Organometallic diphenols: The importance of the organometallic moiety on the expression of a cytotoxic effect on breast cancer cells

Hillard, Elizabeth A.; Vessières, Anne; Top, Siden; Pigeon, Pascal; Kowalski, Konrad; Huché, Michel; Jaouen, Gérard

doi:10.1016/j.jorganchem.2006.10.041

Cited by 69 publications

(55 citation statements)

References 41 publications

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“…The organometallic conjugate 1, in which a [(Cp)Re(CO) 3 ] unit is linked to a hydroxytamoxifen-like structure (Figure 2), [24] is robust in biological media and shows intense CO bands; it has been selected to study cellular uptake and distribution in breast cancer cells (MDA-MB-231) using both transmission-IR spectroscopy for quantification and PTIR spectroscopy for localization and imaging. Organometallic compounds such as 1 are known to be lipophilic, [25,26] thus ensuring good intracellular penetration.…”

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“…Organometallic compounds such as 1 are known to be lipophilic, [25,26] thus ensuring good intracellular penetration. [24] In addition, 1 has been described to interact with estrogen receptors, thus inducing the proliferation of hormone-dependent breast cancer cells. [24] Figure 1. a) Schematic view of the PTIR setup showing the ZnSe prism and the cantilever of the AFM probing the sample.…”

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“…[24] In addition, 1 has been described to interact with estrogen receptors, thus inducing the proliferation of hormone-dependent breast cancer cells. [24] Figure 1. a) Schematic view of the PTIR setup showing the ZnSe prism and the cantilever of the AFM probing the sample. b) Laser pulse.…”

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“…The cells were incubated for 1 hour with solutions of 1 at concentrations in the micromolar range typically used for such biological studies (5 mm, 10 mm, and 50 mm). [24] After treatment (see the Supporting Information), a known number of cells were deposited on a nitrocellulose disk, which is IRtransparent in the region 1800-2500 cm À1 . Very clear signals corresponding to compound 1, with a slight shift of the n antisym band to 1925 cm À1 , [7] were observed in the classical transmission FTIR spectrum (Figure 2 …”

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Subcellular IR Imaging of a Metal–Carbonyl Moiety Using Photothermally Induced Resonance

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Subcellular IR Imaging of a Metal–Carbonyl Moiety Using Photothermally Induced Resonance

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“…It should be noted that other organometallic substituents, such as [Re(CO) 3 (Cp)], [Mn(CO) 3 (Cp)], and [Ru(Cp) 2 ], did not lend cytotoxic properties to the OH À Tam scaffold [35] or phenolic skeleton. [36] Recognizing the sensitive nature of the side chain on antiestrogenicity, and the cytotoxicity of some ferrocenyl compounds, we have recently studied the new ferrocenyl triphenylethylene 5, which showed promising in vitro results against both ER + and ERÀ breast cancer cells. [37,38] In designing this compound, we chose to functionalize the ferrocenyl group with a ketone, which has been shown to pro-mote double metal-ligand exchange reactions to yield other organometallic compounds, such as those containing 188 Re, 186 Re, or 99m Tc.…”

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Synthesis and Structure–Activity Relationships of Ferrocenyl Tamoxifen Derivatives with Modified Side Chains

Nguyen

Top

Pigeon

et al. 2008

Chemistry A European J

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We report here the synthesis and cell-proliferation properties of derivatives of the breast cancer drug tamoxifen, in which the -O(CH(2))(2)N(CH(3))(2) side chain, responsible for the drug's antiestrogenic properties, has been modified by a ferrocenyl moiety. We recently reported the diphenol compound 5, in which this amino chain had been replaced with an acyl-ferrocenyl (-O(CH(2))(2)C(O)[(eta(5)-C(5)H(4))FeCp]) group, and which showed antiproliferative effects against both the hormone-dependent MCF-7 and -independent MDA-MB-231 breast cancer cell lines. We now report the results of a structure-activity relationship (SAR) study, in which the lateral chain length has been varied, the ketone group has been omitted, and the number of phenol groups has been varied. Compounds 1-4, with a side chain lacking the carbonyl function (-O(CH(2))(n)[(eta(5)-C(5)H(4))FeCp], n = 1-4) and which show a decreasing affinity for ERalpha (ER = estrogen receptor) with increasing chain length, act as estrogens on MCF-7 cells, and mild cytotoxics on PC-3 prostate cancer cells, with IC(50) values around 10 microM. The two monophenolic derivatives of 2, 2 a and 2 b, which show a reduced affinity for ERalpha compared to 2, are also estrogenic, but are only slightly cytotoxic. Finally, we have reexamined compound 5 and discovered that its antiproliferative effect against the MCF-7 cell line does not arise from antiestrogenicity as we had originally suspected, but by means of a cytotoxic pathway. This compound is also sensitive to the number of phenol groups as cell death is diminished when one of the hydroxyl groups is omitted (5 a and 5 b). Molecular modeling studies of the ligand-ERalpha binding stability are broadly consistent with the experimental binding affinity results for compounds 2, 2 a, 2 b, 5, 5 a, and 5 b. Electrochemical experiments show that 1-4, 2 a, and 2 b are stable to oxidation on the electrochemical timescale, unlike 5, 5 a, and 5 b, and that cytotoxicity is related to less positive phenol oxidation potentials. The SAR study shows that the presence of a ketone group and two phenol groups is necessary for strong receptor binding and cytotoxic effects, and that all compounds are estrogenic, despite the presence of a bulky side chain.

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The McMurry Coupling and Related Reactions

Takeda

Tsubouchi

2013

Organic Reactions

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The McMurry coupling reaction has been recognized as one of the most efficient methods for the synthesis of alkenes from carbonyl compounds. This reaction can be applied to the preparation of various alkenes that are otherwise difficult to prepare. For example, sterically congested tetrasubstituted alkenes as well as medium to large membered rings involving natural products may be accessed via this process. This coupling utilizes various low‐valent titanium reagents generated by the reduction of titanium (III or IV) chloride with K, Zn, LiAlH 4 , C 8 K, amongst others. Furthermore, a variety of low‐valent metal species other than titanium, including aluminum, zirconium, niobium, molybdenum, indium, tungsten, and samarium, have also been found to promote the reductive coupling of carbonyl compounds. The scope and limitations of these reagent systems are reviewed in this chapter, together with the stereochemistry and reaction mechanism. This reaction is categorized into four coupling modes: i) homocoupling giving symmetrical alkenes, ii) mixed coupling giving unsymmetrical alkenes, iii) intramolecular coupling giving cycloalkenes, and iv) tandem coupling giving cyclic polyenes. Characteristics of these reaction modes are described briefly. A selection of synthetic applications are reviewed, including examples of the preparation of sterically congested and strained alkenes, medium to large‐ring compounds, biologically active targets, as well as substrates applicable in material science. Experimental conditions used for this versatile process are summarized to assist the choice of suitable conditions.

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Organometallic diphenols: The importance of the organometallic moiety on the expression of a cytotoxic effect on breast cancer cells

Cited by 69 publications

References 41 publications

Subcellular IR Imaging of a Metal–Carbonyl Moiety Using Photothermally Induced Resonance

Subcellular IR Imaging of a Metal–Carbonyl Moiety Using Photothermally Induced Resonance

Synthesis and Structure–Activity Relationships of Ferrocenyl Tamoxifen Derivatives with Modified Side Chains

The McMurry Coupling and Related Reactions

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