- Modulation of estrogen-related receptors subtype selectivity: Conversion of an ERRβ/γ selective agonist to ERRα/β/γ pan agonists
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Estrogen Related Receptors (ERRs) are key regulators of energy homeostasis and play important role in the etiology of metabolic disorders, skeletal muscle related disorders, and neurodegenerative diseases. Among the three ERR isoforms, ERRα emerged as a potential drug target for metabolic and neurodegenerative diseases. Although ERRβ/γ selective agonist chemical tools have been identified, there are no chemical tools that effectively target ERRα agonism. We successfully engineered high affinity ERRα agonism into a chemical scaffold that displays selective ERRβ/γ agonist activity (GSK4716), providing novel ERRα/β/γ pan agonists that can be used as tools to probe the physiological roles of these nuclear receptors. We identified the structural requirements to enhance selectivity toward ERRα. Molecular modeling shows that our novel modulators have favorable binding modes in the LBP of ERRα and can induce conformational changes where Phe328 that originally occupies the pocket is dislocated to accommodate the ligands in a rather small cavity. The best agonists up-regulated the expression of target genes PGC-1α and PGC-1β, which are necessary to achieve maximal mitochondrial biogenesis. Moreover, they increased the mRNA levels of PDK4, which play an important role in energy homeostasis.
- Avdagic, Amer,Billon, Cyrielle,Burris, Sheryl L.,Burris, Thomas P.,Elagawany, Mohamed,Elgendy, Bahaa,Goher, Shaimaa S.,Hegazy, Lamees,Sanders, Ryan,Shahien, Mohamed,Sitaula, Sadichha
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- Polystyrene-supported iodobenzene diacetate (PSIBD)-mediated synthesis of 1,2-diacylbenzenes from 2-hydroxyaryl aldehyde/ketone acylhydrazones
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Synthesis of some new 1,2-diacylbenzenes is described by the oxidation of 2-hydroxyaryl aldehyde/ketone acylhydrazones using polystyrene-supported iodobenzene diacetate (PSIBD) in good yield. Copyright Taylor & Francis Group, LLC.
- Kumar, Sunil,Kumar, Devinder
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p. 3683 - 3699
(2008/12/23)
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- Synthesis of New Acylhydrazones as Iron-Chelating Compounds
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Fourteen acylhydrazides have been condensed with three aromatic o-hydroxy aldehydes (pyridoxal, salicylaldehyde, and 2-hydroxy-1-naphthaldehyde) to give 42 acylhydrazones, of which 38 are new.These compounds complex iron and have shown varying abilities to promote the movement of iron across biological membranes.Their infrared and nuclear magnetic resonance spectra support the structures assigned to them.
- Edward, John T.,Gauthier, Mario,Chubb, Francis L.,Ponka, Premysl
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p. 538 - 540
(2007/10/02)
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