Organometallic Antitumor Compounds: Ferrocifens as Precursors to Quinone Methides |
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| Authors: | Dr. Yong Wang Dr. Pascal Pigeon Dr. Siden Top Prof. Michael J. McGlinchey Prof. Gérard Jaouen |
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| Affiliation: | 1. Sorbonne Universités, UPMC Univ Paris 06, UMR 8232, IPCM, 75005 Paris (France);2. CNRS, UMR 8232, IPCM, 75005 Paris (France);3. PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France);4. UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4 (Ireland) |
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| 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)3C(Fc)=C(C6H4OH)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 CH3CH2‐C(Fc)=C(C6H4OH)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. |
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| Keywords: | antitumor agents drug discovery ferrocene metabolism quinones |
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