Article ; Online: Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent.
Molecules (Basel, Switzerland)
2019 Volume 24, Issue 23
Abstract: Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer's disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a ... ...
Abstract | Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer's disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization. |
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MeSH term(s) | Cell Line, Tumor ; Flow Cytometry ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Humans ; Hydroxyquinolines/chemical synthesis ; Hydroxyquinolines/chemistry ; Hydroxyquinolines/pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit/chemistry ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Oxyquinoline/analogs & derivatives ; Protein Stability/drug effects ; Quinidine/chemistry ; Quinine/chemistry ; Stereoisomerism |
Chemical Substances | HIF1A protein, human ; Hydroxyquinolines ; Hypoxia-Inducible Factor 1, alpha Subunit ; Oxyquinoline (5UTX5635HP) ; Quinine (A7V27PHC7A) ; Quinidine (ITX08688JL) |
Language | English |
Publishing date | 2019-11-23 |
Publishing country | Switzerland |
Document type | Journal Article |
ZDB-ID | 1413402-0 |
ISSN | 1420-3049 ; 1431-5165 ; 1420-3049 |
ISSN (online) | 1420-3049 |
ISSN | 1431-5165 ; 1420-3049 |
DOI | 10.3390/molecules24234269 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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