Medicinal chemistry

Keywords:
cancer ; cytotoxic activity ; formulation; gold(III) complexes; half-sandwich iridium complexes; BODIPY; fluorescence imaging; IR spectroscopy

2023

Binuclear Biphenyl Organogold(III) Complexes: Synthesis, Photophysical and Theoretical Investigation, and Anticancer Activity. V. Giuso, J. Yang, J. Forté, H. Dossmann, C. Daniel, C. Gourlaouen, M. Mauro, B. Bertrand. ChemPlusChem 2023, e202300303. https://doi.org/10.1002/cplu.202300303

Four binuclear Au(III) complexes have been synthetized using non-chelating bidentate ligands. When a chelating ligand was used, a digold salt was obtained resulting from the chelation of the diphosphine ligand on one Au moiety and a [(C^C)AuCl2]− anion. The complexes appeared strongly emissive in solid state and the digold salt presented anticancer activities in the nanomolar range with no modification of the [(C^C)Au(P^P)]+ in the presence of biomolecules.


Bond-Dissociation Energies to Probe Pyridine Electronic Effects on Organogold(III) Complexes: From Methodological Developments to Application in π-Backdonation Investigation and Catalysis. L. Bourehil, C. Soep, S. Seng, S. Dutrannoy, S. Igoudjil, J. Forté, G. Gontard, D. Lesage, B. Bertrand, H. Dossmann. Inorganic Chemistry 2023, 33, 13304–13314. http://doi.org/10.1021/acs.inorgchem.3c01584

A complete mass spectrometry-based methodology is developed to determine accurate metal−ligand bond-dissociation energies of 33 organogold(III) complexes. These energies are able to provide a reliable evaluation of the ligand influence over a large range of electronic effects and also help in rationalizing the catalytic activity of the complexes.


Unravelling the Role of Uncommon Hydrogen Bonds in Cyclodextrin Ferrociphenol Supramolecular Complexes: A Computational Modelling and Experimental Study. P. Pigeon, F. Najlaoui, M. J. McGlinchey, J. Sanz Garcia, G. Jaouen, S Gibaud. Int. J. Mol. Sci. 2023, 24, 12288. https://doi.org/10.3390/ijms241512288

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. 13 k models. Modelling and phase solubility experiments seem to indicate the predominance of supramolecular assemblies of SuccFerr with two CDs and the superiority of randomly methylated β-cyclodextrins (RAMEβCDs). In addition, modelling shows that there are several competing combinations of inserted moieties of SuccFerr. Furthermore, the models show that ferrocene can contribute to high stabilization by making atypical hydrogen bonds between Fe and the hydroxyl groups of CDs (single bond with one OH or clamp with two OH of the same glucose unit).
Keywords: cyclodextrin; ferrocene; modelling; phase solubility; database; atypical hydrogen bond


Synthesis and characterization of new neutral Mn(I) tricarbonyl complexes with 8-hydroxyquinoline and imidazole ligands as CO releasing molecules. M. Annereau, F. Martial, J. Forté, G. Gontard, S. Blanchard, H. Dossmann, M. Salmain, V. Corcé. Applied Organometallic Chemistry 2023, e7171, https://doi.org/10.1002/aoc.7171

A series of manganese(I) tricarbonyl complexes formulated as [Mn(8-HQ) (CO)3Imd] (HQ = hydroxyquinoline and Imd = imidazole derivatives) was synthesized and fully characterized. These structures could be easily accessed from a common dimeric edifice formulated as [Mn2(8-HQ)2(CO)6]. The structure of this complex has been confirmed by X-ray diffraction studies. Its reaction with a range of imidazole derivatives (Imd) yielded the monomeric complexes [Mn (8-hydroxyquinoline)(CO)3Imd] with various functional groups as an anchoring point for a vector. Photoactivation of all these complexes by blue-light irradiation led to the liberation of 3 mol of CO per mol of complex as determined experimentally. Spectroscopic and computational methods were employed to explore the mechanism of CO release. Finally, a manganese complex including the more elaborate imidazole ligand N-and C-di-protected histidine was successfully synthesized, opening the way to its direct incorporation in peptides.


Emerging Anticancer Therapeutic Modalities Brought by Gold Complexes: Overview and Perspectives. M. Salmain, B. Bertrand. European Journal of Inorganic Chemistry 2023, e202300340. https://doi.org/10.1002/ejic.202300340

The medicinal chemistry of gold has experienced an exponential development since the 2000s. For long, the mechanisms of action of gold complexes have been limited to direct coordination of the gold ion or supramolecular interactions of the whole gold complex with biomolecules. In the recent years, other modes of action of gold-based drug candidates have emerged. Herein, we review these new modalities, including photo-induced cytotoxicity, selective protein modification and in cellulo catalysis.


Bioorganometallic Chemistry – the Early Years. Vessières, A. ; McGlinchey, M. J. Journal of Organometallic Chemistry 2023, 987–988, 122623. https://doi.org/10.1016/j.jorganchem.2023.122623.

“We review here the first experiments carried out in the early 1980′s at the Ecole Nationale Supérieure de Chimie de Paris under the leadership of Gérard Jaouen, a key figure and visionary in the development of this theme.“


Physicochemical Characterization of Ferrocifen Lipid Nanocapsules : Customized Drug Delivery Systems Guided by the Molecular Structure. Idlas, P. ; Lepeltier, E. ; Bastiat, G. ; Pigeon, P. ; McGlinchey, M. J. ; Lautram, N. ; Vessières, A. ; Jaouen, G. ; Passirani, C. Langmuir 2023, 39 (5), 1885–1896. https://doi.org/10.1021/acs.langmuir.2c02910.

“Chemical modification of a series of five succinimido-ferrocifens to increase the loading of ferrocifens in lipid nanocapsules (LNCs) without compromising their cytotoxicity on the SKOV3 ovarian cancer cell line”

2022

Diversity-Oriented Synthesis and Bioactivity Evaluation of N-Substituted Ferrocifen Compounds as Novel Antiproliferative Agents against TNBC Cancer Cells. Wang, Y. ; Pigeon, P. ; Li, W. ; Yan, J. ; Dansette, P. M. ; Othman, M. ; McGlinchey, M. J. ; Jaouen, G. Eur. J. Med. Chem. 2022, 114202 ; http://dx.doi.org/10.1016/j.ejmech.2022.114202.

“This work describes the syntheses and an SAR study of ferrociphenols bearing a diversity-based range of nitrogen-containing substituents on the alkyl chain. Preliminary oxidative metabolism experiments and ROS-related bioactivity measurements were also carried out to probe the origin of the cytotoxicity of the imido-ferrociphenols. These results suggest that both the formation rate and the stability of QMs could affect the antiproliferative activity of their ferrociphenol precursors.”


Ferrocifen Stealth LNCs and Conventional Chemotherapy : A Promising Combination against Multidrug-Resistant Ovarian Adenocarcinoma. Idlas, P. ; Ladaycia, A. ; Némati, F. ; Lepeltier, E. ; Pigeon, P. ; Jaouen, G. ; Decaudin, D. ; Passirani, C. Int. J. Pharm. 2022, 122164 ; http://dx.doi.org/10.1016/j.ijpharm.2022.122164.

“The aim of this study was to evaluate the in vivo efficacy of ferrocifen stealth lipid nanocapsules on High and Low OXPHOS ovarian Patient-Derived Xenograft models, alone or in combination to standard chemotherapy. Accordingly, two ferrocifens, P53 and P722, were encapsulated in stealth LNCs. The treatment by stealth P722-LNCs in combination with standard chemotherapy induced, with a concentration eight time lower than in stealth P53-LNCs, similar tumour reduction on a Low OXPHOS model, allowing us to conclude that P722 could be a leading ferrocifen to treat ovarian cancer. This combination of treatments may represent a promising synergistic approach to treat resistant ovarian adenocarcinoma.”


Inhibition of Cathepsin B by Ferrocenyl Indenes Highlights a New Pharmacological Facet of Ferrocifens. Sanz Garcia, J. ; Gaschard, M. ; Navizet, I. ; Sahihi, M. ; Top, S. ; Wang, Y. ; Pigeon, P. ; Vessières, A. ; Salmain, M. ; Jaouen, G. Eur. J. Inorg. Chem. 2022, 2022 ; http://dx.doi.org/10.1002/ejic.202101075.


“Ferrocenyl indenes resulting from oxidation of ferrocifen mono- and diphenols act as moderate inhibitors of the lysosomal enzyme cathepsin B as highlighted by in vitro enzymatic assays. These experimental results are substantiated by molecular docking calculations that position the active complexes in the active site of the enzyme.”


Succinimido–Ferrocidiphenol Complexed with Cyclodextrins Inhibits Glioblastoma Tumor Growth In Vitro and In Vivo without Noticeable Adverse Toxicity. Najlaoui, F. ; Busser, B. ; Taïwe, G. S. ; Pigeon, P. ; Sturm, N. ; Giovannini, D. ; Marrakchi, N. ; Rhouma, A. ; Jaouen, G. ; Gibaud, S. ; De Waard, M. Molecules 2022, 27, 4651 ; http://dx.doi.org/10.3390/molecules27144651.

“SuccFerr (P722) was formulated by complexation with randomly methylated cyclodextrins (RAMEßCDs). This supramolecular water-soluble system allowed the in vivo experiments below to proceed. Application of SuccFerr on the glioblastoma cancer cell line U87 indicates that it affects the cellular cycle by inducing a blockade at G0/G1 phase, linked to apoptosis, and another one at the S phase, associated with senescence. Using healthy Fischer rats, we show that both intravenous and subcutaneous SuccFerr : RAMEßCD administration at 5 mg/kg lacks toxic effects on several organs. To reach lethality, doses higher than 200 mg/kg need to be administered. These results prompted us to perform an ectopic in vivo study at 1 mg/kg i.v. ferrocidiphenol SuccFerr using F98 cells xenografted in rats. Halting of cancer progression was observed after six days of injection, associated with an immunological defense response linked to the active principle. These results demonstrate that the properties of P722 transfer successfully to in vivo conditions, leading to interesting therapeutic perspectives based on this chemistry.”


Synthesis, Electrochemical and Fluorescence Properties of the First Fluorescent Member of the Ferrocifen Family and of Its Oxidized Derivatives. Fayolle, C. ; Pigeon, P. ; Fischer-Durand, N. ; Salmain, M. ; Buriez, O. ; Vessières, A. ; Labbé, E. Molecules 2022, 27, 6690 ; http://dx.doi.org/10.3390/molecules27196690.

“The first fluorescent ferrociphenol derivative (P797) has been synthesized via McMurry cross-coupling followed by copper-catalyzed [3 + 2] azide-alkyne cycloaddition of the fluorescent group coumarin. Cyclic voltammograms of P797 exhibit either a monoelectronic oxidation wave ascribed to the ferrocene Fe(II) → Fe(III) conversion or a three-electron oxidation process in the presence of a base, leading to a Fe(III) quinone methide adduct. This general sequence is consistent with those previously described for non-fluorescent ferrociphenols. Furthermore, the fluorescence properties of P797 and its oxidized intermediates appear to strongly depend on the redox state of the ferrocene group. Owing to its switchable fluorescence properties, complex P797 could represent an innovative and useful tool to study the biodistribution and the redox state of ferrocifens in cancer cells.”


α-Hydroxylactams as Efficient Entries to Diversely Functionalized Ferrociphenols : Synthesis and Antiproliferative Activity Studies. Pigeon, P. ; Gaschard, M. ; Othman, M. ; Salmain, M. ; Jaouen, G. Molecules 2022, 27, 4549 ; http://dx.doi.org/10.3390/molecules27144549.

“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 N-acyliminium ions to graft various substituents to the imide motif of phthalimido ferrocidiphenol. Cell viability studies showed that the newly synthesized compounds showed diverse cytotoxic activities on two breast cancer cell lines, while only one compound was significantly less active on the non-tumorigenic cell line hTERT-RPE1.”

2021

[ (C^C)Au(N^N)]+ Complexes as a New Family of Anticancer Candidates : Synthesis, Characterization and Exploration of the Antiproliferative Properties. Khodjoyan, S. ; Remadna, E. ; Dossmann, H. ; Lesage, D. ; Gontard, G. ; Forté, J. ; Hoffmeister, H. ; Basu, U. ; Ott, I. ; Spence, P. ; Waller, Z. ; Salmain, M. ; Bertrand, B. Chem. Eur. J. 2021, 27, 15773–15785 ; http://dx.doi.org/10.1002/chem.202102751.

“A library of eleven cationic gold(III) complexes of the general formula [ (C^C)Au(N^N)]+ when C^C is either biphenyl or 4,4’-ditertbutyldiphenyl and N^N is a bipyridine, phenanthroline or dipyridylamine derivative have been synthesized and characterized. Two complexes stood out for being either highly active or highly selective. Eventually, reactivity studies with biologically meaningful amino acids, glutathione, higher order DNA structures and thioredoxin reductase (TrxR) revealed a markedly different behavior from that of the well-known coordinatively isomeric [ (C^N^C)Au(NHC)]+ structure. This makes the [ (C^C)Au(N N)]+ complexes a new class of organogold compounds with an original mode of action.”


Cytotoxic BODIPY-Appended Half-Sandwich Iridium(III) Complex Forms Protein Adducts and Induces ER Stress. Ramos, R. ; Gilles, J.-F. ; Morichon, R. ; Przybylski, C. ; Caron, B. ; Botuha, C. ; Karaiskou, A. ; Salmain, M. ; Sobczak-Thépot, J. J. Med. Chem. 2021, 64, 16675–16686 ; http://dx.doi.org/10.1021/acs.jmedchem.1c01335.

“IrBDP for which the C^N chelating phenyloxazoline ligand carries a fluorescent and lipophilic BODIPY reporter group was designed for intracellular tracking and hydrophobic compartment tropism. High-resolution analysis of cells cultured with IrBDP showed that it quickly permeates the plasma membrane and accumulates in the mitochondria and endoplasmic reticulum (ER), generating ER stress, dispersal of the Golgi apparatus, cell proliferation arrest and apoptotic cell death. Moreover, IrBDP forms fluorescent adducts with a subset of amino acids, namely histidine and cysteine, via coordination of N or S donor atoms of their side chains. Consistently, in vivo formation of covalent adducts with specific proteins is demonstrated, providing a molecular basis for the observed cytotoxicity and cellular response. Collectively, these results provide a new entry to the development of half-sandwich iridium-based anticancer drugs.”


Heterogeneity of Response to Iron-Based Metallodrugs in Glioblastoma Is Associated with Differences in Chemical Structures and Driven by FAS Expression Dynamics and Transcriptomic Subtypes. Vessières, A. ; Quissac, E. ; Lemaire, N. ; Alentorn, A. ; Domeracka, P. ; Pigeon, P. ; Sanson, M. ; Idbaih, A. ; Verreault, M. Int. J. Mol. Sci. 2021, 22, 10404 ; http://dx.doi.org/10.3390/ijms221910404.

“The antiproliferative activity by wst-1 assay of six ferrocifens was evaluated in 15 molecularly diverse GBM patient-derived cell lines (PDCLs). In five out of six compounds, the half maximal inhibitory concentration (IC50) values varied significantly (10 nM < IC50 < 29.8 µM) while the remaining one (the tamoxifen-like complex) was highly cytotoxic against all PDCLs (mean IC50 = 1.28 µM). The pattern of response was comparable for the four ferrocifens bearing at least one phenol group and differed widely from those of the tamoxifen-like complex and the complex with no phenol group. An RNA sequencing differential analysis showed that response to the diphenol ferrocifen relied on the activation of the Death Receptor signaling pathway and the modulation of FAS expression. Response to this complex was greater in PDCLs from the Mesenchymal or Proneural transcriptomic subtypes compared to the ones from the Classical subtype. These results provide new information on the mechanisms of action of ferrocifens and highlight a broader diversity of behavior than previously suspected among members of this family. They also support the case for a molecular-based personalized approach to future use of ferrocifens in the treatment of GBM.”


Modulating Undruggable Targets to Overcome Cancer Therapy Resistance. Passirani, C. ; Vessières, A. ; La Regina, G. ; Link, W. ; Silvestri, R. Drug Resist. Updat. 2021, 100788 ; http://dx.doi.org/10.1016/j.drup.2021.100788.

“In this review, we discuss emerging targets, small molecule therapeutics and drug delivery strategies to overcome therapy resistance. We focus on rational treatment strategies based on transcription factors, pseudokinases, nuclear export receptors and immunogenic cell death strategy. Historically, unliganded transcription factors and pseudokinases were considered undruggable while blocking the nuclear export e.g., through inhibition of the nuclear export receptor CRM1 was predicted as highly toxic. Recent success inhibiting Gli-1, HIF-1α, HIF-2α and reactivating the tumor suppressor transcription factors p53 and FOXO illustrates the feasibility and power of this targeting approach. Similarly, progress has been made in modulating the activity of pseudokinase proteins implicated in therapy resistance including members of the Tribbles protein family. On the other hand, the recent clinical approval of Selinexor, a specific inhibitor of CRM-1, a protein that mediates the transport of cargos with leucine-rich nuclear export signals and known to be a driver of drug resistance, represents the proof-of-concept for inhibiting the nuclear export as a feasible strategy to overcome therapy resistance.”


Multifaceted Chemical Behaviour of Metallocene (M = Fe, Os) Quinone Methides. Their Contribution to Biology. Vessières, A. ; Wang, Y. ; McGlinchey, M. J. ; Jaouen, G. Coord. Chem. Rev. 2021, 430, 213658 ; http://dx.doi.org/10.1016/j.ccr.2020.213658.

“Organometallic quinone methides (OM-QMs) have unique chemical and biological properties compared to their purely organic counterparts, but their originality has not previously been delineated in review form. These phenomena are particularly evident when they are incorporated into a judiciously chosen substrate, in this specific case the ferrocifens, bioorganometallic modifications of hydroxytamoxifen, the antiestrogen of reference. The newly created architecture reveals an embedded ferrocenyl-ene-phenol motif that is key to the formation of metallocene quinone methides by reversible oxidation, either chemically, electrochemically or enzymatically, whereby the sandwich unit functions as a redox antenna. In cancer cells, the QMs are primary metabolites that behave as selective electrophiles that undergo Michael additions with thiols or selenols of key proteins crucial to maintaining redox balance, thus generating a disruption of cell metabolism. Within this class of metallocene complexes, the ferrocifens are the most cytotoxic of the iron, ruthenium, osmium triad against a wide range of cancer cells, while osmium allows the complexes to be used as an imaging probe. The potential of OM-QMs in chemistry and biology is thus demonstrated in its diversity.”


Novel Luminescent Benzopyranothiophene- and BODIPY-Derived Aroylhydrazonic Ligands and Their Dicopper(II) Complexes : Syntheses, Antiproliferative Activity and Cellular Uptake Studies. Rada, J. P. ; Forté, J. ; Gontard, G. ; Bachelet, C.-M. ; Rey, N. A. ; Salmain, M. ; Corcé, V. J Biol Inorg Chem 2021, 26, 675–688 ; http://dx.doi.org/10.1007/s00775-021-01885-5.

“Two novel unsymmetrical binucleating aroylhydrazonic ligands and four dicopper(II) complexes carrying fluorescent benzopyranothiophene (BPT) or boron dipyrromethene (BODIPY) entities were synthesized and fully characterized. Additionally, the stability of the ligands and complexes was monitored by UV–vis spectroscopy in DMSO and biologically relevant media. All the compounds showed moderate to high cytotoxicity towards the triple negative human breast cancer cell line MDA-MB-231. BPT derivatives were the most cytotoxic, specially H3L1, reaching an IC50 value up to the nanomolar range. Finally, fluorescence microscopy imaging studies employing mitochondria- and nucleus-staining dyes showed that the BODIPY-carrying ligand H3L2 was highly cell permeant and suggested that the compound preferentially accumulates in the mitochondria.”


P722 Ferrocifen Loaded Lipid Nanocapsules Improve Survival of Murine Xenografted-Melanoma via a Potentiation of Apoptosis and an Activation of CD8+ T Lymphocytes. Topin-Ruiz, S. ; Mellinger, A. ; Lepeltier, E. ; Bourreau, C. ; Fouillet, J. ; Riou, J. ; Jaouen, G. ; Martin, L. ; Passirani, C. ; Clere, N. Int. J. Pharm. 2021, 120111 ; http://dx.doi.org/10.1016/j.ijpharm.2020.120111.

“The aim of this study is (i) to evaluate the benefits of a strategy involving encapsulated P722 in lipid nanocapsules (LNC) in B16F10 melanoma mice models and (ii) to compare the beneficial effects with an existing therapy such as anti-CTLA4 mAb. Interestingly, LNC-P722 induces a significant decrease of melanoma cell viability. In vivo data shows a significant improvement in the survival rate and a slower tumor growth with p722-loaded LNC in comparison with anti-CTLA4 mAb. Western blots confirm that LNC-p722 potentiates intrinsic apoptotic pathway. Treatment with LNC-P722 significantly activates CD8+ T lymphocytes compared to treatment with anti-CTLA4 mAb. This study uncovers a new therapeutic strategy with encapsulated p722 to prevent B16F10 melanoma growth and to improve survival of treated mice.”

2020

A Bis-Chelating (O^N^O)/(N^N) Ligand for the Synthesis of Heterobimetallic Pt(II)/Re(I) Complexes : Tools for the Optimization of a New Class of Pt(II) Anticancer Agents. Bertrand, B. ; Botuha, C. ; Forté, J. ; Dossmann, H. ; Salmain, M. Chem. Eur. J. 2020, 26, 12846–12861 ; http://dx.doi.org/10.1002/chem.202001752.

“The two independent coordination sites of a newly synthesized bis[2-(hydroxyphenyl)-1,2,4-triazole] platform have been exploited to prepare four monometallic neutral PtII complexes carrying DMSO, pyridine, triphenylphosphine, or N-heterocyclic carbene as the fourth ligand. Then, the second coordination site was used to introduce an IR-active rhenium tricarbonyl entity, affording the four corresponding heterobimetallic neutral PtII/ReI complexes, as well as a cationic PtII/ReI derivative. X-ray crystallographic studies showed that distortion of the organic platform occurred to accommodate the coordination geometry of both metal centers. Low micromolar activities were reached for the complexes carrying a DMSO ligand, making them the first examples of highly active, but hydrolytically stable, PtII complexes. Finally, the characteristic mid-IR signature of the Re(CO)3fragment in the Pt/Re heterobimetallic complexes was used to quantify their uptake in breast cancer cells.”


Enantioselective Synthesis of Planar Chiral Ferrocifens That Show Chiral Discrimination in Antiproliferative Activity on Breast Cancer Cells. Cunningham, L. ; Wang, Y. ; Nottingham, C. ; Pagsulingan, J. ; Jaouen, G. ; McGlinchey, M. ; Guiry, P. J. ChemBioChem 2020, 21, 2974–2981 ; http://dx.doi.org/10.1002/cbic.202000311.

Inaccessible no longer : Enantiopure ferrocifens and ferrociphenols have been efficiently prepared for biological evaluation via a chiral ketone by palladium-catalysed intramolecular direct C−H bond activation/cyclisation. IC50 values reveal that S-configured molecules perform better against an ER+ breast cancer cell line, but the result is less clear in the ER− case.”


Insights into the Antiproliferative Mechanism of (C^N)-Chelated Half-Sandwich Iridium Complexes. Ramos, R. ; Zimbron, J. M. ; Thorimbert, S. ; Chamoreau, L.-M. ; Munier, A. ; Botuha, C. ; Karaiskou, A. ; Salmain, M. ; Sobczak-Thépot, J. Dalton Trans. 2020 ; http://dx.doi.org/10.1039/D0DT03414B.

“A structure–activity relationship-based methodology was used to investigate the chemical and biological features of a series of ten (C^N)-chelated half-sandwich iridiumIII complexes of the general formula [IrCp*(phox)Cl], where (phox) is a 2-phenyloxazoline ligand forming a 5-membered metallacycle. This series of compounds undergoes a fast exchange of their chlorido ligand once solubilised in DMSO. They were cytotoxic to HeLa cells with IC50 values in the micromolar range and induced a rapid activation of caspase-3, an apoptosis marker. In vitro, the oxidative power of all the complexes towards NADH was highlighted but only the complexes bearing substituents on the oxazoline ring were able to produce H2O2 at the micromolar range. However, we demonstrated using a powerful HyPer protein redox sensor-based flow cytometry assay that most complexes rapidly raised intracellular levels of H2O2. Hence, this study shows that oxidative stress can partly explain the cytotoxicity of these complexes on the HeLa cell line and gives a first entry to their mechanism of action.”


Isoxazole-Derived Aroylhydrazones and Their Dinuclear Copper(II) Complexes Show Antiproliferative Activity on Breast Cancer Cells with a Potentially Alternative Mechanism Of Action. Rada, J. P. ; Forté, J. ; Gontard, G. ; Corcé, V. ; Salmain, M. ; Rey, N. A. ChemBioChem 2020, 21, 2474–2486 ; http://dx.doi.org/10.1002/cbic.202000122.

Cytotoxicity contrast : Two aroylhydrazonic ligands and their acetate/perchlorate dicopper complexes were synthesized and characterized by various spectroscopic and analytical techniques, including X-ray diffraction. They were shown to interact with DNA and display contrasted cytotoxicity on breast cancer cells. Their biological properties were linked to their ability to undergo chelation/transmetallation with biologically relevant metal ions.”


Oxidation of Cymantrene-Tagged Tamoxifen Analogues : Effect of Diphenyl Functionalization on the Redox Mechanism. Wu, K. ; Pudasaini, B. ; Park, J. Y. ; Top, S. ;, G. ; Baik, M.-H. ; Geiger, W. E. Organometallics 2020, 39, 679–687 ; http://dx.doi.org/10.1021/acs.organomet.9b00822.

“The oxidations of 1,1′-di-p-anisolyl-2-cymantrenylbutene (3b) and 1,1′-di-p-hydroxyphenyl-2-cymantrenylbutene (3c) were investigated by electrochemical and spectroscopic experiments and by density functional theory (DFT) calculations.”


Pincer-Based Heterobimetallic Pt(II)/Ru(II), Pt(II)/Ir(III) and Pt(II)/Cu(I) Complexes : Synthesis and Evaluation Antiproliferative Properties. Bertrand, B. ; Gontard, G. ; Botuha, C. ; Salmain, M. Eur. J. Inorg. Chem. 2020, 2020, 3370–3377 ; http://dx.doi.org/10.1002/ejic.202000717.

“The use of an [ (O^N^O)PtL] platform bearing a free (N^N) ligand opened the way to the synthesis of various heterobimetallic complexes Pt/Ru, Pt/Ir, and Pt/Cu, which demonstrated interesting antiproliferative properties in vitro.”

2019

Atypical Lone Pair-π Interaction with Quinone Methides in a Series of Imido-Ferrociphenol Anticancer Drug Candidates. Wang, Y. ; Pigeon, P. ; Top, S. ; García, J. ; Troufflard, C. ; Ciofini, I. ; McGlinchey, M. J. ; Jaouen, G. Angew. Chem. Int. Ed. 2019, 58, 8421–8425 ; http://dx.doi.org/10.1002/anie.201902456.

Heterocycle-substituted ferrociphenols display strong anticancer activity through the generation of active metabolites such as quinone methides (QMs). The specific lone pair–π interaction between an imide carbonyl group and the quinone motif is crucial for the cytotoxic behaviour of their imido-ferrociphenol precursors as it markedly enhances the stability of the QMs and lowers the pKa values of the corresponding phenolates.”


Importance of Combining Advanced Particle Size Analysis Techniques To Characterize Cell-Penetrating Peptide–Ferrocifen Self-Assemblies. Guyon, L. ; Lepeltier, E. ; Gimel, J.-C. ; Calvignac, B. ; Franconi, F. ; Lautram, N. ; Dupont, A. ; Bourgaux, C. ; Pigeon, P. ; Saulnier, P. ; Jaouen, G. ; Passirani, C. J. Phys. Chem. Lett. 2019, 10, 6613–6620 ; http://dx.doi.org/10.1021/acs.jpclett.9b01493.



“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. The study highlights the importance and the complementary contribution of each characterization method to reflect the reality of the studied nanoassembly.”


Intracellular Localization of an Osmocenyl-Tamoxifen Derivative in Breast Cancer Cells Revealed by Synchrotron Radiation X-Ray Fluorescence Nanoimaging. Fus, F. ; Yang, Y. ; Lee, S. ; Top, S. ; Carriere, M. ; Bouron, A. ; Pacureanu, A. ; Da Silva, J. ; Salmain, M. ; Vessières, A. ; Cloetens, P. ; Jaouen, G. ; Bohic, S. Angew. Chem. Int. Ed. 2019, 58, 3461–3465 ; http://dx.doi.org/10.1002/anie.201812336.


The inner light : Elemental mapping of an osmium anticancer complex in human cancer cells, at pharmacologically relevant concentrations, using a synchrotron X-ray nanoprobe, reveals an intracellular distribution that encompasses the endomembrane system.”


New Mechanistic Insights into Osmium-Based Tamoxifen Derivatives. Lee, S. H. Z. ; Chau, F. ; Top, S. ; Jaouen, G. ; Vessières, A. ; Labbé, E. ; Buriez, O. Electrochim. Acta 2019, 302, 130–136 ; http://dx.doi.org/10.1016/j.electacta.2019.02.019.

“The electrochemical behavior of osmociphenol (3, Oc-OH), an organometallic osmium-based anticancer drug candidate, has been investigated by cyclic voltammetry in the absence and presence of lutidine used as a base model.”


Small Structural Differences Between Two Ferrocenyl Diphenols Determine Large Discrepancies of Reactivity and Biological Effects. Tonolo, F. ; Salmain, M. ; Scalcon, V. ; Top, S. ; Pigeon, P. ; Folda, A. ; Caron, B. ; McGlinchey, M. J. ; Toillon, R.-A. ; Bindoli, A. ; Jaouen, G. ; Vessières, A. ; Rigobello, M. P. ChemMedChem 2019, 14, 1717–1726 ; http://dx.doi.org/10.1002/cmdc.201900430.

The trans configuration in the ferrocenyl–double bond–phenol motif drives anticancer activity : Complex 1 is highly cytotoxic to breast cancer cells and induces a redox imbalance, whereas 2 shows only modest cytotoxicity. This difference can be rationalized by the fact that only 1 has the “trans” configuration responsible for its unique redox properties and strong anticancer activity.”


Synthesis and Biodistribution of 1-[2-(Cyclopentadienyltricarbonyltechnetium-99m)-2-Oxo-Ethoxy-Phenyl]-1,2-Di- (p-Hydroxyphenyl)but-1-Ene for Tumor Imaging. Dallagi, T. ; Saidi, M. ; Jaouen, G. ; Top, S. J. Organomet. Chem. 2019, 891, 1–6 ; http://dx.doi.org/10.1016/j.jorganchem.2019.04.006.

“1-[2-(cyclopentadienyltricarbonyltechnetium-99m)-2-oxo-ethoxy-phenyl]-1,2-di-(p-hydroxyphenyl)but-1-ene was prepared and investigated as a potential agent for imaging estrogen receptors (ERs) in associated tumors. The compound was obtained in high radiochemical purity and radiochemical yields. The biodistribution of the radioactive compound in mature female rats showed an ER-mediation in the ovarian target tissues as the uptake was reduced by a blocking dose of estradiol. The nonspecific uptake in muscle was relatively low.”

2018

A New Generation of Ferrociphenols Leads to a Great Diversity of Reactive Metabolites, and Exhibits Remarkable Antiproliferative Properties. Wang, Y. ; Dansette, P. M. ; Pigeon, P. ; Top, S. ; McGlinchey, M. J. ; Mansuy, D. ; Jaouen, G.Chem. Sci. 2018, 9, 70–78 ; http://dx.doi.org/10.1039/C7SC04213B.

“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 IC50 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 GI50 values lower than 100 nM towards a series of melanoma and renal cancer cell lines of the NCI-60 panel. Interestingly, oxidative metabolism of these hydroxypropyl-ferrociphenols yields two kinds of quinone methides (QMs) that readily react with various nucleophiles, such as glutathione, to give 1,6- and 1,8-adducts. Protonation of these quinone methides generates numerous reactive metabolites leading eventually to many rearrangement and cleavage products. This unprecedented and fully characterized metabolic profile involving a wide range of electrophilic metabolites that should react with cell macromolecules may be linked to the remarkable profile of antiproliferative activities of this new series. Indeed, the great diversity of unexpected reactive metabolites found upon oxidation will allow them to adapt to various situations present in the cancer cell. These data initiate a novel strategy for the rational design of anticancer molecules, thus opening the way to new organometallic potent anticancer drug candidates for the treatment of chemoresistant cancers.”


Anticancer Properties of Lipid and Poly(ε-Caprolactone) Nanocapsules Loaded with Ferrocenyl-Tamoxifen Derivatives. Najlaoui, F. ; Pigeon, P. ; Aroui, S. ; Pezet, M. ; Sancey, L. ; Marrakchi, N. ; Rhouma, A. ; Jaouen, G. ; Waard, M. ; Busser, B. ; Gibaud, S. J. Pharm. Pharmacol. 2018, 70, 1474–1484 ; http://dx.doi.org/10.1111/jphp.12998.


Enhanced and Preferential Internalization of Lipid Nanocapsules into Human Glioblastoma Cells : Effect of a Surface-Functionalizing NFL Peptide. Karim, R. ;, E. ; Esnault, L. ; Pigeon, P. ; Lemaire, L. ; Lépinoux-Chambaud, C. ; Clere, N. ; Jaouen, G. ; Eyer, J. ; Piel, G. ; Passirani, C. Nanoscale 2018, 10, 13485–13501 ; http://dx.doi.org/10.1039/C8NR02132E.

“A new ferrocifen-type molecule (FcTriOH), as a potent anticancer candidate, was encapsulated in LNCs and the functionalization improved its in vitro efficacy compared to other tested formulations against U87MG cells. In the preliminary study, on subcutaneous human GBM tumor model in nude mice, a significant reduction of relative tumor volume was observed at one week after the second intravenous injection with FcTriOH-loaded LNCs. These results showed that enhancing NFL peptide concentration on the LNC surface is a promising approach for increased and preferential nanocarrier internalization into human GBM cells, and the FcTriOH-loaded LNCs are a promising therapy approach for GBM.”


Ferrocifens Labelled with an Infrared Rhenium Tricarbonyl Tag : Synthesis, Antiproliferative Activity, Quantification and Nano IR Mapping in Cancer Cells. Wang, Y. ; Heinemann, F. ; Top, S. ; Dazzi, A. ; Policar, C. ; Henry, L. ; Lambert, F. ; Jaouen, G. ; Salmain, M. ; Vessières, A. Dalton Trans. 2018, 47, 9824–9833 ; http://dx.doi.org/10.1039/C8DT01582A.

“Two ferrocifens were tagged 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). Complexes 4–6 retained a high cytotoxicity on breast cancer cells (MDA-MB-231) with IC50 values in the range 0.32–2.5 μM. Transmission IR spectroscopy was used to quantify the amount of cyrhetrenyl tag present in cells incubated with 5 or 6. The results show that after a 1-h incubation of cells at 37 °C, complexes 5 and 6 are mainly present within cells while only a limited percentage, quantified by ICP-OES, remained in the incubation medium. AFM-IR spectroscopy, a technique coupling infrared irradiation with near-field AFM detection, was used to map the cyrhetrenyl unit in a single MDA-MB-231 cell, incubated at 37 °C for 1 h with 10 μM of 6. The results show that signal distribution of the characteristic band of the Re(CO)3 entity at 1950 cm−1 matched those of amide and phosphate, thus indicating a location of the complex mainly in the cell nucleus.”


Metal-Based BODIPY Derivatives as Multimodal Tools for Life Sciences. Bertrand, B. ; Passador, K. ; Goze, C. ; Denat, F. ; Bodio, E. ; Salmain, M. Coord. Chem. Rev. 2018, 358, 108–124 ; http://dx.doi.org/10.1016/j.ccr.2017.12.007.

“This review focuses on the different recent studies dealing with the conception of metal-based-BODIPY derivatives for medical purposes. More precisely, emphasis is put on the use of BODIPY derivatives for the elaboration of BODIPY-based theranostics, multimodal imaging probes, and photodynamic therapy sensitizers.”


Oxidation of Cymantrene Analogues of Ferrocifen : Electrochemical, Spectroscopic, and Computational Studies of the Parent Complex 1,1′-Diphenyl-2-Cymantrenylbutene. Wu, K. ; Park, J. Y. ; Al-Saadon, R. ; Nam, H. ; Lee, Y. ; Top, S. ; Jaouen, G. ; Baik, M.-H. ; Geiger, W. E. Organometallics 2018, 37, 1910–1918 ; http://dx.doi.org/10.1021/acs.organomet.8b00186.



“The oxidative electrochemical behavior of 1,1′-diphenyl-2-cymantrenylbutene (1), a cymantrene analogue of the breast cancer drug ferrocifen, was shown to involve the sequential electron-transfer series 1/1+/12+ in dichloromethane/0.05 M [NBu4][B(C6F5)4] (E1/2 values 0.78 and 1.18 V vs ferrocene).”


Selective Cytotoxicity of Arene Tricarbonylchromium towards Tumour Cell Lines. Elloumi-Mseddi, J. ; Mnif, S. ; Akacha, N. ; Hakim, B. ; Pigeon, P. ; Jaouen, G. ; Top, S. ; Aifa, S. J. Organomet. Chem. 2018, 862, 7–12 ; http://dx.doi.org/10.1016/j.jorganchem.2018.01.036.

“In the present work, mineral chromium (VI) showed that it is cytotoxic on both tumour (MCF-7, HeLa, Hep2 and Caco-2) and non-tumour (HEK293) cell lines. Interestingly, among seven complexes of arene tricarbonylchromium, chromium (0) becomes more efficient in targeting tumour cell lines with less toxicity to non-tumour cells. Three of complexes (formyl benzene tricarbonylchromium 1, anisol tricarbonylchromium 2 and trimethoxybenzene tricarbonylchromium 3) show a decrease of IC50 values for all tested tumour cells compared to the non-tumour cells HEK293. The remaining compounds have an opposite effect ; they are less toxic to tumour cells compared to HEK293. The present work demonstrates that some arene tricarbonylchromium are selectively active against cancer cells by inducing apoptosis. The role of formyl and methoxy groups in arene tricarbonylchromium is shown in complexes acquiring the selective tumour cytotoxicity.”

2017

Approach to Ferrocenyl-Podophyllotoxin Analogs and Their Evaluation as Anti-Tumor Agents. Beaupérin, M. ; Polat, D. ; Roudesly, F. ; Top, S. ; Vessières, A. ; Oble, J. ; Jaouen, G. ; Poli, G. J. Organomet. Chem. 2017, 839, 83–90 ; http://dx.doi.org/10.1016/j.jorganchem.2017.02.005.


“We report here the synthesis of ferrocene-containing podophyllotoxin analogs and preliminary antiproliferative tests.”


A New Series of Succinimido-Ferrociphenols and Related Heterocyclic Species Induce Strong Antiproliferative Effects, Especially against Ovarian Cancer Cells Resistant to Cisplatin. Pigeon, P. ; Wang, Y. ; Top, S. ; Najlaoui, F. ; Alvarez, M. C. G. ; Bignon, J. ; McGlinchey, M. J. ; Jaouen, G. J. Med. Chem. 2017, 60, 8358–8368 ; http://dx.doi.org/10.1021/acs.jmedchem.7b00743.

“This work describes the syntheses and preliminary mechanistic research of unprecedented multitargeting heterocyclic ferrociphenols bearing either a succinimidyl or phthalimidyl group that show exceptional antiproliferative behavior against epithelial ovarian cancer cells resistant to cisplatin. Owing to the failure of the present pharmaceutical options, such as carboplatin a metallodrug based on Pt coordination chemistry, these species may help to overcome the problem of lethal resistance. Currently, ferrociphenolic entities generally operate via apoptotic and senescence pathways. We present here our first results in this new cyclic-imide series.”


Efficient Ferrocifen Anticancer Drug and Bcl-2 Gene Therapy Using Lipid Nanocapsules on Human Melanoma Xenograft in Mouse. Resnier, P. ; Galopin, N. ; Sibiril, Y. ; Clavreul, A. ; Canon, J. ; Briganti, A. ; Legras, P. ; Vessières, A. ; Montier, T. ; Jaouen, G. ; Benoit, J.-P. ; Passirani, C. Pharmacol. Res. 2017, 126, 54–65 ; http://dx.doi.org/10.1016/j.phrs.2017.01.031.

“The objective of this study was to combine two strategies in the same lipid nanocapsules (LNCs) : i) gene therapy to modulate anti-apoptotic proteins by the use of Bcl-2 siRNA, and ii) ferrocifens as a new type of anticancer agent. The efficient gene silencing with LNCs was verified by the specific extinction of Bcl-2 in melanoma cells. The cellular toxicity of ferrocifens (ferrociphenol (FcDiOH) or Ansa-FcDiOH) was demonstrated, showing higher efficacy than dacarbazine. Interestingly, the association of siBcl-2 LNCs with Ansa-FcDiOH demonstrated a significant effect on melanoma cell viability. Moreover, the co-encapsulation of siRNA and ferrocifens was successfully performed into LNCs for animal experiments. A reduction of tumor volume and mass was proved after siBcl-2 LNC treatment and Ansa-FcDiOH LNC treatment, individually (around 25%). Finally, the association of both components into the same LNCs increased the reduction of tumor volume to about 50% compared to the control group. In conclusion, LNCs appeared to provide a promising tool for the co-encapsulation of a metal-based drug and siRNA.”


Side-Chain Effects on the 1-(Bis-Aryl-Methylidene)-[3]Ferrocenophane Skeleton : Antiproliferative Activity against TNBC Cancer Cells and Comparison with the Acyclic Ferrocifen Series. Gormen, M. ; Pigeon, P. ; Wang, Y. ; Vessières, A. ; Top, S. ; Martial, F. ; Gros, C. ; McGlinchey, M. J. ; Jaouen, G. Eur. J. Inorg. Chem. 2017, 2017, 454–465 ; http://dx.doi.org/10.1002/ejic.201601088.


“New [3]ferrocenophane derivatives bearing various side-chains have been synthesized and their biochemical properties studied. These complexes were found to have very strong antiproliferative effects against MDA-MB-231 breast cancer cells (IC50 = 0.05–0.39 µm).”


Synthesis and Antiproliferative Evaluation of Novel Hydroxypropyl-Ferrociphenol Derivatives, Resulting from the Modification of Hydroxyl Groups. Wang, Y. ; Pigeon, P. ; McGlinchey, M. J. ; Top, S. ; Jaouen, G. J. Organomet. Chem. 2017, 829, 108–115 ; http://dx.doi.org/10.1016/j.jorganchem.2016.09.005.

“A series of novel hydroxypropyl-ferrociphenol derivatives with modified terminal hydroxyl groups were synthesized, and their antiproliferative activities against MDA-MB-231 cell lines were evaluated. Biological results showed that compound 8, whose terminal hydroxyl was protected by acetylation, exhibited the greatest cytotoxic effect among this series of hydroxypropyl derivatives. Furthermore, the impact of acetyl as a protecting group on the cytotoxicity of hydroxypropyl-ferrociphenol compounds by incorporating it at alkyl or phenyl hydroxyl positions of the core structure has been studied. Several of the compounds presented in this study revealed lipophilicity more suitable for formulation in lipid nanocapsules (LNCs) for subsequent in vivo studies. They also inhibit the cancer cell growth of MDA-MB-231 at a submicromolar IC50 value, providing an interesting potential for further development as innovative anticancer agents.”


Synthesis, Photophysical Properties, and Living Cell Imaging of Theranostic Half-Sandwich Iridium–4,4-Difluoro-4-Bora-3a,4a-Diaza-s-Indacene (BODIPY) Dyads. Zimbron, J. M. ; Passador, K. ; Gatin-Fraudet, B. ; Bachelet, C.-M. ; Plażuk, D. ; Chamoreau, L.-M. ; Botuha, C. ; Thorimbert, S. ; Salmain, M. Organometallics 2017, 36, 3435–3442 ; http://dx.doi.org/10.1021/acs.organomet.7b00250.

“We report the synthesis, characterization, and photophysical properties of two new cyclometalated half-sandwich iridium(III) complexes having the general formula [(η5-Cp*)Ir(ppy)Z]PF6 where η5-Cp* = pentamethylcyclopentadienyl and ppy = 2-phenyl-pyridine as C∧N-chelating ligand and Z = 3- or 4-pyridyl-BODIPY (BODIPY = 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene dye containing a 3- or 4-pyridyl group at the meso position). Antiproliferative studies demonstrated that one of the compounds was highly active with submicromolar IC50 on a panel of cancer cell lines. The replacement of the chlorido ligand by the pyridyl-BODIPY increased the lipophilicity of the complexes and slowed down the hydrolysis rate, which in turn increased the cytotoxicity of the metallodrug candidate. For the first time, cell uptake of one of the dyads was monitored by living cell fluorescence imaging. Interestingly, extremely fast internalization was observed the rate of which was temperature-dependent.”


Tamoxifen-like Metallocifens Target the Thioredoxin System Determining Mitochondrial Impairment Leading to Apoptosis in Jurkat Cells. Scalcon, V. ; Salmain, M. ; Folda, A. ; Top, S. ; Pigeon, P. ; Lee, H. Z. S. ; Jaouen, G. ; Bindoli, A. ; Vessières, A. ; Rigobello, M. P. Metallomics 2017, 9, 949–959 ; http://dx.doi.org/10.1039/c7mt00121e.


“Metallocifens of Fe, Os and Ru derived from tamoxifen target mitochondria, inhibit the thioredoxin system, determine ROS increase and collapse of the mitochondrial membrane potential triggering cell death.”