Microwave-assisted synthesis and evaluation of acylhydrazones as potential inhibitors of bovine glutathione peroxidase.
Glutathione peroxidases (GPx) were the first selenocysteine enzymes identified. They play critical roles in cellular defense to excessH(2)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.
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Ernst-Moritz-Arndt University Greifswald, 17487 , Greifswald, Germany.
Felix
F
Wilde
Heidi
H
Lemmerhirt
Thomas
T
Emmrich
Patrick J
PJ
Bednarski
Andreas
A
Link
D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008872:Microwaves; D008958:Models, Molecular; D000094765:Glutathione Peroxidase GPX1
D004791:Enzyme Inhibitors; D006835:Hydrazones; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1