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)

Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (1, KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (2, KP1339) are promising redox-active anticancer drug candidates that were investigated with X-ray absorption near edge structure spectroscopy. The analysis was based on the concept of the coordination charge and ruthenium model compounds representing possible coordinations and oxidation states in vivo. 1 was investigated in citrate saline buffer (pH 3.5) and in carbonate buffer (pH 7.4) at 37 °C for different time intervals. Interaction studies on 1 with glutathione in saline buffer and apo-transferrin in carbonate buffer were undertaken, and the coordination of 1 and 2 in tumor tissues was studied too. The most likely coordinations and oxidation states of the compound under the above mentioned conditions were assigned. Microprobe X-ray fluorescence of tumor thin sections showed the strong penetration of ruthenium into the tumor tissue, with the highest concentrations near blood vessels and in the edge regions of the tissue samples.

[1]  B. Ravel,et al.  Analysis of Soils and Minerals Using X‐ray Absorption Spectroscopy , 2015 .

[2]  B. Lai,et al.  Distinct cellular fates for KP1019 and NAMI-A determined by X-ray fluorescence imaging of single cells. , 2012, Metallomics : integrated biometal science.

[3]  S. Lippard,et al.  Redox activation of metal-based prodrugs as a strategy for drug delivery. , 2012, Advanced drug delivery reviews.

[4]  M. Jakupec,et al.  X-ray absorption spectroscopy of an investigational anticancer gallium(III) drug: interaction with serum proteins, elemental distribution pattern, and coordination of the compound in tissue. , 2012, Journal of medicinal chemistry.

[5]  W. Berger,et al.  Anticancer activity of metal complexes: involvement of redox processes. , 2011, Antioxidants & redox signaling.

[6]  P. A. Lay,et al.  Studies on the biotransformations and biodistributions of metal-containing drugs using X-ray absorption spectroscopy. , 2011, Current topics in medicinal chemistry.

[7]  P. Sadler,et al.  Photo-induced pyridine substitution in cis-[Ru(bpy)(2)(py)(2)]Cl(2): a snapshot by time-resolved X-ray solution scattering. , 2010, Inorganic chemistry.

[8]  P. Sadler,et al.  EXAFS, DFT, Light-Induced Nucleobase Binding, and Cytotoxicity of the Photoactive Complex cis-[Ru(bpy)2(CO)Cl]+ , 2010 .

[9]  W. Berger,et al.  Intracellular protein binding patterns of the anticancer ruthenium drugs KP1019 and KP1339 , 2010, JBIC Journal of Biological Inorganic Chemistry.

[10]  K. Takrouri,et al.  New reduction pathways for ctc-[PtCl2(CH3CO2)2(NH3)(Am)] anticancer prodrugs. , 2010, Chemical communications.

[11]  P. A. Lay,et al.  Characterization of a ruthenium(III)/NAMI-A adduct with bovine serum albumin that exhibits a high anti-metastatic activity. , 2010, Angewandte Chemie.

[12]  T. Hambley,et al.  Platinum Drug Distribution in Cancer Cells and Tumors , 2010 .

[13]  S. Best,et al.  Applications of X-ray absorption spectroscopy to biologically relevant metal-based chemistry , 2010 .

[14]  Michael I Webb,et al.  Serum-protein interactions with anticancer Ru(III) complexes KP1019 and KP418 characterized by EPR , 2010, JBIC Journal of Biological Inorganic Chemistry.

[15]  P. A. Lay,et al.  Recent developments in ruthenium anticancer drugs. , 2009, Metallomics : integrated biometal science.

[16]  P. Sadler,et al.  Structure of [Ru(bpy)n(AP)(6-2n)]2+ homogeneous complexes: DFT calculation vs. EXAFS , 2009 .

[17]  P. Sadler,et al.  Influence of oxygenation on the reactivity of ruthenium-thiolato bonds in arene anticancer complexes: insights from XAS and DFT. , 2009, Journal of the American Chemical Society.

[18]  Vittal K. Yachandra,et al.  X-ray absorption spectroscopy , 2009, Photosynthesis Research.

[19]  R. Strange,et al.  Biological X-ray absorption spectroscopy and metalloproteomics. , 2009, Journal of synchrotron radiation.

[20]  Travis V. Harris,et al.  Electronic structural investigations of ruthenium compounds and anticancer prodrugs , 2009, JBIC Journal of Biological Inorganic Chemistry.

[21]  P. Sadler,et al.  Ligand-selective photodissociation from [Ru(bpy)(4AP)4]2+: a spectroscopic and computational study. , 2009, Inorganic chemistry.

[22]  Anna F. A. Peacock,et al.  Medicinal Organometallic Chemistry: Designing Metal Arene Complexes as Anticancer Agents , 2009 .

[23]  A. Beale,et al.  Implementation of a combined SAXS/WAXS/QEXAFS set-up for time-resolved in situexperiments. , 2008, Journal of synchrotron radiation.

[24]  A. Casini,et al.  Exploiting soft and hard X-ray absorption spectroscopy to characterize metallodrug/protein interactions: the binding of [trans-RuCl4(Im)(dimethylsulfoxide)][ImH] (Im = imidazole) to bovine serum albumin. , 2008, Inorganic chemistry.

[25]  W. Berger,et al.  KP1019, A New Redox‐Active Anticancer Agent – Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients , 2008, Chemistry & biodiversity.

[26]  B. Keppler,et al.  Synthesis and reactivity of the aquation product of the antitumor complex trans-[Ru(III)Cl4(indazole)2]-. , 2008, Inorganic chemistry.

[27]  B. Keppler,et al.  CZE-ICP-MS as a tool for studying the hydrolysis of ruthenium anticancer drug candidates and their reactivity towards the DNA model compound dGMP. , 2008, Journal of inorganic biochemistry.

[28]  P. Kennepohl,et al.  Assignment of Pre-edge Features in the Ru K-edge X-ray Absorption Spectra of Organometallic Ruthenium Complexes. , 2008, Inorganica chimica acta.

[29]  M. Jakupec,et al.  Antitumour metal compounds: more than theme and variations. , 2008, Dalton transactions.

[30]  P. Sadler,et al.  The design of organometallic ruthenium arene anticancer agents , 2007 .

[31]  P. Dyson.  Systematic Design of a Targeted Organometallic Antitumour Drug in Pre-clinical Development , 2007 .

[32]  R. Eldik,et al.  Kinetics and mechanism of the reduction of (ImH)[trans-RuCl4(dmso)(Im)] by ascorbic acid in acidic aqueous solution , 2007, JBIC Journal of Biological Inorganic Chemistry.

[33]  W. Ang.  Development of Organometallic Ruthenium(II) Anticancer (RAPTA) Drugs , 2007 .

[34]  A. Bergamo,et al.  Ruthenium complexes can target determinants of tumour malignancy. , 2007, Dalton transactions.

[35]  Keith O. Hodgson,et al.  PySpline: A Modern, Cross‐Platform Program for the Processing of Raw Averaged XAS Edge and EXAFS Data , 2007 .

[36]  P. Dyson,et al.  Classical and Non‐Classical Ruthenium‐Based Anticancer Drugs: Towards Targeted Chemotherapy , 2006 .

[37]  A. Timerbaev,et al.  Interactions of Antitumor Metallodrugs with Serum Proteins: Advances in Characterization Using Modern Analytical Methodology , 2006 .

[38]  M. Jakupec,et al.  From bench to bedside--preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). , 2006, Journal of inorganic biochemistry.

[39]  M. Jakupec,et al.  Redox behavior of tumor-inhibiting ruthenium(III) complexes and effects of physiological reductants on their binding to GMP. , 2006, Dalton transactions.

[40]  P. Sadler,et al.  Organometallic Chemistry, Biology and Medicine: Ruthenium Arene Anticancer Complexes , 2006 .

[41]  A. Timerbaev,et al.  Interactions of a novel ruthenium-based anticancer drug (KP1019 or FFC14a) with serum proteins--significance for the patient. , 2005, International journal of clinical pharmacology and therapeutics.

[42]  Uwe Bergmann,et al.  X-ray damage to the Mn4Ca complex in single crystals of photosystem II: a case study for metalloprotein crystallography. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M Newville,et al.  ATHENA, ARTEMIS, HEPHAESTUS: data analysis for X-ray absorption spectroscopy using IFEFFIT. , 2005, Journal of synchrotron radiation.

[44]  M. Jakupec,et al.  Redox-active antineoplastic ruthenium complexes with indazole: correlation of in vitro potency and reduction potential. , 2005, Journal of medicinal chemistry.

[45]  B. Keppler,et al.  Reactions of potent antitumor complex trans-[Ru(III)Cl4(indazole)2]- with a DNA-relevant nucleobase and thioethers: insight into biological action. , 2005, Inorganic chemistry.

[46]  W. Berger,et al.  Intrinsic and Acquired Forms of Resistance against the Anticancer Ruthenium Compound KP1019 [Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) , 2005, Journal of Pharmacology and Experimental Therapeutics.

[47]  A. Bergamo,et al.  Ruthenium antimetastatic agents. , 2004, Current topics in medicinal chemistry.

[48]  J. Schellens,et al.  A Phase I and Pharmacological Study with Imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a Novel Ruthenium Anticancer Agent , 2004, Clinical Cancer Research.

[49]  G. Allmaier,et al.  Transferrin binding and transferrin-mediated cellular uptake of the ruthenium coordination compound KP1019, studied by means of AAS, ESI-MS and CD spectroscopy , 2004 .

[50]  B. Lai,et al.  The cellular distribution and oxidation state of platinum(II) and platinum(IV) antitumour complexes in cancer cells , 2003, JBIC Journal of Biological Inorganic Chemistry.

[51]  M. Hall,et al.  XANES determination of the platinum oxidation state distribution in cancer cells treated with platinum(IV) anticancer agents. , 2003, Journal of the American Chemical Society.

[52]  G. Pezzoni,et al.  Dual Action of NAMI-A in inhibition of solid tumor metastasis: selective targeting of metastatic cells and binding to collagen. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[53]  M. Hall,et al.  Platinum(IV) antitumour compounds: their bioinorganic chemistry , 2002 .

[54]  B. Keppler,et al.  Hydrolysis of the tumor-inhibiting ruthenium(III) complexes HIm trans-[RuCl4(im)2] and HInd trans-[RuCl4(ind)2] investigated by means of HPCE and HPLC-MS , 2001, JBIC Journal of Biological Inorganic Chemistry.

[55]  M Newville,et al.  IFEFFIT: interactive XAFS analysis and FEFF fitting. , 2001, Journal of synchrotron radiation.

[56]  M. Galanski,et al.  [RuCl3ind3] and [RuCl2ind4]: Two New Ruthenium Complexes derived from the Tumor-inhibiting RuIII Compound HInd (OC-6-11)-[RuCl4ind2] (ind = indazole) , 2001 .

[57]  J. Rehr,et al.  Theoretical approaches to x-ray absorption fine structure , 2000 .

[58]  J. Wong,et al.  Quantitative speciation of Mn-bearing particulates emitted from Autos burning (methylcyclopentadienyl)manganese tricarbonyl-added gasolines using XANES spectroscopy , 2000 .

[59]  J. Penner‐Hahn.  X-ray absorption spectroscopy in coordination chemistry , 1999 .

[60]  W. Peti,et al.  Synthesis of Tumor‐Inhibiting Complex Salts Containing the Anion trans‐Tetrachlorobis(indazole)ruthenate(III) and Crystal Structure of the Tetraphenylphosphonium Salt , 1999 .

[61]  A. Bergamo,et al.  In vitro cell cycle arrest, in vivo action on solid metastasizing tumors, and host toxicity of the antimetastatic drug NAMI-A and cisplatin. , 1999, The Journal of pharmacology and experimental therapeutics.

[62]  A. Ankudinov,et al.  REAL-SPACE MULTIPLE-SCATTERING CALCULATION AND INTERPRETATION OF X-RAY-ABSORPTION NEAR-EDGE STRUCTURE , 1998 .

[63]  J. Berg,et al.  The Limitations of X-ray Absorption Spectroscopy for Determining the Structure of Zinc Sites in Proteins. When Is a Tetrathiolate Not a Tetrathiolate? , 1998 .

[64]  A. Ankudinov,et al.  RELATIVISTIC CALCULATIONS OF SPIN-DEPENDENT X-RAY-ABSORPTION SPECTRA , 1997 .

[65]  E. Baker,et al.  Binding of ruthenium(III) anti-tumor drugs to human lactoferrin probed by high resolution X-ray crystallographic structure analyses , 1996, JBIC Journal of Biological Inorganic Chemistry.

[66]  P. A. Reynolds,et al.  Reconciling the Crystal Structure of [Ru(NH3)6]Cl3 with its ESR Properties , 1995 .

[67]  A. Bergamo,et al.  Effects of ruthenium complexes on experimental tumors: irrelevance of cytotoxicity for metastasis inhibition. , 1995, Chemico-biological interactions.

[68]  L. G. Blackwood.  Factor Analysis in Chemistry (2nd Ed.) , 1994 .

[69]  E. Stern,et al.  Number of relevant independent points in x-ray-absorption fine-structure spectra. , 1993, Physical review. B, Condensed matter.

[70]  R. Strange,et al.  Constrained and Restrained Refinement in EXAFS Data Analysis with Curved Wave Theory , 1992, Biochemistry.

[71]  M. J. Fay,et al.  Determination of the Mo surface environment of Mo/TiO2 catalysts by EXAFS, XANES and PCA , 1992 .

[72]  B. Keppler,et al.  Synthesis, Molecular Structure, and Tumor-Inhibiting Properties of Imidazolium trans-Bis(imidazole)tetrachlororuthenate(III) and Its Methyl-Substituted Derivatives. , 1988 .

[73]  P. Khadikar,et al.  X-Ray K-Absorption Edge Analysis of Cobalt in Some Cobalt Complexes , 1987 .

[74]  H. Kihara.  [Time resolved X-ray solution scattering]. , 1985, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[75]  D. H. Maylotte,et al.  A Study of the K-edge Absorption Spectra of Selected Vanadium Compounds. , 1984 .

[76]  Edmund R. Malinowski,et al.  Factor Analysis in Chemistry , 1980 .

[77]  Edmund R. Malinowski,et al.  Theory of error for target factor analysis with applications to mass spectrometry and nuclear magnetic resonance spectrometry , 1978 .

[78]  K. Hodgson,et al.  Letter: Molybdenum X-ray absorption edge spectra. The chemical state of molybdenum in nitrogenase. , 1976, Journal of the American Chemical Society.

[79]  M. Gupta.  Chemical shift in the X-ray K absorption edge of strontium , 1975 .

[80]  R. Sime,et al.  The crystal and molecular structure of tris-acetylacetonatoruthenium(III) , 1973 .

[81]  L. Hedin,et al.  A local exchange-correlation potential for the spin polarized case. i , 1972 .

[82]  H. H. Jaffé,et al.  Electronegativity. I. Orbital Electronegativity of Neutral Atoms , 1962 .

[83]  A. Allred,et al.  Electronegativity values from thermochemical data , 1961 .

[84]  V. A. Solé,et al.  A multiplatform code for the analysis of energy-dispersive X-ray fluorescence spectra , 2007 .

[85]  I. Ascone,et al.  Experimental aspects of biological X-ray absorption spectroscopy. , 2003, Journal of synchrotron radiation.

[86]  C. S. Allardyce,et al.  [Ru(η6-p-cymene)Cl2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo- [3.3.1.1]decane): a water soluble compound that exhibits pH dependent DNA binding providing selectivity for diseased cells , 2001 .

[87]  P. A. Reynolds,et al.  Structure, covalence and spin polarisation in tris(acetylacetonato)ruthenium(III) studied by X-ray and polarised neutron diffraction† , 1998 .

[88]  B. Keppler,et al.  Synthesis, Characterization and Solution Chemistry of trans-Indazoliumtetrachlorobis(Indazole)Ruthenate(III), a New Anticancer Ruthenium Complex. IR, UV, NMR, HPLC Investigations and Antitumor Activity. Crystal Structures of trans-1-Methyl-Indazoliumtetrachlorobis-(1-Methylindazole)Ruthenate(III) an , 1996, Metal-based drugs.

[89]  Haydn Chen.  X-ray absorption study of effective coordination charges of iron in crystals and amorphous solids , 1980 .

[90]  J. Chatt,et al.  Complexes of ruthenium halides with organic sulphides (thioethers) , 1971 .

[91]  M. A. Whitehead,et al.  Electronegativity. II. Bond and Orbital Electronegativities , 1963 .