Eric Labbé

A [3]Ferrocenophane Polyphenol Showing a Remarkable Antiproliferative Activity on Breast and Prostate Cancer Cell Lines

We have previously shown that modification of polyphenols with a ferrocenyl group can dramatically enhance their cytotoxicity. We now present two new [3]ferrocenophane compounds, one of which has an antiproliferative effect seven times stronger than the corresponding noncyclic species, with IC50 values of 90 and 94 nM on hormone-independent MDA-MB-231 breast and PC-3 prostate cancer cell lines, respectively. Solubility studies in water using methylated beta-cyclodextrin and electron transfer studies are also presented.

Reactivity and Antiproliferative Activity of Ferrocenyl–Tamoxifen Adducts with Cyclodextrins against Hormone-Independent Breast-Cancer Cell Lines

Hydroxyferrocifen compounds are a new and promising class of ferrocifen-type breast-cancer drug candidates. They possess both endocrine-modulating properties and cytotoxic activity, which come from the tamoxifen skeleton and the presence of a ferrocene moiety, respectively. However, they suffer from reduced solubility in water, which presents a problem for their eventual therapeutic use. Herein, we examined the interactions of hydroxyferrocifen compounds with cyclodextrins (CDs) to evaluate whether or not their electron-transfer oxidation pathways were affected by their inclusion. It has been demonstrated that these inclusion complexes are soluble in pure water, which shows that CDs can be used to deliver these biologically active molecules. Therefore, a series of these compounds has been investigated by cyclic voltametry in various media in the presence of CDs (beta-CD and Me-beta-CD). In methanol, the hydroxyferrocifen compounds exhibited a weak interaction with the CD cavity. These interactions became stronger as the amount of added water increased. The complexation effect between the hydroxyferrocifen compounds and beta-CD was found to be stronger if the CD was partially methylated, which is probably due to hydrophobic effects between the cyclopentadienyl ring and/or the aromatic rings and the methoxy groups. Moreover, it appears that the structure of the hydroxyferrocifen compounds affects both their solubility and their complexation dynamics. Investigations in the presence of pyridine show that the base kinetically favors the dissociation of the ferrocifen-CD complex during the electron transfer step, but does not affect the follow-up reactivity of the electrogenerated ferrocenium cation, which leads eventually to the corresponding quinone methide, as reported in the absence of CD. Accordingly, the cytotoxicity of these beta-CD-encapsulated organometallic complexes in hormone-independent breast-cancer cells (MDA-MB231) were confirmed to be similar to those obtained in the absence of cyclodextrin.

Deciphering the Activation Sequence of Ferrociphenol Anticancer Drug Candidates

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.

Ferrocenyl catechols: synthesis, oxidation chemistry and anti-proliferative effects on MDA-MB-231 breast cancer cells

The synthesis and anti-tumoral properties of a series of compounds possessing a ferrocenyl group tethered to a catechol via a conjugated system is presented. On MDA-MB-231 breast cancer cell lines, the catechol compounds display a similar or greater anti-proliferative potency (IC(50) values ranging from 0.48-1.21 μM) than their corresponding phenolic analogues (0.57-12.7 μM), with the highest activity found for species incorporating the [3]ferrocenophane motif. On the electrochemical timescale, phenolic compounds appear to oxidize to the quinone methide, while catechol moieties form the o-quinone by a similar mechanism. Chemical oxidation of selected compounds with Ag(2)O confirms this interpretation and demonstrates the probable involvement of such oxidative metabolites in the in vitro activity of these species.

Synthesis of unsymmetrical biaryls by electroreductive cobalt-catalyzed cross-coupling of aryl halides

The consumable anode process allows the electrochemical cross-coupling reaction between various functionalized aromatic halides (iodides, bromides and chlorides) in the presence of cobalt halides as catalyst in a mixed solvent acetonitrile/pyridine (9:1). A great variety of unsymmetrical biaryls are obtained in moderate to excellent yields.

Ligand-directed reaction products in the nickel-catalyzed electrochemical carboxylation of terminal alkynes

Abstract The influence of a series of N and P ligands in the nickel-catalyzed electrochemical carboxylation of 1-octyne has been studied. Different carboxylic acids are obtained depending on the nature of the ancillary ligand, and results afford an example of high ligand-directed product specificity.

Electroanalytical investigation of the cobalt-catalyzed electrochemical dimerization of allylic acetates. Role played by iron(II) ions

Cyclic voltammetry and preparative-scale electrolyses have been used to investigate the electrochemical behavior of CoBr2 in the presence of allyl acetate, CH2CHCH2OAc, or cinnamyl acetate, PhCHCHCH2OAc, in an acetonitrile+pyridine (v/v=9:1) mixture. A complexation reaction between the electrogenerated cobalt(I) and allyl acetate leading to the corresponding (η2-allyl-OAc)cobalt(I) has been detected. This intermediate undergoes a slow oxidative addition affording a (η3-allyl)cobalt(III) complex which reduces at the same potential as the starting compound CoBr2. The rate constant for the complexation reaction has been estimated. The slow oxidative addition of (η2-allyl-OAc)cobalt(I) allowed us to observe its electrochemical reduction into the corresponding (η2-allyl-OAc)cobalt(0). Preparative-scale electrolyses of cinnamyl acetate in the presence of CoBr2 demonstrate the formation of the dimer 1,6-diphenyl-1,5-hexadiene from (η3-allyl)cobalt(II) or (η2-allyl-OAc)cobalt(0). However, the reduction of allylic acetate derivatives is not strictly catalytic since CoBr2 is poisoned by acetate anions leading to cobalt species of the type Co(OAc)x which are reducible at more negative potentials. However, the presence of iron(II) ions allows the regeneration of the cobalt catalyst precursor owing to its complexation with acetate anions.

Monitoring and Quantifying the Passive Transport of Molecules Through Patch-Clamp Suspended Real and Model Cell Membranes**

Transport of active molecules across biological membranes is a central issue for the success of many pharmaceutical strategies. Herein, we combine the patch-clamp principle with amperometric detection for monitoring fluxes of redox-tagged molecular species across a suspended membrane patched from a macrophage. Solvent- and protein-free lipid bilayers (DPhPC, DOPC, DOPG) patched from single-wall GUV have been thoroughly investigated and the corresponding fluxes measurements quantified. The quality of the patches and their proper sealing were successfully characterized by electrochemical impedance spectroscopy. This procedure appears versatile and perfectly adequate to allow the investigation of transport and quantification of the transport properties through direct measurement of the coefficients of partition and diffusion of the compound in the membrane, thus offering insight on such important biological and pharmacological issues.

Selective Electrochemical Bleaching of the Outer Leaflet of Fluorescently Labeled Giant Liposomes

Electrochemistry and confocal fluorescence microscopy were successfully combined to selectively bleach and monitor the fluorescence of NBD (7-nitrobenz-2-oxa-1,3-diazole)-labeled phospholipids of giant liposomes. Three types of giant unilamellar vesicles have been investigated, the fluorescent phospholipids being localized either mainly on their outer-, inner-, or both inner/outer leaflets. We established that only the fluorescent lipids incorporated in the outer leaflet of the vesicles underwent electrochemical bleaching upon reduction. The relative fluorescence intensity decay was quantified all along the electrochemical extinction through an original fluorescence loss in electrobleaching (FLIE) assay. As expected, the reorganization of the fluorescent phospholipids followed diffusion-driven dynamics. This was also evidenced by comparison with fluorescence loss in photobleaching (FLIP) and the corresponding numerical model. The value of the lateral diffusion coefficient of phospholipids was found to be similar to that obtained by other methods reported in the literature. This versatile and selective bleaching procedure appears reliable to explore important biological and pharmacological issues.

Direct electrochemical reduction of organic halide droplets dispersed in water

The direct electroreductive homocoupling of benzyl bromide has been efficiently achieved using water as the solvent. This process does not involve any organic co-solvent, transition metal catalyst, oil, surfactants, but only a cheap and non-toxic supporting electrolyte (KCl). Benzyl bromide droplets dispersed in water were reduced at a low current density, in an undivided cell fitted with a sacrificial aluminum anode. Various cathode materials have been tested (Ni, Pt, C, Ag) to favor organic halide reduction versus hydrogen evolution. Moreover, it was shown that the presence of aluminum cations generated by the oxidation of the anode played a crucial role in the efficiency of the electrochemical reduction step. Surprisingly, this property was exalted in acidic solutions (pH = 1). Under such acidic conditions, both bibenzyl proportion and faradaic yields were considerably improved. The electrochemical activation of energetically stronger C–X bonds such as those encountered in benzyl chloride (Csp3–Cl) or ethyl 4-iodobenzoate (Csp2–I) could be also achieved in water though resulted in lower faradaic yields. From a mechanistic point of view, both the faradaic yields and the product distribution obtained under various conditions suggested the occurrence of a radical coupling pathway occurring within the organic droplets or at their surface.