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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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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, Erwin Reisner, Christian G Hartinger, 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.
Duddu S Sharada - One of the best experts on this subject based on the ideXlab platform.
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c sp2 h functionalization of 2h indazoles at c3 position via palladium ii catalyzed isocyanide insertion strategy leading to diverse heterocycles
Journal of Organic Chemistry, 2016Co-Authors: Shinde Vidyacharan, Arumugavel Murugan, Duddu S SharadaAbstract:Herein, we have reported an efficient Pd-catalyzed C–H functionalization of 2H-Indazole at C3-position via an isocyanide insertion strategy for the synthesis of unprecedented benzoxazinoindazoles, indazoloquinaoxalines and benzoxazinoindazolones for the first time. Our new method provides an operationally simple and versatile route for a selective synthesis of 2-(2H-indazol-2-yl)phenols. Furthermore, we developed a sequential one-pot strategy for the synthesis of benzoxazinoindazolone under metal-oxidant-free conditions. We also achieved the isocyanide insertion between C(sp2)–H and oxygen heteroatom for the first time. The key features of the present protocol are construction of 4 bonds in one-pot, synthesis of new skeletally diverse scaffolds, broad substrate scope, high yields and environmentally benign conditions.
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bf3 oet2 mediated metal free one pot sequential multiple annulation cascade smac synthesis of complex and diverse tetrahydroisoquinoline fused hybrid molecules
Organic and Biomolecular Chemistry, 2016Co-Authors: Anand H Shinde, Shinde Vidyacharan, Duddu S SharadaAbstract:A highly efficient and distinct BF3·OEt2 mediated metal-free SMAC protocol for the synthesis of complex and diverse hybrid molecules viz. indazole fused tetrahydroisoquinolinoquinoxalines, and tetrahydroisoquinolinodiazepine has been developed. The transformation is based on sequential cascade processes involving 2H-Indazole formation and deprotection Pictet–Spengler cyclization steps in one-pot fashion. The protocol demonstrates the utility of sequential multiple annulations in a cascade fashion. The present one-pot protocol uses the Solid State Melt Reaction (SSMR) strategy for the synthesis of the intermediate 2H-Indazole. The method is operationally simple and represents a new approach for C–C, three C–N and N–N bond formation with a wide substrate scope.
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a new route for the synthesis of highly substituted 4 aminoquinoline drug like molecules via aza hetero diels alder reaction
ChemInform, 2015Co-Authors: Shinde Vidyacharan, A Sagar, Duddu S SharadaAbstract:The title quinolines are obtained using 2H-Indazole as the diene partner in the aza hetero-Diels—Alder reaction via a hetrocyclic-heterocyclic (H-H) strategy.
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a new route for the synthesis of highly substituted 4 aminoquinoline drug like molecules via aza hetero diels alder reaction
Organic and Biomolecular Chemistry, 2015Co-Authors: Shinde Vidyacharan, A Sagar, Duddu S SharadaAbstract:We have demonstrated for the first time the use of 2H-Indazole as a diene partner in an aza hetero–Diels–Alder reaction leading to highly substituted 4-aminoquinolines via a heterocylic–heterocylic (H–H) strategy and have further developed a tandem one-pot method starting from 2-azidobenzaldehyde by the formation of 2C–N, 1N–N and 1C–C bonds. The key features of the present protocol are readily available starting materials, mild reaction conditions, being work-up free and having easy purification. This is the first time where the synthesis of 4-aminoquinoline drug like molecules has been achieved starting from simple starting materials in an atom economical manner.
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A facile synthesis of 2H-Indazoles under neat conditions and further transformation into aza-γ-carboline alkaloid analogues in a tandem one-pot fashion
RSC Advances, 2014Co-Authors: Shinde Vidyacharan, N C Chaitra, A Sagar, Duddu S SharadaAbstract:We have described a facile, microwave-assisted, catalyst-free and solvent-free approach to 2H-Indazoles and further developed a robust tandem one-pot metal-free strategy for C–C bond formation at the C-3 position of 2H-Indazoles leading to a unique class of aza-γ-carboline alkaloid analogues. This straightforward expedient synthesis constitutes an interesting alternative to the existing conventional transition metal catalyzed reactions.
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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osmium iii analogues of kp1019 electrochemical and chemical synthesis spectroscopic characterization x ray crystallography hydrolytic stability and antiproliferative activity
Inorganic Chemistry, 2014Co-Authors: Paul-steffen Kuhn, Gabriel E Buchel, Katarina K Jovanovic, Lana Filipovic, Peter Rapta, Siniša Radulović, Vladimir B ArionAbstract:A one-electron reduction of osmium(IV) complexes trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole ([1]0), 2H-Indazole ([2]0), 1H-imidazole ([3]0), and 1H-benzimidazole ([4]0), afforded a series of eight new complexes as osmium analogues of KP1019, a lead anticancer drug in clinical trials, with the general formula (cation)[trans-OsIIICl4(Hazole)2], where cation = H2pz+ (H2pz[1]), H2ind+ (H2ind[2]), H2im+ (H2im[3]), Ph4P+ (Ph4P[3]), nBu4N+ (nBu4N[3]), H2bzim+ (H2bzim[4]), Ph4P+ (Ph4P[4]), and nBu4N+ (nBu4N[4]). All complexes were characterized by elemental analysis, 1H NMR spectroscopy, electrospray ionization mass spectrometry, UV–vis spectroscopy, cyclic voltammetry, while H2pz[1], H2ind[2], and nBu4[3], in addition, by X-ray diffraction. The reduced species [1]− and [4]− are stable in aqueous media in the absence of air oxygen and do not react with small biomolecules such as amino acids and the nucleotide 5′-dGMP. Cell culture experiments in five different human cancer cell lines (HeLa, A549, FemX, ...
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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, Erwin Reisner, Christian G Hartinger, 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, Erwin Reisner, Christian G Hartinger, 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...
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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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, Erwin Reisner, Christian G Hartinger, 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, Erwin Reisner, Christian G Hartinger, 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...
Shinde Vidyacharan - One of the best experts on this subject based on the ideXlab platform.
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c sp2 h functionalization of 2h indazoles at c3 position via palladium ii catalyzed isocyanide insertion strategy leading to diverse heterocycles
Journal of Organic Chemistry, 2016Co-Authors: Shinde Vidyacharan, Arumugavel Murugan, Duddu S SharadaAbstract:Herein, we have reported an efficient Pd-catalyzed C–H functionalization of 2H-Indazole at C3-position via an isocyanide insertion strategy for the synthesis of unprecedented benzoxazinoindazoles, indazoloquinaoxalines and benzoxazinoindazolones for the first time. Our new method provides an operationally simple and versatile route for a selective synthesis of 2-(2H-indazol-2-yl)phenols. Furthermore, we developed a sequential one-pot strategy for the synthesis of benzoxazinoindazolone under metal-oxidant-free conditions. We also achieved the isocyanide insertion between C(sp2)–H and oxygen heteroatom for the first time. The key features of the present protocol are construction of 4 bonds in one-pot, synthesis of new skeletally diverse scaffolds, broad substrate scope, high yields and environmentally benign conditions.
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bf3 oet2 mediated metal free one pot sequential multiple annulation cascade smac synthesis of complex and diverse tetrahydroisoquinoline fused hybrid molecules
Organic and Biomolecular Chemistry, 2016Co-Authors: Anand H Shinde, Shinde Vidyacharan, Duddu S SharadaAbstract:A highly efficient and distinct BF3·OEt2 mediated metal-free SMAC protocol for the synthesis of complex and diverse hybrid molecules viz. indazole fused tetrahydroisoquinolinoquinoxalines, and tetrahydroisoquinolinodiazepine has been developed. The transformation is based on sequential cascade processes involving 2H-Indazole formation and deprotection Pictet–Spengler cyclization steps in one-pot fashion. The protocol demonstrates the utility of sequential multiple annulations in a cascade fashion. The present one-pot protocol uses the Solid State Melt Reaction (SSMR) strategy for the synthesis of the intermediate 2H-Indazole. The method is operationally simple and represents a new approach for C–C, three C–N and N–N bond formation with a wide substrate scope.
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a new route for the synthesis of highly substituted 4 aminoquinoline drug like molecules via aza hetero diels alder reaction
ChemInform, 2015Co-Authors: Shinde Vidyacharan, A Sagar, Duddu S SharadaAbstract:The title quinolines are obtained using 2H-Indazole as the diene partner in the aza hetero-Diels—Alder reaction via a hetrocyclic-heterocyclic (H-H) strategy.
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a new route for the synthesis of highly substituted 4 aminoquinoline drug like molecules via aza hetero diels alder reaction
Organic and Biomolecular Chemistry, 2015Co-Authors: Shinde Vidyacharan, A Sagar, Duddu S SharadaAbstract:We have demonstrated for the first time the use of 2H-Indazole as a diene partner in an aza hetero–Diels–Alder reaction leading to highly substituted 4-aminoquinolines via a heterocylic–heterocylic (H–H) strategy and have further developed a tandem one-pot method starting from 2-azidobenzaldehyde by the formation of 2C–N, 1N–N and 1C–C bonds. The key features of the present protocol are readily available starting materials, mild reaction conditions, being work-up free and having easy purification. This is the first time where the synthesis of 4-aminoquinoline drug like molecules has been achieved starting from simple starting materials in an atom economical manner.
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A facile synthesis of 2H-Indazoles under neat conditions and further transformation into aza-γ-carboline alkaloid analogues in a tandem one-pot fashion
RSC Advances, 2014Co-Authors: Shinde Vidyacharan, N C Chaitra, A Sagar, Duddu S SharadaAbstract:We have described a facile, microwave-assisted, catalyst-free and solvent-free approach to 2H-Indazoles and further developed a robust tandem one-pot metal-free strategy for C–C bond formation at the C-3 position of 2H-Indazoles leading to a unique class of aza-γ-carboline alkaloid analogues. This straightforward expedient synthesis constitutes an interesting alternative to the existing conventional transition metal catalyzed reactions.
