Binding of a Designed Anti‐Cancer Drug to the Central Cavity of an RNA Three‐Way Junction

Phongtongpasuk, Siriporn; Paulus, Susann; Schnabl, Joachim; Sigel, Roland K. O.; Spingler, Bernhard; Hannon, Michael J.; Freisinger, Eva

doi:10.1002/ange.201305079

Cited by 24 publications

(5 citation statements)

References 32 publications

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“…The interaction of the M− and P−[Fe 2 ( L Pyim ) 3 ] 4+ helicates with DNA has been extensively examined. The complexes have been shown to bind in the major grove of duplex DNA ( Moldrheim et al, 2002 ), and at the center of three-way DNA ( Oleksi et al, 2006 ; Cerasino et al, 2007 ; Malina et al, 2007 ; Cardo et al, 2011 ) and RNA ( Phongtongpasuk et al, 2013 ) junctions (3WJ). More recently, the [Fe 2 ( L Pyim ) 3 ] 4+ helicates were also shown to bind to DNA and RNA bulges ( Malina et al, 2014 ; Malina et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Cavity-Containing [Fe2L3]4+ Helicates: An Examination of Host-Guest Chemistry and Cytotoxicity

et al. 2021

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Two new di(2,2′-bipyridine) ligands, 2,6-bis([2,2′-bipyridin]-5-ylethynyl)pyridine (L1) and bis(4-([2,2′-bipyridin]-5-ylethynyl)phenyl)methane (L2) were synthesized and used to generate two metallosupramolecular [Fe2(L)3](BF4)4 cylinders. The ligands and cylinders were characterized using elemental analysis, electrospray ionization mass spectrometry, UV-vis, 1H-, 13C and DOSY nuclear magnetic resonance (NMR) spectroscopies. The molecular structures of the [Fe2(L)3](BF4)4 cylinders were confirmed using X-ray crystallography. Both the [Fe2(L1)3](BF4)4 and [Fe2(L2)3](BF4)4 complexes crystallized as racemic (rac) mixtures of the ΔΔ (P) and ΛΛ (M) helicates. However, 1H NMR spectra showed that in solution the larger [Fe2(L2)3](BF4)4 was a mixture of the rac-ΔΔ/ΛΛ and meso-ΔΛ isomers. The host-guest chemistry of the helicates, which both feature a central cavity, was examined with several small drug molecules. However, none of the potential guests were found to bind within the helicates. In vitro cytotoxicity assays demonstrated that both helicates were active against four cancer cell lines. The smaller [Fe2(L1)3](BF4)4 system displayed low μM activity against the HCT116 (IC50 = 7.1 ± 0.5 μM) and NCI-H460 (IC50 = 4.9 ± 0.4 μM) cancer cells. While the antiproliferative effects against all the cell lines examined were less than the well-known anticancer drug cisplatin, their modes of action would be expected to be very different.

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Section: Introductionmentioning

confidence: 99%

Cavity-Containing [Fe2L3]4+ Helicates: An Examination of Host-Guest Chemistry and Cytotoxicity

et al. 2021

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“…The prototypical molecular helixes, helicenes, are organic compounds. 48 , 49 However, metal-based molecular helixes have also been described by Lehn, 50 , 51 Sauvage, 52 , 53 and Hannon, 54 − 56 for example. In this work, the helical structures of the gold complexes [1] + and [2] + indicate that gold complexation can be a new strategy to develop helical systems from planar ligands.…”

Section: Resultsmentioning

confidence: 99%

Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

Zhou

Carbo-Bague

Siegler

et al. 2021

JACS Au

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In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au(biqbpy2)Cl ([2]Cl). In [1] + , two pyridyl rings coordinate to the metal via a Au–C bond (C ∧ N ∧ N ∧ C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2] + all four pyridyl rings of the ligand coordinate to the metal via a Au–N bond (N ∧ N ∧ N ∧ N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [ 3 H]dofetilide equally well from cell membranes expressing the K v 11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H 2 biqbpy2 and TrxR-inhibiting Au + ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au + ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells.

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“…Untersuchungen zu Wechselwirkungen von Metallkomplexen mit den Biopolymeren DNA und RNA sind Klassiker der Bioanorganik. In einem weit über herkömmliche Studien hinausgehenden Ansatz setzten die Anorganiker der Universität Zürich mit ihren Kooperationspartnern im englischen Birmingham eine helikale, supramolekulare Eisenverbindung ein und studierten deren Wechselwirkung mit RNA und DNA 2_17. Als Resultat fanden sie die Selbstorganisation von drei RNA‐ und DNA‐Stücken um den Eisenstrang zu einem Superkomplex — ästhetisch ansprechend und erstaunlich stabil in Lösung (Abbildung 5, S.247).…”

Section: Pharmazeutische Anwendungenunclassified

Reaktionen auf die Vollsperrung der Schiersteiner Brücke auf der A643

2015

Bautechnik

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Binding of a Designed Anti‐Cancer Drug to the Central Cavity of an RNA Three‐Way Junction

Cited by 24 publications

References 32 publications

Cavity-Containing [Fe2L3]4+ Helicates: An Examination of Host-Guest Chemistry and Cytotoxicity

Cavity-Containing [Fe2L3]4+ Helicates: An Examination of Host-Guest Chemistry and Cytotoxicity

Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

Reaktionen auf die Vollsperrung der Schiersteiner Brücke auf der A643

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