The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform
Sohyun Chun - One of the best experts on this subject based on the ideXlab platform.
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Streptonigrin inhibits β catenin tcf signaling and shows cytotoxicity in β catenin activated cells
Biochimica et Biophysica Acta, 2011Co-Authors: Seyeon Park, Sohyun ChunAbstract:Abstract Background Activation of β-catenin/T-cell factor (Tcf) signaling plays a role in human carcinogenesis. This suggests a possibility that the β-catenin/Tcf signaling activated by the accumulation of β-catenin in the nucleus is related to some type of human carcinogenesis. Therefore, if β-catenin's transcriptional activity can be markedly down-regulated, tumor growth will be suppressed in β-catenin activated types of cancer. Methods To investigate the activation or suppression of β-catenin/Tcf transcription, we established a transiently transfected cell line with a constitutively active β-catenin mutant gene whose product is not degraded. This cell line was also co-transfected with luciferase reporter gene constructs containing either an optimized (TOPflash) or mutant (FOPflash) Tcf-binding element. Results We identified the inhibitory effect of Streptonigrin against β-catenin/Tcf signaling in β-catenin activated cells. Streptonigrin inhibited the transcriptional activity of β-catenin/Tcf in SW480 cells and HEK293 cells transiently transfected with a constitutively active mutant β-catenin gene. The growth inhibitory effect of Streptonigrin was more evident in β-catenin-activated cancer cells than in non-activated cancer cells. The electrophoresis mobility shift assay showed that the binding of Tcf complexes with their specific DNA-binding sites was suppressed by Streptonigrin. Conclusion: Streptonigrin is a negative regulator of β-catenin/Tcf signaling, and their inhibitory mechanism is related to the proliferation inhibitory effect on β-catenin-activated cancer cells. General significance This report reveals a molecular mechanism underlying the anti-tumor effect of Streptonigrin from the perspective β-catenin/Tcf signaling. Given its function in inhibiting β-catenin/Tcf signaling, Streptonigrin may be of interest as a leading compound for chemotherapeutic agent against β-catenin-activated tumorigenesis.
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Streptonigrin inhibits β-Catenin/Tcf signaling and shows cytotoxicity in β-catenin-activated cells.
Biochimica et Biophysica Acta, 2011Co-Authors: Seyeon Park, Sohyun ChunAbstract:Abstract Background Activation of β-catenin/T-cell factor (Tcf) signaling plays a role in human carcinogenesis. This suggests a possibility that the β-catenin/Tcf signaling activated by the accumulation of β-catenin in the nucleus is related to some type of human carcinogenesis. Therefore, if β-catenin's transcriptional activity can be markedly down-regulated, tumor growth will be suppressed in β-catenin activated types of cancer. Methods To investigate the activation or suppression of β-catenin/Tcf transcription, we established a transiently transfected cell line with a constitutively active β-catenin mutant gene whose product is not degraded. This cell line was also co-transfected with luciferase reporter gene constructs containing either an optimized (TOPflash) or mutant (FOPflash) Tcf-binding element. Results We identified the inhibitory effect of Streptonigrin against β-catenin/Tcf signaling in β-catenin activated cells. Streptonigrin inhibited the transcriptional activity of β-catenin/Tcf in SW480 cells and HEK293 cells transiently transfected with a constitutively active mutant β-catenin gene. The growth inhibitory effect of Streptonigrin was more evident in β-catenin-activated cancer cells than in non-activated cancer cells. The electrophoresis mobility shift assay showed that the binding of Tcf complexes with their specific DNA-binding sites was suppressed by Streptonigrin. Conclusion: Streptonigrin is a negative regulator of β-catenin/Tcf signaling, and their inhibitory mechanism is related to the proliferation inhibitory effect on β-catenin-activated cancer cells. General significance This report reveals a molecular mechanism underlying the anti-tumor effect of Streptonigrin from the perspective β-catenin/Tcf signaling. Given its function in inhibiting β-catenin/Tcf signaling, Streptonigrin may be of interest as a leading compound for chemotherapeutic agent against β-catenin-activated tumorigenesis.
Margaret M Harding - One of the best experts on this subject based on the ideXlab platform.
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assignment of the 13 c and 15 n nmr spectra of the antitumour antibiotic Streptonigrin
Magnetic Resonance in Chemistry, 2002Co-Authors: Pia I Anderberg, Ian J Luck, Margaret M HardingAbstract:The assignments of the two pyridyl nitrogens and two amino nitrogens in the antitumour antibiotic Streptonigrin, and all carbon resonances, were determined by 15N (HSQC, HMBC) and 13C (HSQC, HMBC) NMR techniques. These data provide useful probes for determination of the site(s) of metal complexation in the drug, which are important in the mechanism of antitumour activity. Copyright © 2002 John Wiley & Sons, Ltd.
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the role of ring d in the antitumour antibiotic Streptonigrin metal complexation dna binding and topoisomerase inhibition by abc ring analogues of Streptonigrin
Anti-cancer Drug Design, 2001Co-Authors: Pia I Anderberg, Margaret M HardingAbstract:The interaction of 7-amino-2-(6'-carboxy-2'-pyridyl)-6-methoxy-5,8-quinolinedione, an ABC ring analogue of the antitumour antibiotic Streptonigrin, with zinc(II), oligonucleotides and DNA in the presence of zinc(II), and on the relaxation of DNA by topoisomerase II, has been studied. This ligand contains the key functional groups present in Streptonigrin required for biological activity, but lacks the phenolic ring D which confers optical activity on Streptonigrin. Variable temperature NMR experiments showed that in the presence of zinc(II) triflate, the methyl ester of the ligand forms a mixture of 1:1 and 1:2 metal:ligand bipyridyl complexes, whose relative stabilities are temperature dependent. Titrations of the water-soluble ligand with zinc(II) nitrate at room temperature showed that the predominant species present in aqueous solution at physiological pH is the 1:1 bipyridyl complex. The interaction of the ligand with the hexanucleotides d(GCATGC) 2 and d(ATGCAT) 2 was studied by 1 H- and 31 P-NMR spectroscopy. In the presence of 1 equiv of zinc(II) nitrate and 1 equiv of the ligand, small changes in chemical shifts of the proton resonances associated with the purine resonances were detected consistent with a weak interaction of the zinc(II) complex of the ligand with the oligonucleotides, possibly via a groove binding mechanism. UV-VIS titrations showed a weak interaction of the ligand with calf thymus DNA and poly(dG-dC) 2 in the presence of zinc(II) but negligible interaction with poly(dA-dT) 2 . Gel electrophoresis experiments showed that, in contrast to Streptonigrin, the ligand did not inhibit the relaxation of plasmid DNA by human topoisomerase II. These results show that the interaction of the ABC ligand with zinc(II), oligonucleotides, DNA and topoisomerase II is different to Streptonigrin and hence the design of biologically active ABC ring analogues of streptongrin that operate via different mechanisms should be possible.
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synthesis of abc analogues of the antitumour antibiotic Streptonigrin
Tetrahedron, 2000Co-Authors: Marc C Kimber, Pia I Anderberg, Margaret M HardingAbstract:Abstract ABC analogues of the antitumour antibiotic Streptonigrin, that contain the key metal chelation site and redox-active quinone unit that are essential for biological activity, were prepared via palladium catalysed cross-coupling of 2-iodo-8-nitroquinoline or 2-iodo-6-methoxy-5-nitroquinoline with 2-trimethylstannio-6-methylpyridine. Mild oxidation of the pyridyl methyl group introduced the acid functional group on ring C and Fremy's salt oxidation afforded the quinone unit which was elaborated to give the 5-amino-6-methoxy substitution pattern present in Streptonigrin.
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x ray structure of the zinc complex of the central metal chelation site of the antitumour drug Streptonigrin
Polyhedron, 2000Co-Authors: Georgina V Long, Margaret M Harding, Peter TurnerAbstract:Abstract The X-ray structure of the 1:1 complex between zinc(II) triflate and 3-amino-6,6′-bis(methoxycarbonyl)-2,2′-bipyridine is reported. This ligand contains the central chelation site present in the DNA-binding antitumour antibiotic Streptonigrin. The complex is distorted octahedral involving the 2,2′-bipyridyl site and the carbonyl groups at the 6,6′-positions as well as two axial water molecules. The structure confirms that formation of similar complexes with Streptonigrin is possible.
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interaction of the antitumour antibiotic Streptonigrin with dna and oligonucleotides
Anti-cancer Drug Design, 1997Co-Authors: Georgina V Long, Margaret M Harding, W A DennyAbstract:The interaction of the aminoquinone antitumour antibiotic Streptonigrin with plasmid DNA, calf thymus DNA and oligonucleotides, in the presence and absence of metal ions, has been studied using circular dichroism, NMR spectroscopy and gel electrophoresis experiments. In the absence of metal ions, Streptonigrin does not interact with DNA. Incubation of the two enantiomers of Streptonigrin with calf thymus DNA, in the presence of excess zinc(II), showed no evidence of selective interaction of the natural enantiomer, (R)-Streptonigrin, with the DNA by circular dichroism. The interaction of Streptonigrin with the hexanucleotide d(GCATGC) 2 was studied by Hand 31 P-NMR spectroscopy. In the presence of four equivalents of zinc(II) nitrate and one equivalent of Streptonigrin, small changes in chemical shifts of the proton resonances associated with T4 and G 5 were detected as well as P 4 and P 5 , consistent with a weak interaction of the zinc(II)-Streptonigrin complex with the most accessible binding sites, involving the phosphate groups and guanine N7, at either end of the duplex. In contrast, no significant interaction between the metal complex and d(ATGCAT) 2 was detected. Gel electrophoresis experiments were carried out to probe the sequence specificity of the interaction of the non-covalent Streptonigrin-metal complexes with DNA, the DNA cleavage reaction of supercoiled DNA, and the specificity of the cleavage reaction. DNase I footprinting showed no sequence specific interactions. Zinc(II), copper(II) and manganese(II) enhanced the cleavage of supercoiled DNA into nicked and linear forms of DNA, while magnesium showed no cleavage reactions under identical conditions. The DNA cleavage reaction of Streptonigrin and NADH in the presence and absence of metal ions was studied. Overall, little sequence specificity was observed, but slightly different cleavage patterns suggest that the DNA cleavage can be influenced by the nature of the metal ions.
Guy Queguiner - One of the best experts on this subject based on the ideXlab platform.
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synthesis of new pyridine intermediates as precursors for the elaboration of Streptonigrin analogues by the metalation cross coupling strategy
Journal of Heterocyclic Chemistry, 1996Co-Authors: V Pomel, J C Rovera, A Godard, Francis Marsais, Guy QueguinerAbstract:Starting from available 2-amino-6-chloro-3-nitropyridine, synthesis of 3-amino-6-pyridinecarboxylic acid derivatives precursor for pyridine ring C of Streptonigrin analogues is described.
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metallation in connection with cross coupling reactions coupling of hindered aryls for the synthesis of 4 phenylpyridines as part of Streptonigrin and lavendamycin analogues
Journal of Organometallic Chemistry, 1996Co-Authors: A Godard, V Pomel, J C Rovera, Francis Marsais, Patrick Rocca, L Thomasditdumont, J F Thaburet, Guy QueguinerAbstract:Abstract The synthesis of the CD ring system of Streptonigrin and Lavendamycin alkaloid analogues by cross-coupling under Suzuki's conditions has been studied. Steric hindrance is the main problem. It has been solved either by using strong bases or working in a sealed tube under pressure.
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convergent synthesis of Streptonigrin and lavendamycin analogues
Tetrahedron Letters, 1993Co-Authors: A Godard, J C Rovera, Francis Marsais, Patrick Rocca, J M Fourquez, Guy QueguinerAbstract:Abstract A convergent synthesis of Streptonigrin and lavendamycin analogues incorporating a quinoline-5,8-dione structure is reported. The approach is based on our synthetic methodology which involves such reactions as metalation, heteroring cross-coupling and oxidative demethylation.
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convergent synthesis of the Streptonigrin alkaloid skeleton directed orthometalation connection to aryl aryl cross coupling
Tetrahedron, 1992Co-Authors: A Godard, J C Rovera, Francis Marsais, Guy QueguinerAbstract:Abstract A convergent synthesis of 2-[2-(4-phenyl-3-pivaloylamino) pyridyl]quinolines, the Streptonigrin alkaloid skeleton, is reported. The methodology involves independent elaboration of the three main building blocks by metalation and two coupling reactions catalyzed by palladium.
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Synthesis of 3-amino-4-phenylpyridines : a novel strategy for the preparation of CD ring models of Streptonigrin
Journal of The Chemical Society-perkin Transactions 1, 1990Co-Authors: Francis Marsais, J C Rovera, Alain Turck, Alain Godard, Guy QueguinerAbstract:3-Pivaloylaminopyridines were lithiated by butyl-lithium before reaction with iodine as electrophile to afford 4-iodo-3-pivaloylaminopyridines. Cross-coupling of the latter with suitable phenylboronic acid gives CD ring models of Streptonigrin
Seyeon Park - One of the best experts on this subject based on the ideXlab platform.
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Streptonigrin inhibits β catenin tcf signaling and shows cytotoxicity in β catenin activated cells
Biochimica et Biophysica Acta, 2011Co-Authors: Seyeon Park, Sohyun ChunAbstract:Abstract Background Activation of β-catenin/T-cell factor (Tcf) signaling plays a role in human carcinogenesis. This suggests a possibility that the β-catenin/Tcf signaling activated by the accumulation of β-catenin in the nucleus is related to some type of human carcinogenesis. Therefore, if β-catenin's transcriptional activity can be markedly down-regulated, tumor growth will be suppressed in β-catenin activated types of cancer. Methods To investigate the activation or suppression of β-catenin/Tcf transcription, we established a transiently transfected cell line with a constitutively active β-catenin mutant gene whose product is not degraded. This cell line was also co-transfected with luciferase reporter gene constructs containing either an optimized (TOPflash) or mutant (FOPflash) Tcf-binding element. Results We identified the inhibitory effect of Streptonigrin against β-catenin/Tcf signaling in β-catenin activated cells. Streptonigrin inhibited the transcriptional activity of β-catenin/Tcf in SW480 cells and HEK293 cells transiently transfected with a constitutively active mutant β-catenin gene. The growth inhibitory effect of Streptonigrin was more evident in β-catenin-activated cancer cells than in non-activated cancer cells. The electrophoresis mobility shift assay showed that the binding of Tcf complexes with their specific DNA-binding sites was suppressed by Streptonigrin. Conclusion: Streptonigrin is a negative regulator of β-catenin/Tcf signaling, and their inhibitory mechanism is related to the proliferation inhibitory effect on β-catenin-activated cancer cells. General significance This report reveals a molecular mechanism underlying the anti-tumor effect of Streptonigrin from the perspective β-catenin/Tcf signaling. Given its function in inhibiting β-catenin/Tcf signaling, Streptonigrin may be of interest as a leading compound for chemotherapeutic agent against β-catenin-activated tumorigenesis.
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Streptonigrin inhibits β-Catenin/Tcf signaling and shows cytotoxicity in β-catenin-activated cells.
Biochimica et Biophysica Acta, 2011Co-Authors: Seyeon Park, Sohyun ChunAbstract:Abstract Background Activation of β-catenin/T-cell factor (Tcf) signaling plays a role in human carcinogenesis. This suggests a possibility that the β-catenin/Tcf signaling activated by the accumulation of β-catenin in the nucleus is related to some type of human carcinogenesis. Therefore, if β-catenin's transcriptional activity can be markedly down-regulated, tumor growth will be suppressed in β-catenin activated types of cancer. Methods To investigate the activation or suppression of β-catenin/Tcf transcription, we established a transiently transfected cell line with a constitutively active β-catenin mutant gene whose product is not degraded. This cell line was also co-transfected with luciferase reporter gene constructs containing either an optimized (TOPflash) or mutant (FOPflash) Tcf-binding element. Results We identified the inhibitory effect of Streptonigrin against β-catenin/Tcf signaling in β-catenin activated cells. Streptonigrin inhibited the transcriptional activity of β-catenin/Tcf in SW480 cells and HEK293 cells transiently transfected with a constitutively active mutant β-catenin gene. The growth inhibitory effect of Streptonigrin was more evident in β-catenin-activated cancer cells than in non-activated cancer cells. The electrophoresis mobility shift assay showed that the binding of Tcf complexes with their specific DNA-binding sites was suppressed by Streptonigrin. Conclusion: Streptonigrin is a negative regulator of β-catenin/Tcf signaling, and their inhibitory mechanism is related to the proliferation inhibitory effect on β-catenin-activated cancer cells. General significance This report reveals a molecular mechanism underlying the anti-tumor effect of Streptonigrin from the perspective β-catenin/Tcf signaling. Given its function in inhibiting β-catenin/Tcf signaling, Streptonigrin may be of interest as a leading compound for chemotherapeutic agent against β-catenin-activated tumorigenesis.
Luiz C A Barbosa - One of the best experts on this subject based on the ideXlab platform.
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total synthesis of the antitumor antibiotic Streptonigrin first and second generation routes for de novo pyridine formation using ring closing metathesis
Journal of Organic Chemistry, 2013Co-Authors: Timothy J Donohoe, Christopher R Jones, Anne F Kornahrens, Luiz C A Barbosa, Louise J Walport, Matthew R Tatton, Michael P Ohagan, Akshat H Rathi, David B BakerAbstract:The total synthesis of (±)-Streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (±)-Streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate. This synthesis will allow for the design and creation of druglike late-stage natural product analogues to address pharmacological limitations. Furthermore, assessment of a number of chiral ligands in a challenging asymmetric Suzuki–Miyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic Streptonigrin intermediates to be prepared for the first time.
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Total synthesis of the antitumor antibiotic (±)-Streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis.
Journal of Organic Chemistry, 2013Co-Authors: Timothy J Donohoe, Christopher R Jones, Anne F Kornahrens, Luiz C A Barbosa, Louise J Walport, Matthew R Tatton, Akshat H Rathi, Michael P. O'hagan, David B BakerAbstract:The total synthesis of (±)-Streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (±)-Streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate. This synthesis will allow for the design and creation of druglike late-stage natural product analogues to address pharmacological limitations. Furthermore, assessment of a number of chiral ligands in a challenging asymmetric Suzuki–Miyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic Streptonigrin intermediates to be prepared for the first time.
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total synthesis of Streptonigrin de novo construction of a pentasubstituted pyridine using ring closing metathesis
Journal of the American Chemical Society, 2011Co-Authors: Timothy J Donohoe, Christopher R Jones, Luiz C A BarbosaAbstract:The synthesis of the potent antitumor agent (±)-Streptonigrin has been achieved in 14 linear steps and 11% overall yield from ethyl glyoxalate. The synthesis features a challenging ring-closing metathesis reaction, followed by elimination and aromatization, to furnish a key pentasubstituted pyridine fragment.
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Total synthesis of (±)-Streptonigrin: de novo construction of a pentasubstituted pyridine using ring-closing metathesis.
Journal of the American Chemical Society, 2011Co-Authors: Timothy J Donohoe, Christopher R Jones, Luiz C A BarbosaAbstract:The synthesis of the potent antitumor agent (±)-Streptonigrin has been achieved in 14 linear steps and 11% overall yield from ethyl glyoxalate. The synthesis features a challenging ring-closing metathesis reaction, followed by elimination and aromatization, to furnish a key pentasubstituted pyridine fragment.
