Synthesis, Characterization, and Antiproliferative Activities of Novel

Article pubs.acs.org/Organometallics

Synthesis, Characterization, and Antiproliferative Activities of Novel Ferrocenophanic Suberamides against Human Triple-Negative MDAMB-231 and Hormone-Dependent MCF‑7 Breast Cancer Cells José de Jesús Cázares-Marinero,† Oliver Buriez,‡ Eric Labbé,‡ Siden Top,*,† Christian Amatore,‡ and Gérard Jaouen*,† †

ENSCP Chimie ParisTech, Laboratoire Charles Friedel, UMR CNRS 7223, 11 Rue Pierre et Marie Curie, F75231 Paris Cedex 05, France ‡ Département de Chimie, UMR CNRS 8640, École Normale Supérieure, 24 Rue Lhomond, F75231 Paris Cedex 05, France S Supporting Information *

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

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INTRODUCTION Within medicinal chemistry, bioorganometallic chemistry is becoming an appealing field of research for alternative therapeutics.1 Organometallic compounds, being relatively stable species with wide structural variety, are attractive for designing new classes of compounds with original biological applications. Within the large family of organometallic complexes, ferrocene occupies an important place in medicinal chemistry.2 Its robustness, reactivity, redox properties, lipophilicity, and low cost make ferrocene an attractive raw material for synthesis. Moreover, it has been demonstrated that ferrocene is not toxic to animals.3 The first examples of ferrocenic compounds exerting antiproliferative activity against cancer cells were ferricenium derivatives, albeit with low activity.4 Since then, ferrocene has been considered for the development of compounds with biological applications such as anticancer agents,5 antimalarial agents,6 DNA detection,7 and enzymatic inhibition against HIV (such as topoisomerase8 and integrase9 inactivation). One of the most cited examples demonstrating the antitumor effectiveness of organometallic compounds with low IC50 values is the ferrocifen family, which was first developed in Paris several years ago.10 Our group has been interested in the modification of the hydroxytamoxifen molecule (OHTAM, Chart 1), the active metabolite of tamoxifen (TAM). The latter is a drug used to treat hormone-dependent breast cancers. OHTAM modification consisted of the replacement of the nonsubstituted phenyl group of OHTAM by a ferrocenyl group (Fc) and the homologation of its lateral aminoalkyl chain. The resulting product, called hydroxyferrocifen (FcOHTAM, Chart © XXXX American Chemical Society

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

1), showed an antiproliferative activity better than that of the organic analogue OHTAM, not only against hormone-dependent MCF-7 breast cancer cells but also against triple-negative MDA-MB-231 breast cancer cells.11 MCF-7 and MDA-MB-231 cells are metastatic breast cancer cells isolated from peural effusion. 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 as triple-negative breast cancer (TNBC) because they lack estrogen receptor (ER) and progesterone receptor (PR) expression as well as human epidermal growth factor receptor-2 (HER2).12 This aspect is particularly important since there is no efficient treatment for triple-negative breast cancer. More than 15% of the 1.38 million new cases per year Special Issue: Ferrocene - Beauty and Function Received: May 30, 2013

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dx.doi.org/10.1021/om400490a | Organometallics XXXX, XXX, XXX−XXX

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are designated as TNBC.13 Its prognosis remains bleak, and dealing with the scarcity of well-defined molecular targets is still a 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 s u b st i t ut e d f e r r o c e n e c o m p o u n d s , p a r t i c u la r ly [3]ferrocenophane derivatives. This metallocenophane moiety has already been applied in some disciplines such as catalysis, polymer science, and electrochemistry.14 Supposing that this kind of rigid molecule in an adequate geometry should be able to bind receptors in active sites more strongly than flexible s t r u c t u r e s , w e h a v e i n c o r p o r a t e d t h e i nfle x ib le [3]ferrocenophan-1-ylidene group (Fpd) by replacing the 1ferrocenylpropylidene group (Fcpd) in over 20 molecules bearing a combination of aromatic substituents (R and R′) such as bromo, cyano, amino, acetamido, hydroxy, acetoxy, and dimethylaminoalkoxy on the (metallocenophan-1ylidenemethylene)dibenzene skeleton (Chart 2). Cytotoxic

primary amide function and can be seen as a hybrid between the 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 gene is a tumor suppressor gene that activates p21 expression and controls the G1 checkpoint in the cell cycle. This gene is able to induce either apoptosis or a permanent growth arrest (senescence). It has been shown that p53 protein expression is associated with ROS production.18 Moreover, this effect is also present with quinonic metabolites19 and ferrocenic derivatives20 independently. The latter correlates perfectly with our experimental observations of quinone methide formation,21 ROS production,22 and p21 accumulation16 by our different ferrocenic and ferrocenophanic derivatives. In addition, experimentally, hydroxamic acids such as FcTAM− SAHA showed a strong ability to chelate metallic ions such as Fe3+.23 This reactivity is very important in biochemistry and in therapy, since metalloenzyme overexpression in cancer cells can be controlled by means of chelating effects.24 Furthermore, preliminary studies on ferrocenic compounds bearing shorter alkyl chain lengths showed that the cytotoxic effects of amides are not affected significantly by the lateral alkyl chain length, as occurs in the case of hydroxamic acids. This suggests that ferrocenic amides have a particular effect on biological systems regardless 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 antiproliferative activity and whether the strong cytotoxic properties of the amide function in FcTAM−PSA are affected by this modification. We also wanted to compare the electrochemical behaviors of both series to find some clues about the mechanism(s) of action of these ferrocenic and ferrocenophanic species. For this purpose, we describe here the synthesis, characterization, voltammetric analysis, and evaluation of new compounds bearing the Fpd unit on triple-negative MDA-MB231 and hormone-dependent MCF-7 breast cancer cells. So far, the antiproliferative redox effect in the cyclic series has not been evaluated.

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

studies showed that these new Fpd compounds 2 were much more active than the Fcpd compounds 1 against human glioblastoma, promyelocytic leukemia, colon, prostate, and breast cancer cells.15 Recently, we replaced the dimethylaminoalkoxy chain of FcTAM with the lateral chain of the suberoylanilide hydroxamic acid (SAHA) to afford hybrid derivatives (Chart 3).16 SAHA is a histone deacetylase inhibitor approved for the treatment of T-cell cutaneous lymphoma.17 Biological studies on the FcTAM−SAHA hybrid and related compounds have revealed their strong antiproliferative activity against hormonedependent MCF-7 cells and triple-negative MDA-MB-231 breast cancer cells. Against the latter, FcTAM−SAHA and FcTAM−PSA were around six times more active than SAHA (IC50 = 3.6 μM). FcTAM−PSA is the analogue bearing a

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RESULTS AND DISCUSSION Synthesis. 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 of ferrocene with acryloyl chloride under Friedel−Crafts conditions.25 After that, McMurry cross-coupling was performed on 3 and 4-aminobenzophenone to form aniline 4.15c This type

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

B


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

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

a

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

techniques. All compounds were obtained as a mixture of Z:E isomers with an excess of the Z form over 85%. Antiproliferative Activities. The cytotoxic effects of carboxylic acid 5 and suberamides 5a and 5b were evaluated against triple-negative MDA-MB-231 breast cancer cells (Table 1). All three compounds showed strong antiproliferative activity against this cell line, with IC50 values in the range 0.84−2.72 μM. Less sterically hindered organic analogues were far less active, with IC50 values greater than 10 μM for 8-oxo-8(phenylamino)octanoic acid (OPOA) and PSA. Only N1hydroxy-N8-phenylsuberamide, better known as SAHA, showed good antiproliferative activity (IC50 = 3.64 μM); however, it remained almost four times less active than its ferrocenophanic analogue 5b on this human triple-negative breast cancer cell line. As observed for the case of the Fcpd series, organometallic primary amide 5a was slightly more cytotoxic than organometallic 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

of reaction has been reported to give a mixture of Z and E isomers. Aniline 4 reacted with suberoyl chloride to form carboxylic acid 5 in 50.5% yield. The concomitant formation of bisamide 6 was also observed, and even when the reaction conditions 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 same proportions. 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 in 31% yield from the nucleophilic attack of hydroxylamine (NH2OH) freshly prepared in methanol (MeOH) from hydroxylamine hydrochloride (NH2OH·HCl) and an excess of potassium hydroxide (KOH). Ester 7 was identified as a byproduct of this last reaction and was thought to come from MeOH attack in alkaline medium on activated 5. Yields were obtained after purification by column chromatography, and all compounds were characterized by conventional spectroscopic C


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

a

Measurements 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 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.

estrogenic at lower concentrations.16 Therefore, this dual activity could play an important role in this cancer cell line. These cytotoxic/estrogenic relationships of Fpd derivatives may favor cytotoxicity over the estrogen agonist effect on MCF-7 cells. It is worth mentioning that, in contrast to the superiority of Fpd diphenol over the Fcpd analogue against triple-negative breast cancer cells, in MCF-7, the Fcpd derivative remained the most active. For 4,4′-([3]ferrocenophan-1-ylidene)methylene]diphenol (Chart 2, 2, R = R′ = OH), the IC50 value was estimated to be 4 μM,15a much higher than that of 4,4′-[(1ferrocenylpropylidene)methylene]diphenol (Chart 2, 1, R = R′ = OH) (IC50 = 0.7 μM).26 In the case of suberamides, we found that the Fpd series was more active than Fcpd. Therefore, there is a positive effect of the Fpd complexes over Fcpd complexes for MCF-7 breast cancer cells. Electrochemistry. Similarly to previous investigations,27 the redox properties of the Fpd and Fcpd compounds were evaluated by cyclic voltammetry (Figure 1) in the absence and in the presence of a model base having a pKa value close to those of peptides or DNA nitrogen intracellular bases. Carboxylic acids and suberamides did not show significant differences between the Fpd and Fcpd series, even in the presence of 50 equivalents of imidazole (used as a model base). All the compounds showed the same reversible behavior in the

4,4′-[(1-ferrocenylpropylidene)methylene]diphenol (Chart 2, 1, R = R′ = OH), showing an IC50 of 0.6 μM26 against MDAMB-231), was observed only for the Fpd carboxylic acid 5, which was more active than its corresponding Fcpd analogue FcTAM−OPOA. Suberamides 5a and 5b were even slightly less active that their Fcpd analogues FcTAM−PSA and FcTAM−SAHA. It is likely the suberoyl chain and chemical functionalization play an important role in the modulation of the antiproliferative activity of these compounds. Cytotoxic effects of ferrocenophanic complexes (Fpd) were also seen against hormone-dependent MCF-7 breast cancer cells (Table 2). The compounds showed significant antiproliferative activity against this human cancer cell line with IC50 values in the range 0.87−4.05 μM, while the organic analogues, excepting SAHA, were unable to inhibit 50% of cell growth 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 of Fcpd/Fpd replacement was verified. For example, Fpd carboxylic acid 5 (IC50 = 4.05 μM) was more cytotoxic than the Fcpd derivative OPOA (IC50 = ∼10 μM), and Fpd hydroxamide 5b (IC50 = 0.87 μM) was twice as active as its Fcpd homologue FcTAM−SAHA (IC 50 = 2.01 μM). Preliminary studies on the Fcpd compounds suggest that, despite their strong cytotoxic effects on MCF-7, they are D


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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 the presence (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.

process at O1. In the case of the Fpd series, such differences were also observed between the monoaniline 2a and suberamides. Monoaniline 2a exhibited the first oxidation wave at 473 mV (O1), whereas the second one was ill-defined and located at about 980 mV (O2). As with Fcpd, Fpd suberamides showed only the reversible oxidation process at O1. This reversibility in both suberamide series can be explained by the fact that the electron donor capacities of the nitrogenous aromatic substituents are attenuated by the electron-withdrawing effect of the adjacent carbonyl on the anilide moiety.28 Interestingly, in 2a, aniline moiety oxidation (O2) was located at a more positive potential value than that of 1a. This could be due to the fact that the molecule is incompletely πconjugated in the ferrocenophanic structure. When imidazole was added to monoanilines 1a and 2a, their electrochemical behaviors became different (dashed lines). For 1a, the second oxidation wave O2 was shifted slightly toward a less positive potential, and its reversibility was decreased, while O1 did not show substantial changes. However, for 2a, O2 disappeared and O1 became irreversible, indicating a more reactive process in

presence and absence of the base. Fpd compounds 5, 5a, and 5b showed a reversible oxidation wave around 470 mV assigned to Fe2+ oxidation to Fe3+ in the ferrocene-1,1′-diyl moiety, and no other evolution was observed. Showing the same redox pattern, Fcpd hybrids FcTAM−OPOA, FcTAM−PSA, and FcTAM−SAHA were electrochemically reversibly oxidized at 500 mV. The similar cyclic voltammograms between these two series could reflect their similar antiproliferative activities against cancer. However, it is known that the replacement of Fcpd by the Fpd moiety in related compounds such as anilines increases its cytotoxicity.15b Therefore, electrochemical analysis was also performed on these latter species. Before the addition of imidazole, the cyclic voltammogram of the Fcpd monoaniline (Figure 2, 1a, solid line) was different from that of the corresponding Fcpd suberamides (Figure 1). Monoaniline 1a showed two well-defined oxidation waves located at 460 mV (O1) and 769 mV (O2). The first oxidation wave O1 can be assigned to Fe2+ oxidation in the ferrocenyl moiety, and the second wave O2 corresponds to oxidation of the aniline moiety of the ferricenium species electrogenerated at O1. Fcpd suberamides showed only the reversible oxidation E


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

Other units in ferrocenophanic derivatives are expected to be oxidized as isolated parts because no important π-communication is possible for these constricted molecules. However, it is noted that this peculiar redox behavior of ferrocenophanic molecules correlates with their cytotoxic effects. In order to explain the behavior observed for the irreversible electrochemical oxidation of [3]ferrocenophan-1-one in the presence of a base, we postulated the mechanism in Scheme 2, which amounts to oxidizing (i.e., −2e− − 2H+) the α,β σ-bond, thus extending the π-delocalization in the metallocenophane and resulting in an electrophilic enone moiety.

this case. These modifications in the cyclic voltammograms upon the addition of imidazole indicate the occurrence of a base-triggered oxidation sequence similar to the one reported for the Fcpd monoaniline, featuring base-promoted intramolecular proton-coupled electron transfer between the amine group and ferricenium, ultimately leading to an aminyl radical, which grafts onto the Pt electrode.29 The differences in the cyclic voltammograms of these two series could reflect their differences 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 might be responsible for this interesting electrochemical behavior. Electrochemical analysis of simpler analogues bearing Fcpd and Fpd moieties may indeed prove our hypothesis. Thus, we obtained the cyclic voltammograms for the corresponding ketone analogues: propionylferrocene and [3]ferrocenophan-1one 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 the presence of a base, remained reversible at the same potential. [3]Ferrocenophan-1-one showed the same reversible oxidation of Fe2+ at 738 mV in the absence of a base. However, surprisingly, in the presence of 50 equivalents of a base, this oxidation wave was shifted slightly to a lower potential value and the reversibility was lost. The concomitant increase in the oxidation wave peak current also indicates the occurrence of a second electron transfer. This behavior is very similar to that obtained with ferrociphenol compounds.30 Nevertheless, since these molecules do not bear any phenolic moiety, this particular behavior showed that such surprising electrochemical reactivity could stem only from the ferrocenophanic moiety.

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CONCLUSIONS We have synthesized a new family of ferrocenophanic suberamides that exert potent antiproliferative effects against breast cancer cells. Triple-negative MDA-MB-231 breast cancer cells were very sensitive to our ferrocenic and ferrocenophanic compounds. The replacement of Fcpd with the Fpd group yielded more cytotoxic agents against hormone-dependent MCF-7 breast cancer cells, but not against hormoneindependent MDA-MB-231. The cyclic voltammograms of both the Fcpd and Fpd suberic series, in the absence or in the presence of a base, are similar. However, this behavior is completely different from that of aniline derivatives. The results suggest that redox activation should occur in the [3]ferrocenophane moiety. Despite the differences in reactivity observed in the Fpd and Fcpd series, they are both electrochemically active and therefore oxidizable, so they can be converted into ferricenium intermediates that are able to promote ROS production. This could be the key to the strong antiproliferative activity of ferrocenic and, particularly, ferrocenophanic compounds, which may be able to activate F


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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 (OCO stretch), 1662 (NCO stretch), 1593 (aromatic CC 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.

tumor suppressor genes such as p53 to lead to apoptosis or senescence in cancer cells or may cause direct DNA damage by means of intracellular redox phenomena. Molecular biology assays on this new series are envisaged to explore the impact of Fpd/Fcpd replacement on suppressor gene activation. Further electrochemical studies on nonsubstituted analogues are also planned to support our hypothesis about the differences in reactivity of Fcpd and Fcp compounds.

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EXPERIMENTAL SECTION

General Considerations. All reagents and solvents were obtained from commercial suppliers and used without further purification. Tetrahydrofuran (THF) was distilled from Na/benzophenone under an argon atmosphere, and dichloromethane (DCM) was distilled from P2O5. Thin-layer chromatography (TLC) was performed on silica gel 60 GF254. Column chromatography was performed on silica gel Merck 60 (40−63 μm). All of the products were characterized by conventional techniques. Infrared (IR) spectra were recorded on a Jasco FT/IR-4100 Fourier-transform infrared spectrometer by using the potassium bromide (KBr) pellet technique, and all data are expressed in wave numbers (cm−1). Melting points (mp) were obtained with a Kofler device and are uncorrected. 1H and 13C NMR spectra were recorded on a 300 MHz Bruker spectrometer, and chemical shifts (δ) are expressed in ppm. The mass spectra (MS) were obtained on DSQII and ITQ 1100 Thermo Scientific spectrometers for both electronic impact (EI) and chemical ionization (CI) methods and on an API 3000 PE Sciex Applied Biosystems apparatus for the electrospray ionization (ESI) method. A purity of >99% was confirmed by analytical reverse-phase HPLC with a Kromasil C18 column (10 μm, L = 25 cm, D = 4.6 mm) using MeOH as eluent (flow rate = 1 mL/min, λ = 254 nm). Elemental analyses were performed by the Laboratory of Microanalysis at ICSN of CNRS at Gif sur Yvette, France. HRMS and cytotoxicity measurements on MCF-7 breast cancer cells and some MDA-MB-231 breast cancer cells in vitro were performed by ImaGIF Ciblothèque Cellulaire (Institut de Chimie des Substances Naturelles).

N 1 -(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 solution of 6 (1 mmol, 0.56 g) in 10 mL of THF. The mixture was stirred for 10 min. The formed solid was filtered off, and an excess of sodium amide (NaNH2) was added to the filtrate. After 30 min of stirring, water (20 mL) was added slowly. Subsequently, the mixture was extracted with AcOEt, the organic layer was dried over MgSO4, and solvents were evaporated under reduced pressure. The crude product was separated by silica gel column chromatography using mixtures of hexane/AcOEt. A 0.20 g (36%) amount of 6a was obtained as a yellow solid. 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, 9.93 for 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−H stretch), 3093 (aromatic C−H stretch), 2927, 2854 (alkyl C−H stretch), 1662 (NCO stretch), 1597 (aromatic CC stretch), 1519 (N−H bend). MS (CI, m/z): 578 [MNH4]+, 561 [MH]+, 406 [MHC8H13NO2]+. HRMS (TOF MS ES+, C34H36FeN2O2: [M]+): calcd 560.2126, 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)amino8-oxooctanoic Acid (5). A solution of 5 (2.47 mmol, 1.0 g) in 50 mL of THF was slowly added in 20 min at room temperature to a stirred solution 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 aqueous solution of potassium hydroxide (KOH), then acidified with hydrochloric acid (HCl) and extracted with ethyl acetate (AcOEt). The organic layer was dried with magnesium sulfate (MgSO4) and then filtered. Solvents were evaporated under reduced pressure, and the crude product was separated by silica gel chromatography using a hexane/AcOEt (60:40) mixture. The first fraction was the nonreacted starting product 5, the second fraction was the bisamide 7 obtained as a 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),

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


Organometallics

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2.37 (m, 2H: a), 2.56−2.67 (m, 2H: b), 3.56 (s, 3H: v), 3.95 (t, J = 1.8 Hz, 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 for E 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 (OCO stretch), 1662 (NCO stretch), 1597 (aromatic CC 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, found 575.2130. HPLC (tR): 4.38 min. Rf (AcOEt): 0.90. IC50 Determination. The breast adenocarcinoma cell lines MDAMB-231 and MCF7 were obtained respectively from ATCC and Dr. Matthias Kassack (Bonn, Germany). Cells were grown in RPMI medium supplemented with 10% fetal calf serum, in the presence of penicillin, streptomycin, and fungizone in a 75 cm3 flask under 5% CO2. Cells were plated in 96-well tissue culture plates in 200 μL of medium and treated 24 h later with 2 μL of a stock solution of compounds 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) was added and incubated for 3 h at 37 °C; the absorbance was monitored at 490 nm and the results are expressed as the inhibition of cell proliferation calculated as the ratio [(1 − (OD490 treated/OD490 control) × 100] in triplicate experiments. For IC50 determination [50% inhibition of cell proliferation], cells were incubated for 72 h following the same protocol with compound concentrations ranging from 5 nM to 100 μM in separate duplicate experiments. Electrochemistry. Cyclic voltammograms (CVs) were obtained using a three-electrode cell with a 0.5 mm Pt working electrode, stainless steel rod counter electrode, and Ag/AgCl/LiCl in ethanol reference electrode, with a μ-Autolab 3 potentiostat driven by General Purpose Electrochemical System (GPES) version 4.8, EcoChemie B.V., Utrecht, The Netherlands. Solutions consisted of 5 mL of MeOH, analyte (approximately 0.5 mM), and Bu4NBF4 (0.1 M) as the supporting electrolyte. After the CV was obtained in MeOH, 50 equivalents of imidazole was added to the cell containing the analyte, and after homogenization a new CV was recorded.

solution of NH2OH in MeOH. The resulting mixture was stirred at room temperature for 15 min and then poured into water, acidified with HCl, and extracted with AcOEt. The organic layer was dried over MgSO4 and evaporated. The crude product was separated on a silica gel column using a mixture of hexane and AcOEt as eluent. The first fraction was the ester 8 obtained as a byproduct, and the last fraction was the desired product 6b. An 0.18 g (31%) yield of 6b was obtained as 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 = 1.8 Hz, 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 E isomer), 9.76 (s, 1H: m, 9.93 for E isomer), 10.33 (s, 1H: x). 13C NMR (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 (NCO stretch), 1597 (aromatic CC stretch), 1520 (N−H bend). MS (ESI, m/z): 575 [M − H]− and 599 [MNa]+. Anal. Calcd for C34H36FeN2O3·1/2C4H8O2 (%): 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). 13 C 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 (NCO stretch), 1593 (aromatic CC stretch), 1520 (N−H bend). MS (CI, m/z, %): 966 [MNH4]+, 949 [MH]+, (ESI, m/z, %): 971 [MNa]+, 948 [M]+. HRMS (TOF MS ES+, C60H56Fe2N2O2: [M]+): calcd 948.3041, found 948.3029. HPLC (tR) 7.65 min. Rf (AcOEt): 0.92.

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ASSOCIATED CONTENT

S Supporting Information *

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AUTHOR INFORMATION

Corresponding Author

*(S. Top) Tel: 33-1 44 27 66 99. Fax: 33-1 43 26 00 61. E-mail: [email protected]. (G. Jaouen) Tel: 33-1 43 26 95 55. Fax: 33-1 43 26 00 61. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Agence Nationale de la Recherche for financial support (ANR 2010 BILAN 7061 blanc “Mecaferrol”) and the National Council of Science and Technology of Mexico (CONACyT) for the Ph.D. scholarship of J.J.C.M. This work has benefited from the facilities and expertise of the Small Molecule Mass Spectrometry platform of IMAGIF (Centre de Recherche de Gif, www.imagif.cnrs.fr).

Methyl 8-(4-{[3]Ferrocenophan-1-ylidene(phenyl)methyl}phenyl)amino-8-oxooctanoate (7). 7 is a byproduct of the synthesis of 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− H


Organometallics

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Tanaka, N. Bull. Chem. Soc. Jpn. 1981, 54, 3723−3726. (c) Liptau, P.; Seki, T.; Kehr, G.; Abele, A.; Froehlich, R.; Erker, G.; Grimme, S. Organometallics 2003, 22, 2226−2232. (15) (a) Plazuk, D.; Vessieres, A.; Hillard, E. A.; Buriez, O.; Labbe, E.; Pigeon, P.; Plamont, M. A.; Amatore, C.; Zakrzewski, J.; Jaouen, G. J. Med. Chem. 2009, 52, 4964−4967. (b) Görmen, M.; Pigeon, P.; Top, S.; Vessières, A.; Plamont, M. A.; Hillard, E. A.; Jaouen, G. Med. Chem. Commun. 2010, 1, 149−151. (c) Görmen, M.; Plazuk, D.; Pigeon, P.; Hillard, E. A.; Plamont, M. A.; Top, S.; Vessières, A.; Jaouen, G. Tetrahedron Lett. 2010, 51, 118−120. (d) Görmen, M.; Pigeon, P.; Top, S.; Hillard, E. A.; Huché, M.; Hartinger, C. G.; de Montigny, F.; Plamont, M. A.; Vessières, A.; Jaouen, G. ChemMedChem 2010, 5, 2039−2050. (e) Cabral de Oliveira, A.; Hillard, E. A.; Pigeon, P.; Damasceno Rocha, D.; Rodriguez, F. A. R.; Montenegro, R. C.; CostaLotufo, L. V.; Goulart, M. O. F.; Jaouen, G. Eur. J. Med. Chem. 2011, 46, 3778−3787. (f) Pigeon, P.; Top, S.; Vessières, A.; Huché, M.; Görmen, M.; El Arbi, M.; Plamont, M. A.; McGlinchey, M. J.; Jaouen, G. New J. Chem. 2011, 35, 2212−2218. (16) Cázares-Marinero, J. J.; Lapierre M.; Cavaillès, V.; Saint-Fort, R.; Vessières, A.; Top, S.; Jaouen, G. Submitted. (17) Marks, P. A.; Breslow, R. Nat. Biotechnol. 2007, 25, 84−90. (18) Macip, S.; Igarashi, M.; Berggren, P.; Yu, J.; Lee, S. W.; Aaronson, S. A. Mol. Cell. Biol. 2003, 23, 8576−8585. (19) Qiu, X.; Forman, H. J.; Schönthal, A. H.; Cardenas, E. J. Biol. Chem. 1996, 271, 31915−31921. (20) Hagen, H.; Marzenell, P.; Jentzsch, E.; Wenz, F.; Weldwij, M. R.; Mokhir, A. J. Med. Chem. 2012, 55, 924−934. (21) (a) Hillard, E. A.; Vessières, A.; Thouin, L.; Jaouen, G.; Amatore, C. Angew. Chem., Int. Ed. 2006, 45, 285−290. (b) Hamels, D.; Dansette, P. M.; Hillard, E. A.; Top, S.; Vessières, A.; Herson, P.; Jaouen, G.; Mansuy, D. Angew. Chem., Int. Ed. 2009, 48, 9124−9126. (c) Pigeon, P.; Top, S.; Zekri, O.; Hillard, E. A.; Vessières, A.; Plamont, M. A.; Buriez, O.; Labbe, E.; Huché, M.; Boutamine, S.; Amatore, C.; Jaouen, G. J. Organomet. Chem. 2009, 694, 895−901. (22) Wlassoff, W. A.; Albright, C. D.; Sivanshinki, M. S.; Ivanova, A.; Appelbaum, J. G.; Salganik, R. I. J. Pharm. Pharmacol. 2007, 59, 1549− 1553. (23) Griffith, D. M.; Szöcs, B.; Keogh, T.; Suponitsky, K. Y.; Farkas, E.; Buglyó, P.; Marmion, C. J. J. Inorg. Biochem. 2011, 105, 763−769. (24) Griffith, D.; Parker, J. P.; Marmion, C. J. Anti-cancer Agents Med. Chem. 2010, 10, 354−370. (25) (a) Turbitt, T. D.; Watts, W. E. J. Organomet. Chem. 1972, 46, 109−117. (b) Dogan, O.; Senol, V.; Zeytinci, S.; Koyuncu, H.; Bulut, A. J. Organomet. Chem. 2005, 690, 430−434. (26) Vessières, A.; Top, S.; Pigeon, P.; Hillard, E.; Boubeker, L.; Spera, D.; Jaouen, G. J. Med. Chem. 2005, 48, 3937−3940. (27) (a) Buriez, O.; Heldt, J. M.; Labbé, E.; Vessières, A.; Jaouen, G.; Amatore, C. Chem.Eur. J. 2008, 14, 8195−8203. (b) Tan, Y. L. K.; Pigeon, P.; Top, S.; Labbé, E.; Buriez, O.; Hillard, E. A.; Vessières, A.; Amatore, C.; Leonge, W. K.; Jaouen, G. Dalton Trans. 2012, 41, 7537− 7549. (28) Cázares-Marinero, J. J.; Labbé, E.; Top, S.; Buriez, O.; Amatore, C.; Jaouen, G. J. Organomet. Chem. 2013, http://dx.doi.org/10.1016/j. jorganchem.2013.05.047. (29) (a) Buriez, O.; Labbé, E.; Pigeon, P.; Jaouen, G.; Amatore, G. J. Electroanal. Chem. 2008, 619−620, 169−175. (b) Buriez, O.; Podvorica, F. I.; Galtayries, A.; Labbé, E.; Top, S.; Vessières, A.; Jaouen, G.; Combellas, C.; Amatore, C. J. Electroanal. Chem. 2013, 699, 21−27. (30) Messina, P.; Labbé, E.; Buriez, O.; Hillard, E. A.; Vessières, A.; Hamels, D.; Top, S.; Jaouen, G.; Frapart, Y. M.; Mansuy, D.; Amatore, C. Chem.Eur. J. 2012, 18, 6581−6587.

REFERENCES

(1) (a) Medicinal Organometallic Chemistry; Jaouen, G., MetzlerNolte, N., Eds.; Springer: Berlin, 2010; Topics in Organometallic Chemistry 32. (b) Hartinger, C. G.; Dyson, P. J. Chem. Soc. Rev. 2009, 38, 391−401. (c) Gasser, G.; Ott, I.; Metzler-Nolte, N. J. Med. Chem. 2011, 54, 3−25. (d) Hillard, E. A.; Jaouen, G. Organometallics 2011, 30, 20−27. (e) Hartinger, C. G.; Metzler-Nolte, N.; Dyson, P. J. Organometallics 2012, 31, 5677−5685. (2) (a) Metzler-Nolte, N.; Salmain, M. In Ferrocenes Ligands Materials and Biomolecules; Štěpnička, P., Ed.; Wiley, 2008; pp 499−639. (b) Fouda, M. F. R.; Abd-Elzaher, M. A.; Abdelsamaia, R. A.; Labib, A. A. Appl. Organomet. Chem. 2007, 21, 613−625. (3) Yeary, R. A. Toxicol. Appl. Pharmacol. 1969, 15, 666−676. (4) (a) Köpf-Maier, P.; Köpf, H.; Neuse, E. W. Angew. Chem., Int. Ed. Engl. 1984, 23, 456−447. (b) Köpf-Maier, P.; Köpf, H.; Neuse, E. W. J. Cancer Res. Clin. Oncol. 1984, 108, 336−340. (c) Köpf-Maier, P.; Köpf, H. Struct. Bonding (Berlin) 1988, 70, 103−185. (5) (a) Motohashi, N.; Meyer, R.; Gollapudi, S. R.; Bhattiprolu, K. R. J. Organomet. Chem. 1990, 398, 205−217. (b) Houlton, A.; Roberts, R. M. G.; Silver, G. J. Organomet. Chem. 1991, 418, 107−112. (c) Kovavic, P.; Popp, W. J.; Ames, J. R.; Ryan, M. D. Anti-Cancer Drug Des. 1988, 3, 205−216. (d) Ferle-Vidovic, A.; Poljak-Blazi, M.; Rapic, V.; Skare, D. Cancer Biother. Radiopharm. 2000, 15, 617−624. (e) James, P.; Neudörfl, J.; Eissmann, M.; Jesse, P.; Prokop, A.; Schmalz, H. G. Org. Lett. 2006, 8, 2763−2766. (f) Spencer, J.; Amin, J.; Wang, M.; Packham, G.; Syed Alwi, S. S.; Tizzard, G. J.; Coles, S. J.; Paranal, R. M.; Bradner, J. E.; Heightman, T. D. ACS Med. Chem. Lett. 2011, 2, 358−362. (g) Spencer, J.; Amin, J.; Boddiboyena, R.; Packham, G.; Cavell, B. E.; Syed Alwi, S. S.; Paranal, R. M.; Heightman, T. D.; Wang, M.; Marsden, B.; Coxhead, P.; Guille, M.; Tizzard, G. J.; Coles, S. J.; Bradner, J. E. Med. Chem. Commun. 2012, 3, 61−64. (h) Librizzi, M.; Longo, A.; Chiarelli, R.; Amin, J.; Spencer, J.; Luparello, C. Chem. Res. Toxicol. 2012, 25, 2608−2616. (6) (a) Biot, C.; Glorian, G.; Maciejweski, L. A.; Brocard, J. S. J. Med. Chem. 1997, 40, 3715−3718. (b) Domarle, O.; Blampain, G.; Agnaniet, H.; Nzadiyabi, T.; Lebibi, J.; Brocard, J.; Maciejewski, L.; Biot, C.; Georges, J.; Millet, P. Antimicrob. Agents Chemother. 1998, 42, 540−544. (c) Biot, C.; Taramelli, D.; Forfar-Bares, I.; Maciejewski, L. A.; Boyce, M.; Nowogrocki, G.; Brocard, J. S.; Basilico, N.; Olliaro, P.; Egan, T. J. Mol. Pharmaceutics 2005, 2, 185−193. (d) Dive, D.; Biot, C. ChemMedChem 2008, 3, 383−391. (7) (a) Sato, S.; Nojima, T.; Takenaka, S. J. Organomet. Chem. 2004, 689, 4722−4728. (b) Baldoli, C.; Licandro, E.; Maiorana, S.; Resimini, D.; Rigamonti, C.; Falciola, L.; Longhi, M.; Mussini, P. R. J. Electroanal. Chem. 2005, 585, 197−205. (c) Mukumoto, K.; Ohtsuka, K.; Nojima, T.; Takenaka, S. Anal. Sci. 2006, 22, 349−335. (8) Kondapi, A. K.; Satyanarayana, N.; Saikrishna, A. D. Arch. Biochem. Biophys. 2006, 450, 123−132. (9) Monserrat, J. P.; Al-Safi, R. I.; Tiwari, K. N.; Quentin, L.; Chabot, G. G.; Vessières, A.; Jaouen, A.; Neamati, N.; Hillard, E. A. Bioorg. Med. Chem. Lett. 2011, 21, 6195−6197. (10) Top, S.; Tang, J.; Vessières, A.; Carrez, D.; Provost, C.; Jaouen, G. Chem. Commun. 1996, 8, 955−956. (11) (a) Top, S.; Vessières, A.; Leclercq, G.; Quivy, J.; Tang, J.; Vaissermann, J.; Huché, M.; Jaouen, G. Chem.Eur. J. 2003, 9, 5223− 5236. (b) Nguyen, A.; Vessieres, A.; Hillard, E. A.; Top, S.; Pigeon, P.; Jaouen, G. Chimia 2007, 61, 716−724. (12) (a) Carey, L. A.; Dees, E. C.; Sawyer, L.; Gatti, L.; Moore, D. T.; Collichio, F.; Ollila, D. W.; Sartor, C. I.; Graham, M. L.; Perou, C. M. Clin. Cancer Res. 2007, 13, 2329−2334. (b) Lehmann, B. D.; Bauer, J. A.; Chen, X.; Sanders, M. E.; Chakravarthy, A. B.; Shyr, Y.; Pietenpol, J. A. J. Clin. Invest. 2011, 121, 2750−2767. (13) (a) Tate, C. R.; Rhodes, L. V.; Segar, H. C.; Driver, J. L.; Pounder, F. N.; Burrow, M. E.; Collins-Burrow, B. M. Breast Cancer Res. 2012, 14, R79. (b) Jemal, A.; Bray, F.; Center, M. M.; Ferlay, J.; Ward, E.; Forman, D. CA: Cancer J. Clin. 2011, 61, 69−90. (14) (a) Park, J. S.; Lee, T. R. In Modern Cyclophane Chemistry; Gleiter, R., Hopf, H., Eds.; Wiley, 2004; pp 131−157. (b) Ogata, T.; Oikawa, K.; Fujisawa, T.; Motoyama, S.; Izumi, T.; Kasahara, A.;

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NOTE ADDED AFTER ASAP PUBLICATION This paper was published on the Web on July 29, 2013, with an error in the Abstract and Table of Contents graphics. The corrected version was reposted on August 2, 2013.

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