Abstract
Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor which is strongly associated with tumor survival, progression, and therapeutic resistance. Accordingly, it has been suggested that the inhibition of the HIF-1 pathway can suppress tumor, and it has become an important therapeutic target. In present study, oltipraz, its metabolite M2, and their derivatives were synthesized and evaluated as HIF-1α inhibitors. Among the synthesized, benzyl-substituted pyrrolo[1,2-a]pyrazine 2g most potently inhibited HIF-1α protein accumulation (81% at 10μM) and VEGF, GLUT-1 transcription (77% and 92% at 10μM, respectively).
Keywords:
GLUT-1; Hypoxia inducible factor-1; Oltipraz; Pyrrolopyrazine; VEGF.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Glucose Transporter Type 1 / genetics
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HCT116 Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Insulin / metabolism
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Pyrazines / chemical synthesis
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Pyrazines / chemistry*
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Pyrazines / pharmacology*
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Thiones / chemical synthesis
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Thiones / chemistry*
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Thiones / pharmacology*
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Thiophenes / chemical synthesis
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Thiophenes / chemistry*
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Thiophenes / pharmacology*
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Transcriptional Activation / drug effects
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Vascular Endothelial Growth Factor A / genetics
Substances
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Antineoplastic Agents
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Glucose Transporter Type 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Insulin
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Pyrazines
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Thiones
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Thiophenes
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Vascular Endothelial Growth Factor A
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oltipraz
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1,2-dithiol-3-thione