Reactivity and Transformation of Antimetastatic ... - ACS Publications

Dec 13, 2018 - School of Chemistry, The University of Sydney, Sydney, New South Wales ... ANSTO, 800 Blackburn Road, Clayton, Victoria 3168, Australia...
2 downloads 0 Views 3MB Size
Download PDF
Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

pubs.acs.org/IC

Reactivity and Transformation of Antimetastatic and Cytotoxic Rhodium(III)−Dimethyl Sulfoxide Complexes in Biological Fluids: An XAS Speciation Study Jun Liang,† Aviva Levina,† Junteng Jia,† Peter Kappen,‡ Chris Glover,‡ Bernt Johannessen,‡ and Peter A. Lay*,† Inorg. Chem. Downloaded from pubs.acs.org by UNIV OF LOUISIANA AT LAFAYETTE on 04/02/19. For personal use only.

†

School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia Australian Synchrotron, ANSTO, 800 Blackburn Road, Clayton, Victoria 3168, Australia

‡

S Supporting Information *

ABSTRACT: Rhodium(III) anticancer drugs can exert preferential antimetastatic or cytotoxic activities, which are dependent on subtle structural changes. In order to delineate factors affecting the biotransformations and speciation, mer,cis-[RhCl3(Sdmso)2(O-dmso)] (A1) and mer,cis-[RhCl3(S-dmso)2(2N-indazole)] (A2) have been studied by X-ray absorption spectroscopy (XAS). Interactions of these complexes with saline buffer, cell culture media, serum proteins (albumin and apo-transferrin), native and chemically degraded collagen gels, and A549 cells have been studied using linear combination fitting (LCF) and 3D scatter plots of XAS data. Following initial aquation and hydrolysis reactions involving stepwise displacement of Cl− and S-/Odmso ligands, the Rh(III) complexes underwent further ligand substitution reactions with biological nucleophiles (e.g., amino acid residues of serum proteins). The reaction of A1 with chemically degraded collagen gel was postulated to be a key reason for its antimetastatic activity. Analyses of the XAS of Rh-treated bulk cells were consistent with structure−reactivity relationships in which the more reactive A1 was predominantly antimetastatic and the less reactive A2 was predominantly cytotoxic, showing relationships parallel to typical Ru(III) anticancer agents, i.e., NAMI-A ([ImH] trans-[RuCl4(S-dmso)(N-imidazole)2], ImH = imidazolium cation) and KP1019/NKP1339 (KP1019, [IndH] trans-[RuCl4(N-indazole)2], IndH = indazolium cation; NKP1339, sodium trans-[RuCl4(2N-indazole)2]), respectively.

■

parts.14−16 Notably, the nontoxic mer,cis-[RhCl3(S-dmso)2(Odmso)] (Chart 1, A1) demonstrated remarkable and selective activity against spontaneous lung metastasis of MCa mammary carcinoma in a CBA mice model, and mer,cis-[RhCl3(Sdmso)2(3N-imidazole)] (Chart 1, A3) exhibited cytotoxicity against human cancer cell lines which was comparable to that of cisplatin.17 Conversely, [ImH]-trans-[RhCl4(3N-imidazole)2], the Rh(III)−imidazole analogue of KP1019, and [Na·2DMSO]-trans-[RhCl4(S-dmso)(3N-imidazole)], the Rh(III) analogue of NAMI-A, were inactive both in vitro and in vivo.17,18 Rh has stable oxidation states and coordination geometries of Rh(III) (octahedral), Rh(II) (dimeric lantern),

INTRODUCTION

Although classical Pt-based cytotoxic agents (e.g., cisplatin, carboplatin, oxaliplatin) are effective in treating a wide range of cancers in combination therapies,1 their broader use has been hampered by their high systematic toxicities, limited ranges of activities, the propensity for acquired tumor resistance, and reduced efficacies for metastatic tumors.1,2 Metastasis is responsible for >90% of cancer-related deaths;3 hence, it is of considerable interest to design drugs that target metastases.4 Studies on non-Pt anticancer drugs led to the discovery of many bioactive Ru complexes,2,5−7 and three Ru(III) complexes, the antimetastatic NAMI-A and the cytotoxic KP1019/NKP1339, have entered Phase II clinical trials.8−13 The anticancer properties of some Rh(III) complexes have also been evaluated alongside those of their Ru(III) counter© XXXX American Chemical Society

Received: December 13, 2018

A

DOI: 10.1021/acs.inorgchem.8b03477 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Chart 1. Structures of Rh(III) Anticancer Drugs: mer,cis[RhCl3(S-dmso)2(O-dmso)] (A1), mer,cis-[RhCl3(Sdmso)2(2N-indazole)] (A2), and mer,cis-[RhCl3(Sdmso)2(3N-imidazole)] (A3)

synthesized and fully characterized. The new complex, A2, was studied because of high activities of related Ru(III) complexes with indazole ligands: e.g., KP1019/1339.9,49 Preliminary studies demonstrated that A2 was more stable against aqueous decomposition than both A1 and A3, had greater levels of cellular uptake than A1 and A3 did under identical experimental conditions, and its cytotoxicities on a range of human cancer cell lines were superior to those of A3 and cisplatin (measured with standard MTT assay; experimental details are described in the Supporting Information, and IC50 values of these complexes are given in Table S1).50 This research is aimed at using synchrotron XAS speciation to gain a deeper understanding of structure−reactivity−activity relationships for octahedral Rh(III) anticancer complexes bearing mixed Cl−/(O-/S-dmso)/N-heterocycle ligands with a range of antimetastatic and cytotoxic activities comparable to those observed for NAMI-A and KP1019.17

Rh(I) (square planar), respectively.14,15 A number of bioactive complexes of each oxidation state have been evaluated in recent years (e.g., Rh(I) N-heterocyclic carbenes,19−21 photoactive Rh(II)−polypyridyl complexes,22,23 and organometallic Rh(III)−Cp* agents (Cp* = pentamethylcyclopentadienyl ligand) 2 4 − 2 6 ). Notably, dirhodium(II) tetraacetate, [Rh2(OAc)4], readily reacted with methionine and cysteine under ambient conditions (aqueous solutions, pH 7.4, room temperature, and aerobic conditions) and generated various monomeric Rh(III) species.27−29 The Ru anticancer complexes have oxidation states of either Ru(III) (e.g., NAMI-A and KP1019) or Ru(II) (organometallic Ru(II)−arene complexes30,31). Reduction of Ru(III) to Ru(II) has been proposed to be the key mechanism of action for the anticancer activities of Ru(III) complexes, but the latest biological speciation using X-ray absorption spectroscopy (XAS) argued strongly against this hypothesis.32,33 Although detailed mechanistic studies on these Rh(III) complexes were not pursued, these observations suggested alternative mechanisms of action for the anticancer activities of the Rh(III) complexes in comparison to the much studied Ru and Pt anticancer drugs. The mechanisms of action of many anticancer Ru(III) and Rh(III) complexes remain uncertain, partially due to lack of speciation data from physiologically relevant conditions.2,34,35 The complexity of biological matrices (water, organic molecules, inorganic salts, and paramagnetic species) makes speciation using classical spectroscopic methods (e.g., ESI-MS and NMR, EPR, and electronic absorption spectroscopy) particularly challenging to perform. AAS and ICP-MS are destructive and only provide total metal determination without information on metal speciation unless individual components are separated.36,37 XAS, including X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS), are superior for having elemental specificity, being nondestructive to specimens, and having greater tolerance for biologically relevant matrices.36,38−40 All of these advantages make XAS the preferred technique for the speciation of metallodrugs in biological systems. Notably, XAS speciation has been applied successfully to the speciation of reaction products from bioactive Pt(IV) products,41−43 Ru(III) anticancer drugs,32,44,45 and Cr(III), V(V)/V(IV), and Mo(VI) antidiabetics.46,47 XAS investigations on bioactive Rh complexes have been sporadic in comparison to the studies done on other metals, although Rh K-edge XANES48 and EXAFS27,28 investigations have been carried out on a number of dirhodium(II) complexes. In the pursuit of Rh(III) complexes with higher activities, mer,cis-[RhCl3(S-dmso)2(2N-indazole)] (Chart 1, A2) was

■

EXPERIMENTAL SECTION

Model Compounds. A1 was synthesized according to literature methods,51,52 and A2 was prepared by a procedure similar to that reported for A317 using indazole instead of imidazole. Rh(III) complexes used for fitting the XAS data were synthesized according to literature procedures (S1,53 S2,54 S3,55 S4,56,57 S5,17 M1,58 M2,59 M3,60 M4,61 M5,62 M6,63 M7,64 M8,64 M9,64 O1,65 O266) or purchased from the commercial suppliers (S6, O3). Structures of these Rh(III) model complexes are presented in Chart 2, and their structural formulas, types of donor atoms, and published synthetic procedures are summarized in Table S2 in the Supporting Information. All synthesized compounds were fully characterized by standard analytical techniques; elemental analyses agreed with calculated values. These model complexes had combinations of N, O, S and/or Cl− donors groups that are expected to represent those likely to react with A1 and A2 in biologically relevant matrices (cell culture medium and cytoplasm): e.g., amine/imine/imidazole (Ndonors), aqua/carboxylato/enolato (O-donors), thiolato/thioester (S-donors), and chlorido ligands, respectively.67 Model compounds were classified into three categories according to the types and compositions of donors. Model compounds containing exclusively, or predominantly, S and/or Cl donors were classified as sof t donor models (S1−S6), for the S donors of thiolato/ thiaether are regarded as soft Lewis bases according to Pearson’s acid and base theory.68 Although the same theory classified Cl as a hard Lewis base, it was treated as a soft donor for the convenience of comparison. S4 possesses an N donor in addition to S and Cl, yet it was classified as a soft donor model because the key parameters of its XAS were similar to those of S1, S2, and S4. Model compounds containing exclusively O donors were classified as oxygen donor (O1− O3) models. The remaining model compounds were classified as mixed donor (M1−M9) models on the basis of the following reasons: (1) their first coordination shells are occupied by hard (N, O) and/or soft (S, Cl) donors at various combinations and (2) later studies confirmed the key parameters of their XAS were similar to each other and distinct from those of the model compounds classified into the other groups. In particular, M2−M4 have been prepared to model Rh(III) binding to amine/imine and carboxylato residues of proteins.67,69 It is worth pointing out that a number of ligands, such as methyl phenyl sulfide (S3) and DMSO (M6), while not present in vivo under normal conditions, are models for methionine and DMSO binding to the parent complexes, respectively. Using them in subsequent XAS analysis does not presume the presence of these ligands in biological systems. Materials and Biological Sample Preparation. Solid samples of A1, A2, and Rh(III) models were prepared via diluting neat compounds with boron nitride at a mass ratio of 1:2500. Reaction products of A1 or A2 with biological fluids (buffered saline, buffered protein solutions, serum-free and serum-supplemented cell culture media), Rh-treated cancer cells (A549 human lung adenocarcinoma), B

DOI: 10.1021/acs.inorgchem.8b03477 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Chart 2. Structures of Rh(III) Model Compounds S1−S5, M1−M9, and O1−O3a

a

S6 and O3 were purchased from Sigma-Aldrich and Abcr GmbH, respectively. dry ice, freeze-dried at 223 K under high vacuum (0.8 mbar), and stored in a desiccator at room temperature before the data collection. XAS Data Collection and Processing. Rh K-edge XAS were collected at the wiggler XAS Beamline ID-1270 of the Australian Synchrotron, ANSTO. The synchrotron has an electron storage ring operated at 3 GeV in top-up mode (200 mA). For photon delivery, the beamline had an upstream vertically collimating mirror (Ptcoated), a liquid-nitrogen-cooled Si(311) double-crystal monochromator, and a downstream toroidal focusing mirror (Pt-coated). The monochromator was operated at the peak of the rocking curve (“fully tuned”), with harmonics rejected by the mirrors. Model compounds

and A1-treated native or chemically degraded type I collagen gels were prepared on the basis of the methods used in the sample preparation for XAS speciation of Ru(III) anticancer compounds.32,44 Typically, samples were prepared via diluting the freshly prepared stock solutions of A1 or A2 (100 mM in DMSO) in reaction matrices and then incubating the mixture at 310 K for different periods (1, 4, or 24 h). A summary of conditions for biological sample preparation is given in Table 1. All aqueous samples were centrifuged at 2000g for 3 min to remove solid particles. The supernatant of aqueous samples, bulk cell samples, and Rh-treated collagen gels were snap-frozen in C

DOI: 10.1021/acs.inorgchem.8b03477 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

calibration (23222.0 eV at Rh(0) edge).71 Ion chambers (Oken; U = 2.1 kV; N2 flow at 0.4 L/min) were used to record incident and transmitted beam intensities. Depending on the spectral quality, each sample was measured between 3 and 15 times at different spots of the pellet. The possibility of photodamage was assessed by comparing both the shape of the edge region and the calibrated edge energy in successive scans on a sample.72 No systematic drifting of edge energy or noticeable differences in edge shape can be observed during sequential scans on a sample, and the differences in edge energy between two successive measurements were no more than 0.1 eV, indicating the absence of photodamage.72 The raw spectra were individually evaluated using the Sakura program,73 and those dominated by monochromator glitches or featured low signal to noise ratios were excluded. Subsequent calibration (23222.0 eV at the first peak of the first derivative of Rh foil spectra71), averaging, and normalization of the spectra were performed using the Athena program.74 Analyses of the spectra were carried out via two approaches: linear combination fitting (LCF) and three-dimensional (3D) scatter plots. LCF was performed using the built-in module of the Athena program, via fitting the spectra of biological samples with the spectra of model compounds within the same energy range. Since the XAS of all model compounds and biological samples featured strong postedge EXAFS oscillations, the range of fitting was limited to between 23130 and 23600 eV to accommodate both the XANES region and the low-energy end of the EXAFS region of the experimental data. For a fitted spectrum of a biological sample, the calculated weighted contributions (%) for each spectrum from the individual model compounds were constrained to lie between 0 and 100%, and the sum of the calculated weighted contributions of all model spectra was constrained to be 100%. Model spectra having null or small contributions ( 100 mM, pH 7.4) (Figures 3 and 4A and Figure S5 in the Supporting Information). These intermediates (Scheme 1, 1) are reactive toward substitution reactions with a wide variety of biomolecules in extracellular fluids, in the extracellular matrix, and on cell membranes. Such ligand exchange reactions between 1 and biological nucleophiles (e.g., amino acids, peptides and protein residues) resulted in the formation of Rh(III) species having mixed Rh− N, Rh−O, and Rh−S bonds. LCF results on the XAS from the reaction products with serum albumin and apotransferrin (Figures 3 and 4B and Figure S6 in the Supporting Information) suggested the formation of both covalent (Scheme 1, 2) and noncovalent (Scheme 1, 3) adducts. Formation of covalent Rh−protein adducts proceeded via the stepwise substitution of Cl− and S-/O-dmso ligands of the parent complexes or aqua ligands of the intermediates by amino acid residues. This is consistent with similar mixtures of S, N, and O donors obtained from LCF analysis of XAS from different Rh−protein adducts (Figure 4, A1B4/A2B4, A1B24/ A2B24, A1T/A2T). These results also underlined that the binding of parent A1/A2 to apoBTf proceeded more readily via ligand-substitution reactions with surface residues than at the Fe-binding domains, since the substantial molar contributions from S4 to the fitted XAS of A1T and A2T (Figure 4, A1T/A2T) was inconsistent with the expected donor composition at the domain (two tyrosyl phenolates, a histidyl imidazole, a aspartate carboxyl, and a synergistic carbonate, overall 5O and 1N).78 The minor XAS contributions from the neat A1/A2 in the fitted XAS of reaction products in serumsupplemented cell culture media (Figure 5) represented the formation of noncovalent Rh−protein adducts via hydrophobic interactions, similar to those observed from the albumin adducts of NAMI-A, KP1019, and their analogues.79,80 More importantly, the presence of XAS of Rh−BSA adducts in the fitted XAS of reaction products from the same matrices strongly argued for the formation of covalent Rh−BSA adducts in reaction mixtures, since albumin is the most abundant protein in serum.81 The biological activities of these Rh−protein adducts have yet to be understood. Nevertheless, albumin adducts of A1 and A2 are likely to act as their reservoirs and carriers that facilitate the accumulation of bioactive Rh species in solid tumors, due to the enhanced permeability and retention effect.82,83 Similar BSA reaction products have been deduced in similar XAS experiments with various metal-based anticancer agents, including NAMI-A44 and a series of Ru(II)−halido−thiaether complexes, 84,85 as well as the latest organometallic [RhIII(Cp*)Cl(cur)] complex.24 Owing to the higher reactivities of metal-based anticancer agents toward albumin than I

DOI: 10.1021/acs.inorgchem.8b03477 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry fluids (Scheme 1, 6), thus acting as the intracellular drug reservoir. Due to the significantly decreased Cl− concentration in the cytoplasm, 6 undergoes more extensive ligand-exchange reactions with various intracellular nucleophiles. Species generated subsequently via these reactions were likely the Rh adducts with cytosolic thiols (e.g., GSH) and S-rich enzymes (Scheme 1, 7 and 8). This hypothesis is supported by the degree of Rh speciation in Rh-treated bulk cells (Figures 3 and 6 and Figure S9 in the Supporting Information), which featured predominant soft donor coordination environments. In the case of A2-treated cells, binding of free GSH with Rh species was capable of causing the depletion of this key intracellular antioxidant.96,97 Since many types of cancer cells have increased levels of reactive oxygen species (ROS) in comparison to their normal counterparts,98 depletion of GSH could eventually result in an increase in intracellular ROS and may trigger apoptosis by elevated oxidative stress. The high affinity of Rh toward S donors may also cause the inhibition of cytosolic enzymes having thiol and thiaether residues at the active site, a mode of action that is similar to those discovered in earlier studies on dinuclear Rh(II)−tetracarboxylato complexes.14,99,100 Both factors are believed to be the key contributions to the remarkable cytotoxicities of A2 toward cancer cell lines. Unlike that observed from A2-treated cells, the fitted XAS of the A1-treated bulk cells had XAS contributions from Rh−S, Rh−N, and Rh−O coordination bonds, while an XAS contribution from the parent A1 was absent in the fit. This can be explained on the basis of a common mode of actions proposed for both A1 and A2. In general, the contrasting anticancer efficacies exhibited by these structurally similar analogues (A1, antimetastatic; A2, cytotoxic)50 were the outcomes of two competing processes: extracellular aquation/hydrolysis and subsequent substitution with the cell surface and ECM, or intracellular accumulation. The biotransformation of A1 featured extensive ligand-substitution reactions with extracellular biomolecules, such as the serum proteins and collagen networks of tumor ECM, as well as the cell surface proteins, as was demonstrated by the LCF XAS results of reaction products in HBS, in cell culture media, and on A1-treated cells. Given its low levels of cellular uptake, the proposed biotransformation mode of A1 is believed to impair the mobility and invasiveness of cancer cells, which eventually gives rise to its antimetastatic activities in vivo.17 The bulky and hydrophobic indazole ligand resulted in A2 being more inert to aquation/hydrolysis and ligand substitution than was A1. The hydrophobicity of the indazole ligand would also facilitate the passive diffusion of A2 across the cell membrane. This would lead to rapid accumulation of A2 in its native form in substantial quantities (Figure 6, 40% contribution to the overall fitting) in the cytoplasm of the treated cancer cells. Therefore, A2 acted mainly as an intracellular cytotoxin, and the substantial XAS contribution to the fitted XAS of A2treated cells from the XAS of parent A2 was direct evidence of its inertness. Additional LCF contributions from Rh−N coordination bonds (S4 and M7) to the fitted XAS of A2BC were likely made by the indazole ligands of the parent A2 and the imidazole/amine/imine residues of proteins and/or peptides.32,40 An earlier X-ray fluorescence microprobe (XFM) mapping study on A549 cells treated with 5iodoindazole analogues of NAMI-A and KP1019 showed identical intracellular distributions of Ru and I, which highlighted that N-heterocyclic ligands were less likely to

dissociate from the metal core after cellular uptake and metabolism.101 Although Rh−imidazole coordination can be modeled by model compounds S5 and M1, their XAS had zero contributions to the best LCF fit to the XAS from A2BC. Nevertheless, Figure S9 shows that the point representing A2BC was in close proximity to that of S5, indicating that heir spectral features were similar to a certain extent. This might be due to the imidazole model compounds used in LCF analysis not objectively modeling the spectral features of Rh−N coordination species in A2BC: e.g., any Rh−imidazole species that resulted from the ligand-exchange reactions between A2 and cytosolic proteins/peptides. Pursuing a model XAS library that conclusively addressed all possible ligand combinations and stereochemistries was not practical. The minor molar contribution of Rh−S coordination bonds, together with no contributions from Cl and O donor model complexes to the XAS fits, implied the complete displacement of chlorido ligands from the parent complex by intracellular S donors, such as the GSH, S-rich peptides and proteins. This mode of action has been established for a number of organometallic Ru(II)− arene anticancer complexes, where their cytotoxicity occurred via catalyzing the oxidation of intracellular GSH, which caused apoptosis of cancer cells via elevated oxidative stress.102 Rhodium Speciation in the Nucleus. Similar to the established mode of actions for cisplatin, nuclear DNA might be a potential target of A1/A2.103,104 Synchrotron X-ray fluorescence microprobe (XFM) mapping on single A549 cells treated with A1 or A2 revealed the presence of Rh species in the nucleus.50 However, these findings did not necessarily show that the Pt-based and Rh-based complexes were forming similar nuclear DNA adducts. Earlier investigations had shown that A1 and A3 predominantly formed monofunctional adducts with the plasmid DNA, with greater preference to coordinate with pyrimidines.17 These properties were in stark contrast to those of cisplatin, which interacts with DNA via formation of the covalent adducts with adjacent guanines.105 KP1019 induces nuclear DNA lesions that were different in quantity and nature from those caused by cisplatin,106,107 and its pronounced cytotoxicity has been attributed to the induction of apoptosis via an intrinsic mitochondrial pathway108 (also observed in recent mitochondrial respiration assays)84 and the promotion of intracellular ROS formation.106 Similar to that observed for KP1019, the pronounced mitochondrial toxicity of A2 has also been confirmed via mitochondrial respiration assays.50 This evidence suggested the redox modulation, but not the direct nuclear DNA damage, was most likely to be the mode of action for the anticancer activities of A2. Targeting the defective redox balance of cancerous tissue is becoming an effective approach for the development of metal-based anticancer agents,49 and a number of precious-metal-based organometallic complexes designed on the basis of this principle have produced promising outcomes in preclinical studies.30,109−111

■

CONCLUSIONS Overall, the work presented above consolidated the structure− reactivity−bioactivity relationship reported in previous studies on other metal complexes. The XAS speciation results reported herein lay the foundation for a more detailed understanding of the cellular biochemistry for cancer cells treated with A1 and A2. Also demonstrated was the feasibility and robustness of synchrotron XAS speciation in preclinical studies on metalbased anticancer compounds, especially its capability of J

DOI: 10.1021/acs.inorgchem.8b03477 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

yl)-2,5-diphenyl-2H-tetrazolium bromide; TCEP, tris(2carboxyethyl)phosphine; μE, normalized X-ray absorbance; SOM, second oscillation maximum

providing valuable biochemical information on the physiological transformation and speciation of metallodrugs that would be otherwise difficult to acquire by conventional spectroscopic methods.

■

■

ASSOCIATED CONTENT

(1) Wheate, N. J.; Walker, S.; Craig, G. E.; Oun, R. The Status of Platinum Anticancer Drugs in the Clinic and in Clinical Trials. Dalton Trans. 2010, 39 (35), 8113−8127. (2) Levina, A.; Mitra, A.; Lay, P. A. Recent Developments in Ruthenium Anticancer Drugs. Metallomics 2009, 1 (6), 458−470. (3) Bergamo, A.; Masi, A.; Peacock, A. F.; Habtemariam, A.; Sadler, P. J.; Sava, G. In Vivo Tumour and Metastasis Reduction and In Vitro Effects on Invasion Assays of the Ruthenium RM175 and Osmium AFAP51 Organometallics in the Mammary Cancer Model. J. Inorg. Biochem. 2010, 104 (1), 79−86. (4) Bergamo, A.; Sava, G. Linking the Future of Anticancer MetalComplexes to the Therapy of Tumour Metastases. Chem. Soc. Rev. 2015, 44 (24), 8818−8835. (5) Han Ang, W.; Dyson, P. J. Classical and Non-Classical Ruthenium-Based Anticancer Drugs: Towards Targeted Chemotherapy. Eur. J. Inorg. Chem. 2006, 20, 4003−4018. (6) Bratsos, I.; Gianferrara, T.; Alessio, E.; Hartinger, C. G.; Jakupec, M. A.; Keppler, B. K. In Bioinorganic Medicinal Chemistry; WileyVCH: 2011; pp 151−174. (7) Bergamo, A.; Gaiddon, C.; Schellens, J. H. M.; Beijnen, J. H.; Sava, G. Approaching Tumour Therapy Beyond Platinum Drugs: Status of the Art and Perspectives of Ruthenium Drug Candidates. J. Inorg. Biochem. 2012, 106 (1), 90−99. (8) Rademaker-Lakhai, J. M.; van den Bongard, D.; Pluim, D.; Beijnen, J. H.; Schellens, J. H. A Phase I and Pharmacological Study with Imidazolium-Trans-DMSO-Imidazole-Tetrachlororuthenate, A Novel Ruthenium Anticancer Agent. Clin. Cancer Res. 2004, 10 (11), 3717−3727. (9) Hartinger, C. G.; Jakupec, M. A.; Zorbas-Seifried, S.; Groessl, M.; Egger, A.; Berger, W.; Zorbas, H.; Dyson, P. J.; Keppler, B. K. KP1019, a New Redox-Active Anticancer Agent - Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients. Chem. Biodiversity 2008, 5 (10), 2140−2155. (10) Lentz, F.; Drescher, A.; Lindauer, A.; Henke, M.; Hilger, R. A.; Hartinger, C. G.; Scheulen, M. E.; Dittrich, C.; Keppler, B. K.; Jaehde, U. Pharmacokinetics of a Novel Anticancer Ruthenium Complex (KP1019, FFC14A) in a Phase I Dose-Escalation Study. Anti-Cancer Drugs 2009, 20 (2), 97−103. (11) Trondl, R.; Heffeter, P.; Jakupec, M.; Berger, W.; Keppler, B. NKP-1339, a First-in-Class Anticancer Drug Showing Mild Side Effects and Activity in Patients Suffering from Advanced Refractory Cancer. BMC Pharmacol. Toxicol. 2012, 13 (Suppl1), A82. (12) Leijen, S.; Burgers, S. A.; Baas, P.; Pluim, D.; Tibben, M.; van Werkhoven, E.; Alessio, E.; Sava, G.; Beijnen, J. H.; Schellens, J. H. Phase I/II Study with Ruthenium Compound NAMI-A and Gemcitabine in Patients with Non-Small Cell Lung Cancer after First Line Therapy. Invest. New Drugs 2015, 33 (1), 201−214. (13) Trondl, R.; Heffeter, P.; Kowol, C. R.; Jakupec, M. A.; Berger, W.; Keppler, B. K. NKP-1339, the First Ruthenium-Based Anticancer Drug on the Edge to Clinical Application. Chem. Sci. 2014, 5 (8), 2925−2932. (14) Katsaros, N.; Anagnostopoulou, A. Rhodium and Its Compounds as Potential Agents in Cancer Treatment. Crit. Rev. Oncol./Hematol. 2002, 42 (3), 297−308. (15) Geldmacher, Y.; Oleszak, M.; Sheldrick, W. S. Rhodium(III) and Iridium(III) Complexes as Anticancer Agents. Inorg. Chim. Acta 2012, 393, 84−102. (16) Leung, C.-H.; Zhong, H.-J.; Chan, D. S.-H.; Ma, D.-L. Bioactive Iridium and Rhodium Complexes as Therapeutic Agents. Coord. Chem. Rev. 2013, 257 (11−12), 1764−1776. (17) Mestroni, G.; Alessio, E.; Sessanta Santi, A.; Geremia, S.; Bergamo, A.; Sava, G.; Boccarelli, A.; Schettino, A.; Coluccia, M. Rhodium(III) Analogues of Antitumour-Active Ruthenium(III)

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.8b03477. IC50 values of A1−A3 and cisplatin (cis-[PtCl2(NH3)2]) on selected human cancer cell lines (A2780 and A2780cis, A549, MDA-MB-231) measured with MTT assay, general cell culture procedures, designations, structural formulas, types of donor atoms, and the corresponding literature of synthesis of model compounds, key XAS parameters of model compounds and biological samples, LCF results of the XAS biological samples, including the types of model compounds and weighted contributions, LCF results on reaction products in advanced DMEM supplemented with 10% (v/v) FBS without the inclusion of Rh-BSA adducts as models, comparison of XANES and low-energy EXAFS of all experimental XAS, three-dimensional (3D) scatter plots of key parameters of all experimental XAS, experimental, fitted, and expanded residuals of XAS of the reaction products, and a summary of LCF results of reaction products of A1 and A2 in serum-free and serum-supplemented advanced DMEM using model compounds only (PDF)

■

REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail for P.A.L.: [email protected]. ORCID

Aviva Levina: 0000-0002-7311-3263 Peter A. Lay: 0000-0002-3232-2720 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Financial support was provided by the Australian Research Council (ARC) Discovery (DP0984722 and DP140100176) grants to P.A.L., including a postgraduate scholarship for J.L. We thank Dr. Ian Luck (NMR Facility), Dr. Nick Proschogo (Mass Spectrometry Facility), and Dr. Joonsup Lee (Vibrational Spectroscopy Core Facility, now Sydney Analytical) for user support with instrumental analysis, Dr. Donna Lai and Dr. Sheng Hua (Molecular Biology Facility of Bosch Institute) for help with the Seahorse XF24 Extracellular Flux Analyzer, and Dr. Minh Huynh (Cell Culture Lab, Sydney Microscopy and Microanalysis) for training and support with cell culture and cell biology experiments. This research was undertaken in part on the XAS beamline at the Australian Synchrotron, part of ANSTO (proposal numbers M7645 and M8640).

■

ABBREVIATIONS NAMI-A, [ImH]-trans-[RuCl4(S-dmso)(N-imidazole)2] (ImH = imidazolium cation); KP1019, [IndH]-trans-[RuCl4(Nindazole)2] (IndH = indazolium cation); KP1339, sodium trans-[RuCl4(N-indazole)2]; MTT, 3-(4,5-dimethyl-2-thiazolK

DOI: 10.1021/acs.inorgchem.8b03477 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Compounds: The Crystal Structure of [ImH] [trans-RhCl4(Im)2] (Im = imidazole). Inorg. Chim. Acta 1998, 273 (1−2), 62−71. (18) Pacor, S.; Sava, G.; Mestroni, G.; Alessio, E. Tumor Inhibition and Effects on Host Survival Time by RutheniumIII and RhodiumIII Complexes with Dimethylsulfoxide Ligands. Pharmacol. Res. 1992, 25 (1), 73−74. (19) Oehninger, L.; Küster, L. N.; Schmidt, C.; Mñoz-Castro, A.; Prokop, A.; Ott, I. A Chemical-Biological Evaluation of Rhodium(I) N-heterocyclic Carbene Complexes as Prospective Anticancer Drugs. Chem.Eur. J. 2013, 19 (52), 17871−17880. (20) Oehninger, L.; Spreckelmeyer, S.; Holenya, P.; Meier, S. M.; Can, S.; Alborzinia, H.; Schur, J.; Keppler, B. K.; Wölfl, S.; Ott, I. Rhodium(I) N-heterocyclic Carbene Bioorganometallics as In Vitro Antiproliferative Agents with Distinct Effects on Cellular Signaling. J. Med. Chem. 2015, 58 (24), 9591−9600. (21) Simpson, P. V.; Schmidt, C.; Ott, I.; Bruhn, H.; Schatzschneider, U. Synthesis, Cellular Uptake and Biological Activity against Pathogenic Microorganisms and Cancer Cells of Rhodium and Iridium N-Heterocyclic Carbene Complexes Bearing Charged Substituents. Eur. J. Inorg. Chem. 2013, 2013 (32), 5547−5554. (22) Aguirre, J. D.; Angeles-Boza, A. M.; Chouai, A.; Turro, C.; Pellois, J. P.; Dunbar, K. R. Anticancer Activity of Heteroleptic Diimine Complexes of Dirhodium: A Study of Intercalating Properties, Hydrophobicity and In Cellulo Activity. Dalton Trans. 2009, 48, 10806−10812. (23) Joyce, L. E.; Aguirre, J. D.; Angeles-Boza, A. M.; Chouai, A.; Fu, P. K.; Dunbar, K. R.; Turro, C. Photophysical Properties, DNA Photocleavage, and Photocytotoxicity of a Series of dppn Dirhodium(II, II) Complexes. Inorg. Chem. 2010, 49 (12), 5371−5376. (24) Markham, J.; Liang, J.; Levina, A.; Mak, R.; Johannessen, B.; Kappen, P.; Glover, C. J.; Lai, B.; Vogt, S.; Lay, P. A. (Pentamethylcyclopentadienato)rhodium Complexes for Delivery of the Curcumin Anticancer Drug. Eur. J. Inorg. Chem. 2017, 2017 (12), 1812−1823. (25) Soldevila-Barreda, J. J.; Habtemariam, A.; Romero-Canelon, I.; Sadler, P. J. Half-Sandwich Rhodium(III) Transfer Hydrogenation Catalysts: Reduction of NAD(+) and Pyruvate, and Antiproliferative Activity. J. Inorg. Biochem. 2015, 153, 322−333. (26) Soldevila-Barreda, J. J.; Romero-Canelón, I.; Habtemariam, A.; Sadler, P. J. Transfer Hydrogenation Catalysis in Cells as a New Approach to Anticancer Drug Design. Nat. Commun. 2015, 6, 6582− 6590. (27) Jalilehvand, F.; Enriquez Garcia, A.; Niksirat, P. Reactions of Antitumor Active Dirhodium(II) Tetraacetate Rh2(CH3COO)4 with Cysteine and its Derivatives. ACS Omega 2017, 2 (9), 6174−6186. (28) Enriquez Garcia, A.; Jalilehvand, F. Aerobic Reactions of Antitumor Active Dirhodium(II) Tetraacetate Rh2(CH3COO)4 with Glutathione. J. Biol. Inorg. Chem. 2018, 23 (2), 231−239. (29) Enriquez Garcia, A.; Jalilehvand, F.; Niksirat, P.; Gelfand, B. S. Methionine Binding to Dirhodium(II) Tetraacetate. Inorg. Chem. 2018, 57, 12787. (30) Murray, B. S.; Babak, M. V.; Hartinger, C. G.; Dyson, P. J. The Development of RAPTA Compounds for the Treatment of Tumors. Coord. Chem. Rev. 2016, 306 (1), 86−114. (31) Dougan, S. J.; Sadler, P. J. The Design of Organometallic Ruthenium Arene Anticancer Agents. Chimia 2007, 61 (11), 704− 715. (32) Levina, A.; Aitken, J. B.; Gwee, Y. Y.; Lim, Z. J.; Liu, M.; Mitra Singharay, A.; Wong, P. F.; Lay, P. A. Biotransformations of Anticancer Ruthenium(III) Complexes: An X-Ray Absorption Spectroscopic Study. Chem. - Eur. J. 2013, 19 (11), 3609−3619. (33) Blazevic, A.; Hummer, A. A.; Heffeter, P.; Berger, W.; Filipits, M.; Cibin, G.; Keppler, B. K.; Rompel, A. Electronic State of Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) in Tumor, Liver and Kidney Tissue of a SW480-Bearing Mouse. Sci. Rep. 2017, 7, 40966. (34) Galanski, M.; Arion, V. B.; Jakupec, M. A.; Keppler, B. K. Recent Developments in the Field of Tumor-Inhibiting Metal Complexes. Curr. Pharm. Des. 2003, 9 (25), 2078−2089.

(35) Alessio, E. Thirty Years of the Drug Candidate NAMI-A and the Myths in the Field of Ruthenium Anticancer Compounds: A Personal Perspective. Eur. J. Inorg. Chem. 2017, 2017 (12), 1549− 1560. (36) Dillon, C. T. Synchrotron Radiation Spectroscopic Techniques as Tools for the Medicinal Chemist: Microprobe X-Ray Fluorescence Imaging, X-Ray Absorption Spectroscopy, and Infrared Microspectroscopy. Aust. J. Chem. 2012, 65 (3), 204−217. (37) Levina, A.; Crans, D. C.; Lay, P. A. Speciation of Metal Drugs, Supplements and Toxins in Media and Bodily Fluids Controls In Vitro Activities. Coord. Chem. Rev. 2017, 352, 473−498. (38) Aitken, J. B.; Carter, E. A.; Eastgate, H.; Hackett, M. J.; Harris, H. H.; Levina, A.; Lee, Y.-C.; Chen, C.-I.; Lai, B.; Vogt, S.; Lay, P. A. Biomedical Applications of X-Ray Absorption and Vibrational Spectroscopic Microscopies in Obtaining Structural Information from Complex Systems. Radiat. Phys. Chem. 2010, 79 (2), 176−184. (39) Aitken, J. B.; Levina, A.; Lay, P. A. Studies on the Biotransformations and Biodistributions of Metal-Containing Drugs Using X-Ray Absorption Spectroscopy. Curr. Top. Med. Chem. 2011, 11 (5), 553−571. (40) Hummer, A. A.; Rompel, A. X-ray Absorption Spectroscopy: A Tool to Investigate the Local Structure of Metal-Based Anticancer Compounds In Vivo. Adv. Protein Chem. Struct. Biol. 2013, 93, 257− 305. (41) Hall, M. D.; Foran, G. J.; Zhang, M.; Beale, P. J.; Hambley, T. W. XANES Determination of the Platinum Oxidation State Distribution in Cancer Cells Treated with Platinum(IV) Anticancer Agents. J. Am. Chem. Soc. 2003, 125 (25), 7524−7525. (42) Hall, M. D.; Daly, H. L.; Zhang, J. Z.; Zhang, M.; Alderden, R. A.; Pursche, D.; Foran, G. J.; Hambley, T. W. Quantitative Measurement of the Reduction of Platinum(IV) Complexes using X-Ray Absorption Near-Edge Spectroscopy (XANES). Metallomics 2012, 4 (6), 568−575. (43) Chen, C. K. J.; Zhang, J. Z.; Aitken, J. B.; Hambley, T. W. Influence of Equatorial and Axial Carboxylato Ligands on the Kinetic Inertness of Platinum(IV) Complexes In the Presence of Ascorbate and Cysteine and Within DLD-1 Cancer Cells. J. Med. Chem. 2013, 56 (21), 8757−8764. (44) Liu, M.; Lim, Z. J.; Gwee, Y. Y.; Levina, A.; Lay, P. A. Characterization of a Ruthenium(III)/NAMI-A Adduct with Bovine Serum Albumin that Exhibits a High Anti-Metastatic Activity. Angew. Chem., Int. Ed. 2010, 49 (9), 1661−1664. (45) Hummer, A. A.; Heffeter, P.; Berger, W.; Filipits, M.; Batchelor, D.; Buchel, G. E.; Jakupec, M. A.; Keppler, B. K.; Rompel, A. X-ray Absorption Near Edge Structure Spectroscopy to Resolve the In Vivo Chemistry of the Redox-Active Indazolium Trans-[Tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019). J. Med. Chem. 2013, 56 (3), 1182−1196. (46) Levina, A.; McLeod, A. I.; Gasparini, S. J.; Nguyen, A.; De Silva, W. G. M.; Aitken, J. B.; Harris, H. H.; Glover, C.; Johannessen, B.; Lay, P. A. Reactivity and Speciation of Anti-Diabetic Vanadium Complexes in Whole Blood And its Components: The Important Role of Red Blood Cells. Inorg. Chem. 2015, 54 (16), 7753−7766. (47) Levina, A.; McLeod, A. I.; Pulte, A.; Aitken, J. B.; Lay, P. A. Biotransformations of Antidiabetic Vanadium Prodrugs in Mammalian Cells and Cell Culture Media: A XANES Spectroscopic Study. Inorg. Chem. 2015, 54 (14), 6707−6718. (48) Majer, Z.; Bósze, S.; Szabó, I.; Mihucz, V. G.; Gaál, A.; Szilvágyi, G.; Pepponi, G.; Meirer, F.; Wobrauschek, P.; Szoboszlai, N.; Ingerle, D.; Streli, C. Study of Dinuclear Rh(II) Complexes of Phenylalanine Derivatives as Potential Anticancer Agents by Using XRay Fluorescence and X-Ray Absorption. Microchem. J. 2015, 120, 51−57. (49) Hartinger, C. G.; Zorbas-Seifried, S.; Jakupec, M. A.; Kynast, B.; Zorbas, H.; Keppler, B. K. From Bench to Bedside-Preclinical and Early Clinical Development of the Anticancer Agent Indazolium Trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). J. Inorg. Biochem. 2006, 100 (5−6), 891−904. L

DOI: 10.1021/acs.inorgchem.8b03477 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

(edta = ethylenediaminetetraacetate) in its Biological Activity. Chem. Commun. 2008, No. 25, 2864−2866. (70) Glover, C.; McKinlay, J.; Clift, M.; Barg, B.; Boldeman, J.; Ridgway, M.; Foran, G.; Garrett, R.; Lay, P.; Broadbent, A. Status of the X-Ray Absorption Spectroscopy (XAS) Beamline at the Australian Synchrotron. AIP Conf. Proc. 2007, 882 (1), 884−886. (71) Kraft, S.; Stümpel, J.; Becker, P.; Kuetgens, U. High Resolution X-Ray Absorption Spectroscopy with Absolute Energy Calibration for the Determination of Absorption Edge Energies. Rev. Sci. Instrum. 1996, 67 (3), 681−687. (72) George, G. N.; Pickering, I. J.; Pushie, M. J.; Nienaber, K.; Hackett, M. J.; Ascone, I.; Hedman, B.; Hodgson, K. O.; Aitken, J. B.; Levina, A.; Glover, C.; Lay, P. A. X-Ray-Induced Photo-Chemistry and X-Ray Absorption Spectroscopy of Biological Samples. J. Synchrotron Radiat. 2012, 19 (6), 875−886. (73) Kappen, P.; Ruben, G.; Moll, A. Sakura: A Tool to Pre-Process Fluorescence XAS Data from Multi-Pixel Detectors; http://archive. synchrotron.org.au/aussyncbeamlines/x-ray-absorption-spectroscopy/ sakura, 2015. (74) Ravel, B.; Newville, M. ATHENA, ARTEMIS, HEPHAESTUS: Data Analysis for X-Ray Absorption Spectroscopy using IFEFFIT. J. Synchrotron Radiat. 2005, 12 (4), 537−541. (75) Barth, D.; Musiol, H.-J.; Schütt, M.; Fiori, S.; Milbradt, A. G.; Renner, C.; Moroder, L. The Role of Cystine Knots in Collagen Folding and Stability, Part I. Conformational Properties of (Pro-HypGly)5 and (Pro-(4S)-FPro-Gly)5 Model Trimers with an Artificial Cystine Knot. Chem. - Eur. J. 2003, 9 (15), 3692−3702. (76) Boulègue, C.; Musiol, H.-J.; Götz, M. G.; Renner, C.; Moroder, L. Natural and Artificial Cystine Knots for Assembly of Homo- and Heterotrimeric Collagen Models. Antioxid. Redox Signaling 2008, 10 (1), 113−126. (77) Daly, N. L.; Craik, D. J. Bioactive Cystine Knot Proteins. Curr. Opin. Chem. Biol. 2011, 15 (3), 362−368. (78) Shongwe, M. S.; Smith, R.; Marques, H. M.; van Wyk, J. A. Synergistic Anion-Directed Coordination of Ferric and Cupric Ions to Bovine Serum Transferrin - An Inorganic Perspective. J. Inorg. Biochem. 2004, 98 (2), 199−208. (79) Webb, M. I.; Chard, R. A.; Al-Jobory, Y. M.; Jones, M. R.; Wong, E. W.; Walsby, C. J. Pyridine Analogues of the Antimetastatic Ru(III) Complex NAMI-A Targeting Non-Covalent Interactions with Albumin. Inorg. Chem. 2012, 51 (2), 954−966. (80) Webb, M. I.; Wu, B.; Jang, T.; Chard, R. A.; Wong, E. W. Y.; Wong, M. Q.; Yapp, D. T. T.; Walsby, C. J. Increasing the Bioavailability of RuIII Anticancer Complexes Through Hydrophobic Albumin Interactions. Chem. - Eur. J. 2013, 19 (50), 17031−17042. (81) Webb, M. I.; Walsby, C. J. Control of Ligand-Exchange Processes and the Oxidation State of the Antimetastatic Ru(III) Complex NAMI-A By Interactions with Human Serum Albumin. Dalton Trans. 2011, 40 (6), 1322−1331. (82) Matsumura, Y.; Maeda, H. A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs. Cancer Res. 1986, 46 (12 Part 1), 6387−6392. (83) Maeda, H.; Wu, J.; Sawa, T.; Matsumura, Y.; Hori, K. Tumor Vascular Permeability and the EPR Effect in Macromolecular Therapeutics: A Review. J. Controlled Release 2000, 65 (1−2), 271− 284. (84) O’Riley, H. A. Mechanisms of the Anti-Metastatic and Cytotoxic Properties of Ruthenium Anti-Cancer Drugs. Ph.D. Thesis, The University of Sydney, 2015. (85) O’Riley, H. A.; Levina, A.; Aitken, J. B.; Lay, P. A. Synthesis, Reactivities and Anti-Cancer Properties of Ruthenium(II) Complexes with a Thiaether Macrocyclic Ligand. Inorg. Chim. Acta 2017, 454, 128−138. (86) Timerbaev, A. R.; Rudnev, A. V.; Semenova, O.; Hartinger, C. G.; Keppler, B. K. Comparative Binding of Antitumor Indazolium [Trans-tetrachlorobis(1H-indazole)ruthenate(III)] to Serum Transport Proteins Assayed by Capillary Zone Electrophoresis. Anal. Biochem. 2005, 341 (2), 326−333.

(50) Liang, J. Synthesis, Characterisation, Anticancer Properties and Biological Speciation of Rhodium(III)-Dimethylsulfoxide Complexes. Ph.D. Thesis, The University of Sydney, 2018. (51) James, B. R.; Morris, R. H. Sulfur-Bonded Sulfoxide Complexes of Rhodium(III) and Rhodium(I). Can. J. Chem. 1980, 58 (4), 399− 408. (52) Alessio, E.; Faleschini, P.; Sessanta Santi, A.; Mestroni, G.; Calligaris, M. A New Linkage Isomer of Trichlorotris(Dimethyl Sulfoxide) Rhodium: Photochemical Synthesis, Crystal Structure, and Reactivity of mer, trans-RhCl3(DMSO)2(DMSO). Inorg. Chem. 1993, 32 (25), 5756−5761. (53) Allen, E. A.; Wilkinson, W. Complexes with Ligands Containing Group VB and VIB Atoms. Part IV. Dialkyl Sulphide Complexes of Rhodium(III) and Iridium(III) Halides. J. Chem. Soc., Dalton Trans. 1972, No. 5, 613−617. (54) Timonen, S.; Pakkanen, T. T.; Pakkanen, T. A. Novel SingleSite Catalysts Containing a Platinum Group Metal and a Macrocyclic Sulfur Ligand for Ethylene Polymerization. J. Mol. Catal. A: Chem. 1996, 111 (3), 267−272. (55) Vigo, L.; Poropudas, M. J.; Salin, P.; Oilunkaniemi, R.; Laitinen, R. S. Versatile Coordination Chemistry of Rhodium Complexes Containing the Bis(trimethylsilylmethyl)tellane Ligand. J. Organomet. Chem. 2009, 694 (13), 2053−2060. (56) Konno, T.; Aizawa, S.; Okamoto, K.; Hidaka, J. Preparation and Some Properties of [CoIIorIII{RhIII(aet or L-cys-N, S)3}2]-Type SBridged Trinuclear Complexes. Bull. Chem. Soc. Jpn. 1990, 63 (3), 792−798. (57) Konno, T.; Okamoto, K.; Hidaka, J. Synthesis and Properties of T-Cage-Type S-Bridged Rhodium(III)Zinc(II) Octanuclear Complexes with 2-Aminoethanethiolate of L-Cysteinate. Inorg. Chem. 1994, 33 (3), 538−544. (58) Ganguli, J. N.; Bora, T. Coordination-Compounds of Imidazoles with Rhodium Halides. Transition Met. Chem. 1984, 9 (3), 88−91. (59) Sugiura, K.; Yamasaki, K. Rhodium(III) Complexes Coordinated with Ethylenediaminetetraacetic Acid. Nippon Kagaku Zasshi 1967, 88 (9), 948−952. (60) Dwyer, F. P.; Garvan, F. L. Rhodium(III) Complexes with Ethylenediaminetetraacetic Acid. J. Am. Chem. Soc. 1960, 82 (18), 4823−4826. (61) Lin, G. H. Y.; Leggett, J. D.; Wing, R. M. The Crystal and Molecular Structure of Aquo(ethylenediaminetriacetatoacetic acid)rhodium(III). Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1973, 29 (5), 1023−1030. (62) Bukanova, A. E.; Antsyshk, A. S.; Poraikos, M. A.; Prokofev, I. V.; Dikareva, L. M. Compound of 1,2,3-[Rh(NH2CH2COO)3].H2O. Zh. Neorg. Khim. 1972, 17 (3), 757−759. (63) Abbasi, A.; Skripkin, M. Y.; Eriksson, L.; Torapava, N. Ambidentate Coordination of Dimethyl Sulfoxide in Rhodium(III) Complexes. Dalton Trans. 2011, 40 (5), 1111−1118. (64) Lay, P. A.; Sargeson, A. M. Cis- and Trans-bis(1,2ethanediamine)rhodium(III) Complexes. Inorg. Synth. 1986, 24, 283−287. (65) Kaziro, R.; Hambley, T. W.; Binstead, R. A.; Beattie, J. K. Potassium Tris(oxalato)ruthenate(III). Inorg. Chim. Acta 1989, 164 (1), 85−91. (66) Collins, J. E.; Castellani, M. P.; Rheingold, A. L.; Miller, E. J.; Geiger, W. E.; Rieger, A. L.; Rieger, P. H. Synthesis, Characterization, and Molecular Structure of Bis(tetraphenylcyclopentdienyl)rhodium(II). Organometallics 1995, 14 (3), 1232−1238. (67) Levina, A.; Aitken, J. B.; Gwee, Y. Y.; Lim, Z. J.; Liu, M.; Singharay, A. M.; Wong, P. F.; Lay, P. A. Biotransformations of Anticancer Ruthenium(III) Complexes: An X-Ray Absorption Spectroscopic Study. Chem. - Eur. J. 2013, 19 (11), 3609−3619. (68) Pearson, R. G. Hard and Soft Acids and Bases. J. Am. Chem. Soc. 1963, 85 (22), 3533−3539. (69) Chatterjee, D.; Mitra, A.; Levina, A.; Lay, P. A. A Potential Role for Protein Tyrosine Phosphatase Inhibition by a RuIII-edta Complex M

DOI: 10.1021/acs.inorgchem.8b03477 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry (87) Polec-Pawlak, K.; Abramski, J. K.; Semenova, O.; Hartinger, C. G.; Timerbaev, A. R.; Keppler, B. K.; Jarosz, M. Platinum Group Metallodrug-Protein Binding Studies by Capillary Electrophoresis Inductively Coupled Plasma-Mass Spectrometry: A Further Insight into the Reactivity of a Novel Antitumor Ruthenium(III) Complex Toward Human Serum Proteins. Electrophoresis 2006, 27 (5−6), 1128−1135. (88) Bytzek, A. K.; Boeck, K.; Hermann, G.; Hann, S.; Keppler, B. K.; Hartinger, C. G.; Koellensperger, G. LC- and CZE-ICP-MS approaches for the In Vivo Analysis of the Anticancer Drug Candidate Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1339) in Mouse Plasma. Metallomics 2011, 3 (10), 1049−1055. (89) Sternlicht, M. D.; Werb, Z. How Matrix Metalloproteinases Regulate Cell Behavior. Annu. Rev. Cell Dev. Biol. 2001, 17 (1), 463− 516. (90) Karsenty, G.; Park, R.-W. Regulation of Type I Collagen Genes Expression. Int. Rev. Immunol. 1995, 12 (2−4), 177−185. (91) Raghunand, N.; He, X.; van Sluis, R.; Mahoney, B.; Baggett, B.; Taylor, C. W.; Paine-Murrieta, G.; Roe, D.; Bhujwalla, Z. M.; Gillies, R. J. Enhancement of Chemotherapy by Manipulation of Tumour pH. Br. J. Cancer 1999, 80 (7), 1005−1011. (92) Smallbone, K.; Gavaghan, D. J.; Gatenby, R. A.; Maini, P. K. The role of Acidity in Solid Tumour Growth and Invasion. J. Theor. Biol. 2005, 235 (4), 476−484. (93) Trédan, O.; Galmarini, C. M.; Patel, K.; Tannock, I. F. Drug Resistance and the Solid Tumor Microenvironment. J. Natl. Cancer Inst. 2007, 99 (19), 1441−1454. (94) Yamamoto, N.; Renfrew, A. K.; Kim, B. J.; Bryce, N. S.; Hambley, T. W. Dual Targeting of Hypoxic and Acidic Tumor Environments with a Cobalt(III) Chaperone Complex. J. Med. Chem. 2012, 55 (24), 11013−11021. (95) Sava, G.; Zorzet, S.; Turrin, C.; Vita, F.; Soranzo, M.; Zabucchi, G.; Cocchietto, M.; Bergamo, A.; DiGiovine, S.; Pezzoni, G.; Sartor, L.; Garbisa, S. Dual action of NAMI-A in Inhibition of Solid Tumor Metastasis: Selective Targeting of Metastatic Cells and Binding to Collagen. Clin. Cancer. Res. 2003, 9 (5), 1898−1905. (96) Balendiran, G. K.; Dabur, R.; Fraser, D. The Role of Glutathione in Cancer. Cell Biochem. Funct. 2004, 22 (6), 343−352. (97) Estrela, J. M.; Ortega, A.; Obrador, E. Glutathione in Cancer Biology and Therapy. Crit. Rev. Clin. Lab. Sci. 2006, 43 (2), 143−181. (98) Trachootham, D.; Alexandre, J.; Huang, P. Targeting Cancer Cells by ROS-Mediated Mechanisms: A Radical Therapeutic Approach? Nat. Rev. Drug Discovery 2009, 8 (7), 579−591. (99) Howard, R. A.; Spring, T. G.; Bear, J. L. The Interaction of Rhodium(II) Carboxylates with Enzymes. Cancer Res. 1976, 36 (12), 4402−4405. (100) Rao, P. N.; Smith, M. L.; Pathak, S.; Howard, R. A.; Bear, J. L. Rhodium(II) Butyrate: A Potential Anticancer Drug with Cell Cycle Phase-Specific Effects in HeLa Cells. J. Natl. Cancer Inst. 1980, 64 (4), 905−912. (101) Antony, S.; Aitken, J. B.; Vogt, S.; Lai, B.; Brown, T.; Spiccia, L.; Harris, H. H. X-ray Fluorescence Imaging of Single Human Cancer Cells Reveals that the N-Heterocyclic Ligands of Iodinated Analogues of Ruthenium Anticancer Drugs Remain Coordinated after Cellular Uptake. J. Biol. Inorg. Chem. 2013, 18 (7), 845−853. (102) Dougan, S. J.; Habtemariam, A.; McHale, S. E.; Parsons, S.; Sadler, P. J. Catalytic organometallic anticancer complexes. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (33), 11628−11633. (103) Hambley, T. W. Platinum Binding to DNA: Structural Controls and Consequences. J. Chem. Soc., Dalton Trans. 2001, No. 19, 2711−2718. (104) Alderden, R. A.; Hall, M. D.; Hambley, T. W. The Discovery and Development of Cisplatin. J. Chem. Educ. 2006, 83 (5), 728−734. (105) Coluccia, M.; Sava, G.; Loseto, F.; Nassi, A.; Boccarelli, A.; Giordano, D.; Alessio, E.; Mestroni, G. Anti-Leukaemic Action of RuCl2(DMSO)4 Isomers and Prevention of Brain Involvement on P388 Leukaemia and on Subline. Eur. J. Cancer 1993, 29 (13), 1873− 1879.

(106) Kapitza, S.; Jakupec, M. A.; Uhl, M.; Keppler, B. K.; Marian, B. The Heterocyclic Ruthenium(III) Complex KP1019 (FFC14A) Causes DNA Damage and Oxidative Stress in Colorectal Tumor Cells. Cancer Lett. 2005, 226 (2), 115−121. (107) Stevens, S. K.; Strehle, A. P.; Miller, R. L.; Gammons, S. H.; Hoffman, K. J.; McCarty, J. T.; Miller, M. E.; Stultz, L. K.; Hanson, P. K. The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death in Saccharomyces Cerevisiae. Mol. Pharmacol. 2013, 83 (1), 225−234. (108) Kapitza, S.; Pongratz, M.; Jakupec, M. A.; Heffeter, P.; Berger, W.; Lackinger, L.; Keppler, B. K.; Marian, B. Heterocyclic Complexes of Ruthenium(III) Induce Apoptosis in Colorectal Carcinoma Cells. J. Cancer Res. Clin. Oncol. 2005, 131 (2), 101−110. (109) Yan, Y. K.; Melchart, M.; Habtemariam, A.; Sadler, P. J. Organometallic Chemistry, Biology and Medicine: Ruthenium Arene Anticancer Complexes. Chem. Commun. 2005, No. 38, 4764−4776. (110) Ang, W. H.; Casini, A.; Sava, G.; Dyson, P. J. Organometallic Ruthenium-Based Antitumor Compounds with Novel Modes of Action. J. Organomet. Chem. 2011, 696 (5), 989−998. (111) Nazarov, A. A.; Hartinger, C. G.; Dyson, P. J. Opening the Lid on Piano-Stool Complexes: An Account of Ruthenium(II)-Arene Complexes with Medicinal Applications. J. Organomet. Chem. 2014, 751, 251−260.

N

DOI: 10.1021/acs.inorgchem.8b03477 Inorg. Chem. XXXX, XXX, XXX−XXX