title: Organometallic Antitumor Compounds: Ferrocifens as Precursors to Quinone Methides.
abstract: The synthesis and chemical oxidation profile of a new generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular, the hydroxypropyl derivative HO(CH2 )3 C(Fc)=C(C6 H4 OH)2 (3 b) exhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA-MB-231 TNBC, with IC50 values of 0.07 and 0.11 μM, respectively. Chemical oxidation of 3 b yielded an unprecedented tetrahydrofuran-substituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH3 CH2 -C(Fc)=C(C6 H4 OH)2 merely formed a vinyl QM. The ferrocenyl group in 3 b plays a key role, not only as an intramolecular reversible redox "antenna", but also as a stabilized carbenium ion "modulator". The presence of the oxygen heterocycle in 3 b-QM enhances its stability and leads to a unique chemical oxidation profile, thus revealing crucial clues for deciphering its mechanism of action in vivo.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8232, IPCM, 75005 Paris (France).|CNRS, UMR 8232, IPCM, 75005 Paris (France).|PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France).
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8232, IPCM, 75005 Paris (France).|CNRS, UMR 8232, IPCM, 75005 Paris (France).|PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France).
authors.forename: Pascal
authors.initials: P
authors.lastname: Pigeon
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8232, IPCM, 75005 Paris (France). siden.top@chimie-paristech.fr.|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.
authors.forename: Siden
authors.initials: S
authors.lastname: Top
authors.affiliation: UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4 (Ireland).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGlinchey
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8232, IPCM, 75005 Paris (France). gerard.jaouen@chimie-paristech.fr.|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.
authors.forename: Gérard
authors.initials: G
authors.lastname: Jaouen
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D045563:Indolequinones / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D005296:Ferrous Compounds; D045563:Indolequinones; D009942:Organometallic Compounds; C514120:ferrocifen; C068040:quinone methide
keywords: antitumor agents; drug discovery; ferrocene; metabolism; quinones