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Journal articleCodina AS, Huerta AT, Heiba HF, et al., 2023,
Functionalised polymeric materials for the removal of arsenate from contaminated water, ENVIRONMENTAL SCIENCE-WATER RESEARCH & TECHNOLOGY, ISSN: 2053-1400
Journal articleVilar Compte R, Evans L, Kotar A, et al., 2023,
Identification and characterisation of G-quadruplex DNA-forming sequences in the Pseudomonas aeruginosa genome, RSC Chemical Biology, Vol: 4, Pages: 94-100, ISSN: 2633-0679
A number of Gram-negative bacteria such as Pseudomonas aeruginosa are becoming resistant to front-line antibiotics. Consequently, there is a pressing need to find alternative bio-molecular targets for the development of new drugs. Since non-canonical DNA structures such as guanine-quadruplexes (G4s) have been implicated in regulating transcription, we were interested in determining whether there are putative quadruplex-forming sequences (PQS) in the genome of Pseudomonas aeruginosa. Using bioinformatic tools, we screened 36 genes potentially relevant to drug resistance for the presence of PQS and 10 of these were selected for biophysical characterisation (i.e. circular dichroism and thermal difference UV/Vis spectroscopy). These studies showed that three of these G-rich sequences (linked to murE, ftsB and mexC genes) form stable guanine-quadruplexes which were studied by NMR spectroscopy; detailed analysis of one of the sequences (mexC) confirmed that it adopts a two-quartet antiparallel quadruplex structure in the presence of K+ ions. We also show by FRET melting assays that small molecules can stabilise these three new G4 DNA structures under physiological conditions. These initial results could be of future interest in the development of new antibiotics with alternative bio-molecular targets which in turn would help tackle antimicrobial resistance.
Journal articleLo R, Majid A, Fruhwirth GO, et al., 2022,
Radiolabelling Pt-based quadruplex DNA binders via click chemistry., Bioorganic and Medicinal Chemistry, Vol: 76, Pages: 1-9, ISSN: 0968-0896
Guanine-rich sequences of DNA and RNA can fold into intramolecular tetra-helical assemblies known as G-quadruplexes (G4). Their formation in vivo has been associated to a range of biological functions and therefore they have been identified as potential drug targets. Consequently, a broad range of small molecules have been developed to target G4s. Amongst those are metal complexes with Schiff base ligands. Herein, we report the functionalisation of one of these well-established G4 DNA binders (based on a square planar platinum(II)-salphen complex) with two different radiolabelled complexes. An 111In-conjugate was successfully used to assess its in vivo distribution in a mouse tumour model using single-photon emission computed tomography (SPECT) imaging. These studies highlighted the accumulation of this Pt-salphen-111In conjugate in the tumour.
Journal articleBullen JC, Lapinee C, Miller LA, et al., 2022,
Spectroscopic (XAS, FTIR) investigations into arsenic adsorption onto TiO2/Fe2O3 composites: Evaluation of the surface complexes, speciation and precipitation predicted by modelling, Results in Surfaces and Interfaces, Vol: 9, Pages: 100084-100084, ISSN: 2666-8459
Journal articleNorthover G, Mao Y, Blasco S, et al., 2022,
Synergistic use of siderophores and weak organic ligands during zinc transport in the rhizosphere controlled by pH and ion strength gradients, Scientific Reports, Vol: 12, ISSN: 2045-2322
Citrate (Cit) and Deferoxamine B (DFOB) are two important organic ligands coexisting in soils with distinct different affinities for metal ions. It has been theorized that siderophores and weak organic ligands play a synergistic role during the transport of micronutrients in the rhizosphere, but the geochemical controls of this process remain unknown. Here we test the hypothesis that gradients in pH and ion strength regulate and enable the cooperation. To this end, first we use potentiometric titrations to identify the dominant Zn(II)–Cit and Zn(II)–DFOB complexes and to determine their ionic strength dependent stability constants between 0 and 1 mol dm−3. We parametrise the Extended Debye-Hückel (EDH) equation and determine accurate intrinsic association constants (logβ0) for the formation of the complexes present. The speciation model developed confirms the presence of [Zn(Cit)]−, [Zn(HCit)], [Zn2(Cit)2(OH)2]4−, and [Zn(Cit)2]4−, with [Zn(Cit)]− and [Zn2(Cit)2(OH)2]4− the dominant species in the pH range relevant to rhizosphere. We propose the existence of a new [Zn(Cit)(OH)3]4− complex above pH 10. We also verify the existence of two hexadentate Zn(II)–DFOB species, i.e., [Zn(DFOB)]− and [Zn(HDFOB)], and of one tetradentate species [Zn(H2DFOB)]+. Second, we identify the pH and ionic strength dependent ligand exchange points (LEP) of Zn with citrate and DFOB and the stability windows for Zn(II)–Cit and Zn(II)–DFOB complexes in NaCl and rice soil solutions. We find that the LEPs fall within the pH and ionic strength gradients expected in rhizospheres and that the stability windows for Zn(II)–citrate and Zn(II)–DFOB, i.e., low and high affinity ligands, can be distinctly set off. This suggests that pH and ion strength gradients allow for Zn(II) complexes with citrate and DFOB to dominate in different parts of the rhizosphere and this explains why mixtures of low and h
Journal articlePriessner M, Gaboriau DCA, Sheridan A, et al., 2021,
Content-aware frame interpolation (CAFI): Deep Learning-based temporal super-resolution for fast bioimaging
<jats:p>The development of high-resolution microscopes has made it possible to investigate cellular processes in 4D (3D over time). However, observing fast cellular dynamics remains challenging as a consequence of photobleaching and phototoxicity. These issues become increasingly problematic with the depth of the volume acquired and the speed of the biological events of interest. Here, we report the implementation of two content-aware frame interpolation (CAFI) deep learning networks, Zooming SlowMo (ZS) and Depth-Aware Video Frame Interpolation (DAIN), based on combinations of recurrent neural networks, that are highly suited for accurately predicting images in between image pairs, therefore improving the temporal resolution of image series as a post-acquisition analysis step. We show that CAFI predictions are capable of understanding the motion context of biological structures to perform better than standard interpolation methods. We benchmark CAFI’s performance on six different datasets, obtained from three different microscopy modalities (point-scanning confocal, spinning-disk confocal and confocal brightfield microscopy). We demonstrate its capabilities for single-particle tracking methods applied to the study of lysosome trafficking. CAFI therefore allows for reduced light exposure and phototoxicity on the sample and extends the possibility of long-term live-cell imaging. Both DAIN and ZS as well as the training and testing data are made available for use by the wider community via the ZeroCostDL4Mic platform.</jats:p>
Journal articlePriessner M, Summers PA, Lewis BW, et al., 2021,
Selective Detection of Cu <sup>+</sup> Ions in Live Cells via Fluorescence Lifetime Imaging Microscopy, Angewandte Chemie, Vol: 133, Pages: 23332-23337, ISSN: 0044-8249
Journal articleVilar R, Priessner M, Summers PA, et al., 2021,
Selective detection of Cu+ ions in live cells via fluorescence lifetime imaging microscopy., Angewandte Chemie International Edition, Vol: 60, Pages: 23148-23153, ISSN: 1433-7851
Copper is an essential trace element in living organisms with its levels and localisation being carefully managed by the cellular machinery. However, if misregulated, deficiency or excess of copper ions can lead to several diseases. Therefore, it is important to have reliable methods to detect, monitor and visualise this metal in cells. Herein we report a new optical probe based on BODIPY, which shows a switch-on in its fluorescence intensity upon binding to copper(I), but not in the presence of high concentration of other physiologically relevant metal ions. More interestingly, binding to copper(I) leads to significant changes in the fluorescence lifetime of the new probe, which can be used to visualize copper(I) pools in lysosomes of live cells via fluorescence lifetime imaging microscopy (FLIM).
Journal articleSummers PA, Thomas AP, Kench T, et al., 2021,
Cationic helicenes as selective G4 DNA binders and optical probes for cellular imaging, CHEMICAL SCIENCE, Vol: 12, Pages: 14624-14634, ISSN: 2041-6520
- Author Web Link
- Citations: 6
Journal articleWeiss D, Northover G, Hanif M, et al., 2021,
Isotope fractionation of zinc in the paddy rice soil-water environment and the role of 2’deoxymugineic acid (DMA) as zincophore under Zn limiting conditions, Chemical Geology, Vol: 577, Pages: 1-21, ISSN: 0009-2541
Non-traditional stable isotope systems are increasingly used to study micronutrient cycling and acquisition in terrestrial ecosystems. We previously proposed for zinc (Zn) a conceptual model linking observed isotope signatures and fractionations to biogeochemical processes occurring in the rice soil environment and we suggested that 2’deoxymugineic acid (DMA) could play an important role for rice during the acquisition of Zn when grown under Zn limiting conditions. This proposition was sustained by the extent and direction of isotope fractionation observed during the complexation of Zn with DMA synthesised in our laboratory. Here we report a new set of experimental data from field and laboratory studies designed to further elucidate the mechanisms controlling Zn isotope fractionation in the rice rhizosphere and the role of DMA. First, we present acidity (pKa) and complexation (logK) constants for DMA with H+ and Zn2+, respectively, using synthetic 2’deoxymugineic acid and show that they are significantly different from previously published data using isolates from plants. Our new set of thermodynamic data allows for a more accurate calculation of the formation of ZnDMA complexes over pH ranges typically found in the rhizosphere of flooded lowland rice soils and in rice plant compartments (xylem, phloem). We show that at pH > 6.5, Zn is fully complexed by DMA and at pH <4.5 fully dissociated. This has important implications, i.e. that in alkaline paddy soils, DMA can strip Zn from soil solids (organic and inorganic) and that ZnDMA complexes are stable at the root interface if the pH is alkaline and in the phloem and xylem of the rice shoot. Second, we present a new set of Zn isotope data in rice grown in alkaline soils with low Zn availability with and without Zn addition. We used two genotypes not tested to date, i.e. A69–1, tolerant to low Zn supply, and IR26, sensitive to low Zn supply. We confirm previous findings that, in contrast to obse
Journal articleNorthover G, Mao Y, Ahmed H, et al., 2021,
Effect of salinity on the zinc(II) binding efficiency of siderophore functional groups and implications for salinity tolerance mechanisms in barley, Scientific Reports, Vol: 11, Pages: 1-12, ISSN: 2045-2322
Bacteria, fungi and grasses use siderophores to access micronutrients. Hence, the metal binding efficiency of siderophores is directly related to ecosystem productivity. Salinization of natural solutions, linked to climate change induced sea level rise and changing precipitation patterns, is a serious ecological threat. In this study, we investigate the impact of salinization on the zinc(II) binding efficiency of the major siderophore functional groups, namely the catecholate (for bacterial siderophores), α-hydroxycarboxylate (for plant siderophores; phytosiderophores) and hydroxamate (for fungal siderophores) bidentate motifs. Our analysis suggests that the order of increasing susceptibility of siderophore classes to salinity in terms of their zinc(II) chelating ability is: hydroxamate < catecholate < α-hydroxycarboxylate. Based on this ordering, we predict that plant productivity is more sensitive to salinization than either bacterial or fungal productivity. Finally, we show that previously observed increases in phytosiderophore release by barley plants grown under salt stress in a medium without initial micronutrient deficiencies (i.e., no micronutrient limitations prior to salinization), are in line with the reduced zinc(II) binding efficiency of the α-hydroxycarboxylate ligand and hence important for the salinity tolerance of whole-plant zinc(II) status.
Journal articleChan TG, Ruehl CL, Morse SV, et al., 2021,
Modulation of amyloid-beta aggregation by metal complexes with a dual binding mode and their delivery across the blood-brain barrier using focused ultrasound, Chemical Science, Vol: 12, Pages: 9485-9493, ISSN: 2041-6520
One of the key hallmarks of Alzheimer's disease is the aggregation of the amyloid-β peptide to form fibrils. Consequently, there has been great interest in studying molecules that can disrupt amyloid-β aggregation. While a handful of molecules have been shown to inhibit amyloid-β aggregation in vitro, there remains a lack of in vivo data reported due to their inability to cross the blood–brain barrier. Here, we investigate a series of new metal complexes for their ability to inhibit amyloid-β aggregation in vitro. We demonstrate that octahedral cobalt complexes with polyaromatic ligands have high inhibitory activity thanks to their dual binding mode involving π–π stacking and metal coordination to amyloid-β (confirmed via a range of spectroscopic and biophysical techniques). In addition to their high activity, these complexes are not cytotoxic to human neuroblastoma cells. Finally, we report for the first time that these metal complexes can be safely delivered across the blood–brain barrier to specific locations in the brains of mice using focused ultrasound.
Journal articleKench T, Summers PA, Kuimova MK, et al., 2021,
Rotaxanes as Cages to Control DNA Binding, Cytotoxicity, and Cellular Uptake of a Small Molecule**, Angewandte Chemie, Vol: 133, Pages: 11023-11029, ISSN: 0044-8249
Journal articleCasini A, Vilar R, 2021,
Editorial overview: Bioinorganic chemistry., Curr Opin Chem Biol, Vol: 61, Pages: A4-A5
Journal articleReyes JB, Kuimova MK, Vilar R, 2021,
Metal complexes as optical probes for DNA sensing and imaging, CURRENT OPINION IN CHEMICAL BIOLOGY, Vol: 61, Pages: 179-190, ISSN: 1367-5931
- Author Web Link
- Citations: 13
Journal articleKench T, Summers PA, Kuimova MK, et al., 2021,
Rotaxanes as cages to control DNA binding, cytotoxicity, and cellular uptake of a small molecule, Angewandte Chemie International Edition, Vol: 60, Pages: 1-1, ISSN: 1433-7851
The efficacy of many drugs can be limited by undesirable properties, such as poor aqueous solubility, low bioavailability, and “off‐target” interactions. To combat this, various drug carriers have been investigated to enhance the pharmacological profile of therapeutic agents. In this work, we demonstrate the use of mechanical protection to “cage” a DNA‐targeting metallodrug within a photodegradable rotaxane. More specifically, we report the synthesis of rotaxanes incorporating as a stoppering unit a known G‐quadruplex DNA binder, namely a PtII‐salphen complex. This compound cannot interact with DNA when it is part of the mechanically interlocked assembly. The second rotaxane stopper can be cleaved by either light or an esterase, releasing the PtII‐salphen complex. This system shows enhanced cell permeability and limited cytotoxicity within osteosarcoma cells compared to the free drug. Light activation leads to a dramatic increase in cytotoxicity, arising from the translocation of PtII‐salphen to the nucleus and its binding to DNA.
Journal articleVilar R, Lewis BW, Bisballe N, et al., 2021,
Assessing the key photophysical properties of triangulenium dyes for DNA binding by alteration of the fluorescent core, Chemistry: A European Journal, Vol: 27, Pages: 2523-2536, ISSN: 0947-6539
Four-stranded G-quadruplex (G4) DNA is a non-canonical DNA topology that has been proposed to form in cells and play key roles in how the genome is read and used by the cellular machinery. Previously, a fluorescent triangulenium probe (DAOTA-M2) was used to visualise G4s in cellulo, thanks to its distinct fluorescence lifetimes when bound to different DNA topologies. Herein, we expand the library of available triangulenium probes to explore how modifications to the fluorescent core of the molecule affect its photophysical characteristics, interaction with DNA and cellular localisation. The benzo-bridged and isopropyl-bridged diazatriangulenium dyes, BDATA-M2 and CDATA-M2 respectively, featuring ethyl-morpholino substituents, were synthesised and characterised. The interactions of these molecules with different DNA topologies were studied to determine their binding affinity, fluorescence enhancement and fluorescence lifetime response. Finally, the cellular uptake and localisation of these optical probes were investigated. Whilst structural modifications to the triangulenium core only slightly alter the binding affinity to DNA, BDATA-M2 and CDATA-M2 cannot distinguish between DNA topologies through their fluorescence lifetime. This work presents valuable new evidence into the critical role of PET quenching when using the fluorescence lifetime of triangulenium dyes to discriminate G4 DNA from duplex DNA, highlighting the importance of fine tuning redox and spectral properties when developing new triangulenium-based G4 probes.
Journal articleVilar Compte R, Summers P, Lewis B, et al., 2021,
Visualising G-quadruplex DNA dynamics in live cells by fluorescence lifetime imaging microscopy, Nature Communications, Vol: 12, ISSN: 2041-1723
Guanine rich regions of oligonucleotides fold into quadruple-stranded structures called G-quadruplexes (G4s). Increasing evidence suggests that these G4 structures form in vivo and play a crucial role in cellular processes. However, their direct observation in live cells remains a challenge. Here we demonstrate that a fluorescent probe (DAOTA-M2) in conjunction with fluorescence lifetime imaging microscopy (FLIM) can identify G4s within nuclei of live and fixed cells. We present a FLIM-based cellular assay to study the interaction of non-fluorescent small molecules with G4s and apply it to a wide range of drug candidates. We also demonstrate that DAOTA-M2 can be used to study G4 stability in live cells. Reduction of FancJ and RTEL1 expression in mammalian cells increases the DAOTA-M2 lifetime and therefore suggests an increased number of G4s in these cells, implying that FancJ and RTEL1 play a role in resolving G4 structures in cellulo.
Journal articleVilar Compte R, Reeh K, Summers P, et al., 2020,
Design, synthesis and evaluation of a tripodal receptor for phosphatidylinositol phosphates, Scientific Reports, Vol: 10, ISSN: 2045-2322
Phosphatidylinositol phosphates (PIPs) are membrane phospholipids that play crucial roles in a wide range of cellular processes. Their function is dictated by the number and positions of the phosphate groups in the inositol ring (with seven different PIPs being active in the cell). Therefore, there is significant interest in developing small-molecule receptors that can bind selectively to these species and in doing so affect their cellular function or be the basis for molecular probes. However, to date there are very few examples of such molecular receptors. Towards this aim, herein we report a novel tripodal molecule that acts as receptor for mono- and bis-phosphorylated PIPs in a cell free environment. To assess their affinity to PIPs we have developed a new cell free assay based on the ability of the receptor to prevent alkaline phosphatase from hydrolysing these substrates. The new receptor displays selectivity towards two out of the seven PIPs, namely PI(3)P and PI(3,4)P2. To rationalise these results, a DFT computational study was performed which corroborated the experimental results and provided insight into the host–guest binding mode.
Journal articleRitzau-Reid K, Spicer C, Gelmi A, et al., 2020,
An electroactive oligo-EDOT platform for neural tissue engineering, Advanced Functional Materials, Vol: 30, Pages: 1-11, ISSN: 1616-301X
The unique electrochemical properties of the conductive polymer poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) make it an attractive material for use in neural tissue engineering applications. However, inadequate mechanical properties, and difficulties in processing and lack of biodegradability have hindered progress in this field. Here, we have improved the functionality of PEDOT:PSS for neural tissue engineering by incorporating 3,4-ethylenedioxythiophene (EDOT) oligomers, synthesised using a novel end-capping strategy, into block co-polymers. By exploiting end-functionalised oligoEDOT constructs as macroinitiators for the polymerization of poly(caprolactone) (PCL), we produce a block co-polymer that is electroactive, processable, and bio-compatible. By combining these properties, we were able to produce electroactive fibrous mats for neuronal culture via solution electrospinning and melt electrospinning writing (MEW). Importantly, we also show that neurite length and branching of neural stem cells can be enhanced on our materials under electrical stimulation, demonstrating the promise of these scaffolds for neural tissue engineering.
Journal articleBullen J, Lapinee C, Salaün P, et al., 2020,
On the application of photocatalyst-sorbent composite materials for arsenic(III) remediation: Insights from kinetic adsorption modelling, Journal of Environmental Chemical Engineering, Vol: 8, ISSN: 2213-3437
TiO2-Fe2O3 composites show great promise for the removal of arsenic(III) from drinking water: this single material combines the photocatalytic capabilities of TiO2 for the oxidation of arsenite (i.e. As(III)) with the high adsorption capacity of iron oxides towards the arsenate (i.e. As(V)) subsequently produced. To design an effective treatment, it is necessary to balance high sorbent concentrations, providing long filter lifetimes, with low photocatalyst concentrations, to achieve effective penetration of light into the system. In this work, we construct a predictive model using experimentally determined As(III) adsorption isotherms and kinetics to estimate arsenic treatment plant lifetimes. We considered sorbent loading, treatment time, and batch treatment versus continuous-flow. Our model indicated that batch treatment is more efficient than continuous-flow at low sorbent concentrations (<100 g L-1), and therefore more appropriate for the photocatalyst-sorbent system. However, with <100 g L-1 sorbent, media should be replaced several times per year to maintain effective treatment. In contrast, slurries of >100 g L-1 sorbent could operate for an entire year without media replacement. This work highlights the important implications of sorbent concentration when we consider the multifunctional photocatalysts-sorbent system, and highlights the need for further experimental work to design efficient arsenic treatment plants.
Journal articleMaurice J, Lett A, Skinner C, et al., 2020,
Transcutaneous fluorescence spectroscopy as a tool for non-invasive monitoring of gut function: first clinical experiences, Scientific Reports, Vol: 10, ISSN: 2045-2322
Gastro-intestinal function plays a vital role in conditions ranging from inflammatory bowel disease and HIV through to sepsis and malnutrition. However, the techniques that are currently used to assess gut function are either highly invasive or unreliable. Here we present an alternative, non-invasive sensing modality for assessment of gut function based on fluorescence spectroscopy. In this approach, patients receive an oral dose of a fluorescent contrast agent and a fibre-optic probe is used to make fluorescence measurements through the skin. This provides a readout of the degree to which fluorescent dyes have permeated from the gut into the blood stream. We present preliminary results from our first measurements in human volunteers demonstrating the potential of the technique for non-invasive monitoring of multiple aspects of gastro-intestinal health.
Journal articleBullen JC, Torres-Huerta A, Salaün P, et al., 2020,
Portable and rapid arsenic speciation in synthetic and natural waters by an As(V)-selective chemisorbent, validated against anodic stripping voltammetry, Water Research, Vol: 175, Pages: 1-11, ISSN: 0043-1354
Inorganic arsenic speciation, i.e. the differentiation between arsenite and arsenate, is an important step for any program aiming to address the global issue of arsenic contaminated groundwater, whether for monitoring purposes or the development of new water treatment regimes. Reliable speciation by easy-to-use, portable and cost-effective analytical techniques is still challenging for both synthetic and natural waters. Here we demonstrate the first application of an As(V)-selective chemisorbent material for simple and portable speciation of arsenic using handheld syringes, enabling high sample throughput with minimal set-up costs. We first show that ImpAs efficiently removes As(V) from a variety of synthetic groundwaters with a single treatment, whilst As(III) is not retained. We then exemplify the potential of ImpAs for simple and fast speciation by determining rate constants for the photooxidation of As(III) in presence of a TiO2 photocatalyst. Finally, we successfully speciate natural waters spiked with a mix of As(III) and As(V) in both Indian and UK groundwaters with less than 5 mg L−1 dissolved iron. Experimental results using ImpAs agreed with anodic stripping voltammetry (ASV), a benchmark portable technique, with analysis conditions optimised here for the groundwaters of South Asia. This new analytical tool is simple, portable and fast and should find applications within the overall multi-disciplinary remediation effort that is taking place to tackle this worldwide arsenic problem.
Journal articleVilar R, Torres Huerta A, Chan TG, et al., 2020,
Molecular recognition of bisphosphonate-based drugs by di-zinc receptors in aqueous solution and on gold nanoparticles, Dalton Transactions, Vol: 49, Pages: 5939-5948, ISSN: 1477-9226
Metal-based anion receptors have several important applications in sensing, separation and transport of negatively charged species. Amongst these receptors, di-zinc(II) complexes are of particular interest for the recognition of oxoanions, in particular phosphate derivatives. Herein we report the synthesis of a di-zinc(II) receptor and show that it has high affinity and selectivity for bisphosphonates such as alendronate and etidronate – which are used to treat a number of skeletal disorders as well as showing interesting anticancer properties. The binding mode of the di-zinc(II) receptor with alendronate and etidronate has been unambiguously established by single crystal X-ray crystallography. In addition, by modifying the backbone of the receptor, we show that the drug-loaded receptor can be attached onto gold nanoparticles as potential drug-delivery vehicles.
Journal articlePont I, Martínez-Camarena Á, Galiana-Roselló C, et al., 2020,
Development of polyamine substituted triphenylamine ligands with high affinity and selectivity for G-quadruplex DNA, ChemBioChem: a European journal of chemical biology, Vol: 21, Pages: 1167-1177, ISSN: 1439-4227
Currently significant efforts are devoted to designing small molecules able to bind selectively to guanine-quadruplexes (G4s). These non-canonical DNA structures are implicated in various important biological processes and have been identified as potential targets for drug development. Previously, we reported a series of triphenylamine(TPA)-based compounds including macrocyclic polyamines, which display high affinity towards G4 DNA. Following from this initial work, herein we present a series of second-generation compounds, in which the central TPA has been functionalised with flexible and adaptive linear polyamines, aiming to maximise the selectivity towards G4 DNA. The acid-base properties of the new derivatives have been studied by means of potentiometric titrations, UV-Vis and fluorescence emission spectroscopies. The interaction with G4s and duplex DNA has been explored using FRET melting assays, fluorescence spectroscopy and circular dichroism. Compared to our previously TPA derivatives with macrocyclic substituents, the new ligands reported herein retain the G4 affinity, but display two orders of magnitude higher selectivity for G4 vs. duplex DNA, most likely due to the ability of the linear substituents to embrace the G4 structure.
Book chapterVilar R, 2020,
Interaction of metal complexes with G-quadruplex DNA, MEDICINAL CHEMISTRY, Editors: Sadler, VanEldik, Publisher: ELSEVIER ACADEMIC PRESS INC, Pages: 425-445, ISBN: 978-0-12-819196-5
- Author Web Link
- Citations: 5
Book chapterKench T, Vilar R, 2020,
Metal complexes as G-quadruplex binders, QUADRUPLEX NUCLEIC ACIDS AS TARGETS FOR MEDICINAL CHEMISTRY, Editors: Neidle, Publisher: ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD, Pages: 485-515
- Author Web Link
- Citations: 11
Journal articleVilar R, Ruehl CL, Lim AHM, et al., 2019,
An octahedral cobalt(III) complex with axial NH3 ligands that templates and selectively stabilises G-quadruplex DNA, Chemistry - A European Journal, Vol: 25, Pages: 9691-9700, ISSN: 0947-6539
Guanine-rich sequences of DNA are known to readily fold into tetra-stranded helical structures known as G-quadruplexes (G4). Due to their biological relevance, G4s are potential anticancer drug targets and therefore there is significant interest in molecules with high affinity for these structures. Most G4 binders are polyaromatic planar compounds which π-π stack on the G4's guanine tetrad. However, many of these compounds are not very selective since they can also intercalate into duplex DNA. Herein we report a new class of binder based on an octahedral cobalt(III) complex that binds to G4 via a different mode involving hydrogen-bonding, electrostatic interactions and π-π stacking. We show that this new compound binds selectivity to G4 over duplex DNA (particularly to the G-rich sequence of the c-myc promoter). This new octahedral complex also has the ability to template he formation of G4 DNA from the unfolded sequence. Finally, we show that upon binding to G4, the complex prevents helicase Pif1-p from unfolding the c-myc G4 structure.
Journal articlePaulose Nadappuram B, Cadinu P, Barik A, et al., 2019,
Nanoscale tweezers for single-cell biopsies, Nature Nanotechnology, Vol: 14, Pages: 80-88, ISSN: 1748-3387
Much of the functionality of multicellular systems arises from the spatial organization and dynamic behaviours within and between cells. Current single-cell genomic methods only provide a transcriptional ‘snapshot’ of individual cells. The real-time analysis and perturbation of living cells would generate a step change in single-cell analysis. Here we describe minimally invasive nanotweezers that can be spatially controlled to extract samples from living cells with single-molecule precision. They consist of two closely spaced electrodes with gaps as small as 10–20 nm, which can be used for the dielectrophoretic trapping of DNA and proteins. Aside from trapping single molecules, we also extract nucleic acids for gene expression analysis from living cells without affecting their viability. Finally, we report on the trapping and extraction of a single mitochondrion. This work bridges the gap between single-molecule/organelle manipulation and cell biology and can ultimately enable a better understanding of living cells.
Journal articleFerraro G, Pica A, Petruk G, et al., 2018,
Preparation, structure, cytotoxicity and mechanism of action of ferritin-Pt(II) terpyridine compound nanocomposites, Nanomedicine, Vol: 13, Pages: 2995-3007, ISSN: 1743-5889
Aim: A Pt(II)-terpyridine compound, bearing two piperidine substituents at positions 2 and 2′ of the terpyridine ligand (1), is highly cytotoxic and shows a mechanism of action distinct from cisplatin. 1 has been incorporated within the ferritin nanocage (AFt). Materials & methods: Spectroscopic and crystallographic data of the Pt(II)–AFt nanocomposite have been collected and in vitro anticancer activity has been explored using cancer cells. Results: Pt(II)-containing fragments bind His49, His114 and His132. Pt(II)–AFt nanocomposite is less cytotoxic than 1, but it is more toxic than cisplatin at high concentrations. The Pt(II)–AFt nanocomposite triggers necrosis in cancer cells, as free 1 does. Conclusion: Pt(II)–AFt nanocomposites are promising vehicles to deliver Pt-based drugs to cancer cells.
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