Organometallic Anticancer Compounds

Gasser, Gilles; Ott, Ingo; Metzler‐Nolte, Nils

doi:10.1021/jm100020w

Cited by 1,497 publications

(1,045 citation statements)

References 239 publications

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“…S10 †). Additionally, the resonances of the protein became gradually broadened, indicating an ongoing reaction or an interaction with the metallaprism [2] 6+ . On the other hand, in the presence of [3] 6+ , Mb precipitated almost completely while the signals of the metallaprism remained sharp and well resolved (Fig.…”

Section: Nmr and Ms Investigations Of The Interaction Between Metallamentioning

confidence: 99%

“…Ub was therefore anticipated to react with the metallaprisms, since it was previously shown that metallaprisms rapidly react with lysine. [33][34][35] The only changes observed in the NMR spectra can be ascribed to the disappearance of the signals associated to the metallaprism [1] 6+ , and to a lesser extent to a reduction of the intensity of the signals of metallaprisms [2] 6+ . However, for metallaprism [3] 6+ , additional signals in the aromatic region of the p-cymene protons (5-6 ppm) are observed, together with the signals of the p-cymene ligands of the intact metallaprism.…”

Section: Nmr and Ms Investigations Of The Interaction Between Metallamentioning

confidence: 99%

“…This approach resulted in rather unselective compounds that often exhibit significant side effects. 2 It is now well accepted that one should not focus on DNA when developing new metal-based drugs. Indeed, current research aims at developing new compounds with new biological targets.…”

Section: Introductionmentioning

confidence: 99%

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Interactions of arene ruthenium metallaprisms with human proteins

2015

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Interactions between three hexacationic arene ruthenium metallaprisms, [( p-cymene) 6+ , and a series of human proteins including human serum albumin, transferrin, cytochrome c, myoglobin and ubiquitin have been studied using NMR spectroscopy, mass spectrometry and circular dichroism spectroscopy. All data suggest that no covalent adducts are formed between the proteins and the metallaprisms. Indeed, in most cases electrostatic interactions, leading to precipitation of protein-metallaprism aggregates, have been observed. In addition, with the smallest proteins, ubiquitin, myoglobin and cytochrome c, the presence of the hexacationic arene ruthenium metallaprisms induces structural changes of the proteins, as emphasized by circular dichroism. The results suggest that proteins are certainly a biological target for these metalla-assemblies.

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Section: Nmr and Ms Investigations Of The Interaction Between Metallamentioning

confidence: 99%

Section: Nmr and Ms Investigations Of The Interaction Between Metallamentioning

confidence: 99%

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Interactions of arene ruthenium metallaprisms with human proteins

2015

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“…[1][2][3][4][5] Among them, ruthenium(II) complexes bearing a π-bonded arene ligand are particularly interesting since they have shown promising anticancer activities, [6][7][8] even in cells that had become resistant to cisplatin, such as Sadler's compounds containing N,N-chelating ligands. 1,9,10 In addition, some of the Dyson's RAPTA compounds containing pta ligand have shown antimetastatic activity.…”

Section: Introductionmentioning

confidence: 99%

“…30 In fact, recent studies have revealed that DNA is not always the primary target for some ruthenium anticancer compounds and that they actually bind more strongly to proteins or enzymes than to DNA. 4,31 Hence, it seems important not only to develop efficient targeting strategies to deliver metallodrugs selectively into cancer cells, but also to direct them towards a particular biological target.…”

Section: Introductionmentioning

confidence: 99%

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

et al. 2013

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&These two authors contributed equally to this work. ABSTRACTA straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino-and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η 6 -p-cym)RuCl(PPh 3 ) 2 ] + , allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N'-di-Boc-N"-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semi-preparative HPLC and characterized by ESI and MALDI-TOF MS and NMR spectroscopy. The cytotoxicity of the compounds was tested in and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, neomycin-ruthenium conjugate (2) displayed moderate anti-proliferative activity in both cancer cell lines (IC 50 ≈ 80 µM), whereas that of the neamine conjugate (4) was inactive (IC 50 ≈ 200 µM).However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC 50 = 7.17 µM in DU-145 and IC 50 = 11.33 µM in MCF-7). Although the same ranking in anti-proliferative activity was found in the non-tumorigenic cell line (3 >> 2 > 4), IC 50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g. IC 50 = 49.4 µM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC 50 = 12.75 µM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher anti-proliferative activity of 3.Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular 3 accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

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