14 results on '"Hartinger CG"'
Search Results
2. Analysis of ruthenium anticancer agents by MEEKC-UV and MEEKC-ICP-MS: Impact of structural motifs on lipophilicity and biological activity.
- Author
-
Giringer K, Holtkamp HU, Movassaghi S, Tremlett WDJ, Lam NYS, Kubanik M, and Hartinger CG
- Subjects
- Cell Survival drug effects, Coordination Complexes analysis, Coordination Complexes chemistry, Drug Screening Assays, Antitumor methods, HCT116 Cells, Humans, Structure-Activity Relationship, Antineoplastic Agents analysis, Antineoplastic Agents chemistry, Mass Spectrometry methods, Ruthenium
- Abstract
We present here the first comprehensive study on the lipophilicity of ruthenium anticancer agents encompassing compounds with broad structural diversity, ranging from octahedral Ru
III (azole) through to RuII (arene) complexes. MEEKC was used to determine the capacity factors of the Ru complexes, and after a complex peak was unambiguously assigned using MEEKC-ICP-MS, the results were validated through comparison with the log P determined by octanol/water partitioning experiments. Correlation of the two data sets demonstrated a close relationship despite the limited structural overlap of the compounds studied. The capacity factors found by MEEKC allowed for the clustering of complexes based on their structure and this could be used to rationalize the observed cytotoxicity in the human colon carcinoma HCT116 cell line. It was demonstrated that rather than modification of the mono- or bidentate coordinated ligands much tighter control over a complexes lipophilic properties could be achieved through modification of the Ru(arene) ligand, with minimal detriment to cytotoxicity. This demonstrates the flexibility and potential of the Ru piano-stool scaffold. MEEKC proved to be a highly efficient means of screening the anticancer potential of preclinical ruthenium complex candidates for their lipophilic properties and correlate them with their biological activity and structural properties., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2018
- Full Text
- View/download PDF
3. Electrophoretic separation techniques and their hyphenation to mass spectrometry in biological inorganic chemistry.
- Author
-
Holtkamp H, Grabmann G, and Hartinger CG
- Subjects
- Blood Proteins analysis, Blood Proteins chemistry, Humans, Metal Nanoparticles analysis, Metal Nanoparticles chemistry, Ruthenium Compounds analysis, Ruthenium Compounds chemistry, Chemistry, Bioinorganic methods, Electrophoresis, Capillary methods, Mass Spectrometry methods
- Abstract
Electrophoretic methods have been widely applied in research on the roles of metal complexes in biological systems. In particular, CE, often hyphenated to a sensitive MS detector, has provided valuable information on the modes of action of metal-based pharmaceuticals, and more recently new methods have been added to the electrophoretic toolbox. The range of applications continues to expand as a result of enhanced CE-to-MS interfacing, with sensitivity often at picomolar level, and evolved separation modes allowing for innovative sample analysis. This article is a followup to previous reviews about CE methods in metallodrug research (Electrophoresis, 2003, 24, 2023-2037; Electrophoresis, 2007, 28, 3436-3446; Electrophoresis, 2012, 33, 622-634), also providing a comprehensive overview of metal species studied by electrophoretic methods hyphenated to MS. It highlights the latest CE developments, takes a sneak peek into gel electrophoresis, traces biomolecule labeling, and focuses on the importance of early-stage drug development., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
- View/download PDF
4. Capillary electrophoretic methods in the development of metal-based therapeutics and diagnostics: new methodology and applications.
- Author
-
Bytzek AK and Hartinger CG
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Contrast Media chemistry, Humans, Electrophoresis, Capillary methods, Organometallic Compounds chemistry, Organometallic Compounds pharmacology
- Abstract
In recent years, capillary electrophoresis (CE) has matured to a standard method in medicinal inorganic chemistry. More and more steps of the drug discovery process are followed by CE. However, not only the number of applications has steadily increased but also the variety of used methodology has significantly broadened and, as compared to a few years ago, a wider scope of separation modes and hyphenated systems has been used. Herein, a summary of the newly utilized CE methods and their applications in metallodrug research in the timeframe 2006-2011 is presented, following related reviews from 2003 and 2007 (Electrophoresis, 2003, 24, 2023-2037; Electrophoresis 2007, 28, 3436-3446). Areas covered include impurity profiling, quality control of pharmaceutical formulations, lipophilicity estimation, interactions between metallodrugs and proteins or nucleotides, and characterization and also quantification of metabolites in biological matrices and real-world samples., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
- Full Text
- View/download PDF
5. The first example of MEEKC-ICP-MS coupling and its application for the analysis of anticancer platinum complexes.
- Author
-
Bytzek AK, Reithofer MR, Galanski M, Groessl M, Keppler BK, and Hartinger CG
- Subjects
- Hydrophobic and Hydrophilic Interactions, Oxaliplatin, Sensitivity and Specificity, Sodium Dodecyl Sulfate chemistry, Antineoplastic Agents chemistry, Chromatography, Micellar Electrokinetic Capillary methods, Mass Spectrometry methods, Organoplatinum Compounds chemistry
- Abstract
MEEKC is a powerful electrodriven separation technique with many applications in different disciplines, including medicinal chemistry; however, up to now the coupling to highly sensitive and selective MS detectors was limited due to the ion suppressive effect of the commonly used surfactant SDS. Herein, the first example of the coupling of MEEKC to ICP-MS is presented and an MEEKC method for the separation of Pt(II) and Pt(IV) anticancer drugs and drug candidates was developed. Different compositions of microemulsions were evaluated and the data were compared with those collected with standard ultraviolet/visible (UV/vis) spectroscopy detection. The MEEKC-ICP-MS system was found to be more sensitive than MEEKC-UV/vis and the analysis of UV/vis silent compounds is now achievable. The migration behavior of the Pt(II) and Pt(IV) compounds under investigation is correlated to their different chemical structures.
- Published
- 2010
- Full Text
- View/download PDF
6. Biodistribution of anti-diabetic Zn(II) complexes in human serum and in vitro protein-binding studies by means of CZE-ICP-MS.
- Author
-
Bytzek AK, Enyedy EA, Kiss T, Keppler BK, and Hartinger CG
- Subjects
- Binding, Competitive, Humans, Organometallic Compounds blood, Picolinic Acids blood, Picolinic Acids chemistry, Picolinic Acids pharmacokinetics, Protein Binding, Zinc blood, Blood Proteins metabolism, Electrophoresis, Capillary methods, Mass Spectrometry methods, Organometallic Compounds pharmacokinetics, Zinc pharmacokinetics
- Abstract
Application of modern analytical technology for studying the fate of metallodrugs after administration to the blood is of utmost importance for drug development. Zn(II) compounds are under development as insulin-enhancing drugs with potential use in the treatment of diabetes. In comparison to the well-established vanadium compounds, especially the lower risk of adverse effects due to the essentiality of the element in biological processes is advantageous. Herein, CZE-ICP-MS studies on the interaction of Zn(II)-maltolato, -2-picolinato and -2,6-dipicolinato complexes with human serum proteins are discussed and modeling calculations were confirmed by experimental results. Studies with human serum reveal preference for HSA over other less abundant proteins and serum components.
- Published
- 2009
- Full Text
- View/download PDF
7. The serum protein binding of pharmacologically active gallium(III) compounds assessed by hyphenated CE-MS techniques.
- Author
-
Groessl M, Bytzek A, and Hartinger CG
- Subjects
- Antineoplastic Agents pharmacokinetics, Binding, Competitive, Calibration, Gallium pharmacokinetics, Gallium Isotopes, Humans, Hydrogen-Ion Concentration, Iron metabolism, Kinetics, Models, Biological, Organometallic Compounds pharmacokinetics, Oxyquinoline blood, Oxyquinoline pharmacokinetics, Protein Binding, Electrophoresis, Capillary methods, Gallium blood, Mass Spectrometry methods, Organometallic Compounds blood, Oxyquinoline analogs & derivatives, Serum Albumin metabolism, Transferrin metabolism
- Abstract
Transition metal-based drugs exhibit high affinity to the soft donors of human serum proteins, especially of the high-abundance protein HSA and of transferrin (Tf), whereas Ga(III) salts are known to bind to Tf and other iron-containing metalloproteins, thereby interfering with the iron metabolism. Herein, the utilization of CE-MS methods for studying the binding behavior of a therapeutic gallium nitrate formulation and the anticancer drug candidate Tris(8-oxyquinolinato)gallium(III) to Tf and HSA under simulated physiological conditions is described. Both the Ga(III) salt and the complex were found to bind to Tf exclusively in the presence of carbonate, however, at different kinetics and to a different extent. Fe(III) induces the release of the Ga ions due to the higher affinity constant and also prevents the Ga(III) species from accessing the iron-binding pockets of Tf. In contrast, only low affinity to HSA was observed and even when present at ca. 20-fold excess, the majority of the Ga was attached to Tf.
- Published
- 2009
- Full Text
- View/download PDF
8. Capillary electrophoresis hyphenated to inductively coupled plasma-mass spectrometry: a novel approach for the analysis of anticancer metallodrugs in human serum and plasma.
- Author
-
Groessl M, Hartinger CG, Polec-Pawlak K, Jarosz M, and Keppler BK
- Subjects
- Antineoplastic Agents administration & dosage, Blood Chemical Analysis methods, Blood Proteins metabolism, Humans, In Vitro Techniques, Indazoles administration & dosage, Indazoles blood, Neoplasms blood, Neoplasms drug therapy, Organometallic Compounds administration & dosage, Protein Binding, Ruthenium Compounds administration & dosage, Ruthenium Compounds blood, Serum Albumin metabolism, Transferrin metabolism, Antineoplastic Agents blood, Electrophoresis, Capillary methods, Mass Spectrometry methods, Organometallic Compounds blood
- Abstract
The development of metal-based chemotherapeutics lacks methods which are capable of providing early indication on the potential of new metal complexes as future anticancer drugs. Since most of these compounds are administered intravenously, serum proteins are the first available biological binding partners in the bloodstream. For platinum-based anticancer drugs the interaction with serum proteins is regarded as an important contribution to the side effects accompanying chemotherapy. In contrast, newly developed ruthenium compounds are thought to be transported into the tumor in a protein-bound form. In here, the application of CE hyphenated to inductively coupled plasma (ICP)-MS, applying Polybrene-coated capillaries, is demonstrated for studying the interaction of indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) with HSA and transferrin, which are important transport proteins. Furthermore, the applicability of the method to human serum and plasma and, more importantly, to real-world patient samples was proven. KP1019 was found to bind to a high degree to HSA both in serum, plasma and the patient samples. Only minor fractions of ruthenium were found attached to other proteins.
- Published
- 2008
- Full Text
- View/download PDF
9. CE in anticancer metallodrug research--an update.
- Author
-
Hartinger CG and Keppler BK
- Subjects
- Antineoplastic Agents chemistry, Cisplatin chemistry, Electrophoresis, Capillary instrumentation, Humans, Indazoles chemistry, Molecular Structure, Platinum metabolism, Protein Binding, Ruthenium Compounds chemistry, Spectrometry, Mass, Electrospray Ionization methods, Spectrophotometry, Atomic instrumentation, Spectrophotometry, Atomic methods, Stereoisomerism, Antineoplastic Agents isolation & purification, Cisplatin isolation & purification, Electrophoresis, Capillary methods, Indazoles metabolism, Platinum chemistry, Ruthenium Compounds metabolism
- Abstract
With the current demographic development and the knowledge that the probability to be diagnosed with cancer increases with age, the search for new treatment options in cancer chemotherapy is of utmost importance for the society. Capillary electrophoretic methods have been applied in the last few years for studying the properties of metal-based drugs and drug candidates. Especially, the elucidation of the mode of action of such compounds could contribute significantly to design new drugs for overcoming the threat of cancer. This review article highlights the developments in metallodrug research applying CE during the last 4 years and follows a review from 2003 (Hartinger, C. G., Timerbaev, A. R., Keppler, B. K., Electrophoresis 2003, 24, 2023-2037). Most importantly the broadening of application areas of CE must be noted: especially the binding studies of metal complexes toward proteins (including the determination of association and rate constants), following redox reactions of metal complexes and their influence on the reactivity toward biotargets, etc. are important development areas of the last few years. In parallel with these new applications goes the usage of new or modified separation methods including microemulsion EKC or ACE, or the advantageous use of equipping the CE system with mass spectrometric detectors such as inductively coupled plasma (ICP) or ESI mass spectrometers (MS) for determining the degree of metallation of a protein or characterizing the adducts. Finally, upcoming requirements for expanding the method's application area are discussed including studies on new targets in the cell, analyzing real-world samples, methodological development, and contributions to improve the design of new anticancer agents.
- Published
- 2007
- Full Text
- View/download PDF
10. Probing the stability of serum protein-ruthenium(III) drug adducts in the presence of extracellular reductants using CE.
- Author
-
Timerbaev AR, Foteeva LS, Rudnev AV, Abramski JK, Połeć-Pawlak K, Hartinger CG, Jarosz M, and Keppler BK
- Subjects
- Ascorbic Acid chemistry, Buffers, Drug Stability, Electrolytes chemistry, Glutathione chemistry, Indazoles blood, Mass Spectrometry, Organometallic Compounds, Oxidation-Reduction, Ruthenium Compounds blood, Serum Albumin chemistry, Spectrophotometry, Ultraviolet, Transferrin chemistry, Blood Proteins chemistry, Electrophoresis, Capillary methods, Indazoles chemistry, Ruthenium Compounds chemistry
- Abstract
A CE kinetic assay was developed to study the stability of the adducts of a novel ruthenium(III)-based anticancer agent with serum proteins under simulated reductive physiological conditions. Formation of the reactive Ru(II) species and their release from the serum proteins are thought to play an important role in the mode-of-action of indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) which has successfully finished a clinical phase I study. The CE method was adapted, in zone electrophoresis and affinity CE modes, to make obvious that such transformation would take place in the hypoxic tumor tissue rather than in the bloodstream. Indeed, no measurable effect of extracellular concentration levels of glutathione incorporated into the BGE on the UV signals of albumin and transferrin adducts was observed over 30 min of examination. Incubation of the KP1019-albumin adduct with the major blood reducing agent, ascorbic acid, revealed no changes in the continuously monitored peak areas (average corrected responses were 9.56 +/- 0.86 and 9.87 +/- 0.60 mAU for the adduct and its mixtures with ascorbic acid in the physiological range of 1 x 10(-5) -8 x 10(-5) M, respectively). On the other hand, both the transferrin adduct and transferrin itself accelerated the oxidation of ascorbic acid; however, the oxidation rate constants measured by CE were virtually the same: (19.1 +/- 4.4) x 10(-3) and (18.2 +/- 5.0) x 10(-3) min(-1), respectively. In order to confirm more unambiguously the stability of KP1019-protein adducts in the presence of ascorbic acid (UV absorbance detection does not distinguish the adduct and protein signals), CE with inductively coupled plasma (ICP) MS detection was applied to follow metal-selectively the signal of bound ruthenium, which remained unaffected by this reducing agent. This work appears the first to present the application of CE to the stability studies of the protein-bound metallodrugs.
- Published
- 2007
- Full Text
- View/download PDF
11. 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.
- Author
-
Polec-Pawlak K, Abramski JK, Semenova O, Hartinger CG, Timerbaev AR, Keppler BK, and Jarosz M
- Subjects
- Antineoplastic Agents chemistry, Binding, Competitive, Humans, In Vitro Techniques, Indazoles chemistry, Kinetics, Organometallic Compounds, Platinum metabolism, Protein Binding, Ruthenium Compounds chemistry, Serum Albumin metabolism, Transferrin metabolism, Antineoplastic Agents metabolism, Blood Proteins metabolism, Electrophoresis, Capillary methods, Indazoles metabolism, Mass Spectrometry methods, Ruthenium Compounds metabolism
- Abstract
Biochemical speciation analysis has become a hot area of CE research due largely to growing emergence of inductively coupled plasma (ICP)-MS as a proper detection technique. A benefit of CE-ICP-MS coupling in species-selective analysis of anticancer metal-based drugs is the possibility of distinguishing the signals of the intact drug and its metabolites and hence of quantifying them independently. This advantage (over CE with UV-vis detection) was exploited here in order to gain better knowledge about the rate and degree of the transformation of indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019), a promising tumor-inhibiting agent that successfully finished phase I clinical studies, upon its binding toward individual serum transport proteins. At increasing the KP1019/protein molar ratio, the reaction rate expressed by an evolving peak of the protein adduct became faster, with the equilibrium state being reached after about 40 and 60 min of incubation at 37 degrees C for transferrin and albumin, respectively. The binding reaction was shown to obey the first-order character that enabled for reliable calculation of the corresponding rate constants as (28.7 +/- 1.5) x 10(-4) and (10.6 +/- 0.7) x 10(-4)/s, respectively. When incubated with a ten-fold excess of KP1019, albumin and transferrin bound, respectively, up to 8 and 10 equiv. of ruthenium (Ru). Relative affinity of KP1019 toward different proteins under simulated physiological conditions was also characterized in terms of the overall binding constants (5600 and 10 600/M, respectively). To emphasize the difference in the protein-binding behavior, a competitive interaction of KP1019 was followed by CE-ICP-MS at the actual molar ratio of proteins in blood, i.e. a ten-fold excess of albumin over transferrin. The fact that KP1019 binds to albumin stronger than to transferrin was manifested by finding almost all ruthenium (98-99%) in the albumin fraction.
- Published
- 2006
- Full Text
- View/download PDF
12. Platinum metallodrug-protein binding studies by capillary electrophoresis-inductively coupled plasma-mass spectrometry: characterization of interactions between Pt(II) complexes and human serum albumin.
- Author
-
Timerbaev AR, Aleksenko SS, Polec-Pawlak K, Ruzik R, Semenova O, Hartinger CG, Oszwaldowski S, Galanski M, Jarosz M, and Keppler BK
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cisplatin chemistry, Drug Interactions, Electrolytes chemistry, Humans, Kinetics, Pharmaceutical Preparations analysis, Pharmaceutical Preparations chemistry, Platinum metabolism, Protein Binding, Serum Albumin metabolism, Cisplatin analysis, Electrophoresis, Capillary methods, Mass Spectrometry methods, Platinum chemistry, Serum Albumin chemistry
- Abstract
Characterizing how platinum metallocomplexes bind to human serum albumin (HSA) is essential in evaluating anticancer drug candidates. Using cisplatin as a reference complex, the application of capillary electrophoresis (CE) to reliably assess drug/HSA interactions was validated. Since this complex is small compared to the size of the protein, the binding response could only be recognized when applying CE coupled to a (platinum) metal-specific mode of detection, namely inductively coupled plasma-mass spectrometry (ICP-MS). This coupling allowed for confirmation of a specific affinity of cisplatin and novel Pt complexes to HSA, measurement of the kinetics of binding reactions, and determination of the number of drug molecules attached to the protein. As the cisplatin/HSA molar ratio increased, the reaction rate became faster with a maximum on the kinetic curve appearing at about 50 h of incubation at 20 times excess of cisplatin. The reaction was characterized as a pseudo-first order reaction with the rate constant k = 0.003 min(-1) at 37 degrees C. When incubated with a 20-fold excess of cisplatin, HSA bound up to 10 mol of Pt per mol of the protein. This is indicative for a strong metal-protein coordination occurring at several HSA sites other than the only protein cysteine residue. Structural analogs of cisplatin, bearing aminoalcohol ligands, showed comparable protein binding reactivity and stoichiometry but a common equilibrium was not reached even after one week of incubation. Also apparent was a two-step mechanism of the binding reaction. Results demonstrated the suitability of CE-ICP-MS as a rapid assay for high-throughput studying of drug/HSA interactions.
- Published
- 2004
- Full Text
- View/download PDF
13. Capillary electrophoresis in anti-cancer metallodrug research: advances and future challenges.
- Author
-
Hartinger CG, Timerbaev AR, and Keppler BK
- Subjects
- Antineoplastic Agents chemistry, Stereoisomerism, Antineoplastic Agents isolation & purification, Electrophoresis, Capillary methods, Platinum chemistry
- Abstract
An efficient and convenient separation method has been a long sought after goal for anti-cancer metallodrug developers. For many reasons, capillary electrophoresis (CE) has recently emerged as the method of choice for the separation of intact platinum metal complexes and their metabolites, assessment of drug stability, and studying the interaction of the administered and potential tumor-inhibiting metallocomplexes with biomolecules. Due to the application of gentle separation conditions and successful developments in combinations with molecule-specific detectors, CE is also growing in importance as a versatile tool for the characterization of specific metal-bioligand binding products and thereby for providing mechanism-of-action information. Recent advances in metallodrug monitoring by CE are reviewed and critically evaluated. Likewise, the current limitations of CE in the field, such as the lack of assays involving individual proteins and targeting real-world biological samples, are brought into focus. Further strategies for method's refinement in anti-cancer metallodrug research that should ultimately take place along these lines and result in the development of high-throughput screening CE systems in the near future are finally discussed.
- Published
- 2003
- Full Text
- View/download PDF
14. Tumor-inhibiting platinum(II) complexes with aminoalcohol ligands: comparison of the mode of action by capillary electrophoresis and electrospray ionization-mass spectrometry.
- Author
-
Hartinger CG, Schluga P, Galanski MS, Baumgartner C, Timerbaev AR, and Keppler BK
- Subjects
- Ligands, Antineoplastic Agents chemistry, Electrophoresis, Capillary methods, Platinum Compounds chemistry, Spectrometry, Mass, Electrospray Ionization methods
- Abstract
Capillary electrophoresis (CE) was used as an assay for studying the interaction of (SP-4-2)-bis[(R)-(-)-2-aminobutanol)dichloroplatinum(II) (1) and (SP-4-2)bis(4-aminobutanol)dichloroplatinum(II) (2) with guanosine 5'-monophosphate (GMP). CE kinetic measurements carried out at two physiological pH levels indicated that upon increasing the pH, 1 showed an appreciable change in binding behavior, with the rate of binding increased for more than 10 times as expressed by apparent half-life values of GMP (6.1 and 62.2 h at pH 6.0 and 7.4, respectively). The rate of GMP binding for 2 remained comparatively less affected by pH (half-lives of 8.5 and 10.6 h, respectively). Regardless of the nature of platinum complex and pH, the reaction with GMP tends to be decelerated at increased chloride concentrations in solution, this effect being particularly pronounced when changing from 4 mM (intracellular level) to 100 mM (extracellular level). The kinetic differences of platinum complexes were characterized in terms of the respective GMP-adducts structure, independently identified by means of off-line electrospray ionization-mass spectrometry. Also addressed was the interpretation of binding behavior as based on the structural features of the intact complexes, namely differing inclination to intramolecular chelation.
- Published
- 2003
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.