Synthesis, characterization, in vivo antitumor

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Synthesis, characterization, in vivo antitumor properties of the cluster rhenium compound with GABA ligands and its synergism with cisplatin† Alexander V. Shtemenko,*a Philippe Collery,b Natalia I. Shtemenko,c Konstantin V. Domasevitch,*d Elena D. Zabitskayac and Alexander A. Golichenkoa Received 25th November 2008, Accepted 8th April 2009 First published as an Advance Article on the web 8th May 2009 DOI: 10.1039/b821041a A new dirhenium(III) complex cis-[Re2 (GABA)2 Cl5 (H2 O)]Cl·2H2 O with zwitterionic g-aminobutyrate ligands was prepared and characterized by spectral methods and crystallography. The structure of the ˚ ) involving cis-oriented double compound is comprised of dinuclear complex cations (Re–Re 2.2437(3) A carboxylate bridges, four equatorial chloride ions and two weakly bonded aqua and chloride ligands in ˚ ). Antitumor properties the axial positions at two rhenium centers (Re–O 2.363(3), Re–Cl 2.6735(12) A of the complex were studied in the model of tumor growth with the use of Wistar rats inoculated by tumor carcinoma Guerink cells. The introduction of the compound in dosage according to the scheme of antioxidant therapy, inhibited the tumor growth by ca. 60% and led to stabilization of red blood cells in the tumor-bearing organisms. The combined introduction of the compound and cisplatin had a significant impact on the tumor growth and the disappearance of the tumors in most of the animals.

Introduction An important paradigm for the development of new antitumor pharmaceuticals is represented by dinuclear paddle-wheel carboxylate complexes of rhodium, ruthenium and rhenium.1 It was postulated that such species could bind to DNA and inhibit DNA replication and protein synthesis,2 in a manner similar to cisplatin.3,4 Among this group, the dirhenium(III) compounds may be recognized as especially promising candidates for clinical development due to their very low toxicity.5 This issue is particularly important considering the severe limitations for clinical use of cisplatin originating in its neuro-, hepato- and nephrotoxicity.6 However, since the discovery of the antitumor activity of the Re2 (EtCOO)2 Br4 (H2 O)2 complex,7 this field has remained unexplored for decades. Recently we have shown that dirhenium(III) aliphatic carboxylates inhibit tumor growth by 20–30% when introduced in the liposome form to tumor-bearing animals.8 At the same time, these species reveal potential as biochemical modulators of cisplatin action, which enhance efficiency and decrease toxicity of the latter. The combined use of cisplatin and the dirhenium component led to the interruption of the tumor growth and the disappearance of cancer cells in most of the experimental animals. A new challenge is associated with the ability of the dirhenium carboxylates to stabilize red blood cells (RBC) against haemolysis, as was provided by either in vitro or in vivo studies.8 This property is especially a Department of Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin Ave. 8, Dnipropetrovs’k 49005, Ukraine. E-mail: [email protected], [email protected] b Service de Canc´erologie, Polyclinique Maymard, Bastia, France c Dnipropetrovs’k Nation University, Gagarin Ave. 72, 49050, Dnipropetrovs’k, Ukraine d Department of Inorganic Chemistry, Kiev University, Volodimirska Street 64, Kiev 01033, Ukraine. E-mail: [email protected] † CCDC reference number 710776. For crystallographic data in CIF or other electronic format see DOI: 10.1039/b821041a

5132 | Dalton Trans., 2009, 5132–5136

valuable considering dose-limiting haematotoxic side-effects of chemotherapy. The paddle-wheel structure of dirhenium(III) complexes provides very flexible approaches towards substitution and functionalization, including tuning the number of bridging carboxylate,9 amidate10 or amidinate11 ligands and additional monodentate coligands such as halogenides. It also allows for the introduction of additional binding sites within the structure of the organic portion, and varying the charge of the complex. These factors may be important considering the interaction of the dirhenium species with nucleobases and binding to DNA. Similarly to dirhodium compounds,3,12 two initial steps of such interaction may involve coordination at the axial position of the cluster (which is trans- to the quadruple Re–Re bond) followed by trans/cis rearrangement with substitution of the equatorial group. Thus, the relative lability of the equatorial ligand (for example, chloride vs. bridging carboxylate) is essential for ease of substitution, while weak interactions at the axial positions are sensitive to the overall charge of the complex. In this view, a suitable molecular arrangement may be found for the cationic complex, combining around the dirhenium core, a set of bridging carboxylate and more labile chloride ligands. In this context we have examined zwitterionic g-aminobutyrate (GABA) allowing for the preparation of cationic [Re2 (GABA)2 Cl4 ]2+ species. It was important to explore whether the introduction of the amino acid would influence the antitumor activity. Herein we report synthesis, structure and antitumor properties of a new dirhenium(III) cluster compound.

Results and discussion Synthesis and properties A common procedure for the synthesis of dirhenium(III) carboxylates involving the reduction of perrhenate ions in the presence of a corresponding acid (using SnII , NaH2 PO2 or Ph3 P as the reducing agents)9,13 was insufficient for the preparation of the This journal is © The Royal Society of Chemistry 2009

aminocarboxylate complex due to the high solubility of the product. Therefore the proposed route (Scheme 1) includes isolation of the ionic derivative [GABAH]2 Re2 Cl8 (I) as a suitable starting material14 followed by the interconversion of the GABAH+ cation to the inner sphere carboxylate ligand with the loss of HCl. The latter transformation is feasible by thermal treatment either in the solid state or in acetonitrile solution, and it may be readily monitored by UV-Vis spectra.

acetone and acetonitrile acidified with HCl but is less soluble in other polar solvents. It instantly undergoes hydrolysis in aqueous solutions with a lower acid concentration and in non-acidified alcohols. Compound II is a blue-green crystalline solid, which is stable in the air at room temperature. It is soluble in the most polar organic solvents but insoluble in water. In the solution it slowly transforms into the cis-form. Compound III forms dark-green hygroscopic crystals, which are readily soluble in water, alcohols, DMF, and DMSO, but are less soluble in acetone and acetonitrile, and insoluble in nitromethane and non-polar organic solvents. Aqueous solutions of this compound remain unchanged for a long time. Crystal structure

Scheme 1 Solid-state and solution interconversions of [GABAH]2 Re2 Cl8 yielding trans- and cis-dicarboxylate species.

For compound I this transition was detected from DTA (differential thermal analysis) data, which reveal an endothermic effect and 8.4% mass loss at 220 ◦ C corresponding to elimination of 2 mol of HCl (further decomposition with loss of the organic ligand proceeds at 260 ◦ C) together with the structural rearrangement in the coordination sphere around Re2 6+ yielding trans-[Re2 (GABA)2 Cl4 ]Cl2 (II), as is reflected by characteristic UVVis absorption spectra of the product (Fig. 1). A similar process proceeds at much lower temperature by heating of I in solution. In this case the donor ability of the solvent was essential for further inner-sphere isomerization resulting in a cis-dicarboxylate complex. After recrystallization from acetone the product was identified as cis-[Re2 (GABA)2 Cl5 (H2 O)]Cl·2H2 O (III).

The structure of III is ionic and is based upon complex cations cis-[Re2 (GABA)2 Cl5 (H2 O)]+ (Fig. 2), non-coordinated chloride anions and water molecules. The outer sphere chloride is involved in a relatively strong and directional hydrogen bond with coordinated water molecules and alkylammonium groups (H ◊ ◊ ◊ Cl 2.23– ˚ ; ∠O(N)H ◊ ◊ ◊ Cl 165.8–174.3◦ ) thus supporting complex 2.29 A connectivity for the 3D H-bonded framework. This is the first structure of a dirhenium aminocarboxylate, while some related dinuclear compounds comprising of zwitterionic amino acids were reported for molybdenum, chromium and rhodium.15

Fig. 2 cis-Dicarboxylato complex cation [Re2 (O2 CCH2 CH2 CH2 NH3 )2 Cl5 (H2 O)]+ constituting the structure of III (40% probability thermal ellipsoids. Outer sphere chloride ion and two water molecules are omitted for clarity).

Fig. 1 UV-Vis spectra of trans-[Re2 (GABA)2 Cl4 ]Cl2 ( ), (GABAH)2 Re2 Cl8 (---) and cis-[Re2 (GABA)2 Cl5 (H2 O)]Cl (-·-) in methanol solution (acidified with 1% of 10 M aqueous HCl).

Dark-blue crystals of I are stable under argon but decompose in wet air. The compound is soluble in 3 M HCl, and also in alcohols, This journal is © The Royal Society of Chemistry 2009

˚ ) is typical for related The quadruple Re–Re bond (2.2437(3) A 9,16 and the environment of each of the dicarboxylato clusters, rhenium ions comprises of two chlorides and two oxygen atoms of the zwitterionic carboxylate ligands (Table 1). Distorted octahedral coordination of Re1 is completed with the weakly ˚ ), in a trans-position bonded chloride ion (Re1–Cl5 2.6735(12) A to the Re–Re bond. Weakness of such axial interactions and ease of the ligand exchange in these positions were best illustrated by substitution of the chloride ligand for a water molecule at ˚ ). This may be compared to a the Re2 ion (Re2–O5 2.363(3) A similar weak binding of N- or O-donors, which is characteristic of dicarboxylatodirhenium compounds16,17 and is even more appreciable for cationic tetracarboxylatodirhenium species commonly accommodating a pair of chloride anions at both axial sites (Re–Cl ˚ ).18 Therefore, the presence of the side alkylammonium 2.48–2.52 A groups, which provide a total positive charge for the dirhenium Dalton Trans., 2009, 5132–5136 | 5133

˚ ) and angles (◦ ) for III Table 1 Selected bond lengths (A

Table 2 Weights of isolated tumors and morphological forms of RBC in blood of animals on the 21st day after tumor cells inoculation

Re1–Re2 Re1–O2 Re1–O4 Re1–Cl1 Re1–Cl2 Re1–Cl5

2.2437(3) 2.042(3) 2.049(3) 2.3048(13) 2.3207(12) 2.6735(12)

Re2–O1 Re2–O3 Re2–O5 Re2–Cl3 Re2–Cl4

2.039(3) 2.035(3) 2.363(3) 2.3233(12) 2.3142(12)

O2–Re1–O4 O2–Re1–Re2 O2–Re1–Cl1 O4–Re1–Cl1 Re2–Re1–Cl1 Cl1–Re1–Cl2 O2–Re1–Cl5 Re2–Re1–Cl5 Cl2–Re1–Cl5

88.83(13) 89.17(8) 87.00(10) 167.52(9) 102.16(4) 92.44(5) 80.34(9) 165.75(3) 87.65(4)

O3–Re2–O1 O3–Re2–Re1 O1–Re2–Re1 O3–Re2–Cl4 Re1–Re2–Cl4 Cl4–Re2–Cl3 O1–Re2–O5 Re1–Re2–O5 Cl3–Re2–O5

89.84(13) 89.62(8) 89.79(8) 165.71(9) 104.43(3) 90.08(5) 78.46(13) 161.96(9) 88.38(10)

moieties in III, may be regarded as a factor for enhancing the ability of the dirhenium cluster for axial interactions. Thus, in a closely related cis-[Re2 (AcO)2 Cl5 ]+ cation17 the axial Re–Cl bond ˚ ), while strong trans-influence of the was even longer (2.77 A quadruple bond led to elimination of a second axial ligand at all. Antitumor properties of III In the control group, the growth of T8 (Guerink carcinoma) tumors during 21 days was very rapid and the tumors reached approximately 1/3 of the animal weight on the last day of the experiment (Fig. 3). 25–30% of the animals died during 18–21 days after the tumor transplantation—which is in line with this type of tumor.

Fig. 3 Dynamics of tumor growth in control groups (---) and in groups with III introduction ( ).

Introduction of III alone (in dosage according to the scheme of antioxidant therapy) inhibited the tumor growth by approximately 60% (Fig. 3, Table 2). No animal mortality was registered in this group. The own antitumor effect of III is stronger than the effect found under the same model for dirhenium(III) tetraisobutyrate dichloride (by 28–30%) or cis-di(1-adamantylcarboxylate) tetrachloride (by 20–25%).8 We suppose that cationic III may 5134 | Dalton Trans., 2009, 5132–5136

Group

Weights of isolated Discocytes Echinocytes Damaged tumors/g (%) (%) RBC (%)

Control — T8 44.9 ± 11.8 T8 + III 25.3 ± 5.3 T8 + cisPt 9.9 ± 2.6 T8 + cisPt + III 5.9 ± 1.2

65.0 ± 6.1 8.5 ± 1.9 50.7 ± 5.1 46.4 ± 3.2 65.4 ± 4.4

23.3 ± 3.1 52.6 ± 3.7 26.7 ± 1.6 25.0 ± 3.8 15.8 ± 0.9

11.7 ± 2.2 59.0 ± 4.5 29.5 ± 2.4 28.6 ± 4.0 18.8 ± 1.1

interact with DNA more effectively than simple alkylcarboxylates. Also, the positive charge of III may facilitate DNA binding as electrostatic interactions play a leading role in the binding of platinides to polynucleotides (DNA and RNA), which has been shown in numerous studies.23,24 Introduction of cisplatin (cisPt) led to a significant decrease of tumor growth, as compared to the T8 group. The mortality remained at the same level (20–30%), nevertheless, the weight of the tumors was much less (Table 2). An especially significant effect was observed for the group, where cisplatin and III were introduced together. In this case deaths were not registered for the entire 21 day period of the experiment, while the reduction of the tumor growth was more effective than those in T8 + cisPt group and many of the experimental animals had no tumors at all. This kind of combined chemotherapy is effective comparable to the case of cisPt. However, the effect of III is still weaker than those of the above dirhenium tetracarboxylate complexes and the weights of isolated tumors were approximately twice the size. Development of malignancy caused a morphological shift in RBC population: from the major group of discocytes to the side of damaged RBC through reversible forms (echinocytes). Introduction of III enhanced quantities of discocytes and echinocytes on a rather high level, nevertheless, it prevented the growth of the tumor much lower than cisPt. In the experiment with cisPt, introduction of the rhenium complex also led to the practically normal morphological picture of RBC, and moreover, to the reduction of damaged cell quantities. This is parallel with the data for animal mortality in the experimental groups. It is clear that properties of III are different from those found for dirhenium(III) tetraisobutyrate dichloride.8 A possible reason may involve the differences in mode of interaction of these species with phosphatidylcholines, the main components of biological membranes. In the UV-Vis spectra of Re2 (Pri COO)4 Cl2 (CHCl3 solution), the band at 20 000 cm-1 corresponds to the d → d* electron transition of dirhenium tetra-m-carboxylates. Addition of phosphatidylcholine causes the appearance of a new absorption in the region of 15 600–14 000 cm-1 , which is characteristic for dirhenium(III) m-phosphate complexes and reflects the substitution of the carboxylate ligands with phosphate groups of phosphatidylcholine. Gradual increase of its intensity was accompanied by a decrease of 20 000 cm-1 absorption. Such shift of the d → d* absorption suggests monodentate coordination of phosphatidyl choline in the equatorial positions of the dirhenium core. In the case of the formation of liposomes from III, no shifts of the d → d* absorption occurred. This is suggestive of the substitution of chloride by phosphate ligands, while preserving both cis-oriented carboxylic bridges. Such a difference in the This journal is © The Royal Society of Chemistry 2009

substitution of carboxylates on phosphates in two types of dirhenium compounds may be explained by the strong transinfluence of the carboxylic ligands.19 The mechanism of action of cisPt is not absolutely clear, nevertheless it is a well studied compound. Only 5% of cisPt binds to DNA and stops replication. As cisplatin is a multifunctional molecule, it can bind to a lot of targets in the living cell.25 Re-complexes are more multifunctional than cisPt and more multitargeting should be expected. Some rhenium(I)–carborane derivatives, for example, show high affinity to estrogen receptors.26 In this work, the more bulky ligands, rather than the rhenium core, were responsible for the affinity. Nevertheless, such type of activity of rhenium compounds, together with the possibility of manipulating the ligands nature in rhenium clusters, provides novel interventions based on estrogen receptor targeting. Also, as some modulators of the cisplatin mechanism of action did,25 III may enhance cisplatin accumulation, interfere with the glutathione system, change intracellular ATP-level or manipulate with other biochemical pathway(s) of the cancer cells, that altogether may lead to mighty synergistic effect of both compounds.

Conclusions The new dirhenium(III) dicarboxylate complex III possesses appreciable antitumor activity, which is higher than those of the previously investigated alkylcarboxylates. The compound also reveals a potential as a modulator of cisplatin mechanism of action and as a stabilizer of RBC in tumor-bearing organisms. This may find further applications for the development of new antitumor dirhenium(III) species and suggests a protocol for combined Re–cisPt chemotherapeutic procedures. Studies for the synthesis of active dirhenium(III) compounds involving zwitterionic aminocarboxylate ligands are in progress.

Experimental Synthesis of [GABAH]2 Re2 Cl8 (I) 1.50 g (5.8 mmol) of LiReO4 was dissolved in a mixture of 5 ml of water and 0.5 ml 35% HCl; then 4.00 g (38.8 mmol) of GABA and 5.00 g (22 mmol) of SnCl2 ·2H2 O were added and the mixture was continually stirred for 1.5 h at 90 ◦ C without air access. After this, 30 ml 35% HCl was added and the solution was refluxed for 20 h under argon. The reaction mixture was cooled to 0 ◦ C and saturated with HCl gas. The precipitate of the amino acid hydrochloride was filtered off and the filtrate was left for crystallization for 7 d at 0 ◦ C. The dark-blue crystalline product (2.15 g, 85%) was filtered and dried in air. Anal. for I, C8 H20 Cl8 N2 O4 Re2 . Calc. (%):C, 11.11; H, 2.33; N, 3.24; Re, 43.09. Found (%): C, 10.92; H, 2.21; N, 3.14; Re 42.96. IR-spectrum (n, cm-1 ): 1720 (n(CO)), 1540 (n(NH3 + )), 3160 (d(NH3 + )). UV-Vis (CH3 OH) (n, cm-1 (e, L mol-1 cm-1 )): 14 300 (1520) 32 500 (5000).

Anal. for II, C8 H18 Cl6 N2 O4 Re2 . Calc. (%): C, 12.14; H, 2.29; N, 3.54; Re, 47.06. Found (%): C, 12.01; H, 2.12; N, 3.28; Re, 46.84. IR-spectrum (n, cm-1 ): 1340 (n sym (CO)), 1480 (n asym (CO)), 1540 (n(NH3 + )), 3160 (d(NH3 + )). UV-Vis (CH3 OH) (n, cm-1 (e, L mol-1 cm-1 )): 11 000 (440), 15 000 (1000), 21 000–24 500. Synthesis of cis-[Re2 {GABA}2 Cl5 (H2 O)]Cl·2H2 O (III) 1.00 g (1.16 mmol) of [GABAH]2 Re2 Cl8 was dissolved in 20 ml of acetonitrile and the solution was concentrated to half its initial volume using a rotary evaporator. A new portion (10 ml) of the solvent was added and the solution was evaporated to half its initial volume. This procedure was repeated five times. The dark-green crystals obtained were filtered, washed with two 5 ml portions of cold acetonitrile and diethyl ether and dried in vacuum at 80 ◦ C. The product (0.85 g) was recrystallized from acetone yielding complex III in 86% yield. Anal. for III, C8 H24 Cl6 N2 O7 Re2 . Calc. (%): C, 11.36; H, 2.86; N, 3.31; Re, 44.05. Found (%): C, 11.21; H, 2.74; N, 3.19; Re 43.88. IR-spectrum (n, cm-1 ): 1340, n sym (CO); 1480, n asym (CO); 1540, n(NH3 + ); 3150, d(NH3 + ); 3450, n(H2 O). UV-Vis (CH3 OH) (n, cm-1 (e, L mol-1 cm-1 )): 15 870 (725), 21 500 (120), 31 920 (3610). Crystallography† Crystallographic measurements were made at 220 K using a Siemens SMART area-detector diffractometer (Mo Ka, l = ˚ , correction for absorption using SADABS).20 The 0.71073 A structure was solved by direct methods and subsequent Fourier difference techniques and refined by full-matrix least-squares on F 2 using the programs SHELXS-97 and SHELXL-97.21 The OH and NH hydrogen atoms were located from the difference Fourier synthesis and then fixed, while positions of the CH2 groups were calculated geometrically. Crystal data for cis-[Re2 {GABA}2 Cl5 (H2 O)]Cl·2H2 O (III): C8 H24 Cl6 N2 O7 Re2 , M = 845.39, orthorhombic, space group ˚, P21 21 21 , a = 9.2599(5), b = 12.7434(6), c = 19.1876(10) A ˚ 3 , Z = 4, Dcalc = 2.480 g cm-3 , m(Mo Ka) = V = 2264.2(2) A 11.420 mm-1 , 4424 unique reflections of 13 052 measured, 2q max = 52.0◦ , Rint = 0.023, 226 refined parameters, R1 = 0.017, wR2 = 0.035, GOF = 0.991 based upon 4094 unique reflections with I > 2s(I). Absolute structure parameter x = -0.010(5). CCDC reference number 710776.† Preparation of liposomes Liposomes were prepared from phosphatidylcholine (Reagent, Ukraine) and analyzed following the literature procedure.22 UV-Vis spectra of Re(III) binuclear compounds (0.1 mmol) themselves, and with addition of phosphatidylcholine (0.25 mmol) and obtained liposomal forms were recorded using chloroform solutions (Specord M-40 spectrophotometer; 45 000–11 000 cm-1 range). Animal model

Synthesis of trans-[Re2 (GABA)2 Cl4 ]Cl2 (II) 1.00 g (1.16 mmol) [GABAH]2 Re2 Cl8 was heated for 2 h at 220 ◦ C in a slow stream of pure argon. A blue-green solid product (0.92 g) was obtained in a quantitative yield after elimination of HCl gas. This journal is © The Royal Society of Chemistry 2009

Wistar rats were inoculated by tumor carcinoma Guerink (T8) cells. Tumor transplantation was performed by subcutaneous injection of 20% Guerin’s carcinoma cell suspension in the thigh area. Dalton Trans., 2009, 5132–5136 | 5135

The single intraperitoneal administration of cisPt, in a dose of 8 mg kg-1 , was made on the 9th day after the tumor inoculation in the groups (T8 + cisPt) and (T8 + cisPt + III). The intraperitoneal administration of III, in a dose of 7 mM kg-1 according to the scheme of antioxidant therapy, was started on the third day after inoculation of tumor cells and was repeated every two days until 21 days in groups (T8 + III) and (T8 + cisPt + III). Volumes of the tumors were estimated in vivo every day in all experiments and groups from day 7. On day 21 the animals were sacrificed under chloroform narcosis according to the rules of Ethic Committee and the tumors were isolated and weighed. Morphology of RBC in blood of experimental animals were measured according to commonly accepted methods.

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