Ferrocenyl Quinone Methide–Thiol Adducts as New Antiproliferative Agents: Synthesis, Metabolic Formation from Ferrociphenols, and Oxidative Transformation

Abstract

Ferrociphenols (FCs)a nd their oxidized, electrophilic quinone methide metabolites (FC-QMs)a re organometallic compounds related to tamoxifent hat exhibit strong antiproliferative properties.T oe valuate the reactivity of FC-QMs toward cellular nucleophiles,w es tudied their reaction with selected thiols.Aseries of new compounds resulting from the addition of these nucleophiles,t he FC-SR adducts,w ere 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.U nder oxidizing conditions they either revert to their FC-QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC-SR-QM.T hese results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs, and also open the way to an ew series of organometallic antitumor compounds.

A New Series of Succinimido-ferrociphenols and Related Heterocyclic Species Induce Strong Antiproliferative Effects, Especially against Ovarian Cancer Cells Resistant to Cisplatin

“…We focused initially on the "ferrociphenol" motif (Fc-CC-C 6 H 4 -OH), known to lead to oxidation with formation of a QM in a biological medium. 27,28 Subsequently, we looked at the imide component, which is capable of producing specific ring-opened metabolites.…”

“…The 1 H NMR spectrum revealed an approximate 3:1 ratio of E/Z isomers, which can be explained by the steric issue we proposed recently. 28 Molecule 3-QM showed a far better stability profile (half-life in acetone of about 10 days!) than the corresponding QM of 1a which was unstable and even started to decompose before oxidation was complete.…”

“…13 It is only recently that we have begun to consider modification of the alkyl chain by attaching an OH group to the end, and we have obtained particularly low IC 50 values (IC 50 = 0.11 μM) with 2a on triple negative breast cancer cell lines (MDA-MB-231); 26 moreover, the bioactivity of their metabolites, all of which have been identified, was also evaluated. 27,28 Meanwhile, a number of recent research projects have focused on biologically oriented ferrocene compounds substituted by heterocyclic skeletons, including for example nucleobases, sugars, or flavonoids. 29−41 In this context, the novel series shown below seems particularly appealing whereby a heterocyclic group such as succinimidyl or phthalimidyl, as in 3 or 4, respectively, has been incorporated into the molecule.…”

Anticancer properties of lipid and poly(ε-caprolactone) nanocapsules loaded with ferrocenyl-tamoxifen derivatives

“…Previous in vitro studies demonstrated that at least some Ferr metabolites produced in the cell are electrophilic quinonemethides that can induce growth arrest with senescence and apoptosis phenomena . Recently, adducts of these quinonemethides with compounds bearing thiol functional group, as models of some cellular nucleophiles were identified …”

“…[10,11] Recently, adducts of these quinonemethides with compounds bearing thiol functional group, as models of some cellular nucleophiles were identified. [12] Metal-based anticancer drugs, such as PhtFerr and Succ-Ferr, are very hydrophobic compounds that cannot be formulated in aqueous solutions easily. [13] Therefore, we both synthetized their respective ester prodrugs Phtester and Succester and also encapsulated them into nanocarriers to overcome the issue of their poor solubility.…”