Abstract
A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI(50)) using the MTT assay. Among the compounds synthesized, 1g and 1l showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity (IC(50): 1.9 ± 0.4 and 1.4 ± 0.2 μM, respectively). Both compounds suppressed HIF-1α accumulation in a concentration-dependent manner. The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited human Hsp60 chaperone activity (IC(50): 6.80 ± 0.25 μM) and this inhibition activity was higher than that of ETB (IC(50): 10.9 ± 0.63 μM).
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetanilides / chemical synthesis*
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Acetanilides / chemistry
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Acetanilides / pharmacology*
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Anaerobiosis / physiology
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Animals
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Benzoquinones / chemical synthesis
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Benzoquinones / chemistry
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Benzoquinones / pharmacology
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Boron Compounds / chemistry*
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Boronic Acids / chemical synthesis*
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Boronic Acids / chemistry
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Boronic Acids / pharmacology*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects*
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HeLa Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
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Inhibitory Concentration 50
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Lactams, Macrocyclic / chemical synthesis
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Lactams, Macrocyclic / chemistry
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Lactams, Macrocyclic / pharmacology
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Molecular Structure
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Swine
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Topotecan / chemical synthesis
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Topotecan / chemistry
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Topotecan / pharmacology
Substances
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Acetanilides
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Benzoquinones
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Boron Compounds
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Boronic Acids
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Enzyme Inhibitors
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GN 26361
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lactams, Macrocyclic
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tanespimycin
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Topotecan