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Inhibition of Cathepsin B by Ferrocenyl Indenes Highlights a new Pharmacological Facet of Ferrocifens
Author(s) -
Sanz Garcia Juan,
Gaschard Marie,
Navizet Isabelle,
Sahihi Mehdi,
Top Siden,
Wang Yong,
Pigeon Pascal,
Vessières Anne,
Salmain Michèle,
Jaouen Gérard
Publication year - 2022
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/ejic.202101075
Subject(s) - chemistry , electrophile , nucleophile , stereochemistry , quinone methide , biochemistry , cysteine protease , alkylation , cysteine , enzyme , quinone , catalysis
Abstract The family of ferrocifens initially built up from the anti‐oestrogen tamoxifen shows a broad antitumor activity both in vitro and in vivo . Their mechanism of action relies on the presence of the redox motif [ferrocene‐ene‐phenol] that, under oxidative conditions, generates reactive oxygen species (ROS) and affords electrophilic quinone methides (QMs) having the ability to alkylate biological nucleophiles and in turn elicit a strong antiproliferative activity. In this context, the cysteine protease cathepsin B was initially presumed to be a target for ferrocenyl QMs. In vitro enzymatic assays ruled out this hypothesis but unexpectedly revealed that other ferrocifen metabolites, i. e. ferrocenyl indenes, acted as moderate inhibitors of cathepsin B. These experimental results were nicely confirmed by molecular docking calculations, that showed that the monophenol ferrocenyl indene and to a lower extent the diphenol interacted with the active site of cathepsin B, making it an unanticipated target of ferrocifens.