title: Enzymatic oxidation of ansa-ferrocifen leads to strong and selective thioredoxin reductase inhibition in vitro.
abstract: This paper reports the inhibitory effect on the cytosolic thioredoxin reductase (TrxR1) in vitro by the ansa-ferrocifen derivative (ansa-FcdiOH, 1). We found that 1 decreased only slightly enzyme activity (IC50=8μM), while 1*, the species generated by enzymatic oxidation by the HRP (horseradish peroxidase)/H2O2mixture, strongly inhibited TrxR1 (IC50=0.15μM). At the same concentrations, neither 1 nor 1* had effect on glutathione reductase (GR). The most potent TrxR1 inhibitor did not appear to be the corresponding quinone methide as it was the case for ferrocifens of the acyclic series, or the stabilized carbocation as in the osmocifen series, but rather the quinone methide radical. This hypothesis was confirmed by ab-initio calculations of the species generated by oxidation of 1 and by EPR spectroscopy. BIAM (biotin-conjugated iodoacetamide) assay showed that 1* targeted both cysteine and selenocysteine of the C-terminal redox center of TrxR1.
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
authors: Valeria
authors: V
authors: Scalcon
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
authors: Anna
authors: A
authors: Citta
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy.
authors: Alessandra
authors: A
authors: Folda
authors: Istituto di Neuroscienze (CNR) Sezione di Padova, c/o Dipartimento di Scienze Biomediche, Via Ugo Bassi, 58/b, 35131 Padova, Italy.
authors: Alberto
authors: A
authors: Bindoli
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), 75005 Paris, France.
authors: Michèle
authors: M
authors: Salmain
authors: PSL Research University, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris, France.
authors: Ilaria
authors: I
authors: Ciofini
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), 75005 Paris, France.
authors: Sébastien
authors: S
authors: Blanchard
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), 75005 Paris, France.
authors: José
authors: J
authors: de Jésús Cázares-Marinero
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), 75005 Paris, France; PSL Research University, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris, France.
authors: Yong
authors: Y
authors: Wang
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), 75005 Paris, France; PSL Research University, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris, France.
authors: Pascal
authors: P
authors: Pigeon
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), 75005 Paris, France; PSL Research University, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris, France.
authors: Gérard
authors: G
authors: Jaouen
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moléculaire (IPCM), 75005 Paris, France.
authors: Anne
authors: A
authors: Vessières
authors: Dipartimento di Scienze Biomediche, Università di Padova, Via Ugo Bassi 58/b, 35131 Padova, Italy. Electronic address: mariapia.rigobello@unipd.it.
authors: Maria Pia
authors: MP
authors: Rigobello
mesh_terms: D005296:Ferrous Compounds / Q000737:chemistry*; D006735:Horseradish Peroxidase / Q000737:chemistry; D010084:Oxidation-Reduction; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D005296:Ferrous Compounds; D029701:Saccharomyces cerevisiae Proteins; C514120:ferrocifen; D006735:Horseradish Peroxidase; D013880:Thioredoxin-Disulfide Reductase
keywords: Ansa-ferrocifen; Enzymatic oxidation; Ferrocene; Quinone methide radical; Thioredoxin reductase