Synthesis, Characterization, and Antiproliferative Activities of NovelFerrocenophanic Suberamides against Human Triple-Negative MDA-MB-231 and Hormone-Dependent MCF‑7 Breast Cancer CellsJose de Jesus Cazares-Marinero,† Oliver Buriez,‡ Eric Labbe,‡ Siden Top,*,† Christian Amatore,‡

and Gerard Jaouen*,†

†ENSCP Chimie ParisTech, Laboratoire Charles Friedel, UMR CNRS 7223, 11 Rue Pierre et Marie Curie, F75231 Paris Cedex 05,France‡Departement de Chimie, UMR CNRS 8640, Ecole Normale Superieure, 24 Rue Lhomond, F75231 Paris Cedex 05, France

*S Supporting Information

ABSTRACT: We report the synthesis and characterization of a new family of organometallicsuberamides with strong antiproliferative activities against triple-negative MDA-MB-231 breastcancer cell lines with IC50 values ranging from 0.84 to 0.94 μM. Similar studies on hormone-dependent MCF-7 breast cancer cells were also carried out, revealing the positive effect of theferrocenophanic moiety on disubstituted ferrocene-1,1′-diyl derivatives versus their monosub-stituted ferrocenyl analogues. Cyclic voltammetry analysis showed no substantial differencesbetween ferrocenic and ferrocenophanic suberamides in the absence or presence of a base.However, similar studies performed on related compounds strongly suggest that ferrocenophanicand ferrocenic complexes do not undergo the same redox activation patterns. The electrochemical behavior seems to be inagreement with the antiproliferative activity of this type of organometallic compound.

■ INTRODUCTION

Within medicinal chemistry, bioorganometallic chemistry isbecoming an appealing field of research for alternativetherapeutics.1 Organometallic compounds, being relativelystable species with wide structural variety, are attractive fordesigning new classes of compounds with original biologicalapplications. Within the large family of organometalliccomplexes, ferrocene occupies an important place in medicinalchemistry.2 Its robustness, reactivity, redox properties, lip-ophilicity, and low cost make ferrocene an attractive rawmaterial for synthesis. Moreover, it has been demonstrated thatferrocene is not toxic to animals.3 The first examples offerrocenic compounds exerting antiproliferative activity againstcancer cells were ferricenium derivatives, albeit with lowactivity.4 Since then, ferrocene has been considered for thedevelopment of compounds with biological applications such asanticancer agents,5 antimalarial agents,6 DNA detection,7 andenzymatic inhibition against HIV (such as topoisomerase8 andintegrase9 inactivation).One of the most cited examples demonstrating the antitumor

effectiveness of organometallic compounds with low IC50 valuesis the ferrocifen family, which was first developed in Parisseveral years ago.10 Our group has been interested in themodification of the hydroxytamoxifen molecule (OHTAM,Chart 1), the active metabolite of tamoxifen (TAM). The latteris a drug used to treat hormone-dependent breast cancers.OHTAM modification consisted of the replacement of thenonsubstituted phenyl group of OHTAM by a ferrocenyl group(Fc) and the homologation of its lateral aminoalkyl chain. Theresulting product, called hydroxyferrocifen (FcOHTAM, Chart

1), showed an antiproliferative activity better than that of theorganic analogue OHTAM, not only against hormone-depend-ent MCF-7 breast cancer cells but also against triple-negativeMDA-MB-231 breast cancer cells.11 MCF-7 and MDA-MB-231cells are metastatic breast cancer cells isolated from peuraleffusion. MCF-7 cells, which contain alpha estrogen receptors(ERα), are sensitive to selective estrogen receptor modulators(SERM) such as tamoxifen. MDA-MB-231 cells are known astriple-negative breast cancer (TNBC) because they lackestrogen receptor (ER) and progesterone receptor (PR)expression as well as human epidermal growth factorreceptor-2 (HER2).12 This aspect is particularly importantsince there is no efficient treatment for triple-negative breastcancer. More than 15% of the 1.38 million new cases per year

Special Issue: Ferrocene - Beauty and Function

Received: May 30, 2013Published: July 29, 2013

Chart 1. Chemical Structures of Hydroxytamoxifen(OHTAM) and Hydroxyferrocifen (FcOHTAM)

Article

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are designated as TNBC.13 Its prognosis remains bleak, anddealing with the scarcity of well-defined molecular targets is stilla challenge.On the other hand, over the last four years, we have reported

the biological responses of a new family of cyclic 1,1′-d i subst i tuted fer rocene compounds , par t i cu la r ly[3]ferrocenophane derivatives. This metallocenophane moietyhas already been applied in some disciplines such as catalysis,polymer science, and electrochemistry.14 Supposing that thiskind of rigid molecule in an adequate geometry should be ableto bind receptors in active sites more strongly than flexibles t ructures , we have incorpora ted the inflex ib le[3]ferrocenophan-1-ylidene group (Fpd) by replacing the 1-ferrocenylpropylidene group (Fcpd) in over 20 moleculesbearing a combination of aromatic substituents (R and R′) suchas bromo, cyano, amino, acetamido, hydroxy, acetoxy, anddimethylaminoalkoxy on the (metal locenophan-1-ylidenemethylene)dibenzene skeleton (Chart 2). Cytotoxic

studies showed that these new Fpd compounds 2 were muchmore active than the Fcpd compounds 1 against humanglioblastoma, promyelocytic leukemia, colon, prostate, andbreast cancer cells.15

Recently, we replaced the dimethylaminoalkoxy chain ofFcTAM with the lateral chain of the suberoylanilidehydroxamic acid (SAHA) to afford hybrid derivatives (Chart3).16 SAHA is a histone deacetylase inhibitor approved for thetreatment of T-cell cutaneous lymphoma.17 Biological studieson the FcTAM−SAHA hybrid and related compounds haverevealed their strong antiproliferative activity against hormone-dependent MCF-7 cells and triple-negative MDA-MB-231breast cancer cells. Against the latter, FcTAM−SAHA andFcTAM−PSA were around six times more active than SAHA(IC50 = 3.6 μM). FcTAM−PSA is the analogue bearing a

primary amide function and can be seen as a hybrid betweenthe FcTAM and the N1-phenylsuberamide (PSA).In addition, molecular biology assays on these hybrids

showed strong p53 target mRNA accumulation (namely, p21,PIG, and PUMA) in MCF-7 breast cancer cells. The p53 geneis a tumor suppressor gene that activates p21 expression andcontrols the G1 checkpoint in the cell cycle. This gene is able toinduce either apoptosis or a permanent growth arrest(senescence). It has been shown that p53 protein expressionis associated with ROS production.18 Moreover, this effect isalso present with quinonic metabolites19 and ferrocenicderivatives20 independently. The latter correlates perfectlywith our experimental observations of quinone methideformation,21 ROS production,22 and p21 accumulation16 byour different ferrocenic and ferrocenophanic derivatives. Inaddition, experimentally, hydroxamic acids such as FcTAM−SAHA showed a strong ability to chelate metallic ions such asFe3+.23 This reactivity is very important in biochemistry and intherapy, since metalloenzyme overexpression in cancer cells canbe controlled by means of chelating effects.24 Furthermore,preliminary studies on ferrocenic compounds bearing shorteralkyl chain lengths showed that the cytotoxic effects of amidesare not affected significantly by the lateral alkyl chain length, asoccurs in the case of hydroxamic acids. This suggests thatferrocenic amides have a particular effect on biological systemsregardless of the chain length.Our aim now is to determine whether the positive impact of

Fcpd/Fpd replacement is also verified in the case of FcTAM−SAHA and FcTAM−PSA hybrids in terms of antiproliferativeactivity and whether the strong cytotoxic properties of theamide function in FcTAM−PSA are affected by thismodification. We also wanted to compare the electrochemicalbehaviors of both series to find some clues about themechanism(s) of action of these ferrocenic and ferroceno-phanic species. For this purpose, we describe here the synthesis,characterization, voltammetric analysis, and evaluation of newcompounds bearing the Fpd unit on triple-negative MDA-MB-231 and hormone-dependent MCF-7 breast cancer cells. So far,the antiproliferative redox effect in the cyclic series has not beenevaluated.

■ RESULTS AND DISCUSSIONSynthesis. All of the syntheses were performed as described

in Scheme 1. The traditional pathway for the synthesis of[3]ferrocenophan-1-one 3 was followed by the reaction offerrocene with acryloyl chloride under Friedel−Crafts con-ditions.25 After that, McMurry cross-coupling was performedon 3 and 4-aminobenzophenone to form aniline 4.15c This type

Chart 2. Chemical Structures of the 4,4′-[(1-Ferrocenylpropylidene)methylene]diphenyl, 1, and 4,4′-([3]Ferrocenophan-1-ylidene)methylene]diphenyl, 2, Series

Chart 3. Chemical Structures of Ferrocifen (FcTAM) and Ferrocenic Suberamides FcTAM−PSA and FcTAM−SAHA withTheir Corresponding IC50 Values against Breast Cancer Cells

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of reaction has been reported to give a mixture of Z and Eisomers. Aniline 4 reacted with suberoyl chloride to formcarboxylic acid 5 in 50.5% yield. The concomitant formation ofbisamide 6 was also observed, and even when the reactionconditions were modified (e.g., temperature, addition order,addition times, and solvent nature) to improve the yield of 5,bisamide 6 formation was always observed in the sameproportions.Suberamide 5a was obtained in 36% yield from the

nucleophilic attack of an excess of sodium amide (NaNH2)to 5 previously activated with ethyl chloroformate (ClCO2Et).In the same manner, N-hydroxy suberamide 5b was obtained in31% yield from the nucleophilic attack of hydroxylamine(NH2OH) freshly prepared in methanol (MeOH) fromhydroxylamine hydrochloride (NH2OH·HCl) and an excessof potassium hydroxide (KOH). Ester 7 was identified as abyproduct of this last reaction and was thought to come fromMeOH attack in alkaline medium on activated 5. Yields wereobtained after purification by column chromatography, and allcompounds were characterized by conventional spectroscopic

techniques. All compounds were obtained as a mixture of Z:Eisomers with an excess of the Z form over 85%.

Antiproliferative Activities. The cytotoxic effects ofcarboxylic acid 5 and suberamides 5a and 5b were evaluatedagainst triple-negative MDA-MB-231 breast cancer cells (Table1). All three compounds showed strong antiproliferative activityagainst this cell line, with IC50 values in the range 0.84−2.72μM. Less sterically hindered organic analogues were far lessactive, with IC50 values greater than 10 μM for 8-oxo-8-(phenylamino)octanoic acid (OPOA) and PSA. Only N1-hydroxy-N8-phenylsuberamide, better known as SAHA, showedgood antiproliferative activity (IC50 = 3.64 μM); however, itremained almost four times less active than its ferrocenophanicanalogue 5b on this human triple-negative breast cancer cellline. As observed for the case of the Fcpd series, organometallicprimary amide 5a was slightly more cytotoxic than organo-metallic hydroxamide 5b.Surprisingly, the superiority of the Fpd series over the Fcpd

series (which was observed in the case of 4,4′-([3]-ferrocenophan-1-ylidene)methylene]diphenol (Chart 2, 2, R= R′ = OH), showing an IC50 of 0.09 μM,15a much lower than

Scheme 1. Synthesis of Carboxylic Acid 5 and Suberamides 5a and 5b

Table 1. IC50 (μM) for MDA-MB-231 Breast Cancer Cell Linea

aMeasurements were performed in duplicate after 72 h. Values are reported with SD.

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4,4′-[(1-ferrocenylpropylidene)methylene]diphenol (Chart 2,1, R = R′ = OH), showing an IC50 of 0.6 μM26 against MDA-MB-231), was observed only for the Fpd carboxylic acid 5,which was more active than its corresponding Fcpd analogueFcTAM−OPOA. Suberamides 5a and 5b were even slightlyless active that their Fcpd analogues FcTAM−PSA andFcTAM−SAHA. It is likely the suberoyl chain and chemicalfunctionalization play an important role in the modulation ofthe antiproliferative activity of these compounds.Cytotoxic effects of ferrocenophanic complexes (Fpd) were

also seen against hormone-dependent MCF-7 breast cancercells (Table 2). The compounds showed significant anti-proliferative activity against this human cancer cell line withIC50 values in the range 0.87−4.05 μM, while the organicanalogues, excepting SAHA, were unable to inhibit 50% of cellgrowth even at 10 μM. Again, ferrocenophanic hydroxamide 5b(IC50 = 0.87 μM) was slightly more active than SAHA (IC50 =1.04 μM). In the case of MCF-7 cells, the positive impact ofFcpd/Fpd replacement was verified. For example, Fpdcarboxylic acid 5 (IC50 = 4.05 μM) was more cytotoxic thanthe Fcpd derivative OPOA (IC50 = ∼10 μM), and Fpdhydroxamide 5b (IC50 = 0.87 μM) was twice as active as itsFcpd homologue FcTAM−SAHA (IC50 = 2.01 μM).Preliminary studies on the Fcpd compounds suggest that,despite their strong cytotoxic effects on MCF-7, they are

estrogenic at lower concentrations.16 Therefore, this dualactivity could play an important role in this cancer cell line.These cytotoxic/estrogenic relationships of Fpd derivatives mayfavor cytotoxicity over the estrogen agonist effect on MCF-7cells.It is worth mentioning that, in contrast to the superiority of

Fpd diphenol over the Fcpd analogue against triple-negativebreast cancer cells, in MCF-7, the Fcpd derivative remained themost active. For 4,4′-([3]ferrocenophan-1-ylidene)methylene]-diphenol (Chart 2, 2, R = R′ = OH), the IC50 value wasestimated to be 4 μM,15a much higher than that of 4,4′-[(1-ferrocenylpropylidene)methylene]diphenol (Chart 2, 1, R = R′= OH) (IC50 = 0.7 μM).26 In the case of suberamides, wefound that the Fpd series was more active than Fcpd.Therefore, there is a positive effect of the Fpd complexesover Fcpd complexes for MCF-7 breast cancer cells.

Electrochemistry. Similarly to previous investigations,27

the redox properties of the Fpd and Fcpd compounds wereevaluated by cyclic voltammetry (Figure 1) in the absence andin the presence of a model base having a pKa value close tothose of peptides or DNA nitrogen intracellular bases.Carboxylic acids and suberamides did not show significantdifferences between the Fpd and Fcpd series, even in thepresence of 50 equivalents of imidazole (used as a model base).All the compounds showed the same reversible behavior in the

Table 2. IC50 (μM) for the MCF-7 Breast Cancer Cell Linea

aMeasurements were performed in duplicate after 72 h. Values are reported with SD.

Figure 1. Cyclic voltammograms of Fcpd (FcTAM−OPOA, FcTAM−PSA, and FcTAM−SAHA) and Fpd hybrids (5, 5a, and 5b) at 0.5 mM inMeOH in the absence (solid line) and in the presence (dashed line) of 50 equivalents of imidazole. Pt electrode (⦶ = 0.5 mm). Scan rate is 0.5 Vs−1.

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presence and absence of the base. Fpd compounds 5, 5a, and5b showed a reversible oxidation wave around 470 mV assignedto Fe2+ oxidation to Fe3+ in the ferrocene-1,1′-diyl moiety, andno other evolution was observed. Showing the same redoxpattern, Fcpd hybrids FcTAM−OPOA, FcTAM−PSA, andFcTAM−SAHA were electrochemically reversibly oxidized at500 mV. The similar cyclic voltammograms between these twoseries could reflect their similar antiproliferative activitiesagainst cancer. However, it is known that the replacement ofFcpd by the Fpd moiety in related compounds such as anilinesincreases its cytotoxicity.15b Therefore, electrochemical analysiswas also performed on these latter species.Before the addition of imidazole, the cyclic voltammogram of

the Fcpd monoaniline (Figure 2, 1a, solid line) was differentfrom that of the corresponding Fcpd suberamides (Figure 1).Monoaniline 1a showed two well-defined oxidation waveslocated at 460 mV (O1) and 769 mV (O2). The first oxidationwave O1 can be assigned to Fe2+ oxidation in the ferrocenylmoiety, and the second wave O2 corresponds to oxidation ofthe aniline moiety of the ferricenium species electrogeneratedat O1. Fcpd suberamides showed only the reversible oxidation

process at O1. In the case of the Fpd series, such differenceswere also observed between the monoaniline 2a andsuberamides. Monoaniline 2a exhibited the first oxidationwave at 473 mV (O1), whereas the second one was ill-definedand located at about 980 mV (O2). As with Fcpd, Fpdsuberamides showed only the reversible oxidation process atO1. This reversibility in both suberamide series can beexplained by the fact that the electron donor capacities of thenitrogenous aromatic substituents are attenuated by theelectron-withdrawing effect of the adjacent carbonyl on theanilide moiety.28

Interestingly, in 2a, aniline moiety oxidation (O2) waslocated at a more positive potential value than that of 1a. Thiscould be due to the fact that the molecule is incompletely π-conjugated in the ferrocenophanic structure. When imidazolewas added to monoanilines 1a and 2a, their electrochemicalbehaviors became different (dashed lines). For 1a, the secondoxidation wave O2 was shifted slightly toward a less positivepotential, and its reversibility was decreased, while O1 did notshow substantial changes. However, for 2a, O2 disappeared andO1 became irreversible, indicating a more reactive process in

Figure 2. Cyclic voltammograms of Fcpd monoaniline (1a) and Fpd monoaniline (2a) at 0.5 mM in MeOH in the absence (solid line) and in thepresence (dashed line) of 50 equivalents of imidazole. Pt electrode (⦶ = 0.5 mm). Scan rate is 0.5 V s−1.

Figure 3. Cyclic voltammograms of [3]ferrocenophan-1-one (left) and propionylferrocene (right) at 0.5 mM in MeOH in the absence (solid line)and in the presence (dashed line) of 50 equivalents of imidazole. Pt electrode (⦶ = 0.5 mm). Scan rate is 0.5 V s−1.

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this case. These modifications in the cyclic voltammogramsupon the addition of imidazole indicate the occurrence of abase-triggered oxidation sequence similar to the one reportedfor the Fcpd monoaniline, featuring base-promoted intra-molecular proton-coupled electron transfer between the aminegroup and ferricenium, ultimately leading to an aminyl radical,which grafts onto the Pt electrode.29 The differences in thecyclic voltammograms of these two series could reflect theirdifferences in antiproliferative activities against cancer (IC50 =0.8 μM for 1a and 0.2 μM for 2a, against MDA-MB-231).Since organometallic monoanilines 1a and 2a differ only on

one side of the vinylic system, the Fcpd and Fpd moieties mightbe responsible for this interesting electrochemical behavior.Electrochemical analysis of simpler analogues bearing Fcpd andFpd moieties may indeed prove our hypothesis. Thus, weobtained the cyclic voltammograms for the correspondingketone analogues: propionylferrocene and [3]ferrocenophan-1-one for the Fcpd and Fpd series, respectively (Figure 3).As expected, propionylferrocene showed reversible Fe2+

oxidation of the ferrocenyl moiety at 752 mV, which, in thepresence of a base, remained reversible at the same potential.[3]Ferrocenophan-1-one showed the same reversible oxidationof Fe2+ at 738 mV in the absence of a base. However,surprisingly, in the presence of 50 equivalents of a base, thisoxidation wave was shifted slightly to a lower potential valueand the reversibility was lost. The concomitant increase in theoxidation wave peak current also indicates the occurrence of asecond electron transfer. This behavior is very similar to thatobtained with ferrociphenol compounds.30 Nevertheless, sincethese molecules do not bear any phenolic moiety, this particularbehavior showed that such surprising electrochemical reactivitycould stem only from the ferrocenophanic moiety.

Other units in ferrocenophanic derivatives are expected to beoxidized as isolated parts because no important π-communica-tion is possible for these constricted molecules. However, it isnoted that this peculiar redox behavior of ferrocenophanicmolecules correlates with their cytotoxic effects. In order toexplain the behavior observed for the irreversible electro-chemical oxidation of [3]ferrocenophan-1-one in the presenceof a base, we postulated the mechanism in Scheme 2, whichamounts to oxidizing (i.e., −2e− − 2H+) the α,β σ-bond, thusextending the π-delocalization in the metallocenophane andresulting in an electrophilic enone moiety.

■ CONCLUSIONSWe have synthesized a new family of ferrocenophanicsuberamides that exert potent antiproliferative effects againstbreast cancer cells. Triple-negative MDA-MB-231 breast cancercells were very sensitive to our ferrocenic and ferrocenophaniccompounds. The replacement of Fcpd with the Fpd groupyielded more cytotoxic agents against hormone-dependentMCF-7 breast cancer cells, but not against hormone-independent MDA-MB-231. The cyclic voltammograms ofboth the Fcpd and Fpd suberic series, in the absence or in thepresence of a base, are similar. However, this behavior iscompletely different from that of aniline derivatives. The resultssuggest that redox activation should occur in the[3]ferrocenophane moiety. Despite the differences in reactivityobserved in the Fpd and Fcpd series, they are bothelectrochemically active and therefore oxidizable, so they canbe converted into ferricenium intermediates that are able topromote ROS production. This could be the key to the strongantiproliferative activity of ferrocenic and, particularly,ferrocenophanic compounds, which may be able to activate

Scheme 2. Tentative Mechanism of Electrochemical Oxidation of [3]Ferrocenophan-1-one in the Presence of a Base

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tumor suppressor genes such as p53 to lead to apoptosis orsenescence in cancer cells or may cause direct DNA damage bymeans of intracellular redox phenomena. Molecular biologyassays on this new series are envisaged to explore the impact ofFpd/Fcpd replacement on suppressor gene activation. Furtherelectrochemical studies on nonsubstituted analogues are alsoplanned to support our hypothesis about the differences inreactivity of Fcpd and Fcp compounds.

■ EXPERIMENTAL SECTIONGeneral Considerations. All reagents and solvents were obtained

from commercial suppliers and used without further purification.Tetrahydrofuran (THF) was distilled from Na/benzophenone underan argon atmosphere, and dichloromethane (DCM) was distilled fromP2O5. Thin-layer chromatography (TLC) was performed on silica gel60 GF254. Column chromatography was performed on silica gelMerck 60 (40−63 μm). All of the products were characterized byconventional techniques. Infrared (IR) spectra were recorded on aJasco FT/IR-4100 Fourier-transform infrared spectrometer by usingthe potassium bromide (KBr) pellet technique, and all data areexpressed in wave numbers (cm−1). Melting points (mp) wereobtained with a Kofler device and are uncorrected. 1H and 13C NMRspectra were recorded on a 300 MHz Bruker spectrometer, andchemical shifts (δ) are expressed in ppm. The mass spectra (MS) wereobtained on DSQII and ITQ 1100 Thermo Scientific spectrometersfor both electronic impact (EI) and chemical ionization (CI) methodsand on an API 3000 PE Sciex Applied Biosystems apparatus for theelectrospray ionization (ESI) method. A purity of >99% was confirmedby analytical reverse-phase HPLC with a Kromasil C18 column (10μm, L = 25 cm, D = 4.6 mm) using MeOH as eluent (flow rate = 1mL/min, λ = 254 nm). Elemental analyses were performed by theLaboratory of Microanalysis at ICSN of CNRS at Gif sur Yvette,France. HRMS and cytotoxicity measurements on MCF-7 breastcancer cells and some MDA-MB-231 breast cancer cells in vitro wereperformed by ImaGIF Ciblotheque Cellulaire (Institut de Chimie desSubstances Naturelles).

8-(4-{[3]Ferrocenophan-1-ylidene(phenyl)methyl}phenyl)amino-8-oxooctanoic Acid (5). A solution of 5 (2.47 mmol, 1.0 g) in 50 mLof THF was slowly added in 20 min at room temperature to a stirredsolution of suberoyl chloride (3.70 mmol, 0.78 g) in 20 mL of THF.After stirring for 20 min, the mixture was poured into a basic aqueoussolution of potassium hydroxide (KOH), then acidified withhydrochloric acid (HCl) and extracted with ethyl acetate (AcOEt).The organic layer was dried with magnesium sulfate (MgSO4) andthen filtered. Solvents were evaporated under reduced pressure, andthe crude product was separated by silica gel chromatography using ahexane/AcOEt (60:40) mixture. The first fraction was the nonreactedstarting product 5, the second fraction was the bisamide 7 obtained asa byproduct, and the third fraction was the desired product 6. A 0.70 g(50.5%) amount of carboxylic acid 6 was obtained as a yellow solid.Z:E isomer ratio, 88:12. Mp: 174−178 °C. 1H NMR (300 MHz,(CD3)2SO, ppm): Z isomer, δ 1.20−1.35 (m, 4H: r, q), 1.44−1.54 (m,4H: s, p), 2.18 (t, J = 7.3 Hz, 2H: t), 2.22 (t, J = 7.3 Hz, 2H: o), 2.25−2.35 (m, 2H: a), 2.55−2.65 (m, 2H: b), 3.95 (t, J = 1.8 Hz, 2H: β′),4.00 (s, 4H: β, α), 4.30 (t, J = 1.8 Hz, 2H: α′), 6.87 (d, J = 8.5 Hz, 2H:j), 7.20 (d, J = 7.0 Hz, 2H: f), 7.23−7.33 (m, 1H: h), 7.30 (d, J = 8.5,2H: k), 7.38 (t, J = 7.2 Hz, 2H: g), 9.74 (s, 1H: m, 9.91 for E isomer),11.97 (s, 1H: x). 13C NMR (75 MHz, (CD3)2SO, ppm): δ 24.4 (s),

25.0 (p), 28.0 (a), 28.3 (r), 28.4 (q), 33.6 (t), 36.3 (o), 40.2 (b), 68.2(β′), 68.6 (β), 69.8 (α), 70.1 (α′), 83.1 (ι), 86.4 (ι′), 118.0 (k), 126.7(h), 128.3 (g), 128.9 (f), 130.3 (j), 134.1 (c), 137.3 (l), 137.5 (i),139.9 (d), 143.2 (e), 171.0 (n), 174.4 (u). IR (KBr, νmax/cm

−1): 3313(N−H and O−H stretch), 3089, 3051 (aromatic C−H stretch), 2927,2854 (alkyl C−H stretch), 1701 (OCO stretch), 1662 (NCOstretch), 1593 (aromatic CC stretch), 1520 (N−H bend). MS (CI,m/z): 579 [MNH4]

+, 562 [MH]+. Anal. Calcd for C34H35FeNO3·1/2H2O (%): C, 71.58; H, 6.36; N, 2.46. Found: C, 71.60; H, 6.44; N,2.08. HPLC (tR): 3.25 min. Rf (AcOEt): 0.68.

N1-(4-{[3]Ferrocenophan-1-ylidene(phenyl)methyl}phenyl)-suberamide (5a). Ethyl chloroformate (ClCO2Et, 2 mmol, 0.19 mL)and triethylamine (Et3N, 2.5 mmol, 0.35 mL) were added to a solutionof 6 (1 mmol, 0.56 g) in 10 mL of THF. The mixture was stirred for10 min. The formed solid was filtered off, and an excess of sodiumamide (NaNH2) was added to the filtrate. After 30 min of stirring,water (20 mL) was added slowly. Subsequently, the mixture wasextracted with AcOEt, the organic layer was dried over MgSO4, andsolvents were evaporated under reduced pressure. The crude productwas separated by silica gel column chromatography using mixtures ofhexane/AcOEt. A 0.20 g (36%) amount of 6a was obtained as a yellowsolid. Z:E isomer ratio, 96:4. Mp: 171−172 °C. 1H NMR (300 MHz,(CD3)2SO, ppm): Z isomer, δ 1.24 (brs, 4H: r, q), 1.42−1.60 (m, 4H:s, p), 2.01 (t, J = 7.3 Hz, 2H: t), 2.22 (t, J = 7.3 Hz, 2H: o), 2.26−2.38(m, 2H: a), 2.55−2.70 (m, 2H: b), 3.95 (brs, 2H: β′), 4.01 (s, 4H: β,α), 4.29 (brs, 2H: α′), 6.66 (s, 1H: w′), 6.86 (d, J = 8.5 Hz, 2H: j),7.20 (d, J = 7.0 Hz, 2H: f), 7.15−7.25 (s, 1H: w), 7.24−7.34 (t, 1H: h),7.30 (d, J = 8.5, 2H: k), 7.37 (t, J = 7.2 Hz, 2H: g), 9.76 (s, 1H: m, 9.93for E isomer). 13C NMR (75 MHz, (CD3)2SO, ppm): δ 25.1 (s, p),28.0 (a), 28.5 (r, q), 35.1 (t), 36.4 (o), 40.3 (b), 68.2 (β′), 68.7 (β),69.8 (α), 70.2 (α′), 83.2 (ι), 86.5 (ι′), 118.0 (k), 126.8 (h), 128.3 (g),129.0 (f), 130.3 (j), 134.2 (c), 137.3 (l), 137.6 (i), 140.0 (d), 143.3(e), 171.2 (n), 174.4 (u). IR (KBr, νmax/cm

−1): 3394, 3325 (N−Hstretch), 3093 (aromatic C−H stretch), 2927, 2854 (alkyl C−Hstretch), 1662 (NCO stretch), 1597 (aromatic CC stretch), 1519(N−H bend). MS (CI, m/z): 578 [MNH4]

+, 561 [MH]+, 406 [MH-C8H13NO2]

+. HRMS (TOF MS ES+, C34H36FeN2O2: [M]+): calcd560.2126, found 560.2109. Anal. Calcd for C34H36FeN2O2·1/2H2O(%): C, 71.70; H, 6.55; N, 4.92. Found: C, 70.82; H, 6.51; N, 5.10.HPLC (tR): 3.70 min. Rf (AcOEt): 0.18.

8-(4-{[3]Ferrocenophan-1-ylidene(phenyl)methyl}phenyl)-N8-hy-droxysuberamide (5b). A solution of hydroxylamine hydrochloride(NH2OH·HCl, 4.0 mmol, 0.28 g) in 5 mL of methanol (MeOH) wasadded to a stirred solution of KOH (8.0 mmol, 0.45 g). After stirringfor 15 min, the precipitate was removed and the filtrate was placed in aflask. In another flask, ethyl chloroformate (ClCO2Et, 2 mmol, 0.19mL) and triethylamine (Et3N, 2.5 mmol, 0.35 mL) were added to asolution of 6 (1 mmol, 0.56 g) in 10 mL of THF, and the mixture wasstirred for 10 min. The filtrate was added to the freshly prepared

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solution of NH2OH in MeOH. The resulting mixture was stirred atroom temperature for 15 min and then poured into water, acidifiedwith HCl, and extracted with AcOEt. The organic layer was dried overMgSO4 and evaporated. The crude product was separated on a silicagel column using a mixture of hexane and AcOEt as eluent. The firstfraction was the ester 8 obtained as a byproduct, and the last fractionwas the desired product 6b. An 0.18 g (31%) yield of 6b was obtainedas a yellow solid. Z:E isomer ratio, 89:11. Mp: 118−120 °C. 1H NMR(300 MHz, (CD3)2SO, ppm): Z isomer, δ 1.18−1.33 (m, 4H: r, q),1.41−1.57 (m, 4H: s, p), 1.92 (t, J = 7.3 Hz, 2H: t), 2.22 (t, J = 7.3 Hz,2H: o), 2.26−2.36 (m, 2H: a), 2.56−2.65 (m, 2H: b), 3.95 (t, J = 1.8Hz, 2H: β′), 4.00 (s, 4H: β, α), 4.29 (t, J = 1.8 Hz, 2H: α′), 6.87 (d, J =8.5 Hz, 2H: j), 7.20 (d, J = 7.0 Hz, 2H: f), 7.24−7.34 (t, 1H: h), 7.30(d, J = 8.5, 2H: k), 7.37 (t, J = 7.2 Hz, 2H: g), 8.67 (s, 1H: w, 9.0 for Eisomer), 9.76 (s, 1H: m, 9.93 for E isomer), 10.33 (s, 1H: x). 13CNMR (75 MHz, (CD3)2SO, ppm): δ 25.1 (s, p), 28.0 (a), 28.4 (r, q),32.3 (t), 36.4 (o), 40.3 (b), 68.2 (β′), 68.6 (β), 69.8 (α), 70.1 (α′),83.2 (ι), 86.4 (ι′), 118.0 (k), 126.8 (h), 128.3 (g), 128.9 (f), 130.3 (j),134.1 (c), 137.3 (l), 137.6 (i), 140.0 (d), 143.3 (e), 169.1 (u), 171.1(n). IR (KBr, νmax/cm

−1): 3240 (N−H and O−H stretch), 3089, 3051(aromatic C−H stretch), 2923, 2854 (alkyl C−H stretch), 1658(NCO stretch), 1597 (aromatic CC stretch), 1520 (N−H bend).MS (ESI, m/z): 575 [M − H]− and 599 [MNa]+. Anal. Calcd forC34H36FeN2O3·1/2C4H8O2 (%): C, 69.68; H, 6.50; N, 4.51. Found: C,69.67; H, 6.87; N, 4.62. HPLC (tR): 3.62 min. Rf (AcOEt): 0.12.

N1,N8-Bis(4-{[3]ferrocenophan-1-ylidene(phenyl)methyl}phenyl)-suberamide (6). 6 is a byproduct of the synthesis of carboxylic acid 5.Major isomer: 73%. Mp: 184−186 °C. 1H NMR (300 MHz,(CD3)2SO, ppm): major isomer, δ 1.20−1.40 (m, 4H: q), 1.45−1.55(m, 4H: p), 2.14−2.24 (m, 4H: o), 2.25−2.40 (m, 4H: a), 2.55−2.65(m, 4H: b), 3.95 (t, J = 1.8 Hz, 4H: β′), 4.00 (s, 8H: β, α), 4.30 (t, J =1.8 Hz, 4H: α′), 6.86 (d, J = 8.5 Hz, 4H: j), 7.20 (d, J = 7.0 Hz, 4H: f),7.24−7.32 (m, 6H: h, k), 7.37 (t, J = 7.2 Hz, 4H: g), 9.73 (s, 2H: m).13C NMR (75 MHz, (CD3)2SO, ppm): 25.0 (p), 28.0 (a), 28.4 (q),36.3 (o), 40.2 (b), 68.1(β′), 68.6 (β), 69.8(α), 70.1(α′), 83.1(ι), 86.4(ι′), 118.0 (k), 126.7 (h), 128.3 (g), 128.9 (f), 130.3(j), 134.1 (c),137.3 (l), 137.5 (i), 139.9 (d), 143.2 (e), 171.0 (n). IR (KBr, νmax/cm−1): 3321 (N−H stretch), 3086 (aromatic C−H stretch), 2924,2854 (alkyl C−H stretch), 1666 (NCO stretch), 1593 (aromaticCC stretch), 1520 (N−H bend). MS (CI, m/z, %): 966 [MNH4]

+,949 [MH]+, (ESI, m/z, %): 971 [MNa]+, 948 [M]+. HRMS (TOF MSES+, C60H56Fe2N2O2: [M]+): calcd 948.3041, found 948.3029. HPLC(tR) 7.65 min. Rf (AcOEt): 0.92.

Methyl 8-(4-{[3]Ferrocenophan-1-ylidene(phenyl)methyl}-phenyl)amino-8-oxooctanoate (7). 7 is a byproduct of the synthesisof 6b. Z:E isomer ratio, 85:15. Mp: 103−107 °C. 1H NMR (300 MHz,(CD3)2SO, ppm): Z isomer, δ 1.19−1.34 (m, 4H: r, q), 1.43−1.63 (m,4H: s, p), 2.22 (t, J = 7.3 Hz, 2H: t), 2.27 (t, J = 7.4 Hz, 2H: o), 2.26−

2.37 (m, 2H: a), 2.56−2.67 (m, 2H: b), 3.56 (s, 3H: v), 3.95 (t, J = 1.8Hz, 2H: β′), 4.01 (s, 4H: β, α), 4.30 (t, J = 1.8 Hz, 2H: α′), 6.86 (d, J =8.5 Hz, 2H: j), 7.20 (d, J = 7.0 Hz, 2H: f), 7.24−7.34 (t, 1H: h), 7.30(d, J = 8.5, 2H: k), 7.37 (t, J = 7.2 Hz, 2H: g), 9.76 (s, 1H: m, 9.93 forE isomer). 13C NMR (75 MHz, (CD3)2SO, ppm): δ 24.3 (s), 24.9 (p),28.0 (a), 28.2 (r), 28.3 (q), 33.2 (t), 36.3 (o), 40.3 (b), 51.2 (v), 68.2(β′), 68.6 (β), 69.8 (α), 70.1 (α′), 83.1 (ι), 86.4 (ι′), 118.0 (k), 126.7(h), 128.3 (g), 128.9 (f), 130.3 (j), 134.1 (c), 137.3 (l), 137.5 (i),139.9 (d), 143.2 (e), 171.1 (n), 173.3 (u). IR (KBr, νmax/cm

−1): 3302(N−H stretch), 3086, 3051 (aromatic C−H stretch), 2931, 2854(alkyl C−H stretch), 1735 (OCO stretch), 1662 (NCO stretch),1597 (aromatic CC stretch), 1523 (N−H bend). MS (CI, m/z):593 [MNH4]

+, 576 [MH]+. (ESI, m/z): 598 [MNa]+, 575 [M]+.HRMS (TOF MS ES+, C35H37FeNO3: [M]+): calcd 575.2123, found575.2130. HPLC (tR): 4.38 min. Rf (AcOEt): 0.90.

IC50 Determination. The breast adenocarcinoma cell lines MDA-MB-231 and MCF7 were obtained respectively from ATCC and Dr.Matthias Kassack (Bonn, Germany). Cells were grown in RPMImedium supplemented with 10% fetal calf serum, in the presence ofpenicillin, streptomycin, and fungizone in a 75 cm3

flask under 5%CO2. Cells were plated in 96-well tissue culture plates in 200 μL ofmedium and treated 24 h later with 2 μL of a stock solution ofcompounds dissolved in DMSO using a Biomek 3000 instrument(Beckman-Coulter). The controls received the same volume of DMSO(1% final volume). After 72 h exposure, MTS reagent (Promega) wasadded and incubated for 3 h at 37 °C; the absorbance was monitoredat 490 nm and the results are expressed as the inhibition of cellproliferation calculated as the ratio [(1 − (OD490 treated/OD490control) × 100] in triplicate experiments. For IC50 determination[50% inhibition of cell proliferation], cells were incubated for 72 hfollowing the same protocol with compound concentrations rangingfrom 5 nM to 100 μM in separate duplicate experiments.

Electrochemistry. Cyclic voltammograms (CVs) were obtainedusing a three-electrode cell with a 0.5 mm Pt working electrode,stainless steel rod counter electrode, and Ag/AgCl/LiCl in ethanolreference electrode, with a μ-Autolab 3 potentiostat driven by GeneralPurpose Electrochemical System (GPES) version 4.8, EcoChemieB.V., Utrecht, The Netherlands. Solutions consisted of 5 mL ofMeOH, analyte (approximately 0.5 mM), and Bu4NBF4 (0.1 M) as thesupporting electrolyte. After the CV was obtained in MeOH, 50equivalents of imidazole was added to the cell containing the analyte,and after homogenization a new CV was recorded.

■ ASSOCIATED CONTENT

*S Supporting InformationThis material is available free of charge via the Internet athttp://pubs.acs.org.

■ AUTHOR INFORMATION

Corresponding Author*(S. Top) Tel: 33-1 44 27 66 99. Fax: 33-1 43 26 00 61. E-mail:siden-top@chimie-paristech.fr. (G. Jaouen) Tel: 33-1 43 26 9555. Fax: 33-1 43 26 00 61. E-mail: gerard-jaouen@chimie-paristech.fr.

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

We thank the Agence Nationale de la Recherche for financialsupport (ANR 2010 BILAN 7061 blanc “Mecaferrol”) and theNational Council of Science and Technology of Mexico(CONACyT) for the Ph.D. scholarship of J.J.C.M. This workhas benefited from the facilities and expertise of the SmallMolecule Mass Spectrometry platform of IMAGIF (Centre deRecherche de Gif, www.imagif.cnrs.fr).

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■ NOTE ADDED AFTER ASAP PUBLICATIONThis paper was published on the Web on July 29, 2013, with anerror in the Abstract and Table of Contents graphics. Thecorrected version was reposted on August 2, 2013.

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