title: Evaluation of (S)- and (R)-misonidazole as GPX inhibitors: synthesis, characterization including circular dichroism and in vitro testing on bovine GPx-1.
abstract: Racemic misonidazole, a radiosensitizer formally used in radiation therapy of cancer and to date still applied, was once reported to exhibit strong inhibitory effects on mouse glutathione peroxidases (GPX). This appeared to qualify misonidazole as a lead structure for the development of novel GPX inhibitors to cause oxidative stress in chemotherapy-resistant tumors. A unique feature of misonidazole as an inhibitor of GPX is the absence of a thiol functionality. Therefore, it was expected to selectively target inhibition devoid of promiscuous interactions with cations and sulfhydryl groups. We synthesized the isomers of misonidazole and analyzed the ability of chiroptical high-performance liquid chromatography (HPLC) to identify the particular enantiomers. Due to the chiral pool synthesis, the assignment of the correct configuration could be verified. Finally, we evaluated both isomers for their inhibitory activities on bovine erythrocyte GPx-1, which is 87% homologous to the human enzyme. Despite the previously reported inhibition of racemic misonidazole on the less homologous mouse GPx-1, we did not find any significant inhibitory activity on the bovine enzyme for either isomer. Though misonidazole appears unlikely to be an inhibitor of human GPx-1 activity, we still spotlight misonidazole as a promising fragment-like lead structure in general.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Wilde
authors.forename: Chamseddin
authors.initials: C
authors.lastname: Chamseddin
authors.forename: Heidi
authors.initials: H
authors.lastname: Lemmerhirt
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bednarski
authors.forename: Thomas
authors.initials: T
authors.lastname: Jira
authors.forename: Andreas
authors.initials: A
authors.lastname: Link
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007536:Isomerism; D008920:Misonidazole / Q000138:chemical synthesis* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016877:Oxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D000094765:Glutathione Peroxidase GPX1
chemical_list: D004791:Enzyme Inhibitors; D016877:Oxidants; D008920:Misonidazole; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1
keywords: Circular dichroism; Glutathione peroxidase; In vitro inhibition; Lead structure; Misonidazole