NDLI: Microwave-assisted synthesis and evaluation of acylhydrazones as potential inhibitors of bovine glutathione peroxidase

Content Provider	Springer Nature Link
Author	Wilde, Felix Lemmerhirt, Heidi Emmrich, Thomas Bednarski, Patrick J. Link, Andreas
Copyright Year	2014
Abstract	Glutathione peroxidases (GPx) were the first selenocysteine enzymes identified. They play critical roles in cellular defense to excess $$\hbox {H}_{2}\hbox {O}_{2}$$ and lipid peroxides, with GPx1 contributing the most cellular activity. In the treatment of cancer, for example, in lymphomas and leukaemias, evidence has been accumulating that up-regulation of the GPx system may serve to protect cancer cells from oxidative stress caused by anticancer drugs. We hypothesize that small molecules which block GPx1 could help overcome acquired resistance to anticancer drugs by raising the level of oxidative stress in cancer cells. Our previous efforts identified an acylhydrazone as a lead structure for the inhibition of GPx1. Now we report the microwave-supported synthesis and inhibitory screening of a series of 78 analogs. The special conformational isomerism resulting of the acylhydrazone functionality was investigated by the analysis of distinct NMR data and crystal structures, indicating that conformers at the C(O)–N hydrazide bond are responsible for this phenomena. Though some of the analogs showed poor aqueous solubility and could not be tested in the enzyme assay, the combinatorial approach led to the identification of a closely related isomer of the lead compound with increased inhibitory activity: $${N'}$$ -[1-(4-hydroxyphenyl)ethylidene]-2-(1H-imidazol-1-yl)acetohydrazide. This success supports the idea that novel GPx1 inhibitors can be developed by drug-design methods and paves the way for a new class of GPx1 inhibitors.
Starting Page	307
Ending Page	322
Page Count	16
File Format	PDF
ISSN	13811991
Journal	Molecular Diversity
Volume Number	18
Issue Number	2
e-ISSN	1573501X
Language	English
Publisher	Springer International Publishing
Publisher Date	2014-01-19
Publisher Place	Cham
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Glutathione peroxidase Microwave synthesis Hydrazones Inhibitors Antitumor agents Biochemistry Organic Chemistry Polymer Sciences Pharmacy
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Medicine Drug Discovery Molecular Biology Physical and Theoretical Chemistry Information Systems Catalysis Inorganic Chemistry

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