Modification of the Estrogenic Properties of Diphenols by the Incorporation of Ferrocene. Generation of Antiproliferative Effects in Vitro

Vessières, Anne; Top, Siden; Pigeon, Pascal; Hillard, Elizabeth A.; Boubeker, Leila; Spera, Daniela; Jaouen, Gérard

doi:10.1021/jm050251o

Cited by 202 publications

(166 citation statements)

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“…[2][3][4][5][6][7][8][9][10][11][12] We have shown that some ferrocene derivatives are very active against cancer cells. The addition of a ferrocenyl moiety to selected polyaromatic phenols, [13][14][15][16] amines, 17,18 amides, 19 and esters 19,20 can potentiate their antiproliferative effects against breast and prostate cancer cells. For example, 4-hydroxytamoxifen, the active metabolite of the breast cancer drug tamoxifen, 21 shows limited cytotoxicity against hormone-refractory breast cancer cells (LC 50 for MDA-MB-231 cells:…”

Section: Introductionmentioning

confidence: 99%

Oxidative Metabolism of Ferrocene Analogues of Tamoxifen: Characterization and Antiproliferative Activities of the Metabolites

et al. 2015

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Keywords: breast cancer, ferrocifen, indene metabolites, P450-dependent oxidation, quinone methides Ferrociphenols have been found to have high antiproliferative activity against estrogenindependent breast cancer cells. The rat and human liver microsome-mediated metabolism of three compounds of the ferrocifen (FC) family, 1,1-bis(4-hydroxy-phenyl)-2-ferrocenylbut-1-ene (FC1), 1-(4-hydroxyphenyl)-1-(phenyl)-2-ferrocenyl-but-1-ene (FC2), and 1-[4-(3-dimethylaminopropoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC3), was studied.Three main metabolite classes were identified: quinone methides (QMs) deriving from twoelectron oxidation of FCs, cyclic indene products (CPs) deriving from acid-catalyzed cyclization of QMs, and allylic alcohols (AAs) deriving from hydroxylation of FCs. These metabolites are generated by cytochromes P450 (P450s), as shown by experiments with either N-benzylimidazole as a P450 inhibitor or recombinant human P450s. Such P450-dependent oxidation of the phenol function and hydroxylation of the allylic CH 2 group of FCs leads to the formation of QM and AA metabolites, respectively. Some of the new ferrociphenols obtained in this study were found to exhibit remarkable antiproliferative effects toward MDA-MB-231 hormone-independent breast cancer cells.

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Section: Introductionmentioning

confidence: 99%

Oxidative Metabolism of Ferrocene Analogues of Tamoxifen: Characterization and Antiproliferative Activities of the Metabolites

et al. 2015

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“…These features provide a versatile platform for drug design that is now being exploited in several areas. For example, the redox activity of the organometallic ferrocenylphenol substitutents enhances the anticancer activity of tamoxifen derivatives by conferring an ability to generate reactive oxygen species in cells (3). Here we consider the anticancer activity of ruthenium(II) arene complexes.…”

mentioning

confidence: 99%

Catalytic organometallic anticancer complexes

Dougan

Habtemariam

McHale

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

281

296

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Organometallic complexes offer chemistry that is not accessible to purely organic molecules and, hence, potentially new mechanisms of drug action. We show here that the presence of both an iodido ligand and a -donor/ -acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich ''piano-stool'' ruthenium arene complexes [( 6 -arene)Ru(azpy)I] ؉ (where arene ‫؍‬ p-cymene or biphenyl, and azpy ‫؍‬ N,Ndimethylphenyl-or hydroxyphenyl-azopyridine) in aqueous solution. Surprisingly, despite this inertness, these complexes are highly cytotoxic to human ovarian A2780 and human lung A549 cancer cells. Fluorescence-trapping experiments in A549 cells suggest that the cytotoxicity arises from an increase in reactive oxygen species. Redox activity of these azopyridine Ru II complexes was confirmed by electrochemical measurements. The first one-electron reduction step (half-wave potential ؊0.2 to ؊0.4 V) is assignable to reduction of the azo group of the ligand. In contrast, the unbound azopyridine ligands are not readily reduced. Intriguingly the ruthenium complex acted as a catalyst in reactions with the tripeptide glutathione (␥-L-Glu-L-Cys-Gly), a strong reducing agent present in cells at millimolar concentrations; millimolar amounts of glutathione were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations. A redox cycle involving glutathione attack on the azo bond of coordinated azopyridine is proposed. Such ligand-based redox reactions provide new concepts for the design of catalytic drugs.arenes ͉ cytotoxicity ͉ glutathione ͉ redox reactions ͉ ruthenium complexes O rganometallic complexes offer potential for the development of new materials with a wide range of applications (1, 2). Organometallic complexes can exhibit chemical reactivity not possessed by either the metal or organic ligands alone and this reactivity can be fine-tuned by subtle changes in the electronic and steric properties of the bound ligands, or by variation of the metal and its oxidation state. These features provide a versatile platform for drug design that is now being exploited in several areas. For example, the redox activity of the organometallic ferrocenylphenol substitutents enhances the anticancer activity of tamoxifen derivatives by conferring an ability to generate reactive oxygen species in cells (3). Here we consider the anticancer activity of ruthenium(II) arene complexes. Such complexes are well known as catalysts in industry, for example, for hydrogenation reactions (4). Although organometallic complexes can catalyze hydrogenation of intracellular biomolecules (5), metal-centered catalysts might be readily poisoned and be ineffective in biological media.Organometallic half-sandwich Ru II arenes of the type [( 6 -arene)Ru(YZ)(X)] ϩ where YZ is typically a chelating diamine ligand (e.g., ethylenediamine, en) and X is a halide (e.g., Cl) exhibit anticancer activity in vitro and in vivo (6, 7). As with many metal-based anticancer drugs, the primary cellula...

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“…[8] This cytotoxic effect is also observed with the diphenolic compound Fc-diOH (3). [9] We have found that the most effective compounds (IC 50 values less than 1 μM) possess, like 2 and 3, a ferrocene-ene-para-phenol entity. [10,11] The ferrocene appears to act as a stimulus for a mild intramolecular oxidation involving the phenol group, leading to the facile production of quinone methides, the formation, structure, and electrophilic behavior of which we have established.…”

Section: Introductionmentioning

confidence: 82%

“…[3] [h] Values from ref. [9] [i] Value from ref. [4] Relative Binding Affinities for the α Form of the Estrogen Receptor (ER) and Log P o/w of the Compounds…”

Section: Study Of Thementioning

confidence: 99%

Side‐Chain Effects on the 1‐(Bis‐aryl‐methylidene)‐[3]ferrocenophane Skeleton: Antiproliferative Activity against TNBC Cancer Cells and Comparison with the Acyclic Ferrocifen Series

Görmen

Pigeon

Wang³

et al. 2016

Eur J Inorg Chem

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Abstract:As part of our ongoing study of the toxicity of compounds derived from 1,1-bis(4-hydroxyphenyl)-2-ferrocenylbut-1-ene, we have recently shown that closely analogous [3]ferrocenophane complexes have an in vitro toxicity level substantially higher than that of their ferrocene counterparts, particularly in the case of mono-and diphenol complexes. In this study we have examined whether the presence of a dimethylamino chain, analogous to the chain in hydroxytamoxifen, is capable of producing in the ferrocenophane series the same antiestrogenic effect observed for OH- Tam

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Modification of the Estrogenic Properties of Diphenols by the Incorporation of Ferrocene. Generation of Antiproliferative Effects in Vitro

Cited by 202 publications

References 26 publications

Oxidative Metabolism of Ferrocene Analogues of Tamoxifen: Characterization and Antiproliferative Activities of the Metabolites

Oxidative Metabolism of Ferrocene Analogues of Tamoxifen: Characterization and Antiproliferative Activities of the Metabolites

Catalytic organometallic anticancer complexes

Side‐Chain Effects on the 1‐(Bis‐aryl‐methylidene)‐[3]ferrocenophane Skeleton: Antiproliferative Activity against TNBC Cancer Cells and Comparison with the Acyclic Ferrocifen Series

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