Selective Lability of Ruthenium(II) Arene Amino Acid Complexes

Scrase, Tom G; O’Neill, Michael; Peel, Andrew J.; Senior, Paul W; Matthews, Peter D.; Shi, Heyao; Boss, Sally R.; Barker, Paul D.

doi:10.1021/ic502051y

Cited by 18 publications

(13 citation statements)

References 19 publications

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“…16 Upon addition of 1 equivalent of L-His, an adduct was observed, consistent with replacement of H 2 O for L-His, binding though an imidazole N. When the sample was subjected to a second equivalent of L-His and left to equilibrate over 16 h, a species formed in which the pyridylphosphinate ligand is displaced and the L-His binds κ 3 (Figure 7). The observed Ru-(L-His) complex, 1c, is known to be non-cytotoxic 31 and its formation presents a potential explanation of the low cytotoxicity of Ru chloride complexes described in this report. It follows that the higher cytotoxicity of the iodide-complexes, 10, 21 and 22, is due to the metal-iodide bond being less labile towards aquation and therefore less likely to undergo decomplexation by chelating biomolecules.…”

Section: Binding Studiessupporting

confidence: 52%

Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity

et al. 2016

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Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. structural preference for one of a possible two diastereomers. The metal chlorides hydrolyse rapidly in D2O to form a 1:1 equilibrium ratio between the aqua and chloride adducts. The pKa of the aqua adduct depends upon the pyridyl substituent and the metal but has little dependence upon the phosphinate R' group. Toxicity was measured in vitro against non-small cell lung carcinoma H460 cells, with the most potent complexes reporting IC50 values around 50 μM. Binding studies with selected amino acids and nucleobases provide a rationale for the variation in toxicity observed within the series. Finally, an investigation into the ability of the chelating amino acid L-His to displace the phosphinate O-metal bond shows the potential for phosphinate complexes to act as prodrugs that can be activated in the intracellular environment.

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Section: Binding Studiessupporting

confidence: 52%

Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity

et al. 2016

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“…Very few studies in which protonation of the binding functional group in the tether plays an important role in the dynamics of the metal–tether bond in aqueous solution have been reported . Pizarro et al.…”

Section: Resultsmentioning

confidence: 93%

“…Very few studies in which protonation of the binding functional group in the tether plays an important role in the dynamics of the metal-tether bond in aqueous solutionh ave been reported. [7,21,23] Pizarroe tal. reported the synthesis of [Ru{h 6 -C 6 H 5 (C 6 H 4 )NH 3 }Cl 3 ]f rom its closed-tether counterpart [Ru{h 6 :k 1 -C 6 H 5 (C 6 H 4 )NH 2 }Cl 2 ], by suspending the former in concentrated HCl (ca.…”

Section: Activation Undera Cidicconditionsmentioning

confidence: 99%

Control of Reversible Activation Dynamics of [Ru{η⁶:κ¹‐C₆H₅(C₆H₄)NH₂}(XY)]ⁿ⁺ and the Effect of Chelating‐Ligand Variation

Martínez‐Peña

Pizarro

2017

Chemistry A European J

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The potential use of organoruthenium complexes as anticancer drugs is well known. Herein, a family of activatable tethered ruthenium(II) arene complexes of general formula [Ru{η :κ -C H (C H )NH }(XY)] (closed tether ring) bearing different chelating XY ligands (XY=aliphatic diamine, phenylenediamine, oxalato, bis(phosphino)ethane) is reported. The activation of these complexes (closed- to open-tether conversion) occurs in methanol and DMSO at different rates and to different reaction extents at equilibrium. Most importantly, Ru -complex activation (cleavage of the Ru-N bond) occurs in aqueous solution at high proton concentration (upon N protonation). The activation dynamics can be modulated by rational variation of the XY chelating ligand. The electron-donating capability and steric hindrance of XY have a direct impact on the reactivity of the Ru-N bond, and XY=N,N'-dimethyl-, N,N'-diethyl-, and N,N,N',N'-tetramethylethylenediamine afford complexes that are more prone to activation. Such activation in acidic media is fully reversible, and proton concentration also governs the deactivation rate, that is, tether-ring closure slows down with decreasing pH. Interaction of a closed-tether complex and its open-tether counterpart with 5'-guanosine monophosphate revealed selectivity of the active (open) complex towards interaction with nucleobases. This work presents ruthenium tether complexes as exceptional pH-dependent switches with potential applications in cancer research.

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“…The closed form of the complexes, achieved through an arene ligand η 6 :κ 1 -C6H5(C6H4)NH2 coordination mode ( Figure 1D), dominates The pH-dependent intramolecular chelation of a range of ligands in half-sandwich ruthenium complexes to regulate ligand coordination at the ruthenium center has also been explored. Scrase et al reported that a L-2,3-diaminopropionic acid ligand coordinated in a tridentate manner to a ruthenium-η 6 -arene moiety was found to be labilized on lowering of pH, leading to partial reactivity of the complex on incubation with a protected methionine ligand at pH 2.5 [12]. Pizarro et al have shown reversible intramolecular chelation can be achieved in half-sandwich ruthenium complexes utilizing an hemilabile 2-aminobiphenyl arene ligand [13].…”

Section: Introductionmentioning

confidence: 99%

The Application of Reversible Intramolecular Sulfonamide Ligation to Modulate Reactivity in Organometallic Ruthenium(II) Diamine Complexes

et al. 2020

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Metallation of biomacromolecular species forms the basis for the anticancer activity of many metallodrugs. A major limitation of these compounds is that their reactivity is indiscriminate and can, in principle, occur in healthy tissue as well as cancerous tissue, potentially leading to side effects in vivo. Here we present pH-dependent intramolecular coordination of an arene-tethered sulfonamide functionality in organometallic ruthenium(II) ethylenediamine complexes as a route to controlling the coordination environment about the central metal atom. Through variation of the sulfonamide R group and the length of the tether linking it to the arene ligand the acidity of the sulfonamide NH group, and hence the pH-region over which regulation of metal coordination occurs, can be modulated. Intramolecular sulfonamide ligation controlled the reactivity of complex 4 within the physiologically relevant pH-region, rendering it more reactive towards 5 -GMP in mildly acidic pH-conditions typical of tumour tissue compared to the mildly alkaline pH-conditions typical of healthy tissue. However, the activation of 4 by ring-opening of the chelate was found to be a slow process relative to the timescale of typical cell culture assays and members of this series of complexes were found not to be cytotoxic towards the HT-29 cell line. These complexes provide the basis for the development of analogues of increased potency where intramolecular sulfonamide ligation regulates reactivity and therefore cytotoxicity in a pH-dependent, and potentially, tissue-dependent manner.Sadler et al. explored the reversible and pH-dependent equilibrium between ring-open and ring-closed forms of bis(aminophosphine) Pt(II) complexes [6,7].pH titrations with cis-[PtCl(Me 2 N(CH 2 ) 2 PPh 2 -N,P)(Me 2 N(CH 2 ) 2 PPh 2 -P)]Cl ( Figure 1A) yielded a pK a value of 6.9 and the equilibrium was also found to be dependent on Cl − concentration. cis-[PtCl(Me 2 N(CH 2 ) 2 PPh 2 -N,P)(Me 2 N(CH 2 ) 2 PPh 2 -P)]Cl was reported to be active against several cell lines, in conditions in which the open form of the complex would be present, but both cis-[PtCl(Me 2 N(CH 2 ) 2 PPh 2 -N,P)(Me 2 N(CH 2 ) 2 PPh 2 -P)]Cl and the ring closed form were found to react rapidly with 5 -GMP. This indicates the closed form of the complex is unable to regulate coordination of DNA to the metal center, although coordination of S-donor ligands to Pt(II) was prevented in the ring-closed form of the complex. A series of bis(O-alkyldithiocarbonato)platinum(II) complexes ( Figure 1B) were found to be more active at pH 6.8 versus 7.4 with average IC 50 (pH 7.0)/IC 50 (pH 6.8) ratios >2 found across six tumor cell lines for selected complexes [8]. The increase in activity of the complexes at acidic pH was attributed to increased ligand protonation and consequential destabilization of the complex, leading to increased reactivity. A bis(2-aminoethanolato-κ 2 N,O) platinum(II) complex ( Figure 1C) was also shown to exhibit increased reactivity toward 5 -GMP at pH 6.0 versus pH 7.4 [9], although r...

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Selective Lability of Ruthenium(II) Arene Amino Acid Complexes

Cited by 18 publications

References 19 publications

Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity

Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity

Control of Reversible Activation Dynamics of [Ru{η⁶:κ¹‐C₆H₅(C₆H₄)NH₂}(XY)]ⁿ⁺ and the Effect of Chelating‐Ligand Variation

The Application of Reversible Intramolecular Sulfonamide Ligation to Modulate Reactivity in Organometallic Ruthenium(II) Diamine Complexes

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Selective Lability of Ruthenium(II) Arene Amino Acid Complexes

Cited by 18 publications

References 19 publications

Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity

Pyridylphosphinate metal complexes: synthesis, structural characterisation and biological activity

Control of Reversible Activation Dynamics of [Ru{η6:κ1‐C6H5(C6H4)NH2}(XY)]n+ and the Effect of Chelating‐Ligand Variation

The Application of Reversible Intramolecular Sulfonamide Ligation to Modulate Reactivity in Organometallic Ruthenium(II) Diamine Complexes

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Control of Reversible Activation Dynamics of [Ru{η⁶:κ¹‐C₆H₅(C₆H₄)NH₂}(XY)]ⁿ⁺ and the Effect of Chelating‐Ligand Variation