Elizabeth New
Research interests
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InterestsMolecular Imaging, Redox Signaling
Publications
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5.50Impact points
A selective reaction-based fluorescent probe for detecting cobalt in living cells.
Chemical communications (Cambridge, England). 04/2012;
A reaction-based strategy exploiting cobalt-mediated oxidative C-O bond cleavage affords a selective turn-on fluorescent probe for paramagnetic Co(2+) in water and in living cells.... [more] A reaction-based strategy exploiting cobalt-mediated oxidative C-O bond cleavage affords a selective turn-on fluorescent probe for paramagnetic Co(2+) in water and in living cells.
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8.58Impact points
Reaction-based fluorescent probes for selective imaging of hydrogen sulfide in living cells.
Journal of the American Chemical Society. 06/2011; 133(26):10078-80.
Hydrogen sulfide (H(2)S) is emerging as an important mediator of human physiology and pathology but remains difficult to study, in large part because of the lack of methods for selective monitoring of this small signaling molecule in live biological specimens. We now report a pair of new reaction-ba... [more] Hydrogen sulfide (H(2)S) is emerging as an important mediator of human physiology and pathology but remains difficult to study, in large part because of the lack of methods for selective monitoring of this small signaling molecule in live biological specimens. We now report a pair of new reaction-based fluorescent probes for selective imaging of H(2)S in living cells that exploit the H(2)S-mediated reduction of azides to fluorescent amines. Sulfidefluor-1 (SF1) and Sulfidefluor-2 (SF2) respond to H(2)S by a turn-on fluorescence signal enhancement and display high selectivity for H(2)S over other biologically relevant reactive sulfur, oxygen, and nitrogen species. In addition, SF1 and SF2 can be used to detect H(2)S in both water and live cells, providing a potentially powerful approach for probing H(2)S chemistry in biological systems.
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3.76Impact points
Enantioselective binding of a lanthanide(III) complex to human serum albumin studied by 1H STD NMR techniques.
Organic & biomolecular chemistry. 06/2011; 9(14):5047-50.
The enantioselective binding of the (SSS)-Δ isomer of an yttrium(III) tetraazatriphenylene complex to 'drug-site II' of human serum albumin (HSA) was detected by the intensity differences of its STD (1)H NMR spectrum relative to the (RRR)-Λ isomer, by the effect of the competitive binder to ... [more] The enantioselective binding of the (SSS)-Δ isomer of an yttrium(III) tetraazatriphenylene complex to 'drug-site II' of human serum albumin (HSA) was detected by the intensity differences of its STD (1)H NMR spectrum relative to the (RRR)-Λ isomer, by the effect of the competitive binder to that site, N-dansyl sarcosine, upon the STD spectrum of each isomer, in the presence of HSA and by 3D docking simulations.
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8.58Impact points
Light-Activated Regulation of Cofilin Dynamics Using a Photocaged Hydrogen Peroxide Generator.
Journal of the American Chemical Society. 11/2010;
Hydrogen peroxide (H(2)O(2)) can exert diverse signaling and stress responses within living systems depending on its spatial and temporal dynamics. Here we report a new small-molecule probe for producing H(2)O(2) on demand upon photoactivation and its application for optical regulation of cofilin-ac... [more] Hydrogen peroxide (H(2)O(2)) can exert diverse signaling and stress responses within living systems depending on its spatial and temporal dynamics. Here we report a new small-molecule probe for producing H(2)O(2) on demand upon photoactivation and its application for optical regulation of cofilin-actin rod formation in living cells. This chemical method offers many potential opportunities for dissecting biological roles for H(2)O(2) as well as remote control of cell behavior via H(2)O(2)-mediated pathways.
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8.30Impact points
Development of responsive lanthanide probes for cellular applications.
Current opinion in chemical biology. 10/2009;
Useful probes of the intracellular environment are required for a wide range of bioactive species including metal ions, oxyanions and pH. These probes need to be targeted to specific organelles (mitochondria, nucleus and lysosomes) in order to allow direct observation of the changes in these regions... [more] Useful probes of the intracellular environment are required for a wide range of bioactive species including metal ions, oxyanions and pH. These probes need to be targeted to specific organelles (mitochondria, nucleus and lysosomes) in order to allow direct observation of the changes in these regions. Critical probe design features for luminescent lanthanide complexes are defined, together with a review of published sub-cellular localisation profiles. Cell uptake by macropinocytosis has been demonstrated for a wide range of probes and the importance of minimising perturbation of cellular homeostasis emphasised, so that cell viability, proliferation and membrane permeability are not compromised.
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3.25Impact points
Fluorescent analogues of quinoline reveal amine ligand loss from cis and trans platinum(II) complexes in cancer cells.
Journal of inorganic biochemistry. 06/2009;
Analogues of cytotoxic cis and trans dichloridoplatinum(II) complexes with one ammonia and one aromatic amine (cis- and trans-[PtCl(2)(aromatic amine)(NH(3))]) were synthesised in which the aromatic group was replaced by the fluorescent ligand 7-azaindole (1). Coordination resulted in almost complet... [more] Analogues of cytotoxic cis and trans dichloridoplatinum(II) complexes with one ammonia and one aromatic amine (cis- and trans-[PtCl(2)(aromatic amine)(NH(3))]) were synthesised in which the aromatic group was replaced by the fluorescent ligand 7-azaindole (1). Coordination resulted in almost complete quenching of the fluorescence and the ligand had a effect on the biological activities of the cis and trans isomers similar to that previously reported for aromatic amines as is exemplified by them having similar cytotoxicities (IC(50) 3.6(5) and 6.0(19)muM, respectively). Observation of fluorescence following treatment of the cis complex with cysteine, glutathione, or methionine suggests labilisation and subsequent loss of the putative non-leaving group ligands. No such effect was observed for the trans complex which does not experience trans labilisation. Two-photon excitation of cells that had been treated with the complexes gave rise to observable fluorescence, suggesting ligand displacement for both complexes. The fluorescence appears to be localised in the lysosomes or late endosomes. These complexes are excellent models of analogues of cytotoxic cis and trans complexes with aromatic amine ligands and can be used to study the metabolism of the non-leaving group positions.
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4.08Impact points
Investigations using fluorescent ligands to monitor platinum(iv) reduction and platinum(ii) reactions in cancer cells.
Dalton transactions (Cambridge, England : 2003). 05/2009;
Coordination of the aniline containing fluorophores, coumarin 120 (C120) and coumarin 151 (C151) at the non-leaving group positions of cisplatin analogues (giving cis-[PtCl(2)(C120)(NH(3))] and cis-[PtCl(2)(C151)(NH(3))]) resulted in partial and complete quenching of the fluorescence, respectively. ... [more] Coordination of the aniline containing fluorophores, coumarin 120 (C120) and coumarin 151 (C151) at the non-leaving group positions of cisplatin analogues (giving cis-[PtCl(2)(C120)(NH(3))] and cis-[PtCl(2)(C151)(NH(3))]) resulted in partial and complete quenching of the fluorescence, respectively. Oxidation of the coumarin 120 complex to the Pt(iv) form (cis,trans,cis-[PtCl(2)(OH)(2)(C120)(NH(3))]) resulted in further quenching compared to that seen for the Pt(ii) complex. The fluorescence profiles of these coumarin complexes were collected to evaluate their suitability for studying the metabolism of cisplatin-based anticancer drugs. C151 has the more suitable profile with a lower energy excitation peak and a better separation between the excitation and emission spectra. The complete damping of fluorescence on coordination to Pt(ii) makes it unsuitable for monitoring the reduction process, but does allow it to be used to monitor loss of the aniline type ligand. All of the coumarin complexes revealed moderate cyotoxcities in the range 10-22 muM indicating that they are suitable models of anticancer agents. DNA dampens the fluorescence of both Pt(ii) complexes and that of C120 has a much higher DNA binding affinity (10 000 M(-1)) than does the complex of C151 (300 M(-1)). Treatment of A2780 human ovarian carcinoma cells with the Pt-coumarin complexes resulted in fluorescence visible by confocal microscopy, and co-localisation studies with organelle specific dyes suggest they are concentrated in the late endosomes or lysosomes. Cells treated with the Pt(iv) complex of C120 revealed strong fluorescence and a somewhat different distribution to cells treated with the Pt(ii) complex indicating reduction following uptake.
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3.76Impact points
The mechanism of cell uptake for luminescent lanthanide optical probes: the role of macropinocytosis and the effect of enhanced membrane permeability on compartmentalisation.
Organic & biomolecular chemistry. 04/2009; 7(5):851-5.
Inhibition studies and co-localisation experiments with several emissive lanthanide complexes reveal cell uptake by macropinocytosis.
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18.20Impact points
Cell-Penetrating Metal Complex Optical Probes: Targeted and Responsive Systems Based on Lanthanide Luminescence.
Accounts of chemical research. 03/2009;
To understand better the structure and function of biological systems, cell biologists and biochemists would like to have methods that minimally perturb living systems. The development of emissive optical probes is essential for improving our observation of intracellular signaling and recognition pr... [more] To understand better the structure and function of biological systems, cell biologists and biochemists would like to have methods that minimally perturb living systems. The development of emissive optical probes is essential for improving our observation of intracellular signaling and recognition processes. Following excitation of the probe, photons emitted from the probe may be observed by spectroscopy or microscopy and encode information about their environments in their energy, lifetime, and polarization. Such optical probes may be based on organic fluorophores, quantum dots, recombinant proteins, or emissive metal complexes. In this Account, we trace the emergence of lanthanide coordination complexes as emissive optical probes. These probes benefit from sharp emission bands and long lifetimes. We can design these complexes to report on the concentration of key biochemical variables by modulation of spectral form, lifetime, or circular polarization. These properties allow us to apply ratiometric methods of analysis in spectroscopy or microscopy to report on local pH, pM (M = Ca, Zn), or the concentration of certain anionic metabolites, such as citrate, lactate, bicarbonate, or urate. For optical microscopy studies in living cells, these probes must be cell-permeable and, ideally, should localize in a given cell organelle. We undertook systematic studies of more than 60 emissive complexes, examining the time dependence of cellular uptake and compartmentalization, cellular toxicity, protein affinity, and quenching sensitivity. These results and their relationship to probe structure have allowed us to identify certain structure-activity relationships. The nature and linkage mode of the integral sensitizing groupintroduced to harvest incident light efficientlyis of primary importance in determining protein affinity and cellular uptake and trafficking. In many cases, uptake may occur via macropinocytosis. We have defined three main classes of behavior: complexes exhibit predominant localization profiles in protein-rich regions (nucleoli/ribosomes), in cellular mitochondria, or in endosomes/lysosomes. Therefore, these systems offer considerable promise as intracellular optical probes, amenable to single- or two-photon excitation, that may report on the local ionic composition of living cells subjected to differing environmental stresses.
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4.08Impact points
Comparative study of the constitution and chiroptical properties of emissive terbium and europium complexes with a common tetraazatriphenylene sensitiser; the nature of the sensitiser determines quenching sensitivity and cellular uptake.
Dalton transactions (Cambridge, England : 2003). 02/2009;
Six pairs of Eu(III) and Tb(III) complexes of macrocyclic ligands, incorporating a common tetraazatriphenylene sensitiser, have been examined in terms of their solution structure, sensitivity to excited state quenching, protein affinity, cell toxicity and preliminary cell localisation profiles. A co... [more] Six pairs of Eu(III) and Tb(III) complexes of macrocyclic ligands, incorporating a common tetraazatriphenylene sensitiser, have been examined in terms of their solution structure, sensitivity to excited state quenching, protein affinity, cell toxicity and preliminary cell localisation profiles. A complex with three (S)-phenylalanine-derived ligating groups possesses distinctive 1H NMR, Eu emission and circularly polarised emission properties, consistent with a unique A-configuration in the 9-coordinate complex, where an amide carbonyl group occupies the capping position of the coordination polyhedron. Each complex possesses similar sensitivity to quenching by ascorbate, urate and iodide, has similar toxicity behaviour and shows a common intracellular localisation profile that is consistent with compartmentalisation in lysosomes or late endosomes. Such behaviour accords with the hypothesis that it is the nature of the sensitising moiety that determines each of these properties.
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5.50Impact points
Enantioselective regulation of a metal complex in reversible binding to serum albumin: dynamic helicity inversion signalled by circularly polarised luminescence.
Chemical communications (Cambridge, England). 10/2008;
The helicity of the (SSS)-Delta enantiomer of a terbium and europium(iii) complex is inverted on reversible binding to 'drug site II' of serum albumin, signalled by a switch in its circularly polarised emission; no such behaviour occurs with the (RRR)-Lambda complexes, thereby defining a uni... [more] The helicity of the (SSS)-Delta enantiomer of a terbium and europium(iii) complex is inverted on reversible binding to 'drug site II' of serum albumin, signalled by a switch in its circularly polarised emission; no such behaviour occurs with the (RRR)-Lambda complexes, thereby defining a unique chiroptical probe of albumin binding.
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3.76Impact points
The nature of the sensitiser substituent determines quenching sensitivity and protein affinity and influences the design of emissive lanthanide complexes as optical probes for intracellular use.
Organic & biomolecular chemistry. 08/2008; 6(13):2256-8.
Introduction of different substituents at the 7-position of a sensitising azaxanthone group in a series of emissive Eu and Tb complexes can determine the intracellular uptake and distribution profile and may be linked to modulation of protein affinity.... [more] Introduction of different substituents at the 7-position of a sensitising azaxanthone group in a series of emissive Eu and Tb complexes can determine the intracellular uptake and distribution profile and may be linked to modulation of protein affinity.
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5.50Impact points
Two-photon microscopy study of the intracellular compartmentalisation of emissive terbium complexes and their oligo-arginine and oligo-guanidinium conjugates.
Chemical communications (Cambridge, England). 07/2008;
An emissive terbium complex has been conjugated to a C12 chain, Lys-Arg7, Arg7, a tetraguanidinium cation and human serum albumin; two-photon excitation at 720 nm facilitated microscopy studies revealing cell localisation profiles with the oligo-guanidinium conjugate localising in mitochondria but c... [more] An emissive terbium complex has been conjugated to a C12 chain, Lys-Arg7, Arg7, a tetraguanidinium cation and human serum albumin; two-photon excitation at 720 nm facilitated microscopy studies revealing cell localisation profiles with the oligo-guanidinium conjugate localising in mitochondria but causing apoptotic cell death (IC(50)12 microM), the C12-amide complex giving rise to necrotic cell death in skin fibroblasts (IC50 8 microM) and the peptide conjugates and the methyl ester generating punctuate cytosolic intracellular distributions.
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3.76Impact points
Critical evaluation of five emissive europium(III) complexes as optical probes: correlation of cytotoxicity, anion and protein affinity with complex structure, stability and intracellular localisation profile.
Organic & biomolecular chemistry. 07/2008; 6(12):2085-94.
Five structurally related europium(iii) complexes of heptadentate macrocyclic ligands bearing azaxanthone or azathiaxanthone chromophores have been evaluated comparatively as responsive probes of the intracellular environment. Protein binding (HSA) and oxy-anion binding constants have been measured ... [more] Five structurally related europium(iii) complexes of heptadentate macrocyclic ligands bearing azaxanthone or azathiaxanthone chromophores have been evaluated comparatively as responsive probes of the intracellular environment. Protein binding (HSA) and oxy-anion binding constants have been measured by titrimetric analysis, examining ratiometric emission changes for three examples, and systems exhibiting selectivity for citrate or hydrogencarbonate identified. The cytotoxicity of each ligand and complex has been assessed and correlated with the observed chemical stability profile in competitive aqueous media. The europium complex of L(2) is non-toxic, exhibits a large change in its emission spectral profile to variation in HCO(3)(-) (or citrate) concentration allowing ratiometric analysis, and localises in cellular mitochondria. Such features augur well for its future application as a responsive probe in microscopy to monitor local changes in pHCO(3).
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3.42Impact points
Cellular uptake and distribution of cobalt complexes of fluorescent ligands.
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 05/2008;
The development of complexes that allow the monitoring of the release and distribution of fluorescent models of anticancer drugs initially bound to cobalt(III) moieties is reported. Strong quenching of fluorescence upon ligation to cobalt(III) was observed for both the carboxylate- and the hydroxima... [more] The development of complexes that allow the monitoring of the release and distribution of fluorescent models of anticancer drugs initially bound to cobalt(III) moieties is reported. Strong quenching of fluorescence upon ligation to cobalt(III) was observed for both the carboxylate- and the hydroximate-bound fluorophores as was the partial return of fluorescence following addition of ascorbate and cysteine. The extent of the increase in the fluorescence intensity observed following addition of these potential reductants is indicative of the fluorophore being displaced from the complex by the action of ascorbate or cysteine, by ligand exchange. The cellular distribution of the fluorescence revealed that coordination to cobalt can dramatically alter the subcellular distribution of a bound fluorophore. This work shows that fluorescence can be an effective means of monitoring these agents in cells, and of determining their sites of activation. The results also reveal that the cytotoxicity of such agents correlates with their uptake and distribution patterns and that these are influenced by the types of ligands attached to the complex.
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3.76Impact points
A mechanistic study of the dynamic quenching of the excited state of europium(III) and terbium(III) macrocyclic complexes by charge- or electron transfer.
Organic & biomolecular chemistry. 10/2007; 5(18):2975-82.
Dynamic quenching of the metal-based excited state of Eu(III) and Tb(III) complexes of sixteen different macrocyclic ligands has been studied. Quenching by urate, ascorbate and selected catechols is most effective for Tb(III) systems, and involves intermediate formation of an excited state complex (... [more] Dynamic quenching of the metal-based excited state of Eu(III) and Tb(III) complexes of sixteen different macrocyclic ligands has been studied. Quenching by urate, ascorbate and selected catechols is most effective for Tb(III) systems, and involves intermediate formation of an excited state complex (exciplex) between the electron-poor heterocyclic sensitising moiety incorporated into the ligand (tetraazatriphenylene, azaxanthone or a pyrazoyl-azaxanthone) and the electron-rich reductant. The process is sensitive to steric inhibition created by the local ligand environment; quenching is reduced as temperature increases as exciplex formation is entropically disfavoured. In contrast, iodide quenches each complex studied according to a classical collisional encounter model; increasing temperature enhances the rate of quenching, and the process is more sensitive to local electrostatic fields generated by ligand substitution, conforming to a traditional Stern-Volmer kinetic model. Quenching may be inhibited by protein association, allowing the identification of candidates for use as optical imaging probes in cellulo.
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3.76Impact points
Identification of emissive lanthanide complexes suitable for cellular imaging that resist quenching by endogenous anti-oxidants.
Organic & biomolecular chemistry. 08/2007; 5(13):2055-62.
Excited state quenching by urate and ascorbate of selected europium and terbium(III) macrocyclic complexes has been assessed and related to the ease of complex visualisation by optical microscopy inside various living cells, e.g. CHO, COS and NIH 3T3. It is the relative insensitivity of certain ster... [more] Excited state quenching by urate and ascorbate of selected europium and terbium(III) macrocyclic complexes has been assessed and related to the ease of complex visualisation by optical microscopy inside various living cells, e.g. CHO, COS and NIH 3T3. It is the relative insensitivity of certain sterically encumbered complexes to dynamic quenching by urate that favours their usage for in cellulo applications. Non-covalent binding of the complex by protein also shields the excited lanthanide(III) ion from collisional quenching; this effect is most marked for a cationic triamide complex, [Ln.1](3+), consistent with its ease of visualisation by luminescence microscopy.
