ligands, demonstrated promising cytotoxic activities with lower toxicity.³ Recently, the exploitation of the titanium isopropoxide compounds supported by diamino bis(phenolato) “salan” type and substituted cyclopentene ligands systems has provided a number of spectacular results, by researching the hydrolytic stability, the cytotoxicity and the antitumor activity.⁴ However, the potential cytoactivity of the isopropyl titanate complexes supported by pyrrolyl ligands, especially the pyrrolyl Schiff base ligands, has not been explored.

The deprotonated pyrrole, named pyrrolide anion, is among the most favorable ligands in organometallic chemistry.⁵ Isoelectronic with the Cp anion, pyrrolide anion is also a competent η⁵ ligand and can offer the possibility of forming ơ-bond through the ring nitrogen atom. Thus, pyrrolyl ligand provides tunable steric and electronic features required for compensating coordinative unsaturation of metal centers. It is reasoned that the reaction of Ti(OⁱPr)₄ with bi- or tridentate pyrrolyl Schiff base ligands could provide the titanium isopropoxide complexes, in which the ligand chelates to the Ti(IV) center to form a five-membered ring. These complexes may possess enhanced hydrolytic stability and improved antitumor properties.^4a,f Consequently, we have explored the reactions of Ti(OⁱPr)₄ with one tridentate ligand HL1, and three bidentate ligands HL2-HL4 (Scheme 1), and four complexes of compositions Ti(OⁱPr)₂(L1)₂ (1), Ti(OⁱPr)₂(L2)₂ (2), Ti(OⁱPr)₂(L3)₂ (3) and Ti(OⁱPr)₂(L4)₂ (4) were generated. Herein, we report the syntheses and characterizations of these complexes. High cytotoxicity was obtained for 1, 2 and 3, identifying that pyrrolyl titanium(IV) complexes could serve as a new family of antitumor agents towards HCT-116, PC3 and MCF-7 cells.

Scheme 1 Structures of the ligands.

Results and discussion

Syntheses of ligands and titanium complexes

The ligands HL1 (HL1 = N-(1H-Pyrrol-2-ylmethylene)(2-pyridinyl)methanimine),⁶ HL2 (HL2 = 2-pyrrolecarbaldmethylimine),⁷ HL3 (HL3 = N-((1H-pyrrol-2-yl)methylene)(phenyl)methanimine),⁸ and HL4 (HL4 = N-((1H-pyrrol-2-yl) methylene)-2-phenylethanimine)⁸ were prepared by condensation reactions between pyrrole-2-carboxaldehyde with the corresponding amines. Treatment of Ti(OⁱPr)₄ with one equiv. of HL1, HL2, HL3 and HL4, respectively, led to the formations of 1–4. The one ligand set chelated tri-isopropyl titanate was not afforded. Then the reaction of Ti(OⁱPr)₄ with 2 equiv. of HL1, HL2, HL3 and HL4, respectively, was conducted, and 1–4 were readily afforded in good yields after recrystallization in THF/Hexane (Scheme 2). They were also characterized by ¹H and ¹³C NMR spectra and elemental analyses.

Scheme 2 Syntheses of 1–4 in THF.

Structure descriptions of complexes 1 and 3

The molecular structures of 1 and 3 in the solid states have been confirmed by X-ray analysis and are shown in Fig. 1 and 2, respectively. The crystallographic data and experimental details for structural analyses are summarized in Table 1. Selected bond distances and angles are listed in Table 2.

Fig. 1 ORTEP structural drawing of 1. Ellipsoids are drawn at the 30% probability level, and hydrogen atoms are omitted for clarity.

Fig. 2 ORTEP structural drawing of 3. Ellipsoids are drawn at the 30% probability level, and hydrogen atoms are omitted for clarity.

Table 1 Crystal data and structure refinements for 1 and 3

	1	3
Formula^a	C28H34N6O2Ti	C30H36N4O2Ti
a Including solvent molecules.b R1 = Σ(|Fo| − |Fc|)/Σ(|Fo|) for observed reflections.c w = 1/[σ^2(Fo^2) + (αP)^2 + bP] and P = [max(Fo^2,0) + 2Fc^2]/3.d wR2 = {Σ[w(Fo^2 − Fc^2)^2]/Σ[w(Fo^2)^2]}^1/2 for all data.
M^a/g mol^−1	534.51	532.53
T/K	100(2)	100(2)
Crystal system	Monoclinic	Monoclinic
Space group	P21/c	P21/c
a/Å	10.2191(8)	10.268(2)
b/Å	11.4180(10)	11.468(3)
c/Å	24.491(2)	24.648(6)
α/°	90.00	90.00
β/°	100.554(2)	100.635(4)
γ/°	90.00	90.00
V/Å^3	2809.3(4)	2852.6(11)
Z	4	4
ρc/g cm^−3	1.264	1.240
μ/mm^−1	0.340	0.332
F(000)	1128.0	1128.0
θ range/°	3.94 to 54.24°	3.36 to 50°
Measd/independent	6183	5014
Rint reflections	0.0258	0.0538
obsd reflns [I > 2σ(I)]	6183/4/330	5014/24/338
GOF on F^2	1.026	1.109
R1^b	0.0668	0.0894
wR2^c^,^d	0.1906	0.2362
(Δρ)max,min/E Å^−3	1.27/−1.17	1.29/−0.56

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Table 2 Selected bond lengths (Å) and angles (°) for 1 and 3

1
Ti(1)–O(2)	1.761(2)	Ti(1)–N(1)	2.106(2)
Ti(1)–O(1)	1.783(2)	Ti(1)–N(5)	2.255(2)
Ti(1)–N(4)	2.094(2)	Ti(1)–N(2)	2.293(2)
O(2)–Ti(1)–O(1)	101.42(10)	N(4)–Ti(1)–N(5)	74.38(9)
O(2)–Ti(1)–N(4)	95.06(10)	N(1)–Ti(1)–N(5)	86.43(8)
O(1)–Ti(1)–N(4)	101.54(9)	O(2)–Ti(1)–N(2)	91.38(9)
O(2)–Ti(1)–N(1)	100.58(9)	O(1)–Ti(1)–N(2)	164.15(9)
O(1)–Ti(1)–N(1)	94.27(9)	N(4)–Ti(1)–N(2)	86.44(8)
N(4)–Ti(1)–N(1)	155.09(9)	N(1)–Ti(1)–N(2)	74.00(8)
O(2)–Ti(1)–N(5)	165.49(9)	N(5)–Ti(1)–N(2)	78.25(8)
O(1)–Ti(1)–N(5)	90.61(9)
3
Ti(1)–O(2)	1.764(3)	Ti(1)–N(1)	2.109(4)
Ti(1)–O(1)	1.787(3)	Ti(1)–N(4)	2.264(4)
Ti(1)–N(3)	2.103(4)	Ti(1)–N(2)	2.304(4)
O(2)–Ti(1)–O(1)	101.50(18)	N(3)–Ti(1)–N(4)	74.27(14)
O(2)–Ti(1)–N(3)	95.35(16)	N(1)–Ti(1)–N(4)	86.24(15)
O(1)–Ti(1)–N(3)	101.51(16)	O(2)–Ti(1)–N(2)	91.37(16)
O(2)–Ti(1)–N(1)	100.58(16)	O(1)–Ti(1)–N(2)	164.19(15)
O(1)–Ti(1)–N(1)	94.32(16)	N(3)–Ti(1)–N(2)	86.21(14)
N(3)–Ti(1)–N(1)	154.82(16)	N(1)–Ti(1)–N(2)	74.11(14)
O(2)–Ti(1)–N(4)	165.64(16)	N(4)–Ti(1)–N(2)	78.26(14)
O(1)–Ti(1)–N(4)	90.47(15)

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The single crystal analysis revealed that 1 crystallizes in monoclinic crystal system of the P2₁/c space group. The central Ti(IV) ion possesses a distorted octahedral coordination environment with four nitrogen atoms from two bidentate L1⁻ anions and two oxygen atoms from isopropoxide groups, which are in a cis arrangement. The bond lengths between titanium atom and donor imine nitrogen atoms (Ti1–N2 = 2.293(2) Å, and Ti1–N5 = 2.255(2) Å) are apparently longer than those of the Ti–N(pyrrolyl) distances (Ti1–N1 = 2.106(2) Å, and Ti1–N4 = 2.094(2) Å). Compared with the other six-coordinated titanium complexes (Ti–N(imine) = 2.282 Å, Ti–N(pyrrolyl) = 2.136 Å),⁹ the Ti–N(imine) and Ti–N(pyrrolyl) distances in 1 are much shorter. One donor imine nitrogen atom of the ligand and one oxygen atom are in trans arrangement, with bond angles of 86.43(8)° (N1–Ti1–N5) and 100.58(9)° (N1–Ti1–O2), summing to 187.0°. The atoms N1, N2, N4 and O1 are almost coplanar, with the bond angles of 101.54(9)° (O1–Ti1–N4), 86.44(8)° (N2–Ti1–N4), 74.00(8)° (N1–Ti1–N2) and 91.38(9)° (O2–Ti1–N2), respectively, summing to 353.36°, with the deviation being 6.6° compared with 360°.

Fig. 3 Cell survivals in response to complexes 1–4: (a) towards cell HCT-116. (b) Towards cell PC3. (c) Towards cell MCF-7.

The crystal structure of 3 is almost identical to that of 1. The Ti(IV) center which is coordinated by two deprotonated ligands L4⁻ and two oxygen atoms of isopropoxide groups with a cis orientation, is of a distorted octahedral configuration.

Cytotoxicity

The cytotoxicity of 1–4 was studied on HCT-116, PC3 and MCF-7 cells based on the methylthiazolyl-diphenyl-tetrazolium bromide (MTT) assay as described in the experimental section. Complexes 1–4 exhibit variable cytotoxicity activities. Relative IC₅₀ and maximal inhibition values for 1–4 are listed in Table 3. Cell survival in response to 1–4 are presented in Fig. 3. The most promising results were obtained for complex 1. Compared with cisplatin,¹⁰ complex 1 shows an obvious cytotoxic effect towards HCT-116, PC3 and MCF-7 cells, with the IC₅₀ values of 25.03, 13.65 and 14.56 μM, respectively. These IC₅₀ data are close to or better than cisplatin (3.79, 33.3, and 46.9 μM towards HCT-116, PC3 and MCF-7 cells, respectively). In contrast to cisplatin, complexes 2 and 3 show a slightly lower cytotoxicity when tested on HCT-116, PC3 and MCF-7 cells (Table 3); whereas the cytotoxicity of 2 and 3 are much better than the titanocenes reported in the literature.¹⁰ Complex 4 shows a significant less cytotoxicity in comparison to cisplatin,¹⁰ with the IC₅₀ values of 266.5 and 276.3 μM towards HCT-116 and PC3 respectively.

Table 3 Relative IC₅₀ and maximal inhibition values for 1–4

Compound	IC50 (μM)			Maximal inhibition^a (%)
	HCT-116	PC3	MCF-7	HCT-116	PC3	MCF-7
a The concentrations of complexes 1–4 are all 500 μM.b The concentration of 1 is 250 μM.
Ti(O^iPr)2(L1)2 (1)	25.03	13.65	14.56	90	83	78^b
Ti(O^iPr)2(L2)2 (2)	66.9	87.17	53.85	89	90	76
Ti(O^iPr)2(L3)2 (3)	63.8	67.55	53.85	91	83	81
Ti(O^iPr)2(L4)2 (4)	266.5	276.3	—	87	64	57

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The reasons for this different behavior are not clear. However, it is found that a strong bound chelating ligand, which possesses a high hydrolytic stability and is in a favored geometry to give the ideal short Ti–N bonds, could form the titanium complexes with higher cytotoxicity.^4a,f We assumed that the structures of the ligands in 1–4 play a significant role in the activity observed. In 1, 2 and 3, the ligands chelate to the Ti(IV) center in a bidentate fashion, with the pyridine ring (or benzene ring) being vertical to the equatorial plane, giving a very stable octahedron complex. This configuration supports the notion that stableness and the favorable configuration of a chelating ligand are important to the cytotoxicity.^4a,f

The solid state structure of 4 is not available. However, the ethyl benzene group of the L4⁻ ligand of 4 might flap, resulting in the low activity towards the HCT-116, PC3 and MCF-7 cells.

Conclusions

In conclusion, four new complexes Ti(OⁱPr)₂(L1)₂ (1), Ti(OⁱPr)₂(L2)₂ (2), Ti(OⁱPr)₂(L3)₂ (3) and Ti(OⁱPr)₂(L4)₂ (4) were synthesized and characterized. High cytotoxicities were obtained for complexes 1, 2 and 3, indicating that pyrrolyl–titanium(IV) complexes may serve as a new family of antitumor agents towards HCT-116, PC3 and MCF-7 cells.

Experimental section

General considerations

All manipulations of air-sensitive complexes were carried out in a MBraun drybox under a purified nitrogen atmosphere. Anhydrous THF, Hexane and toluene were freshly distilled from purple sodium benzophenone ketone for at least 4 days. ¹H and ¹³C spectra were recorded on Innova-400 spectrometers at ambient temperature using TMS as an internal standard, and chemical shifts were reported in ppm. Elemental analyses for carbon, hydrogen and nitrogen atom were performed on a Carlo-Erba EA1110 CHNO-S microanalyzer.

Cytotoxicity was measured on colorectal cancer cell HCT-116, adenocarcinoma MCF-7 and PC3 using the methylthiazolyldiphenyl tetrazolium bromide (MTT) assay. HCT-116 cells were cultured at 37 °C in a 5% CO₂ atmosphere incubator in modified McCoy's 5A medium (sigma) complemented with 10% fetal bovine serum (FBS, Hyclone) containing 1% penicillin and 1% streptomycin (Sigma). MCF-7 was maintained in RPMI 1640 medium with 10% FBS and PC3 in F-12K medium with 10% FBS. For cytotoxicity assay, HCT-116 cells were seeded into 96-well plates at densities of 3000 cells per well and maintained for 24 h. Next, the cells were incubated with the reagents tested at different concentrations for another 72 h in modified McCoy's 5A medium containing 10% FCS. After that, MTT (5 mg mL⁻¹ in 20 μL) was added and the cells were incubated for additional 4 h. The supernatant was removed, and the precipitates were dissolved in 150 mL of DMSO. The absorbance at 490 nm was measured. Relative IC₅₀ values with standard error of means were determined by a nonlinear regression of a variable slope model. For MCF-7 and PC3, the cells were seeded into 96-well plates at densities of 5000 cells per well for each and operated similar to that described above.

X-ray crystallography

Crystals grown from concentrated solutions at room temperature were quickly selected and mounted on a glass fiber in wax. The data collections were carried out on a Mercury CCD detector equipped with graphite-monochromated Mo Kα radiation by using the φ/ω scan technique at room temperature. The structures were solved by direct methods with SHELXS-97.¹¹ The hydrogen atoms were assigned with common isotropic displacement factors and included in the final refinement by use of geometrical restraints. A full-matrix least-squares refinement on F² was carried out using SHELXL-97.¹¹

Syntheses of complexes 1–4

Ti(OⁱPr)₂(L1)₂ (1). To a solution of Ti(ⁱOPr)₄ (0.2842 g, 1.0 mmol) in tetrahydrofuran (2 mL), HL1 (0.3702 g, 2.0 mmol) in tetrahydrofuran was added at −35 °C. After stirring at room temperature for 24 h, the volatiles were removed under reduced pressure to give a yellow solid. The product was obtained as light yellow block crystals after crystallized from tetrahydrofuran/hexane. Yield: 87%. ¹H NMR (300 MHz, CDCl₃) δ 8.44 (s, 2H, N=CH), 7.87 (s, 2H, pyridine-H), 7.47 (t, 2H, pyridine-H), 7.19 (s, 2H, pyridine-H), 7.07 (d, 2H, pyridine-H), 6.82 (d, 2H, pyrrole-H), 6.48 (s, 2H, pyrrole-H), 6.18 (s, 2H, pyrrole-H), 4.59–4.44 (m, 2H, OCH), 4.05 (m, 4H, NCH₂), 1.03 (d, 6H, CH₃), 0.95 (d, 6H, CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 160.69, 157.96, 149.11, 137.46, 136.45, 136.27, 123.71, 122.12, 114.55, 110.27, 79.61, 61.39, 25.72, 25.60. Anal. calc. for C₂₈H₃₄N₆O₂Ti: C, 62.92; H, 6.41; N, 15.72. Found: C, 62.57; H, 6.27; N, 16.01%.

Ti(OⁱPr)₂(L2)₂ (2). Following a procedure similar to that described for the preparation of 1, treatment of Ti(ⁱOPr)₄ (0.2842 g, 1.0 mmol) in tetrahydrofuran (2 mL) with 2 equiv. of HL2 (0.3404 g, 2.0 mmol) in tetrahydrofuran (5 mL) at −35 °C. The reaction mixture was stirred at room temperature overnight after which time volatiles were removed under reduced pressure. The product was obtained as yellow solid. Yield: 85%. ¹H NMR (300 MHz, CDCl₃) δ 7.88 (s, 2H, N=CH), 7.41 (s, 8H, Ar-H), 7.15(m, 4H, Ar-H + pyrrole-H), 6.61 (s, 2H, pyrrole-H), 6.38 (s, 2H, pyrrole-H), 4.85 (s, 2H, OCH), 4.27 (d, 2H, NCH₂), 1.36–1.32 (m, 6H, CH₃), 1.27 (d, 6H, CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 157.68, 136.23, 137.41, 136.34, 129.26, 128.32, 127.39, 114.14, 110.09, 79.54, 25.71, 25.74. Anal. calc. for C₂₈H₃₂N₄O₂Ti: C, 66.67; H, 6.39; N, 11.11. Found: C, 66.59; H, 6.81; N, 11.07%.

Ti(OⁱPr)₂(L3)₂ (3). Following a procedure similar to that described for the preparation of 1, treatment of Ti(ⁱOPr)₄ (0.2842 g, 1.0 mmol) in tetrahydrofuran (2 mL) with 2 equiv. of HL3 (0.3684 g, 2.0 mmol) in tetrahydrofuran (5 mL) at −35 °C. The reaction mixture was stirred at room temperature overnight after which time volatiles were removed under reduced pressure. The product crystallized from tetrahydrofuran/hexane to give yellow crystals. Yield: 89%. ¹H NMR (300 MHz, CDCl₃) δ 8.48 (s, 2H, N=CH), 7.94 (s, 4H, Ar-H), 7.54 (s, 2H, Ar-H), 7.16 (s, 2H, Ar-H), 6.96 (s, 2H, Ar-H), 6.89 (m, 2H, pyrrole-H), 6.56 (t, 2H, pyrrole-H), 6.16 (d, 2H, pyrrole-H), 5.05 (dt, 2H, OCH), 1.32 (d, 12H, CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 159.12, 138.31, 137.69, 136.82, 129.48, 128.66, 127.58, 114.31, 110.41, 79.86, 26.12, 26.02. Anal. calc. for C₃₀H₃₆N₄O₂Ti: C, 67.67; H, 6.81; N, 10.52. Found: C, 67.98; H, 6.46; N, 11.20%.

Ti(OⁱPr)₂(L4)₂ (4). This complex was prepared as a red solid from reaction of HL4 (0.3965 g, 2.0 mmol) in tetrahydrofuran (5 mL) with Ti(ⁱOPr)₄ (0.2842 g, 1.0 mmol) in tetrahydrofuran (2 mL) at −35 °C, and recrystallized from tetrahydrofuran/hexane by a similar procedure as in the synthesis of 1. Yield: 87%. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 2H, N=CH), 7.43 (s, 2H, Ar-H), 7.19 (d, 4H, Ar-H), 7.17–7.11 (m, 2H, Ar-H), 6.97 (d, 4H, Ar-H + pyrrole-H), 6.55 (d, 2H, pyrrole-H), 6.31 (d, 2H, pyrrole-H), 4.92–4.80 (m, 2H, OCH), 3.13 (t, 2H, CH₂-pyridine), 3.02–2.93 (m, 2H, CH₂-pyridine), 2.83–2.69 (m, 2H, NCH₂), 2.56–2.46 (m, 2H, NCH₂), 1.22 (t, 6H, CH₃), 1.15 (d, 6H, CH₃). ¹³C NMR (101 MHz, CDCl₃) δ 158.93, 139.65, 137.38, 136.46, 129.15, 128.35, 126.18, 113.66, 110.31, 79.87, 60.02, 38.03, 25.92, 25.79. Anal. calc. for C₃₂H₄₀N₄O₂Ti: C, 68.56; H, 7.19; N, 9.99. Found: C, 68.32; H, 7.07; N, 9.74%.

Acknowledgements

We thank Professor Zhijun Zhang of Suzhou Institute of Nano-tech and Nano-bionics for assistance with cytotoxicity measurement. The authors appreciate the financial supports of Natural Science Foundation of China (21272167 and 21201127), and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

References

1. (a) C. H. Zhou, Y. Y. Zhang, C. Y. Yan, K. Wan, L. L. Gan and Y. Shi, Anti-Cancer Agents Med. Chem., 2010, 10, 371; (b) C. G. Hartinger and P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391; (c) P. C. A. Bruijnincx and P. J. Sadler, Adv. Inorg. Chem., 2009, 61, 1; (d) S. K. Hadjikakou and N. Hadjiliadis, Coord. Chem. Rev., 2009, 253, 235; (e) S. H. van Rijt and P. J. Sadler, Drug Discovery Today, 2009, 14, 1089; (f) P. C. A. Bruijnincx and P. J. Sadler, Curr. Opin. Chem. Biol., 2008, 12, 197; (g) K. Strohfeldt and M. Tacke, Chem. Soc. Rev., 2008, 37, 1174; (h) M. A. Jakupec, M. Galanski, V. B. Arion, C. G. Hartinger and B. K. Keppler, Dalton Trans., 2008, 183; (i) I. Ott and R. Gust, Arch. Pharm. Chem. Life Sci., 2007, 340, 117; (j) Y. K. Yan, M. Melchart, A. Habtemariam and P. J. Sadler, Chem. Commun., 2005, 4764; (k) B. Desoize, Anticancer Res., 2004, 24, 1529.
2. (a) Platinum and Other Coordination Compounds in Cancer Chemotherapy, ed. M. Nikolini, Martinus-Nijhoff, Boston, MA, 1988; (b) V. Cepeda, M. A. Fuertes, J. Castilla, C. Alonso, C. Quevedo and J. M. Perez, Anti-Cancer Agents Med. Chem., 2007, 7, 3; (c) A. S. Abu-Surrah and M. Kettunen, Curr. Med. Chem., 2006, 13, 1337.
3. (a) P. M. Abeysinghe and M. M. Harding, Dalton Trans., 2007, 3474; (b) F. Caruso and M. Rossi, Mini-Rev. Med. Chem., 2004, 4, 49; (c) G. Kelter, N. J. Sweeney, K. Strohfeldt, H. H. Fiebig and M. Tacke, Anti-Cancer Drugs, 2005, 16, 1091; (d) C. V. Christodoulou, A. G. Eliopoulos, L. S. Young, L. Hodgkins, D. R. Ferry and D. J. Kerr, Br. J. Cancer, 1998, 77, 2088.
4. (a) E. Y. Tshuva and D. Peri, Coord. Chem. Rev., 2009, 253, 2098; (b) S. Meker, C. M. Manna, D. Peri and E. Y. Tshuva, Dalton Trans., 2011, 40, 9082; (c) J. Schur, C. M. Manna, A. Deally, R. W. Koster, M. Tacke, E. Y. Tshuva and I. Ott, Chem. Commun., 2013, 49, 4785; (d) S. Gómez-Ruiza, T. P. Stanojkovićb and G. N. Kaluđerovićc, Appl. Organomet. Chem., 2012, 26, 383; (e) C. M. Manna, G. Armony and E. Y. Tshuva, Chem. – Eur. J., 2011, 17, 14094; (f) C. M. Manna, O. Braitbard, E. Weiss, J. Hochman and E. Y. Tshuva, ChemMedChem, 2012, 7, 703; (g) D. Peri, S. Meker, C. M. Manna and E. Y. Tshuva, Inorg. Chem., 2011, 50, 1030; (h) C. M. Manna and E. Y. Tshuva, Dalton Trans., 2010, 39, 1182; (i) D. Peri, S. Meker, M. Shavit and E. Y. Tshuva, Chem. – Eur. J., 2009, 15, 2403; (j) E. Y. Tshuva and J. A. Ashenhurst, Eur. J. Inorg. Chem., 2009, 2203; (k) M. Shavit, D. Peri, C. M. Manna, J. S. Alexander and E. Y. Tshuva, J. Am. Chem. Soc., 2007, 129, 12098; (l) A. Tzubery and E. Y. Tshuva, Inorg. Chem., 2011, 50, 7946; (m) C. M. Manna, G. Armony and E. Y. Tshuva, Inorg. Chem., 2011, 50, 10284.
5. (a) F. Y. Zhou, M. S. Lin, L. Li, X. Q. Zhang, Z. Chen, Y. H. Li, Y. Zhao, J. Wu, G. M. Qian, B. Hu and W. Li, Organometallics, 2011, 30, 1283; (b) Z. Chen, J. Wu, Y. M. Chen, L. Li, Y. Z. Xia, Y. H. Li, W. Liu, T. Lei, L. J. Yang, D. D. Gao and W. Li, Organometallics, 2012, 31, 6005; (c) M. S. Lin, W. Liu, Z. Chen, L. J. Yang, H. Pei, J. Wu, X. Y. Wan, T. Lei and Y. H. Li, RSC Adv., 2012, 2, 3451; (d) A. L. Odom, Dalton Trans., 2005, 225; (e) Y. H. Li, Y. Shi and A. L. Odom, J. Am. Chem. Soc., 2004, 126, 1794; (f) G. F. Zi, F. Zhang, L. Xiang, Y. Chen, W. Fang and H. Song, Dalton Trans., 2010, 39, 4048; (g) G. F. Zi, X. Liu, L. Xiang and H. B. Song, Organometallics, 2009, 28, 1127.
6. R. Q. Li, B. Moubaraki, K. S. Murray and S. Brooker, Dalton Trans., 2008, 6014.
7. B. C. Xu, T. Hu, J. Q. Wu, N. H. Hu and Y. S. Li, Dalton Trans., 2009, 8854.
8. G. L. Regina, R. Silvertri, M. Artico, A. Lavecchia, E. Novellino, Q. Befani, P. Turini and E. Agostinelli, J. Med. Chem., 2007, 50, 922.
9. (a) D. J. Timothy, B. Jaume, C. J. Patrick and W. J. Patrick, Org. Lett., 2001, 3, 699; (b) B. J. Timothy, O. M. A. Leigh, R. A. Mark, S. M. Robin, A. M. Todd and M. K. Sarah, Inorg. Chem., 2008, 47, 10708.
10. G. Kelter, N. J. Sweeney, K. Strohfeldt, H. Fiebig and M. Tacke, Anticancer Drugs, 2005, 16, 1091.
11. G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008, 64, 112.

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Footnote

† Electronic supplementary information (ESI) available. CCDC reference numbers 862428 and 870370 for complexes 1 and 3, respectively. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra45823g

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