Deciphering the Activation Sequence of Ferrociphenol Anticancer Drug Candidates

Abstract

The complete oxidation sequence of a model for ferrociphenols, a new class of anticancer drug candidate, is reported. Cyclic voltammetry was used to monitor the formation of oxidation intermediates on different timescales, thereby allowing the electrochemical characterization of both the short-lived and stable species obtained from the successive electron-transfer and deprotonation steps. The electrochemical preparation of the ferrocenium intermediate enabled a stepwise voltammetric determination of the stable oxidation compounds obtained upon addition of a base as well as the electron stoichiometry observed for the overall oxidation process. A mechanism has been established from the electrochemical data, which involves a base-promoted intramolecular electron transfer between the phenol and the ferrocenium cation. The resulting species is further oxidized then deprotonated to yield a stable quinone methide. To further characterize the transient species successively formed during the two-electron oxidation of the ferrociphenol to its quinone methide, EPR was used to monitor the fate of the paramagnetic species generated upon addition of imidazole to the electrogenerated ferrocenium. The study revealed the passage from an iron-centered to a carbon-centered radical, which is then oxidized to yield the quinone methide, namely, the species that interacts with proteins and so forth under biological conditions.

Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

“…Jurkat cells (4×10 4 per well) were seeded in PBS/10 mM glucose. After 1 h cells were loaded with 1 μM CM-DCFH2-DA and with increasing concentrations of the compounds.…”

“…For this reason, the unusual mechanistic properties of organometallic medicinal chemistry are presently the subject of an exponentially growing number of studies [1]. These entities offer inventive strategic approaches [2][3][4][5][6] in terms of optimized space filling, intracellular redox behavior and antitumoral activity, with pharmacophores possessing varied and multiple targeting options that make it possible to counteract the phenomena of resistance to proapoptotic stimuli [7]. To that can be added the variety of available metals [2] and, for the transition elements, the potential availability of several degrees of oxidation.…”

Oxidative Metabolism of Ferrocene Analogues of Tamoxifen: Characterization and Antiproliferative Activities of the Metabolites

“…22 However, the ferrociphenol FC3 (Figure 1), resulting from replacement of a phenyl group of hydroxytamoxifen with a ferrocenyl moiety, displays a dramatic improvement in cytotoxicity toward MDA-MB-231 cells (IC 50 = 0.5µM). 14 Ferrociphenols (FCs, Figure 1) are easily oxidized at relatively low redox potentials, with formation of the corresponding quinone methides (QMs, Figure 1), 23,24 and it was recently shown that these reactive compounds are formed as a result of FC metabolism by liver microsomes, 25 and could play a role in the antitumor properties of FCs. The aim of the work described herein was to study the metabolism of FCs by liver microsomes to determine whether some metabolites are cytotoxic toward MDA-MB-231 breast cancer cells, and, in a more general manner, to potentially find new molecules that are cytotoxic toward hormone-independent breast cancer cells.…”

The length of the bridging chain in ansa-metallocenes influences their antiproliferative activity against triple negative breast cancer cells (TNBC)

“…[56][57][58][59] They also possess an electrochemically oxidizable Fe (II). 48,60,61 However the 3-carbon ansa derivative 1b remains more active on MDA-MB-231, as well as on the NCI-60 cell lines, 38,45,46 than the acyclic form. 38,46 In the case of the ansa derivative we were unable to characterize or isolate a species of the quinone methide type 60 suggesting that the oxidized form is more active and less stable than in the acyclic series.…”