Synthesis and redox properties of novel ferrocenes with redox active 2,6-di-tert-butylphenol fragments: The first example of 2,6-di-tert-butylphenoxyl radicals in ferrocene system

Meleshonkova, N. N.; Shpakovsky, D. B.; Fionov, A. V.; Dolganov, Alexander V.; Magdesieva, Tatiana V.; Милаева, Е. Р.

doi:10.1016/j.jorganchem.2007.08.013

Cited by 26 publications

(20 citation statements)

References 19 publications

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“…Other investigators have also shown a correlation between the toxicity of a tamoxifen-ferrocene conjugate and the production of ROS [16]. Ferricenium-promoted intramolecular electron transfer in phenolic systems has been recognized [17][18][19][20][21], although our work is the first application of this mechanism to oxidation-activated drug development.…”

Section: Introductionmentioning

confidence: 65%

The replacement of a phenol group by an aniline or acetanilide group enhances the cytotoxicity of 2-ferrocenyl-1,1-diphenyl-but-l-ene compounds against breast cancer cells

Pigeon

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Zekri

et al. 2009

Journal of Organometallic Chemistry

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a b s t r a c tWe have previously shown that conjugated ferrocenyl p-phenols show strong cytotoxic effects against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines, possibly via oxidative quinone methide formation. We now present a series of analogous amine and acetamide compounds: 2-ferrocenyl-1-(4-aminophenyl)-1-phenyl-but-1-ene (Z+E-2), 2-ferrocenyl-1-(4-Nacetylaminophenyl)-1-phenyl-but-1-ene (Z-3), and their corresponding organic molecules 1-(4-aminophenyl)-1,2-bis-phenyl-but-1-ene (Z+E-4) and 1-(4-N-acetamidophenyl)-1,2-bis-phenyl-but-1-ene (Z+E-5). All of the compounds have adequate relative binding affinity values for the estrogen receptor; between 2.8% and 5.7% for ERa, and between 0.18% and 15.5% for ERb, as well as exothermic ligand binding in in silico ER docking experiments. Compounds 2 and 3 show dual estrogenic/cytotoxic activity on the MCF-7 cell line; they are proliferative at low concentrations (0.1 lM) and antiproliferative at high concentrations (10 lM). On the MDA-MB-231 cell line, the ferrocenyl complexes 2 and 3 are antiproliferative with IC 50 values of 0.8 lM for 2 and 0.65 lM for 3, while the purely organic molecules 4 and 5 show no effect. Electrochemical experiments suggest that both 2 and 3 can be transformed to oxidized quinoidtype species, analogous to what had previously been observed for the ferrocene phenols.

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Section: Introductionmentioning

confidence: 65%

The replacement of a phenol group by an aniline or acetanilide group enhances the cytotoxicity of 2-ferrocenyl-1,1-diphenyl-but-l-ene compounds against breast cancer cells

Pigeon

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Zekri

et al. 2009

Journal of Organometallic Chemistry

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“…We have posited that these compounds can be activated by in situ oxidation to form a cytotoxic quinone methide (QM) species. Electrochemical experiments have suggested that this transformation can occur at low potentials, due to the role of the ferricenium cation as an intramolecular oxidant of the phenol group in basic conditions [8][9][10]. We now wish to understand how the replacement of the oxygen atom by a sulfur atom will influence the cytotoxicity of these types of molecules.…”

Section: Introductionmentioning

confidence: 99%

Ferrocenyl compounds possessing protected phenol and thiophenol groups: Synthesis, X-ray structure, and in vitro biological effects against breast cancer

Heilmann

Hillard

Plamont

et al. 2008

Journal of Organometallic Chemistry

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We have previously shown that conjugated ferrocenyl p-phenols show strong cytotoxic effects against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines, possibly via metabolic quinone methide (QM) formation. To further evaluate this proposed mechanism, we have created a series of ferrocenyl prodrugs containing methyl and acetyl-protected thio-and oxo-phenols: 2-ferrocenyl-1,1-bis(4-acetoxyphenyl)-but-1-ene (5), 2-ferrocenyl-1,1-bis(4-thioacetylphenyl)-but-1-ene (6), 2-ferrocenyl-1,1-bis(4-methoxyphenyl)-but-1-ene (7), and 2-ferrocenyl-1,1-bis(4-thiomethylphenyl)-but-1-ene (8), which might be activated by hydrolysis enzymes in situ. Only the acetoxy 5 displayed antiproliferative effects (IC 50 on MDA-MB-231 of 0.5 lM) while 6-8 act as pure estrogens (proliferative on MCF-7 and little to no effect on MDA-MB-231). The behaviour of 5 is similar to that previously found for the free phenol 2-ferrocenyl-1,1-di(4-hydroxyphenyl)-but-1-ene (2), indicating that 5 is metabolized in situ to 2, which could then undergo oxidative QM formation. The observation that the thioacetyl 6 is not cytotoxic suggests that the in situ oxidative chemistry of the putative ferrocenyl thiophenol is different from that of 2. Because p-thioquinone methides are practically unknown, the negative results for 6 further implicate the bioformation of the QM in the case of 2 and related compounds. The lack of cytotoxicity of 7 and 8 can be attributed to lack of efficient hydrolysis in situ. Estrogen receptor binding affinity studies for the compounds and the X-ray structure of 8 are also reported.

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“…Such a shape of CVA can probably be explained by the following sequence of steps: oxidation of the ferrocene fragment to ferricini um cation with subsequent intramolecular reduction of the Fe 3+ ion due to the electron transfer from the phenol fragment and elimination of proton (the first wave), re peated oxidation of Fe 2+ to Fe 3+ at more positive anode potential (the second wave), and oxidation of the phenoxy radical formed. 23 When МeCN is replaced by DMF and CH 2 Cl 2 , the shift of potential peaks to the anodic region is observed (Table 1). Such a displacement was observed for the oxidation of other substituted ferrocenes, that is ap parently due to the change of solvation energy when an other solvent is taken.…”

Section: Methodsmentioning

confidence: 97%

Electrochemical method in determination of antioxidative activity using ferrocene derivatives as examples

et al. 2011

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Electrochemical method for the evaluation of antioxidative activity of compounds based on their reaction with the stable radical, 2,2 diphenyl 1 picrylhydrazyl, was suggested with moni toring of the reaction by cyclic voltammetry (CVA). Antioxidative properties of new ferrocene derivatives Fc(L)R (where Fc is the ferrocenyl, R is the fragment of 2,6 di tert butylphenol or its aromatic analog, L is the spacer) were studied. Anodic oxidation of the compounds Fc(L)R, which contain azomethine and 2,6 di tert butylphenol moities, proceeds in three steps, that suggests a possibility of intramolecular proton coupled electron transfer process. Conjugates of ferrocene and 2,6 di tert butylphenol are efficient antioxidants.

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Synthesis and redox properties of novel ferrocenes with redox active 2,6-di-tert-butylphenol fragments: The first example of 2,6-di-tert-butylphenoxyl radicals in ferrocene system

Cited by 26 publications

References 19 publications

The replacement of a phenol group by an aniline or acetanilide group enhances the cytotoxicity of 2-ferrocenyl-1,1-diphenyl-but-l-ene compounds against breast cancer cells

The replacement of a phenol group by an aniline or acetanilide group enhances the cytotoxicity of 2-ferrocenyl-1,1-diphenyl-but-l-ene compounds against breast cancer cells

Ferrocenyl compounds possessing protected phenol and thiophenol groups: Synthesis, X-ray structure, and in vitro biological effects against breast cancer

Electrochemical method in determination of antioxidative activity using ferrocene derivatives as examples

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