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

Wang, Yong; Dansette, Patrick M.; Pigeon, Pascal; Top, Siden; McGlinchey, Michael J.; Mansuy, Daniel; Jaouen, Gérard

doi:10.1039/c7sc04213b

Cited by 45 publications

(39 citation statements)

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“…[16] Prolonged drug residence times inside the cell, close to important targets,may result in longer-lasting efficacy, an important factor for drug optimisation. [16] Prolonged drug residence times inside the cell, close to important targets,may result in longer-lasting efficacy, an important factor for drug optimisation.…”

Section: Angewandte Chemiementioning

confidence: 99%

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

et al. 2019

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Ferrociphenols,especially those possessing aheterocycle at the terminus of an aliphatic chain, displays trong anticancer activity through an ovel redox mechanismt hat generates active metabolites such as quinone methides (QMs). X-ray crystallography and UV/Vis spectroscopyreveal that the specific lone pair (lp)-p interaction between acarbonyl 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.T his intramolecular lp-p interaction markedly enhanced the stability of the QMs and lowered the pK a values of the corresponding phenol/phenolate couples.Asthe first example of such anon-covalent interaction that stabilizes QMs remotely,itn ot only expands the scope of the lp-p interaction in supramolecular chemistry,b ut also represents an ew mode of stabilization of aQ M. This unprecedented application of lp-p interactions in imidoferrociphenol anticancer drug candidates maya lso have great potential in drug discovery and organocatalyst design.With the goal of circumventing the drawbacks [1] associated with the widely used coordination complexes of Pt 2+ , transition-metal bioorganometallic chemistry has gradually come to the fore. [2] Antitumor agents based on iron, an abundant and inexpensive metal, occupy ap rivileged position, and mostly feature ferrocene,acompact, stable,n ontoxic metallocene showing reversible redox properties. [3] We have investigated the possible use of ferrocenes in oncology in the so-called ferrocifen family (Figure 1a), such as compounds 1 and 2,w hose IC 50 values against triple-negative breast cancer (TNBC) cell lines (MDA-MB-231) are 0.6 and 0.5 mm,r espectively.T hese singular entities possess ar edox motif of the ferrocenyl-ene-phenol type,g iving rise to reactive oxygen species (ROS) in cancer cells.T he initial reversible oxidation of the ferrocenyl antenna permits electronic delocalization, leading selectively to electrophilic quinone methides (QMs,see below), which induce senescence and/or apoptosis,d epending on the particular parameters. [3a] Functionalization of the alkyl chain of 1 by attaching aterminal hydroxy substituent [4] or aheterocyclic group, [5] as in 3 or 4,resulted in extremely low IC 50 values (0.035 mm)on TNBC MDA-MB-231 cells;m oreover,f or the epithelial ovarian cancer cell line A2780 and the cisplatin-resistant species A2780cisR, the IC 50 values were 0.035 and 0.049 mm, respectively.T he first metabolite obtained either in the chemical (Ag + )o re nzymatic oxidation of 1 in cancer cells is the quinone methide 1-QM (Figure 1a), which can react in a1 ,8-Michael addition with selective nucleophiles in the cancer cells. [6] Them echanism of action of 4 may follow asimilar pathway to that of 1.Thelone pair-p (lp-p)interaction, depicted schematically in Figure 1b,r efers to the stabilizing association between al one pair of electrons and the face of a p system. First invoked in 1995 for the stabilization of Z-DNA, [7] it is now widely recognised as anew supramolecul...

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Section: Angewandte Chemiementioning

confidence: 99%

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

et al. 2019

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“…Its high cytotoxicity can be associated with the fact that its oxidation can lead, as for its parent complex 2, to a tetrahydrofuran-substituted quinone methide (Scheme S2), which is assumed to be very reactive. 2,29…”

Section: Antiproliferative Activity Of the Complexes On Breast Cancermentioning

confidence: 99%

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

et al. 2018

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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). 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-hour 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 hour 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.

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“…For example, a series of ferrocifens, constituted by the ferrocene unit bearing hydroxytamoxifen‐type substituents on one of the two cyclopentadienyl rings, display significant cytotoxicity against a panel of cancer cell lines, which was attributed to a synergic effect between the organic moiety and the iron center . The redox chemistry of the Fe II center is believed to be an influential factor in the cytotoxicity of these compounds, as the oxidation to Fe III inside the cancer cell generates reactive metabolites and triggers the production of toxic substances . However, ferrocifens usually possess insufficient water solubility and consequently must be carefully formulated for potential clinical applications …”

Section: Introductionmentioning

confidence: 99%

Anticancer Potential of Diiron Vinyliminium Complexes

Rocco

Batchelor

Agonigi

et al. 2019

Chemistry A European J

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Although ferrocene derivatives have attracted considerable attention as possible anticancer agents, the medicinal potential of diiron complexes has remained largely unexplored. Herein, we describe the straightforward multigram‐scale synthesis and the antiproliferative activity of a series of diiron cyclopentadienyl complexes containing bridging vinyliminium ligands. IC50 values in the low‐to‐mid micromolar range were determined against cisplatin sensitive and resistant human ovarian carcinoma (A2780 and A2780cisR) cell lines. Notable selectivity towards the cancerous cells lines compared to the non‐tumoral human embryonic kidney (HEK‐293) cell line was observed for selected compounds. The activity seems to be multimodal, involving reactive oxygen species (ROS) generation and, in some cases, a fragmentation process to afford monoiron derivatives. The large structural variability, amphiphilic character and good stability in aqueous media of the diiron vinyliminium complexes provide favorable properties compared to other widely studied classes of iron‐based anticancer candidates.

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

Abstract: Two chemotypes of quinone methide pathways from a single substrate are reported, which may be linked to its remarkable antiproliferative activity.

Cited by 45 publications

References 59 publications

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

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

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

Anticancer Potential of Diiron Vinyliminium Complexes

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