179 results found
Vilar R, Kench T, Summers PA, et al., 2021, Rotaxanes as cages to control DNA binding, cytotoxicity and cellular uptake of a small molecule., Angew Chem Int Ed Engl
The efficacy of many drugs can be limited by undesirable properties such as poor aqueous solubility, low bioavailability, and "off-target" interactions in the body. To combat these deficiencies, various drug carriers have been investigated to enhance the pharmacological profile of therapeutic agents. Inspired by the high degree of spatiotemporal control afforded by photopharmacology, in this work we demonstrate the potential for using mechanical protection to 'cage' a DNA-targeting metallodrug within a photodegradable rotaxane. More specifically, we report the synthesis of rotaxanes which incorporate as a stoppering unit a known G-quadruplex DNA binder, namely a PtII-salphen complex. This compound is prevented from interacting with DNA when it is part of the mechanically interlocked assembly. The second rotaxane stopper was designed to be cleaved by either light or the activity of an esterase. In the presence of such stimuli, the rotaxane breaks apart, releasing the PtII-salphen complex and activating its ability to bind to DNA. We also show the mechanically interlocked system shows enhanced cell permeability and limited cytotoxicity within osteosarcoma cells compared to the free drug. Light activation, however, leads to a dramatic increase in cytotoxicity, concluded to arise from translocation to the nucleus and subsequent binding to DNA.
Vilar 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.
Vilar 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.
Vilar R, Lewis BW, Bisballe N, et al., 2020, Assessing the key photophysical properties of triangulenium dyes for DNA binding by alteration of the fluorescent core, Chemistry: A European Journal, 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.
Ritzau-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.
Bullen 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.
Maurice 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.
Bullen 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.
Vilar 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.
Pont 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.
Kench 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
Vilar 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
Vilar 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.
Much of the functionality of multi-cellular systems arises from the spatial organisation 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-cellanalysis. 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 usedfor 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.
Ferraro 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.
Łęczkowska A, Gonzalez-Garcia J, Perez-Arnaiz C, et al., 2018, Binding studies of metal-salphen and metal-bipyridine complexes towards G-quadruplex DNA, Chemistry - A European Journal, Vol: 24, Pages: 11785-11794, ISSN: 0947-6539
The proposed in vivo formation of G-quadruplex DNA (G4 DNA) in promoter regions of oncogenes and in telomeres has prompted the development of small molecules with high affinity and selectivity for these structures. Herein we report the synthesis of a new di-substituted bipyridine ligand and the corresponding complexes with Ni2+ and VO2+ . Both these new complexes have been characterized spectroscopically and by X-ray crystallography. Detailed DNA binding studies of these two complexes, together with three previously reported metal salphen complexes, are presented. Using FRET melting assays, the binding affinity and selectivity of the five metal complexes against six different G4 DNA structures as well as a duplex DNA have been determined. In addition, we present detailed ITC and UV/Vis studies to characterize the interaction of the complexes with human telomeric G4 DNA. Finally, we show via a polymerase stop assay that these complexes are able to stabilize a G4 DNA structure (from the c-Myc oncogene promoter) and halt the activity of Taq polymerase.
Pont I, González-García J, Inclán M, et al., 2018, Aza-macrocyclic triphenylamine ligands for G-quadruplex recognition, Chemistry - A European Journal, Vol: 24, Pages: 10850-10858, ISSN: 0947-6539
A new series of triphenylamine-based ligands with one (TPA1PY), two (TPA2PY) or three pending aza-macrocycle(s) (TPA3PY) have been synthesised and studied by means of pH-metric titrations, UV/Vis spectroscopy and fluorescence experiments. The affinity of these ligands for G-quadruplex (G4) DNA and its selectivity over duplex DNA were investigated by FRET melting assays, fluorimetric titrations and circular dichroism (CD) spectroscopy. Interestingly, the interaction of the bi- and specially the tri-branched ligand with G4 leads to a very intense red-shifted fluorescence emission band which may be associated with intermolecular aggregation between the molecule and the DNA. This light-up effect allows the application of the ligands as fluorescence probes to selectivity detect G4.
Ferraro G, Marzo T, Infrasca T, et al., 2018, A case of extensive protein platination: the reaction of lysozyme with a Pt(ii)-terpyridine complex, Dalton Transactions, Vol: 47, Pages: 8716-8723, ISSN: 1477-9234
An antiproliferative platinum(ii)-terpyridine complex bearing two piperidine substituents at positions 2 and 2' (compound 1, hereafter) interacts non-covalently with DNA and induces cell death through necrosis, i.e. a mode of action that is distinct from that exhibited by cisplatin (Suntharalingam, et al., Metallomics, 2013, 5, 514). Here, the interaction between this Pt compound and the model protein hen egg white lysozyme (HEWL) was studied by both electrospray ionization mass spectrometry (ESI MS) and X-ray crystallography. The ESI MS data collected after 24 h protein incubation with compound 1 at two different pH values offer evidence that the metal complex degrades upon reaction with HEWL, forming adducts with 1 : 1, 2 : 1 and 3 : 1 Pt/protein ratios. Two different X-ray structures of Pt-protein adducts, obtained by the reaction of HEWL with the Pt compound under different experimental conditions and incubation times, are then reported. An unexpected extensive platination of the protein is clearly observed: Pt containing fragments bind close to the NZ atom of Lys1 and OE1 atom of Glu7, NE2 atom of His15 and NH1 atom of Arg14, ND1 atom of His15, NZ atom of Lys96, NZ atom of Lys97 and ND1 atom of Asn93, NZ atom of Lys13 and the C-terminal carboxylate, and the N-terminal amine. An additional binding site was observed close to the NZ atom of Lys33. These results suggest that both N- and C-terminal tails, as well as Lys side chains, have to be considered as potential binding sites of Pt-containing drugs. The peculiar reactivity of compound 1 with biological macromolecules could play a role in its mode of action.
Chan T, Morse S, Copping M, et al., 2018, Targeted delivery of DNA-Au nanoparticles across the blood-brain barrier using focused ultrasound, ChemMedChem, Vol: 13, Pages: 1311-1314, ISSN: 1860-7187
Nanoparticles have been widely studied as versatile platforms for in vivo imaging and therapy. However, their use to image and/or treat the brain is limited, as they are often unable to cross the blood–brain barrier (BBB). To overcome this problem, herein we report the use of focused ultrasound in vivo to successfully deliver DNA‐coated gold nanoparticles to specific locations in the brains of mice.
Rakers V, Cadinu P, Edel JB, et al., 2018, Development of microfluidic platforms for the synthesis of metal complexes and evaluation of their DNA affinity using online FRET melting assays, Chemical Science, Vol: 9, Pages: 3459-3469, ISSN: 2041-6520
Guanine-rich DNA sequences can fold into quadruple-stranded structures known as G-quadruplexes. These structures have been proposed to play important biological roles and have been identified as potential drug targets. As a result, there is increasing interest in developing small molecules that can bind to G-quadruplexes. So far, these efforts have been mostly limited to conventional batch synthesis. Furthermore, no quick on-line method to assess new G-quadruplex binders has been developed. Herein, we report on two new microfluidic platforms to: (a) readily prepare G-quadruplex binders (based on metal complexes) in flow, quantitatively and without the need for purification before testing; (b) a microfluidic platform (based on FRET melting assays of DNA) that enables the real-time and on-line assessment of G-quadruplex binders in continuous flow.
Vilar R, 2018, Nucleic acid quadruplexes and metallo-drugs, Metallo-Drugs: Development and Action of Anticancer Agents, Pages: 325-349, ISBN: 9783110469844
© Walter de Gruyter GmbH, Berlin, Germany 2018. Guanine-rich sequences of DNA can readily fold into tetra-stranded helical assemblies known as G-quadruplexes (G4s). It has been proposed that these structures play important biological roles in transcription, translation, replication, and telomere maintenance. Therefore, over the past 20 years they have been investigated as potential drug targets for small molecules including metal complexes. This chapter provides an overview of the different classes of metal complexes as G4-binders and discusses the application of these species as optical probes for G-quadruplexes as well as metallo-drugs.
Vilar R, 2018, Nucleic Acid Quadruplexes and Metallo-Drugs., Met Ions Life Sci, Vol: 18, ISSN: 1559-0836
Guanine-rich sequences of DNA can readily fold into tetra-stranded helical assemblies known as G-quadruplexes (G4s). It has been proposed that these structures play important biological roles in transcription, translation, replication, and telomere maintenance. Therefore, over the past 20 years they have been investigated as potential drug targets for small molecules including metal complexes. This chapter provides an overview of the different classes of metal complexes as G4-binders and discusses the application of these species as optical probes for G-quadruplexes as well as metallo-drugs.
Bandeira S, Gonzalez-Garcia J, Pensa E, et al., 2018, A Redox-Activated G-Quadruplex DNA Binder Based on a Platinum(IV)-Salphen Complex, Angewandte Chemie, Vol: 130, Pages: 316-319, ISSN: 0044-8249
Cowell S, Carroll L, Lavdas I, et al., 2017, Towards an MMP-2-activated molecular agent for cancer imaging, Dalton Transactions, Vol: 47, Pages: 1530-1534, ISSN: 1477-9234
Matrix metalloproteinases (MMPs) have been identified as biomarkers for cancer, offering prognostic potential; however, non-invasive detection protocols are currently lacking. Herein, we describe the synthesis of a DOTA-containing peptide sequence that can be radiolabelled easily with 68Gallium or can be incorporated with gadolinium for possible MRI applications with clear selectivity for MMP-2 over other members of the MMP family, giving MMP-2 selective cleavage of the labelled peptides.
Vilar R, Bandeira S, Gonzalez Garcia J, et al., 2017, A redox-activated G-quadruplex DNA binder based on a platinum(IV)-salphen complex., Angewandte Chemie International Edition, Vol: 57, Pages: 310-313, ISSN: 1521-3757
There has been increasing interest in the development of small molecules that can selectively bind to G-quadruplex DNA structures. The latter have been associated to a number of key biological processes and therefore are proposed to be potential targets for drug development. In this paper we report the first example of a reduction-activated G-quadruplex DNA binder. We show that a new octahedral platinum(IV)-salphen complex does not interact with DNA in aqueous media at pH 7.4; however, upon addition of bio-reductants such as ascorbic acid or glutathione, the compound readily reduces to the corresponding square planar platinum(II) complex. In contrast to the parent platinum(IV) complex, the in situ generated platinum(II) complex binds to HTelo and c-Myc G-quadruplex DNA with affinity constants up to 106 M-1.
Pyne ALB, Hoogenboom BW, Vilar R, et al., 2017, Visualisation of DNA conformational changes in situ at nanometre resolution, 19th IUPAB Congress / 11th EBSA Congress, Publisher: SPRINGER, Pages: S369-S369, ISSN: 0175-7571
Gonzalez-Garcia J, Vilar R, 2017, Supramolecular Principles for Small Molecule Binding to DNA Structures, Comprehensive Supramolecular Chemistry II, Pages: 39-70, ISBN: 9780128031995
© 2017 Elsevier Ltd. All rights reserved. Small molecules that interact with deoxyribonucleic acid (DNA) are important for the development of drugs and biomolecular tools. There are indeed several drugs in clinical use whose main biological target is DNA; likewise, a range of optical probes that bind to DNA are routinely used to study biological systems. Therefore, understanding, rationalizing, and predicting the interaction of small molecules with DNA is an important area of research. This article provides an overview of the key noncovalent interactions used by small organic and metal-organic molecules to bind to DNA. The first part of the article provides an overview of the different DNA structures/topologies and the key supramolecular interactions they display. The subsequent sections of the article have been divided by the type of DNA structure that is being targeted as well as by the binding mode displayed by the molecules discussed. Rather than providing an exhaustive and comprehensive review of the very extensive literature, the main aim of this article is to highlight the key supramolecular principles that drive these interactions.
Cilibrizzi A, Fedorova M, Collins J, et al., 2017, A tri-functional vanadium(IV) complex to detect cysteine oxidation, DALTON TRANSACTIONS, Vol: 46, Pages: 6994-7004, ISSN: 1477-9226
The development of effective molecular probes to detect and image the levels of oxidative stress in cells remains a challenge. Herein we report the design, synthesis and preliminary biological evaluation of a novel optical probe to monitor oxidation of thiol groups in cysteine-based phosphatases (CBPs). Following orthogonal protecting approaches we synthesised a new vanadyl complex designed to bind to CBPs. This complex is functionalised with a well-known dimedone derivative (to covalently trap sulfenic acids, SOHs) and a coumarin-based fluorophore for optical visualization. We show that this new probe efficiently binds to a range of phosphatases in vitro with nanomolar affinity. Moreover, preliminary flow cytometry and microscopy studies in live HCT116 cells show that this probe can successfully image cellular levels of sulfenic acids – one of the species resulting from protein oxidative damage.
Cilibrizzi A, Terenghi M, Fedorova M, et al., 2017, Small-molecule optical probes for cell imaging of protein sulfenylation and their application to monitor cisplatin induced protein oxidation, Sensors and Actuators B: Chemical, Vol: 248, Pages: 437-446, ISSN: 0925-4005
Reactive oxygen species (ROS) are considered versatile second messengers mediating fundamental biological functions. A molecular pathway by which ROS determine functional diversity is the selective oxidation of cysteine residues to form sulfenic acid (SOH) products, known as sulfenylation or S-hydroxylation. This crucial post-translational modification is responsible for the alteration of protein stability, function and signalling. Despite considerable advances on the identification of sulfenic residues on individual proteins, improved methods are needed for direct visualization and accurate quantification of the extent of total protein sulfenylation. Herein we present the synthesis of two new cell-permeable fluorescent probes containing dimedone (a cyclic β-diketone with high specificity for sulfenic acids), and apply them to study oxidation processes in individual cells via microscopy. The low cytotoxicity, cell permeability and optical features of the probes allowed us to visualize and quantify the oxidation of cysteine residues in live cells during H2O2-mediated oxidative burst (i.e. exogenously administered H2O2). We present preliminary cellular imaging studies with these probes to analyse the oxidation process in cells treated with the anticancer drug cisplatin.
Zhou CQ, Liao TC, Li ZQ, et al., 2017, Di-nickel-salphen complexes as binders of human telomeric dimeric G-quadruplexes, Chemistry - A European Journal, Vol: 23, Pages: 4713-4722, ISSN: 0947-6539
Three new polyether-tethered di-nickel-salphen complexes (2a-c) have been synthesized and fully characterized by NMR spectroscopy, mass spectrometry and elemental analyses. The binding affinity and selectivity of these complexes and of the parent mono-nickel complex (1) towards dimeric quadruplex DNA have been determined by UV-Vis titrations, fluorescence spectroscopy, CD spectroscopy and electrophoresis. These studies have shown that the di-nickel-salphen complex with the longest polyether linker (2c) has higher binding affinity and selectivity towards dimeric quadruplexes (over monomeric quadruplexes) than the di-nickel-salphen complexes with the shorter polyether linkers (2a and 2b). Complex 2c also has higher selectivity towards human telomeric dimeric quadruplexes with one TTA linker than the monometallic complex 1. Based on the spectroscopic data, a possible binding mode between complex 2c and the dimeric G-quadruplex DNA under study is proposed.
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