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Bernhard K Keppler - One of the best experts on this subject based on the ideXlab platform.
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x ray structure analysis of indazolium trans tetrachlorobis 1h indazole ruthenate iii kp1019 bound to human serum albumin reveals two ruthenium binding sites and provides insights into the drug binding mechanism
Journal of Medicinal Chemistry, 2016Co-Authors: Aleksandar Bijelic, Bernhard K Keppler, Sarah Theiner, Annette RompelAbstract:Ruthenium(III) complexes are promising candidates for anticancer drugs, especially the clinically studied indazolium trans-[tetrachlorobis(1H-Indazole)ruthenate(III)] (KP1019) and its analogue sodium trans-[tetrachlorobis(1H-Indazole)ruthenate(III)] (NKP-1339). Several studies have emphasized the likely role of human serum proteins in the transportation and accumulation of ruthenium(III) complexes in tumors. Therefore, the interaction between KP1019 and human serum albumin was investigated by means of X-ray crystallography and inductively coupled plasma mass spectrometry (ICP-MS). The structural data unambiguously reveal the binding of two ruthenium atoms to histidine residues 146 and 242, which are both located within well-known hydrophobic binding pockets of albumin. The ruthenium centers are octahedrally coordinated by solvent molecules revealing the dissociation of both indazole ligands from the ruthenium-based drug. However, a binding mechanism is proposed indicating the importance of the indazole li...
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En Route to Osmium Analogues of KP1019: Synthesis, Structure, Spectroscopic Properties and Antiproliferative Activity of trans-[OsIVCl4(Hazole)2]
2015Co-Authors: Gabriel E. Büchel, Michael A Jakupec, Bernhard K Keppler, Iryna N Stepanenko, Michaela Hejl, Vladimir B ArionAbstract:By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-Indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human cancer cell lines CH1 (ovarian carcinoma), A549 (nonsmall cell lung carcinoma), and SW480 (colon carcinoma) is reported
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NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application
Chemical Science, 2014Co-Authors: Robert Trondl, Petra Heffeter, Michael A Jakupec, Christian R Kowol, Walter Berger, Bernhard K KepplerAbstract:NKP-1339 is the first-in-class ruthenium-based anticancer drug in clinical development against solid cancer and has recently been studied successfully in a phase I clinical trial. Ruthenium compounds such as KP1019 (indazolium trans-[tetrachloridobis(1H-Indazole)ruthenate(III)]) and NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-Indazole)ruthenate(III)]) have a high tumour targeting potential based (1) on their strong binding to serum proteins such as albumin and transferrin as well as (2) on their activation in the reductive tumour milieu. The redox activity of ruthenium compounds is believed to represent one major mode of action leading to disturbance of the cellular redox balance and, consequently, induction of G2/M cell cycle arrest, blockage of DNA synthesis, and induction of apoptosis via the mitochondrial pathway. Moreover, potent synergistic activities of NKP-1339 with the clinically approved tyrosine kinase inhibitor sorafenib were recently reported in vitro and in vivo. Taken together, KP1019 and NKP-1339 are promising drug candidates, and especially the very limited side effects observed so far in clinical phase I trials seem to be a major advantage of this class of ruthenium drugs as compared to other chemotherapeutics and targeted anticancer compounds.
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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
Journal of Medicinal Chemistry, 2013Co-Authors: Alfred A Hummer, Petra Heffeter, Michael A Jakupec, Bernhard K Keppler, Gabriel E Buchel, David V Batchelor, Walter Berger, Martin Filipits, Annette RompelAbstract: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 conce...
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en route to osmium analogues of kp1019 synthesis structure spectroscopic properties and antiproliferative activity of trans osivcl4 hazole 2
Inorganic Chemistry, 2011Co-Authors: Gabriel E Buchel, Michael A Jakupec, Bernhard K Keppler, Iryna N Stepanenko, Michaela Hejl, Vladimir B ArionAbstract:By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-Indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human ca...
Michael A Jakupec - One of the best experts on this subject based on the ideXlab platform.
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En Route to Osmium Analogues of KP1019: Synthesis, Structure, Spectroscopic Properties and Antiproliferative Activity of trans-[OsIVCl4(Hazole)2]
2015Co-Authors: Gabriel E. Büchel, Michael A Jakupec, Bernhard K Keppler, Iryna N Stepanenko, Michaela Hejl, Vladimir B ArionAbstract:By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-Indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human cancer cell lines CH1 (ovarian carcinoma), A549 (nonsmall cell lung carcinoma), and SW480 (colon carcinoma) is reported
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NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application
Chemical Science, 2014Co-Authors: Robert Trondl, Petra Heffeter, Michael A Jakupec, Christian R Kowol, Walter Berger, Bernhard K KepplerAbstract:NKP-1339 is the first-in-class ruthenium-based anticancer drug in clinical development against solid cancer and has recently been studied successfully in a phase I clinical trial. Ruthenium compounds such as KP1019 (indazolium trans-[tetrachloridobis(1H-Indazole)ruthenate(III)]) and NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-Indazole)ruthenate(III)]) have a high tumour targeting potential based (1) on their strong binding to serum proteins such as albumin and transferrin as well as (2) on their activation in the reductive tumour milieu. The redox activity of ruthenium compounds is believed to represent one major mode of action leading to disturbance of the cellular redox balance and, consequently, induction of G2/M cell cycle arrest, blockage of DNA synthesis, and induction of apoptosis via the mitochondrial pathway. Moreover, potent synergistic activities of NKP-1339 with the clinically approved tyrosine kinase inhibitor sorafenib were recently reported in vitro and in vivo. Taken together, KP1019 and NKP-1339 are promising drug candidates, and especially the very limited side effects observed so far in clinical phase I trials seem to be a major advantage of this class of ruthenium drugs as compared to other chemotherapeutics and targeted anticancer compounds.
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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
Journal of Medicinal Chemistry, 2013Co-Authors: Alfred A Hummer, Petra Heffeter, Michael A Jakupec, Bernhard K Keppler, Gabriel E Buchel, David V Batchelor, Walter Berger, Martin Filipits, Annette RompelAbstract: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 conce...
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en route to osmium analogues of kp1019 synthesis structure spectroscopic properties and antiproliferative activity of trans osivcl4 hazole 2
Inorganic Chemistry, 2011Co-Authors: Gabriel E Buchel, Michael A Jakupec, Bernhard K Keppler, Iryna N Stepanenko, Michaela Hejl, Vladimir B ArionAbstract:By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-Indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human ca...
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structure activity relationships for nami a type complexes hl trans rucl4l s dmso ruthenate iii l imidazole indazole 1 2 4 triazole 4 amino 1 2 4 triazole and 1 methyl 1 2 4 triazole aquation redox properties protein binding and antiproliferative act
Journal of Medicinal Chemistry, 2007Co-Authors: Michael Groessl, Michael A Jakupec, Vladimir B Arion, Christian G. Hartinger, Erwin Reisner, Rene Eichinger, Olga Semenova, Andrei R Timerbaev, Bernhard K KepplerAbstract:Imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)] (NAMI-A) and indazolium [trans-tetrachlorobis(1H-Indazole)ruthenate(III)] (KP1019) are the most promising ruthenium complexes for anticancer chemotherapy. In this study, the azole ligand of NAMI-A was systematically varied (from imidazole of NAMI-A to indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole), and the respective complexes were evaluated with regard to the rate of aquation and protein binding, redox potentials, and cytotoxicity by means of capillary zone electrophoresis, electrospray ionization mass spectrometry, cyclic voltammetry, and colorimetric microculture assays. Stability studies demonstrated low stability of the complexes at pH 7.4 and 37 degrees C and a high reactivity toward proteins (binding rate constants in the ranges of 0.02-0.34 and 0.01-0.26 min-1 for albumin and transferrin, respectively). The redox potentials (between 0.25 and 0.35 V) were found to be biologically accessible for activation of the complexes in the tumor, and the indazole-containing compound shows the highest antiproliferative activity in vitro.
Vladimir B Arion - One of the best experts on this subject based on the ideXlab platform.
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En Route to Osmium Analogues of KP1019: Synthesis, Structure, Spectroscopic Properties and Antiproliferative Activity of trans-[OsIVCl4(Hazole)2]
2015Co-Authors: Gabriel E. Büchel, Michael A Jakupec, Bernhard K Keppler, Iryna N Stepanenko, Michaela Hejl, Vladimir B ArionAbstract:By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-Indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human cancer cell lines CH1 (ovarian carcinoma), A549 (nonsmall cell lung carcinoma), and SW480 (colon carcinoma) is reported
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en route to osmium analogues of kp1019 synthesis structure spectroscopic properties and antiproliferative activity of trans osivcl4 hazole 2
Inorganic Chemistry, 2011Co-Authors: Gabriel E Buchel, Michael A Jakupec, Bernhard K Keppler, Iryna N Stepanenko, Michaela Hejl, Vladimir B ArionAbstract:By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-Indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human ca...
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structure activity relationships for nami a type complexes hl trans rucl4l s dmso ruthenate iii l imidazole indazole 1 2 4 triazole 4 amino 1 2 4 triazole and 1 methyl 1 2 4 triazole aquation redox properties protein binding and antiproliferative act
Journal of Medicinal Chemistry, 2007Co-Authors: Michael Groessl, Michael A Jakupec, Vladimir B Arion, Christian G. Hartinger, Erwin Reisner, Rene Eichinger, Olga Semenova, Andrei R Timerbaev, Bernhard K KepplerAbstract:Imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)] (NAMI-A) and indazolium [trans-tetrachlorobis(1H-Indazole)ruthenate(III)] (KP1019) are the most promising ruthenium complexes for anticancer chemotherapy. In this study, the azole ligand of NAMI-A was systematically varied (from imidazole of NAMI-A to indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole), and the respective complexes were evaluated with regard to the rate of aquation and protein binding, redox potentials, and cytotoxicity by means of capillary zone electrophoresis, electrospray ionization mass spectrometry, cyclic voltammetry, and colorimetric microculture assays. Stability studies demonstrated low stability of the complexes at pH 7.4 and 37 degrees C and a high reactivity toward proteins (binding rate constants in the ranges of 0.02-0.34 and 0.01-0.26 min-1 for albumin and transferrin, respectively). The redox potentials (between 0.25 and 0.35 V) were found to be biologically accessible for activation of the complexes in the tumor, and the indazole-containing compound shows the highest antiproliferative activity in vitro.
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structure activity relationships for nami a type complexes hl trans rucl4l s dmso ruthenate iii l imidazole indazole 1 2 4 triazole 4 amino 1 2 4 triazole and 1 methyl 1 2 4 triazole aquation redox properties protein binding and antiproliferative act
Journal of Medicinal Chemistry, 2007Co-Authors: Michael Groessl, Michael A Jakupec, Vladimir B Arion, Christian G. Hartinger, Erwin Reisner, Rene Eichinger, Olga Semenova, Andrei R Timerbaev, Bernhard K KepplerAbstract:Imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)] (NAMI-A) and indazolium [trans-tetrachlorobis(1H-Indazole)ruthenate(III)] (KP1019) are the most promising ruthenium complexes for anticancer chemotherapy. In this study, the azole ligand of NAMI-A was systematically varied (from imidazole of NAMI-A to indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole), and the respective complexes were evaluated with regard to the rate of aquation and protein binding, redox potentials, and cytotoxicity by means of capillary zone electrophoresis, electrospray ionization mass spectrometry, cyclic voltammetry, and colorimetric microculture assays. Stability studies demonstrated low stability of the complexes at pH 7.4 and 37 °C and a high reactivity toward proteins (binding rate constants in the ranges of 0.02−0.34 and 0.01−0.26 min-1 for albumin and transferrin, respectively). The redox potentials (between 0.25 and 0.35 V) were found to be biologically accessible for...
Annette Rompel - One of the best experts on this subject based on the ideXlab platform.
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x ray structure analysis of indazolium trans tetrachlorobis 1h indazole ruthenate iii kp1019 bound to human serum albumin reveals two ruthenium binding sites and provides insights into the drug binding mechanism
Journal of Medicinal Chemistry, 2016Co-Authors: Aleksandar Bijelic, Bernhard K Keppler, Sarah Theiner, Annette RompelAbstract:Ruthenium(III) complexes are promising candidates for anticancer drugs, especially the clinically studied indazolium trans-[tetrachlorobis(1H-Indazole)ruthenate(III)] (KP1019) and its analogue sodium trans-[tetrachlorobis(1H-Indazole)ruthenate(III)] (NKP-1339). Several studies have emphasized the likely role of human serum proteins in the transportation and accumulation of ruthenium(III) complexes in tumors. Therefore, the interaction between KP1019 and human serum albumin was investigated by means of X-ray crystallography and inductively coupled plasma mass spectrometry (ICP-MS). The structural data unambiguously reveal the binding of two ruthenium atoms to histidine residues 146 and 242, which are both located within well-known hydrophobic binding pockets of albumin. The ruthenium centers are octahedrally coordinated by solvent molecules revealing the dissociation of both indazole ligands from the ruthenium-based drug. However, a binding mechanism is proposed indicating the importance of the indazole li...
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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
Journal of Medicinal Chemistry, 2013Co-Authors: Alfred A Hummer, Petra Heffeter, Michael A Jakupec, Bernhard K Keppler, Gabriel E Buchel, David V Batchelor, Walter Berger, Martin Filipits, Annette RompelAbstract: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 conce...
Andrei R Timerbaev - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationships for nami a type complexes hl trans rucl4l s dmso ruthenate iii l imidazole indazole 1 2 4 triazole 4 amino 1 2 4 triazole and 1 methyl 1 2 4 triazole aquation redox properties protein binding and antiproliferative act
Journal of Medicinal Chemistry, 2007Co-Authors: Michael Groessl, Michael A Jakupec, Vladimir B Arion, Christian G. Hartinger, Erwin Reisner, Rene Eichinger, Olga Semenova, Andrei R Timerbaev, Bernhard K KepplerAbstract:Imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)] (NAMI-A) and indazolium [trans-tetrachlorobis(1H-Indazole)ruthenate(III)] (KP1019) are the most promising ruthenium complexes for anticancer chemotherapy. In this study, the azole ligand of NAMI-A was systematically varied (from imidazole of NAMI-A to indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole), and the respective complexes were evaluated with regard to the rate of aquation and protein binding, redox potentials, and cytotoxicity by means of capillary zone electrophoresis, electrospray ionization mass spectrometry, cyclic voltammetry, and colorimetric microculture assays. Stability studies demonstrated low stability of the complexes at pH 7.4 and 37 degrees C and a high reactivity toward proteins (binding rate constants in the ranges of 0.02-0.34 and 0.01-0.26 min-1 for albumin and transferrin, respectively). The redox potentials (between 0.25 and 0.35 V) were found to be biologically accessible for activation of the complexes in the tumor, and the indazole-containing compound shows the highest antiproliferative activity in vitro.
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structure activity relationships for nami a type complexes hl trans rucl4l s dmso ruthenate iii l imidazole indazole 1 2 4 triazole 4 amino 1 2 4 triazole and 1 methyl 1 2 4 triazole aquation redox properties protein binding and antiproliferative act
Journal of Medicinal Chemistry, 2007Co-Authors: Michael Groessl, Michael A Jakupec, Vladimir B Arion, Christian G. Hartinger, Erwin Reisner, Rene Eichinger, Olga Semenova, Andrei R Timerbaev, Bernhard K KepplerAbstract:Imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)] (NAMI-A) and indazolium [trans-tetrachlorobis(1H-Indazole)ruthenate(III)] (KP1019) are the most promising ruthenium complexes for anticancer chemotherapy. In this study, the azole ligand of NAMI-A was systematically varied (from imidazole of NAMI-A to indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole), and the respective complexes were evaluated with regard to the rate of aquation and protein binding, redox potentials, and cytotoxicity by means of capillary zone electrophoresis, electrospray ionization mass spectrometry, cyclic voltammetry, and colorimetric microculture assays. Stability studies demonstrated low stability of the complexes at pH 7.4 and 37 °C and a high reactivity toward proteins (binding rate constants in the ranges of 0.02−0.34 and 0.01−0.26 min-1 for albumin and transferrin, respectively). The redox potentials (between 0.25 and 0.35 V) were found to be biologically accessible for...
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Comparative binding of antitumor indazolium [trans-tetrachlorobis(1H-Indazole)ruthenate(III)] to serum transport proteins assayed by capillary zone electrophoresis.
Analytical biochemistry, 2005Co-Authors: Andrei R Timerbaev, Olga Semenova, Christian G. Hartinger, Alexander V. Rudnev, Bernhard K KepplerAbstract:Abstract The indazolium [trans-tetrachlorobis(1H-Indazole)ruthenate(III)] coordination compound shows notable antiproliferative activity in different tumor models and has recently ended phase I clinical trials as a lead anticancer metallodrug candidate. Its approval could be greatly facilitated if more precise information was available on the rate and degree of the drug’s transformation occurring upon interaction with serum transport proteins and on the stability of the adducts formed. With this objective, a new method has been developed for the determination of the protein-binding rate and association constants under simulated physiological conditions by capillary zone electrophoresis (CZE). These binding parameters were assessed by monitoring the time- and concentration-dependent changes in peak area responses of reaction components, constructing the corresponding binding curves, and conducting a mathematical analysis. Comparison of the apparent rate constants determined by CZE revealed that indazolium [trans-tetrachlorobis(1H-Indazole)ruthenate(III)] binds to transferrin much faster than to albumin: k = 39.5 × 10−4 and 3.3 × 10−4 s−1, respectively. The corresponding association constants are indicative of moderate metal–protein coordination, with a somewhat higher affinity of the Ru complex toward albumin (9910 and 6460 M−1, respectively). The results of our study confirm in a quantitative manner that, in real bloodstream circumstances, plasma albumin may serve as a reservoir and a natural carrier of the administered ruthenium drug and hence mediate its accumulation in tumors.
