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Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.

Chan MC, Atasoylu O, Hodson E, Tumber A, Leung IK, Chowdhury R, Gómez-Pérez V, Demetriades M, Rydzik AM, Holt-Martyn J, Tian YM, Bishop T, Claridge TD, Kawamura A, Pugh CW, Ratcliffe PJ, Schofield CJ - PLoS ONE (2015)

Bottom Line: As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs).Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate.One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.

View Article: PubMed Central - PubMed

Affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom; Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom.

ABSTRACT
As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.

No MeSH data available.


Related in: MedlinePlus

Hydroxylation of HIFα and the chemical structures of IOX4 and other PHD inhibitors used in this study.(a) Prolyl-hydroxylation (as catalyzed by the PHDs) of HIFα. (b) Structures of the dihydropyrazoles (1 and IOX4) in comparison to structures of 2-oxoglutarate (2OG), N-oxalylglycine (NOG) (a catalytically inactive analogue of 2OG), dimethyloxalylglycine (DMOG) (a cell-permeable ester derivative of NOG) and IOX2 [9]. Chemical structures of previously reported PHD inhibitors (compound 2, bicyclic isoquinolinyl inhibitor IOX3 and bicyclic naphthalenylsulfone hydroxythiazole BNS) used in this study are also shown.
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pone.0132004.g001: Hydroxylation of HIFα and the chemical structures of IOX4 and other PHD inhibitors used in this study.(a) Prolyl-hydroxylation (as catalyzed by the PHDs) of HIFα. (b) Structures of the dihydropyrazoles (1 and IOX4) in comparison to structures of 2-oxoglutarate (2OG), N-oxalylglycine (NOG) (a catalytically inactive analogue of 2OG), dimethyloxalylglycine (DMOG) (a cell-permeable ester derivative of NOG) and IOX2 [9]. Chemical structures of previously reported PHD inhibitors (compound 2, bicyclic isoquinolinyl inhibitor IOX3 and bicyclic naphthalenylsulfone hydroxythiazole BNS) used in this study are also shown.

Mentions: In metazoans, the α/β heterodimeric hypoxia-inducible factor (HIF) complex activates the expression of hundreds of target genes in response to hypoxia, including those involved in cell growth, apoptosis, energy metabolism and angiogenesis [1]. Prolyl hydroxylation of human HIFα in its C- and N-terminal oxygen dependent degradation domains (CODD and NODD), as catalyzed by three HIF prolyl hydroxylases (PHD1-3, Fig 1A), leads to subsequent HIFα polyubiquitination by the von Hippel-Lindau (VHL) protein complex and proteasomal degradation [2,3,4,5,6] HIFα is also regulated via asparaginyl hydroxylation as catalyzed by factor inhibiting HIF (FIH), a modification which blocks the recruitment of the transcriptional co-activators CBP/p300 to HIFα, so causing reduced HIF transcriptional activity [7,8]. The activities of both the PHDs and FIH are suppressed by limiting oxygen, resulting in HIFα stabilization and activation of the HIF system.


Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.

Chan MC, Atasoylu O, Hodson E, Tumber A, Leung IK, Chowdhury R, Gómez-Pérez V, Demetriades M, Rydzik AM, Holt-Martyn J, Tian YM, Bishop T, Claridge TD, Kawamura A, Pugh CW, Ratcliffe PJ, Schofield CJ - PLoS ONE (2015)

Hydroxylation of HIFα and the chemical structures of IOX4 and other PHD inhibitors used in this study.(a) Prolyl-hydroxylation (as catalyzed by the PHDs) of HIFα. (b) Structures of the dihydropyrazoles (1 and IOX4) in comparison to structures of 2-oxoglutarate (2OG), N-oxalylglycine (NOG) (a catalytically inactive analogue of 2OG), dimethyloxalylglycine (DMOG) (a cell-permeable ester derivative of NOG) and IOX2 [9]. Chemical structures of previously reported PHD inhibitors (compound 2, bicyclic isoquinolinyl inhibitor IOX3 and bicyclic naphthalenylsulfone hydroxythiazole BNS) used in this study are also shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492579&req=5

pone.0132004.g001: Hydroxylation of HIFα and the chemical structures of IOX4 and other PHD inhibitors used in this study.(a) Prolyl-hydroxylation (as catalyzed by the PHDs) of HIFα. (b) Structures of the dihydropyrazoles (1 and IOX4) in comparison to structures of 2-oxoglutarate (2OG), N-oxalylglycine (NOG) (a catalytically inactive analogue of 2OG), dimethyloxalylglycine (DMOG) (a cell-permeable ester derivative of NOG) and IOX2 [9]. Chemical structures of previously reported PHD inhibitors (compound 2, bicyclic isoquinolinyl inhibitor IOX3 and bicyclic naphthalenylsulfone hydroxythiazole BNS) used in this study are also shown.
Mentions: In metazoans, the α/β heterodimeric hypoxia-inducible factor (HIF) complex activates the expression of hundreds of target genes in response to hypoxia, including those involved in cell growth, apoptosis, energy metabolism and angiogenesis [1]. Prolyl hydroxylation of human HIFα in its C- and N-terminal oxygen dependent degradation domains (CODD and NODD), as catalyzed by three HIF prolyl hydroxylases (PHD1-3, Fig 1A), leads to subsequent HIFα polyubiquitination by the von Hippel-Lindau (VHL) protein complex and proteasomal degradation [2,3,4,5,6] HIFα is also regulated via asparaginyl hydroxylation as catalyzed by factor inhibiting HIF (FIH), a modification which blocks the recruitment of the transcriptional co-activators CBP/p300 to HIFα, so causing reduced HIF transcriptional activity [7,8]. The activities of both the PHDs and FIH are suppressed by limiting oxygen, resulting in HIFα stabilization and activation of the HIF system.

Bottom Line: As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs).Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate.One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.

View Article: PubMed Central - PubMed

Affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom; Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, United Kingdom.

ABSTRACT
As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs). Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs). Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4) induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.

No MeSH data available.


Related in: MedlinePlus