Synthesis, Characterization, and Antiproliferative Activities of Novel Ferrocenophanic Suberamides against Human Triple-Negative MDA-MB-231 and Hormone-Dependent MCF‑7 Breast Cancer Cells

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 hormone-dependent 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

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

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

Evidence for Targeting Thioredoxin Reductases with Ferrocenyl Quinone Methides. A Possible Molecular Basis for the Antiproliferative Effect of Hydroxyferrocifens on Cancer Cells

Many anticancer compounds are strong inhibitors of thioredoxin reductases (TrxRs), selenoenzymes involved in cellular redox regulation. This study examined the effect of two hydroxyferrocifens (<b>1</b>, FcOH; <b>2</b>, FcOHTAM) and of their corresponding quinone methides (QMs), <b>1</b>-<b>QM</b>, and <b>2</b>-<b>QM</b>, on these enzymes. In vitro, both QMs were more potent TrxR inhibitors (IC₅₀ ≈ 2.5 μM) than the hydroxyferrocifens (IC₅₀ ≈ 15 μM). This inhibition was due to a Michael addition of the penultimate selenocysteine residue of TrxRs to the QMs. In Jurkat cancer cells, both <b>2</b> and <b>2</b>-<b>QM</b> inhibited TrxRs in the same proportion, leading to accumulation of oxidized forms of thioredoxin, while <b>1</b> and <b>1</b>-<b>QM</b> were scarcely effective. This difference of behavior was ascribed to the competitive conversion of <b>1</b>-<b>QM</b> to an inactive indene in protic medium. This set of experiments confirms for the first time the role played by ferrocenyl quinone methides on several biological targets and gives a molecular basis for these effects. It also highlights differences in the mechanisms of action of <b>1</b> and <b>2</b> in cancer cells

Evidence for Targeting Thioredoxin Reductases with Ferrocenyl Quinone Methides. A Possible Molecular Basis for the Antiproliferative Effect of Hydroxyferrocifens on Cancer Cells

Many anticancer compounds are strong inhibitors of thioredoxin reductases (TrxRs), selenoenzymes involved in cellular redox regulation. This study examined the effect of two hydroxyferrocifens (<b>1</b>, FcOH; <b>2</b>, FcOHTAM) and of their corresponding quinone methides (QMs), <b>1</b>-<b>QM</b>, and <b>2</b>-<b>QM</b>, on these enzymes. In vitro, both QMs were more potent TrxR inhibitors (IC₅₀ ≈ 2.5 μM) than the hydroxyferrocifens (IC₅₀ ≈ 15 μM). This inhibition was due to a Michael addition of the penultimate selenocysteine residue of TrxRs to the QMs. In Jurkat cancer cells, both <b>2</b> and <b>2</b>-<b>QM</b> inhibited TrxRs in the same proportion, leading to accumulation of oxidized forms of thioredoxin, while <b>1</b> and <b>1</b>-<b>QM</b> were scarcely effective. This difference of behavior was ascribed to the competitive conversion of <b>1</b>-<b>QM</b> to an inactive indene in protic medium. This set of experiments confirms for the first time the role played by ferrocenyl quinone methides on several biological targets and gives a molecular basis for these effects. It also highlights differences in the mechanisms of action of <b>1</b> and <b>2</b> in cancer cells

Synthesis and Antiproliferative Effects of [3]Ferrocenophane Transposition Products and Pinacols Obtained from McMurry Cross-Coupling Reactions

We here report the synthesis and antiproliferative activities of two new series of ferrocenophanes obtained from McMurry cross-coupling reactions of [3]­ferrocenophan-1-one with benzophenone, 4-hydroxybenzophenone, 4,4′-dihydroxybenzophenone, and 4,4′-diacetylaminobenzophenone. In addition to the main formation of olefins at reflux, tetrahedral transposition products, resulting from a pinacolic rearrangement, were also isolated in about 10% yields. Lowering the temperature of the reaction to 0 °C allowed the isolation of pinacols, which could be transformed into transposition compounds in good yields. Three ferrocenophane compounds have been characterized by X-ray crystallography: 1-(<i>p</i>-hydroxyphenyl)-1-phenyl-2-oxo­[4]­ferrocenophane (<b>7b</b>), 1,1-diphenyl-2-oxo[4]­ferrocenophane (<b>7c</b>), and 1-hydroxy-1-[1-hydroxy-1-[3]­ferrocenophanyl][3]­ferrocenophane (<b>12</b>) crystallize in monoclinic <i>P</i>2₁/<i>n</i>, triclinic <i>P</i>1̅, and monoclinic <i>P</i>2₁/<i>c</i> space groups, respectively. The antiproliferative effects on hormone-independent breast cancer cells (MDA-MB-231) of the transposition compounds are generally lower than those of their corresponding butene analogues (IC₅₀ values in micromolar versus nanomolar range). In contrast and quite surprisingly, the pinacol complexes are significantly cytotoxic (IC₅₀ in the nanomolar range), among the most cytotoxic ferrocene compounds prepared so far. This antiproliferative activity may be linked to their oxidative cleavage

Oxidation of Cymantrene Analogues of Ferrocifen: Electrochemical, Spectroscopic, and Computational Studies of the Parent Complex 1,1′-Diphenyl-2-cymantrenylbutene

The oxidative electrochemical behavior of 1,1′-diphenyl-2-cymantrenylbutene (<b>1</b>), a cymantrene analogue of the breast cancer drug ferrocifen, was shown to involve the sequential electron-transfer series <b>1</b>/<b>1</b>⁺/<b>1</b>²⁺ in dichloromethane/0.05 M [NBu₄]­[B­(C₆F₅)₄] (<i>E</i>_1/2 values 0.78 and 1.18 V vs ferrocene). By a combination of spectroscopic and computational techniques, it was shown that the cymantrene functionality plays an important role in dissipating the positive charges in the oxidized compounds and is therefore an active participant in the redox events. The redox-active orbital goes from roughly equal degrees of organometallic and π-organic (diphenylolefin) makeup in <b>1</b> to increasingly organic based fractions in <b>1</b>⁺ and <b>1</b>²⁺. Structural changes mimicking those of oxidized tetrakis­(aryl)­ethylenes accompany the one-electron oxidations. There is sufficient unpaired electron density on the manganese center in <b>1</b>⁺ to allow for oxidatively induced ligand exchange of one or more of the carbonyl ligands with donor ligands, including phosphites and pyridine. The complex Mn­(CO)₂P­(OPh)₃(η⁵-C₅H₄(Et)­CC­(C₆H₅)₂) was prepared by the “electrochemical switch” method, wherein [Mn­(CO)₂P­(OPh)₃(η⁵-C₅H₄(Et)­CC­(C₆H₅)₂)]⁺, produced by the oxidation of <b>1</b> in the presence of P­(OPh)₃, was reduced back to the neutral CO-substituted complex

Synthesis and Antiproliferative Effects of [3]Ferrocenophane Transposition Products and Pinacols Obtained from McMurry Cross-Coupling Reactions

We here report the synthesis and antiproliferative activities of two new series of ferrocenophanes obtained from McMurry cross-coupling reactions of [3]­ferrocenophan-1-one with benzophenone, 4-hydroxybenzophenone, 4,4′-dihydroxybenzophenone, and 4,4′-diacetylaminobenzophenone. In addition to the main formation of olefins at reflux, tetrahedral transposition products, resulting from a pinacolic rearrangement, were also isolated in about 10% yields. Lowering the temperature of the reaction to 0 °C allowed the isolation of pinacols, which could be transformed into transposition compounds in good yields. Three ferrocenophane compounds have been characterized by X-ray crystallography: 1-(<i>p</i>-hydroxyphenyl)-1-phenyl-2-oxo­[4]­ferrocenophane (<b>7b</b>), 1,1-diphenyl-2-oxo[4]­ferrocenophane (<b>7c</b>), and 1-hydroxy-1-[1-hydroxy-1-[3]­ferrocenophanyl][3]­ferrocenophane (<b>12</b>) crystallize in monoclinic <i>P</i>2₁/<i>n</i>, triclinic <i>P</i>1̅, and monoclinic <i>P</i>2₁/<i>c</i> space groups, respectively. The antiproliferative effects on hormone-independent breast cancer cells (MDA-MB-231) of the transposition compounds are generally lower than those of their corresponding butene analogues (IC₅₀ values in micromolar versus nanomolar range). In contrast and quite surprisingly, the pinacol complexes are significantly cytotoxic (IC₅₀ in the nanomolar range), among the most cytotoxic ferrocene compounds prepared so far. This antiproliferative activity may be linked to their oxidative cleavage