Antihypoxic activity of adaptaquin enantiomers

Adaptaquin, 7-{(4-chlorophenyl)[(3-hydroxypyridin-2-yl)amino]methyl}quinolin-8-ol ( 1 ), was identified in our earlier study as a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor by high-throughput screening of cell lines, which stably express the reporter construct encoding a fusion prot...

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Bibliographic Details
Published in:Russian chemical bulletin 2018-12, Vol.67 (12), p.2320-2322
Main Authors: Gaisina, I. N., Khristichenko, A. Yu, Gaisin, A. M., Smirnova, N. A., Gazaryan, I. G., Poloznikov, A. A.
Format: Article
Language:English
Subjects:
ANOXIA
ATOMS
Brief Communications
CARBON
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
CHIRAL SYMMETRY
Enantiomers
HYDROXYLASES
Hypoxia
IN VIVO
Inhibitors
Inorganic Chemistry
INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY
LUCIFERASE
MOLECULES
Organic Chemistry
OXIDATION
OXYGEN
Proteins
STRUCTURE-ACTIVITY RELATIONSHIPS
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Summary:Adaptaquin, 7-{(4-chlorophenyl)[(3-hydroxypyridin-2-yl)amino]methyl}quinolin-8-ol ( 1 ), was identified in our earlier study as a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor by high-throughput screening of cell lines, which stably express the reporter construct encoding a fusion protein composed of the HIF oxygen degradable domain and firefly luciferase (HIF1 ODD-luc). Adaptaquin is a specific inhibitor of this enzyme and exhibits neuroprotective properties in cell models of oxidative stress and in vivo models of hemorrhagic stroke. The role of the chiral carbon atom in the inhibitor molecule was studied in order to further improve the adaptaquin structure. The separation into two enantiomers was performed. Both enantiomers were shown to equally activate the HIF1 ODD-luc reporter. The adaptaquin structure can be significantly modified and made more sophisticated in order to improve specificity toward this group of enzymes and subsequently toward individual isozymes.
ISSN:1066-5285
1573-9171
DOI:10.1007/s11172-018-2376-0