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Ian R Hardcastle - One of the best experts on this subject based on the ideXlab platform.
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dna dependent protein kinase dna pk inhibitors synthesis and biological activity of quinolin 4 one and pyridopyrimidin 4 one surrogates for the chromen 4 one chemotype
Journal of Medicinal Chemistry, 2010Co-Authors: Celine Cano, Xiaoling Fan Cockcroft, Nicola J Curtin, Mark Frigerio, Bernard T Golding, Ian R Hardcastle, Olivier Barbeau, Christine Bailey, Heather Mary Ellen Duggan, Marc Geoffrey HummersoneAbstract:Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083−6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)nNR1R2, where n = 1 or 2 and the moiety R1R2N was derived from a library of primary and secondary amines (e.g., Morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki−Miyaura cro...
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pyranone thiopyranone and pyridone inhibitors of phosphatidylinositol 3 kinase related kinases structure activity relationships for dna dependent protein kinase inhibition and identification of the first potent and selective inhibitor of the ataxia t
Journal of Medicinal Chemistry, 2007Co-Authors: Jonathan J Hollick, Laurent Rigoreau, Celine Canosoumillac, Xiaoling Fan Cockcroft, Nicola J Curtin, Mark Frigerio, Bernard T Golding, Sophie Guiard, Ian R Hardcastle, Ian HicksonAbstract:Structure−activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50 = 13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50 = 220 nM) effectivel...
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discovery of potent chromen 4 one inhibitors of the dna dependent protein kinase dna pk using a small molecule library approach
Journal of Medicinal Chemistry, 2005Co-Authors: Ian R Hardcastle, Laurent Rigoreau, Xiaoling Fan Cockcroft, Nicola J Curtin, Bernard T Golding, Marine Desage Elmurr, Justin J J Leahy, Martin Stockley, Caroline Richardson, Graeme C M SmithAbstract:Structure−activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a Morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxy-substituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNA-PK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6‘,7‘,8‘,9‘-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32...
Xiaoling Fan Cockcroft - One of the best experts on this subject based on the ideXlab platform.
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dna dependent protein kinase dna pk inhibitors synthesis and biological activity of quinolin 4 one and pyridopyrimidin 4 one surrogates for the chromen 4 one chemotype
Journal of Medicinal Chemistry, 2010Co-Authors: Celine Cano, Xiaoling Fan Cockcroft, Nicola J Curtin, Mark Frigerio, Bernard T Golding, Ian R Hardcastle, Olivier Barbeau, Christine Bailey, Heather Mary Ellen Duggan, Marc Geoffrey HummersoneAbstract:Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083−6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)nNR1R2, where n = 1 or 2 and the moiety R1R2N was derived from a library of primary and secondary amines (e.g., Morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki−Miyaura cro...
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pyranone thiopyranone and pyridone inhibitors of phosphatidylinositol 3 kinase related kinases structure activity relationships for dna dependent protein kinase inhibition and identification of the first potent and selective inhibitor of the ataxia t
Journal of Medicinal Chemistry, 2007Co-Authors: Jonathan J Hollick, Laurent Rigoreau, Celine Canosoumillac, Xiaoling Fan Cockcroft, Nicola J Curtin, Mark Frigerio, Bernard T Golding, Sophie Guiard, Ian R Hardcastle, Ian HicksonAbstract:Structure−activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50 = 13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50 = 220 nM) effectivel...
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discovery of potent chromen 4 one inhibitors of the dna dependent protein kinase dna pk using a small molecule library approach
Journal of Medicinal Chemistry, 2005Co-Authors: Ian R Hardcastle, Laurent Rigoreau, Xiaoling Fan Cockcroft, Nicola J Curtin, Bernard T Golding, Marine Desage Elmurr, Justin J J Leahy, Martin Stockley, Caroline Richardson, Graeme C M SmithAbstract:Structure−activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a Morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxy-substituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNA-PK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6‘,7‘,8‘,9‘-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32...
Nicola J Curtin - One of the best experts on this subject based on the ideXlab platform.
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dna dependent protein kinase dna pk inhibitors synthesis and biological activity of quinolin 4 one and pyridopyrimidin 4 one surrogates for the chromen 4 one chemotype
Journal of Medicinal Chemistry, 2010Co-Authors: Celine Cano, Xiaoling Fan Cockcroft, Nicola J Curtin, Mark Frigerio, Bernard T Golding, Ian R Hardcastle, Olivier Barbeau, Christine Bailey, Heather Mary Ellen Duggan, Marc Geoffrey HummersoneAbstract:Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083−6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)nNR1R2, where n = 1 or 2 and the moiety R1R2N was derived from a library of primary and secondary amines (e.g., Morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki−Miyaura cro...
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pyranone thiopyranone and pyridone inhibitors of phosphatidylinositol 3 kinase related kinases structure activity relationships for dna dependent protein kinase inhibition and identification of the first potent and selective inhibitor of the ataxia t
Journal of Medicinal Chemistry, 2007Co-Authors: Jonathan J Hollick, Laurent Rigoreau, Celine Canosoumillac, Xiaoling Fan Cockcroft, Nicola J Curtin, Mark Frigerio, Bernard T Golding, Sophie Guiard, Ian R Hardcastle, Ian HicksonAbstract:Structure−activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50 = 13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50 = 220 nM) effectivel...
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discovery of potent chromen 4 one inhibitors of the dna dependent protein kinase dna pk using a small molecule library approach
Journal of Medicinal Chemistry, 2005Co-Authors: Ian R Hardcastle, Laurent Rigoreau, Xiaoling Fan Cockcroft, Nicola J Curtin, Bernard T Golding, Marine Desage Elmurr, Justin J J Leahy, Martin Stockley, Caroline Richardson, Graeme C M SmithAbstract:Structure−activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a Morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxy-substituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNA-PK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6‘,7‘,8‘,9‘-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32...
Bernard T Golding - One of the best experts on this subject based on the ideXlab platform.
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dna dependent protein kinase dna pk inhibitors synthesis and biological activity of quinolin 4 one and pyridopyrimidin 4 one surrogates for the chromen 4 one chemotype
Journal of Medicinal Chemistry, 2010Co-Authors: Celine Cano, Xiaoling Fan Cockcroft, Nicola J Curtin, Mark Frigerio, Bernard T Golding, Ian R Hardcastle, Olivier Barbeau, Christine Bailey, Heather Mary Ellen Duggan, Marc Geoffrey HummersoneAbstract:Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) (Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083−6087) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2)nNR1R2, where n = 1 or 2 and the moiety R1R2N was derived from a library of primary and secondary amines (e.g., Morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki−Miyaura cro...
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pyranone thiopyranone and pyridone inhibitors of phosphatidylinositol 3 kinase related kinases structure activity relationships for dna dependent protein kinase inhibition and identification of the first potent and selective inhibitor of the ataxia t
Journal of Medicinal Chemistry, 2007Co-Authors: Jonathan J Hollick, Laurent Rigoreau, Celine Canosoumillac, Xiaoling Fan Cockcroft, Nicola J Curtin, Mark Frigerio, Bernard T Golding, Sophie Guiard, Ian R Hardcastle, Ian HicksonAbstract:Structure−activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50 = 13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50 = 220 nM) effectivel...
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discovery of potent chromen 4 one inhibitors of the dna dependent protein kinase dna pk using a small molecule library approach
Journal of Medicinal Chemistry, 2005Co-Authors: Ian R Hardcastle, Laurent Rigoreau, Xiaoling Fan Cockcroft, Nicola J Curtin, Bernard T Golding, Marine Desage Elmurr, Justin J J Leahy, Martin Stockley, Caroline Richardson, Graeme C M SmithAbstract:Structure−activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a Morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxy-substituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNA-PK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6‘,7‘,8‘,9‘-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32...
M Penso - One of the best experts on this subject based on the ideXlab platform.
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regioselective o sulfonylation of n n bis 2 hydroxyalkyl tosylamides as a synthetic key step to enantiopure Morpholines
Organic Letters, 2017Co-Authors: Francesca Foschi, Domenico Albanese, Ilir Pecnikaj, Aaron Tagliabue, M PensoAbstract:The synthesis of enantiopure 2,6-disubstituted Morpholines was realized through sequential ring opening of two different optically pure oxiranes by a tosylamide, under solid–liquid phase-transfer catalysis (SL-PTC) conditions, mono-O-sulfonylation of the resulting tosylamido-2,2′-diol, and cyclization to the Morpholine. The crucial step, the regioselective formation of the monosulfonate, was controlled by taking advantage of the different stereo, electronic, and coordination properties of the oxirane-derived side chains in the diol backbone. As an application of this protocol, a new Morpholine-3-carboxamide was synthesized starting from threonine.
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Regioselective O‑Sulfonylation of N,N‑Bis(2-hydroxyalkyl)tosylamides as a Synthetic Key Step to Enantiopure Morpholines
2016Co-Authors: Francesca Foschi, Domenico Albanese, Ilir Pecnikaj, Aaron Tagliabue, M PensoAbstract:The synthesis of enantiopure 2,6-disubstituted Morpholines was realized through sequential ring opening of two different optically pure oxiranes by a tosylamide, under solid–liquid phase-transfer catalysis (SL-PTC) conditions, mono-O-sulfonylation of the resulting tosylamido-2,2′-diol, and cyclization to the Morpholine. The crucial step, the regioselective formation of the monosulfonate, was controlled by taking advantage of the different stereo, electronic, and coordination properties of the oxirane-derived side chains in the diol backbone. As an application of this protocol, a new Morpholine-3-carboxamide was synthesized starting from threonine
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a straightforward synthesisof enantiopure 2 6 disubstituted Morpholines by a regioselectiveo protection activation protocol
Synlett, 2008Co-Authors: M Penso, Francesca Foschi, Domenico Albanese, Vittoria Lupi, Dario Landini, Aaron TagliabueAbstract:: Enantiopure 2,6-disubstituted Morpholines have been synthesized through the ring opening of chiral, nonracemic oxiranes with nitrogen nucleophiles, under solid-liquid phase-transfer catalysis (SL-PTC) conditions. The β-hydroxytosyi amides resulting from the ring opening of a first epoxide with TsNH 2 was used as nucleophile, after protection of the hydroxyl group, in the reaction with a second oxirane. The Morpholine skeleton has been generated through standard functional group chemistry, followed by cyclization of the intermediate p-hydroxy-β'-tosyloxy-tosylamides carried out under SL-PTC conditions. N-Tosyl Morpholines produced can be employed as building blocks in the synthesis of pharmaceuticals and as chiral tools.
