Ferrocenyl Quinone Methide-Thiol Adducts as New Antiproliferative Agents: Synthesis, Metabolic Formation from Ferrociphenols, and Oxidative Transformation.
Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC-QMs) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC-QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC-SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC-SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC-QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC-SR-QM. These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs, and also open the way to a new series of organometallic antitumor compounds.
Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 8232, IPCM, 75005, Paris, France.|PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005, Paris, France.
Yong
Y
Wang
Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 8232, IPCM, 75005, Paris, France.|PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005, Paris, France.
Marie-Aude
MA
Richard
Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 8232, IPCM, 75005, Paris, France. siden.top@chimie-paristech.fr.|PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005, Paris, France. siden.top@chimie-paristech.fr.
Siden
S
Top
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, PRES Paris Cité Sorbonne, 45 rue des Saints Pères, 75270, Paris Cedex 06, France.
Patrick M
PM
Dansette
Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 8232, IPCM, 75005, Paris, France.|PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005, Paris, France.
Pascal
P
Pigeon
Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 8232, IPCM, 75005, Paris, France.|PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005, Paris, France.
Anne
A
Vessières
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, PRES Paris Cité Sorbonne, 45 rue des Saints Pères, 75270, Paris Cedex 06, France. Daniel.Mansuy@parisdescartes.fr.
Daniel
D
Mansuy
Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 8232, IPCM, 75005, Paris, France. gerard.jaouen@chimie-paristech.fr.|PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005, Paris, France. gerard.jaouen@chimie-paristech.fr.
Gérard
G
Jaouen
Michael addition; antitumor agents; glutathione; liver microsomes; organometallic compounds