Deciphering the Diversified Metabolic Behavior of Hydroxyalkyl Ferrocidiphenols as Anticancer Complexes.

Ferrocidiphenols possessing appropriate substituents in the aliphatic chain have very promising anticancer properties, but a systematic approach to deciphering their diversified metabolic behavior has so far been lacking. Herein, we show that a series of novel ferrocidiphenols bearing different hydroxyalkyl substituents exhibit strong anticancer activity as revealed in a range of and experiments. Moreover, they display diversified oxidative transformation profiles very distinct from those of previous complexes, shown by the use of chemical and enzymatic methods and and metabolism studies.

Thioredoxin Reductase and Organometallic Complexes: A Pivotal System to Tackle Multidrug Resistant Tumors?

Cancers classified as multidrug-resistant (MDR) are a family of diseases with poor prognosis despite access to increasingly sophisticated treatments. Several mechanisms explain these resistances involving both tumor cells and their microenvironment. It is now recognized that a multi-targeting approach offers a promising strategy to treat these MDR tumors.

Unravelling the Role of Uncommon Hydrogen Bonds in Cyclodextrin Ferrociphenol Supramolecular Complexes: A Computational Modelling and Experimental Study.

We sought to determine the cyclodextrins (CDs) best suited to solubilize a patented succinimido-ferrocidiphenol (SuccFerr), a compound from the ferrociphenol family having powerful anticancer activity but low water solubility. Phase solubility experiments and computational modelling were carried out on various CDs. For the latter, several CD-SuccFerr complexes were built starting from combinations of one or two CD(s) where the methylation of CD oxygen atoms was systematically changed to end up with a database of ca.

Physicochemical Characterization of Ferrocifen Lipid Nanocapsules: Customized Drug Delivery Systems Guided by the Molecular Structure.

Ferrocifens, lipophilic organometallic complexes, comprise a biologically active redox motif [ferrocenyl-ene--phenol] which confers very interesting cytotoxic properties to this family. However, because of their highly lipophilic nature, a formulation stage is required before being administered . In recent decades, ferrocifen lipid nanocapsules (LNCs) have been successfully formulated and have demonstrated anticancer activity on multidrug-resistant cancers in several mice and rat models (glioblastoma, breast cancer, and metastatic melanoma).

Ferrocifen stealth LNCs and conventional chemotherapy: A promising combination against multidrug-resistant ovarian adenocarcinoma.

Ovarian cancer is one of the deadliest epithelial malignancies in women, owing to the multidrug resistance that restricts the success of conventional chemotherapy, carboplatin and paclitaxel. High grade serous ovarian carcinoma can be classified into two subtypes, the chemosensitive High OXPHOS and the Low OXPHOS tumour, less sensitive to chemotherapy. This difference of treatment efficacy could be explained by the redox status of these tumours, High OXPHOS exhibiting a chronic oxidative stress and an accumulation of reactive oxygen species.

Succinimido-Ferrocidiphenol Complexed with Cyclodextrins Inhibits Glioblastoma Tumor Growth In Vitro and In Vivo without Noticeable Adverse Toxicity.

SuccFerr has remarkable antiproliferative effects in vitro, attributed to the formation of a stabilized quinone methide. The present article reports in vivo results for a possible preclinical study. SuccFerr is lipophilic and insoluble in water, so the development of a formulation to obviate this inconvenience was necessary.

α-Hydroxylactams as Efficient Entries to Diversely Functionalized Ferrociphenols: Synthesis and Antiproliferative Activity Studies.

The [ferrocene-ene-phenol] motif has been identified as the pharmacophore responsible for the anticancer activity of the family of ferrocene-based molecules coined ferrocifens, owing to its unique redox properties. The addition of imide entities to the historical ferrociphenol scaffold tremendously enhanced the cytotoxic activity of a large panel of cancer cell cultures and preliminary studies showed that the reduction of one of the carbonyl groups of the imide groups to the corresponding α-hydroxylactams only slightly affected the antiproliferative activity. As a continuation to these studies, we took advantage of the facile conversion of α-hydroxylactams to highly electrophilic -acyliminium ions to graft various substituents to the imide motif of phthalimido ferrocidiphenol.

Diversity-oriented synthesis and bioactivity evaluation of N-substituted ferrocifen compounds as novel antiproliferative agents against TNBC cancer cells.

Ferrociphenols are characterized by the presence of a biologically active redox motif [ferrocenyl-ene-p-phenol], and are known to exhibit anticancer properties. Recent studies have identified a new series of ferrociphenols that bear an imido-type heterocycle at the terminus of a short alkyl chain, and which showed very strong antiproliferativity against multiple types of cancer cells. This work describes the syntheses and an SAR study of ferrociphenols bearing a diversity-based range of nitrogen-containing substituents on the alkyl chain.

Ferrocifen Loaded Lipid Nanocapsules: A Promising Anticancer Medication against Multidrug Resistant Tumors.

Resistance of cancer cells to current chemotherapeutic drugs has obliged the scientific community to seek innovative compounds. Ferrocifens, lipophilic organometallic compounds composed of a tamoxifen scaffold covalently bound to a ferrocene moiety, have shown very interesting antiproliferative, cytotoxic and immunologic effects. The formation of ferrocenyl quinone methide plays a crucial role in the multifaceted activity of ferrocifens.

p722 ferrocifen loaded lipid nanocapsules improve survival of murine xenografted-melanoma via a potentiation of apoptosis and an activation of CD8 T lymphocytes.

Metastatic melanoma is a malignant tumor with a poor prognosis. Recent new therapeutics improved the survival of patients at a metastatic stage. However, the low response rate to immunotherapy, explained in part by resistance to apoptosis, needs to develop new strategies.

Antimicrobial, Antitumor and Side Effects Assessment of a Newly Synthesized Tamoxifen Analog.

Background: Tamoxifen citrate is a very prevalent drug marketed under several trade names like Apo-Tamox, Nolvadex, Tamec, Tamizam, and Tamoplex. This molecule is approved by the FDA for breast cancer treatment. Some studies have shown that tamoxifen has anti-tuberculosis and antiparasitic activities.

Enantioselective Synthesis of Planar Chiral Ferrocifens that Show Chiral Discrimination in Antiproliferative Activity on Breast Cancer Cells.

The design and first enantioselective synthesis of a series of chiral ferrocifens and ferrociphenols was realised by enantioselective palladium-catalysed intramolecular direct C-H bond activation followed by McMurry coupling. Biological evaluation revealed moderate anticancer activities on breast cancer cells and evidence of chiral discrimination between enantiomers. Treatment of the novel ferrocifens with Ag O revealed that these systems are unable to form a neutral quinone methide, yet still demonstrate marked antiproliferative properties against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 cell lines.

Importance of Combining Advanced Particle Size Analysis Techniques To Characterize Cell-Penetrating Peptide-Ferrocifen Self-Assemblies.

The design of a simple platform to target the delivery of notably hydrophobic drugs into cancer cells is an ultimate goal. Here, three strategies were combined in the same nanovector, in limiting the use of excipients: cell-penetrating peptides, an amphiphilic prodrug, and self-assembly. Light scattering and cryogenic transmission electron microscopy revealed one size population of objects around 100 nm with a narrow size distribution.

Small Structural Differences between Two Ferrocenyl Diphenols Determine Large Discrepancies of Reactivity and Biological Effects.

The ferrocenyl diphenol complexes 1,1-bis(4'-hydroxyphenyl)-2-ferrocenyl-but-1-ene (1) and 1,2-bis(4'-hydroxyphenyl)-1-ferrocenyl-but-1-ene [(Z)-2], which differ by the relative position of the two phenolic substituents, display dramatically different antiproliferative activities on cancer cells (1 is far more cytotoxic than 2). In this study, our goal was to discover the origin of this difference by comparing their reactivity and biological behaviour. In terms of common behaviour, we found that 1 and 2 are both efficient inhibitors of thioredoxin reductase (TrxR) in vitro after oxidation by a horseradish peroxidase/H O system.

Atypical Lone Pair-π Interaction with Quinone Methides in a Series of Imido-Ferrociphenol Anticancer Drug Candidates.

Ferrociphenols, especially those possessing a heterocycle at the terminus of an aliphatic chain, display strong anticancer activity through a novel redox mechanism that generates active metabolites such as quinone methides (QMs). X-ray crystallography and UV/Vis spectroscopy reveal that the specific lone pair (lp)-π interaction between a carbonyl group of the imide and the quinone motif of the QM plays an important role in the exceptional cytotoxic behaviour of their imido-ferrociphenol precursors. This intramolecular lp-π interaction markedly enhanced the stability of the QMs and lowered the pK values of the corresponding phenol/phenolate couples.

Intracellular Localization of an Osmocenyl-Tamoxifen Derivative in Breast Cancer Cells Revealed by Synchrotron Radiation X-ray Fluorescence Nanoimaging.

A series of tamoxifen-like metallocifens of the group-8 metals (Fe, Ru, and Os) has strong antiproliferative activity on the triple-negative breast cancer cells (MDA-MB-231). To shed light on the mechanism of action of these molecules, synchrotron radiation X-ray fluorescence nanoimaging studies were performed on cells exposed to osmocenyl-tamoxifen (Oc-OH-Tam) to disclose its intracellular distribution. High-resolution mapping of the lipophilic Oc-OH-Tam in cells revealed its preferential accumulation in the endomembrane system.

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

Objective: We synthesized new tamoxifen derivatives as anticancer drug candidates and elaborated on convection-enhanced delivery (CED) as a strategy for delivery.

Methods: To overcome the issue of their poor solubility, these ferrocenyl-tamoxifen derivatives were esterified and encapsulated into different nanocarriers, that is lipid (LNC) and polymeric nanocapsules (PNL-NC). We describe the chemistry, the encapsulation and the physicochemical characterization of these formulations.

Ferrocifens labelled with an infrared rhenium tricarbonyl tag: synthesis, antiproliferative activity, quantification and nano IR mapping in cancer cells.

Antiproliferative activities of several members of the ferrocifen family, both in vitro and in vivo, are well documented although their precise location in cancer cells has not yet been elucidated. However, two different infrared imaging techniques have been used to map the non-cytotoxic cyrhetrenyl analogue of ferrociphenol in a single cell. This observation prompted us to tag two ferrocifens with a cyrhetrenyl unit [CpRe(CO)3; Cp = η5-cyclopentadienyl] by grafting it, via an ester bond, either to one of the phenols (4, 5) or to the hydroxypropyl chain (6).

Enhanced and preferential internalization of lipid nanocapsules into human glioblastoma cells: effect of a surface-functionalizing NFL peptide.

Increasing intracellular drug concentration using nanocarriers can be a potential strategy to improve efficacy against glioblastoma (GBM). Here, the fluorescent-labelled NFL-TBS·40-63 peptide (fluoNFL) concentration on a lipid nanocapsule (LNC) was studied to enhance nanovector internalization into human GBM cells. LNC surface-functionalization with various fluoNFL concentrations was performed by adsorption.

A new generation of ferrociphenols leads to a great diversity of reactive metabolites, and exhibits remarkable antiproliferative properties.

Organometallic compounds bearing the redox motif [ferrocenyl--phenol] have very promising antiproliferative properties which have been further improved by incorporating pertinent substituents able to engender new mechanisms. Here we show that novel ferrociphenols bearing a hydroxypropyl chain exhibit strong antiproliferative effects, in most cases much better than those of cisplatin, tamoxifen, or of previously described ferrociphenols devoid of this terminal OH. This is illustrated, in the case of one of these compounds, by its IC values of 110 nM for MDA-MB-231 triple negative breast cancer cells and of 300 nM for cisplatin-resistant A2780cisR human ovarian cancer cells, and by its GI values lower than 100 nM towards a series of melanoma and renal cancer cell lines of the NCI-60 panel.

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

Ferrociphenols are known to display anticancer properties by original mechanisms dependent on redox properties and generation of active metabolites such as quinone methides. Recent studies have highlighted the positive impact of oxidative stress on chemosensitivity and prognosis of ovarian cancer patients. Ovarian adenocarcinomas are shown to be an excellent model for defining the impact of selected ferrociphenols as new therapeutic drugs for such cancers.

Review on Bioorganometallic Chemistry and New Outcomes in the Synthesis and Substitution of Tetracarbonyl(pyrrolylimine) Complexes of Rhenium with Organophosphorus Ligands.

: After a short review dealing with bioorganometallic chemistry, the synthesis of tetracarbonyl (pyrrolylimine) complexes of rhenium bearing chirality on the pyrrolyl ligands was reported.The reactivity of these compounds towards the substitution of one carbonyl ligand with triphenyl phosphine, tricyclohexyl phosphine and trimethyl phosphite was studied. The rhenium becoming a stereogenic center in that transformation, the resulting tricarbonyl species were obtained as mixtures of diastereomers, with diastereomeric excesses varying from 8 to 84%, according to the reaction conditions and the relative steric hindrances of the pyrrolylimine and the organophosphorus ligands.

Tamoxifen-like metallocifens target the thioredoxin system determining mitochondrial impairment leading to apoptosis in Jurkat cells.

Tamoxifen-like metallocifens (TLMs) of the group-8 metals (Fe, Ru, and Os) show strong anti-proliferative activity on cancer cell lines resistant to apoptosis, owing to their unique redox properties. In contrast, the thioredoxin system, which is involved in cellular redox balance, is often overexpressed in cancer cells, especially in tumour types resistant to standard chemotherapies. Therefore, we investigated the effect of these three TLMs on the thioredoxin system and evaluated the input of the metallocene unit in comparison with structurally related organic tamoxifens.