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  • Journal article
    Gama S, Rodrigues I, Mendes F, Santos IC, Gabano E, Klejevskaja B, Gonzalez-Garcia J, Ravera M, Vilar R, Paulo Aet al., 2016,

    Anthracene-terpyridine metal complexes as new G-quadruplex DNA binders

    , Journal of Inorganic Biochemistry, Vol: 160, Pages: 275-286, ISSN: 1873-3344

    The formation of quadruple-stranded DNA induced by planar metal complexes has particular interest in the development of novel anticancer drugs. This is especially relevant for the inhibition of telomerase, which plays an essential role in cancer cell immortalization and is overexpressed in ca. 85-90% of cancer cells. Moreover, G-quadruplexes also exist in other locations in the human genome, namely oncogene promoter regions, and it has been hypothesized that they play a regulatory role in gene transcription. Herein we report a series of new anthracene-containing terpyridine ligands and the corresponding Cu(II) and Pt(II) complexes, with different linkers between the anthracenyl moiety and the terpyridine chelating unit. The interaction of these ligands and metal complexes with different topologies of DNA was studied by several biophysical techniques. The Pt(II) and Cu(II) complexes tested showed affinity for quadruplex-forming sequences with a good selectivity over duplex DNA. Importantly, the free ligands do not have significant affinity for any of the DNA sequences used, which shows that the presence of the metal is essential for high affinity (and selectivity). This effect is more evident in the case of the Pt(II) complexes. Moreover, the presence of a longer linker between the chelating terpyridine unit and the anthracene moiety enhances the interaction with G-quadruplex-forming sequences. We further evaluated the ability of the Cu(II) complexes to interact with, and stabilize G-quadruplex containing regions in oncogene promoters via a polymerase stop assay. These studies indicated that the metal complexes are able to induce G-quadruplex formation and stop polymerase activity.
  • Journal article
    Vilar Compte R, Shivalingam A, Vysniauskas A, Albrecht T, White AJ, Kuimova MKet al., 2016,

    Trianguleniums as optical probes for G-quadruplexes: A photophysical, electrochemical and computational study

    , Chemistry - A European Journal, Vol: 22, Pages: 4129-4139, ISSN: 0947-6539

    Nucleic acids can adopt non-duplex topologies such as G-quadruplexes in vitro. Yet it hasbeen challenging to establish their existence and function in vivo due to a lack of suitabletools. Recently, we identified the triangulenium compound DAOTA-M2 as a uniquefluorescence probe for such studies. This probe’s emission lifetime is highly dependent onthe topology of the DNA it interacts with opening up the possibility of carrying out live cellimaging studies. Herein we describe the origin of its fluorescence selectivity for Gquadruplexes.Cyclic voltammetry predicts that the appended morpholino groups can act asintra-molecular photo-induced electron transfer (PET) quenchers. Photophysical studies showthat a delicate balance between this effect and inter-molecular PET with nucleobases is key tothe overall fluorescence enhancement observed upon nucleic acid binding. We utilisedcomputational modelling to demonstrate a conformational dependence of intra-molecularPET. Finally, we performed orthogonal studies with a triangulenium compound where themorpholino groups were removed and demonstrate that this change inverts trianguleniumfluorescence selectivity from G-quadruplex to duplex DNA, thus highlighting the importanceof fine-tuning the molecular structure not only for target affinity but also for fluorescenceresponse.
  • Journal article
    Ang DL, Harper BWJ, Cubo L, Mendoza O, Vilar R, Aldrich-Wright Jet al., 2016,

    Quadruplex DNA-Stabilising Dinuclear Platinum(II) Terpyridine Complexes with Flexible Linkers

    , CHEMISTRY-A EUROPEAN JOURNAL, Vol: 22, Pages: 2317-2325, ISSN: 0947-6539
  • Journal article
    Ang DL, Harper BWJ, Cubo L, Mendoza O, Vilar R, AldrichWright Jet al., 2016,

    Back Cover: Quadruplex DNA‐Stabilising Dinuclear Platinum(II) Terpyridine Complexes with Flexible Linkers (Chem. Eur. J. 7/2016)

    , Chemistry – A European Journal, Vol: 22, Pages: 2540-2540, ISSN: 0947-6539
  • Journal article
    Turek VA, Francescato Y, Cadinu P, Crick CR, Elliott L, Chen Y, Urland V, Ivanov AP, Hong M, Vilar R, Maier SA, Giannini V, Edel JBet al., 2015,

    Self-Assembled Spherical Supercluster Metamaterials from Nanoscale Building Blocks

    , ACS Photonics, Vol: 3, Pages: 35-42, ISSN: 2330-4022

    We report on a simple, universal and large scale self-assembly method for generation of spherical superclusters from nanoscopic building blocks. The fundamentals of this approach relies on the ultra-high pre-concentration of nanoparticles (NP) followed by either using emulsification strategies or alternatively multiphase microfluidic microdroplets. In both cases drying of the NP droplets yield highly spherical self-assembled superclusters with unique optical properties. We demonstrate that the behaviour of these spheres can be controlled by surface functionalization before and after the self-assembly process. These structures show unique plasmonic collective response both on the surface and within the supercluster in the visible and infrared regions. Furthermore, we demonstrate that these strong, tunable optical modes can be used towards ultra-sensitive, reproducible, surface-enhanced spectroscopies.
  • Journal article
    Mion G, Gianferrara T, Bergamo A, Gasser G, Pierroz V, Rubbiani R, Vilar R, Leczkowska A, Alessio Eet al., 2015,

    Phototoxic Activity and DNA Interactions of Water-Soluble Porphyrins and Their Rhenium(I) Conjugates

    , CHEMMEDCHEM, Vol: 10, Pages: 1901-1914, ISSN: 1860-7179
  • Journal article
    Shivalingam A, Izquierdo MA, Le Marois A, Vyšniauskas A, Suhling K, Kuimova MK, Vilar Ret al., 2015,

    The interactions between a small molecule and G-quadruplexes are visualised by fluorescence lifetime imaging microscopy

    , Nature Communications, Vol: 6, Pages: 1-10, ISSN: 2041-1723

    Guanine-rich oligonucleotides can fold into quadruple-stranded helical structures known as G-quadruplexes. Mounting experimental evidence has gathered suggesting that these non-canonical nucleic acid structures form in vivo and play essential biological roles. However, to date, there are no small-molecule optical probes to image G-quadruplexes in live cells. Herein, we report the design and development of a small fluorescent molecule, which can be used as an optical probe for G-quadruplexes. We demonstrate that the fluorescence lifetime of this new probe changes considerably upon interaction with different nucleic acid topologies. Specifically, longer fluorescence lifetimes are observed in vitro for G-quadruplexes than for double- and single-stranded nucleic acids. Cellular studies confirm that this molecule is cell permeable, has low cytotoxicity and localizes primarily in the cell nucleus. Furthermore, using fluorescence lifetime imaging microscopy, live-cell imaging suggests that the probe can be used to study the interaction of small molecules with G-quadruplexes in vivo.
  • Journal article
    Mendoza C, Jansat S, Vilar R, Pericas MAet al., 2015,

    Clickable complexing agents: functional crown ethers for immobilisation onto polymers and magnetic nanoparticles

    , RSC ADVANCES, Vol: 5, Pages: 87352-87363, ISSN: 2046-2069
  • Journal article
    Moffat CD, Weiss DJ, Shivalingam A, White AJP, Salauen P, Vilar Ret al., 2014,

    Molecular recognition and scavenging of arsenate from aqueous solution using dimetallic receptors

    , Chemistry: A European Journal, Vol: 20, Pages: 17168-17177, ISSN: 0947-6539

    A series of copper(II), nickel(II) and zinc(II) dimetallic complexes were prepared and their affinities towards arsenate investigated. Indicator displacement assays (IDAs) were carried out to establish the complexes with best affinities towards arsenate. A di-zinc complex (3) was selected and its arsenate-binding abilities investigated by isothermal titration calorimetry (ITC). The X-ray crystal structure of this metallo-receptor bound to arsenate is also reported, which allowed us to establish the binding mode between 3 and this oxyanion. Immobilising 3 onto HypoGel resin yielded a novel adsorbent (Zn–HypoGel) with high affinity for arsenate. Adsorption of arsenate from competitive solutions and natural groundwater was greater than that of the commercially used iron oxide Bayoxide E33. Zn–HypoGel could be efficiently and simply regenerated by washing with sodium acetate solution.
  • Journal article
    Stafford VS, Suntharalingam K, Shivalingam A, White AJP, Mann DJ, Vilar Ret al., 2014,

    Syntheses of polypyridyl metal complexes and studies of their interaction with quadruplex DNA

    , Dalton Transactions, Vol: 44, Pages: 3686-3700, ISSN: 1477-9226

    A series of mono- and bi-metallic metal complexes (with CuII, PtII and ZnII) with substituted polypyridylligands have been prepared and their binding affinities towards quadruplex (c-Myc and human telomeric)and duplex DNA (ds26 and calf thymus) determined using fluorescent indicator displacement (FID) assaysand UV/vis spectroscopic titrations. These studies have shown that the number of aromatic rings andnumber/position of cyclic amine substituents on the ligands, play an important role in defining the DNAbinding abilities of the resulting metal complexes. We also show that bi-metallic complexes preparedusing a novel terpyridine-cyclen ligand have higher affinity towards G-quadruplex DNA as compared totheir mono-metallic counterparts. Cytotoxicity assays were carried out for all the new complexes againstan osteosarcoma cancer cell line (U2OS) as well as a normal fibroblast cell line (GM05757). Several ofthese compounds displayed cytotoxicity similar to that of cisplatin.
  • Conference paper
    Cilibrizzi A, Collins J, Woscholski R, Leatherbarrow R, Vilar Ret al., 2014,

    New vanadium complexes as optical probes to detect Cys sulfenic modifications in PTEN

    , 12th European Biological Inorganic Chemistry Conference (EuroBIC), Publisher: Springer Verlag (Germany), Pages: S873-S873, ISSN: 1432-1327
  • Conference paper
    Stafford V, Shivalingam A, Suntharalingam K, Mann D, Vilar Ret al., 2014,

    Interaction of metal complexes with G-quadruplex DNA and their effects on gene expression

    , 12th European Biological Inorganic Chemistry Conference (EuroBIC), Publisher: SPRINGER, Pages: S740-S740, ISSN: 0949-8257
  • Journal article
    Zhou W, Vilar R, Ying L, Harding SEet al., 2014,

    Transcriptional regulatory roles of G-quadruplex DNA in promoters of genes involved in beta-adrenergic signaling pathway

    , CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
  • Journal article
    Sala R, Quang-De N, Patel CBK, Mann D, Steinke JHG, Vilar R, Aboagye EOet al., 2014,

    Phosphorylation Status of Thymidine Kinase 1 Following Antiproliferative Drug Treatment Mediates 3′-Deoxy-3′-[<SUP>18</SUP>F]-Fluorothymidine Cellular Retention

    , PLOS ONE, Vol: 9, ISSN: 1932-6203
  • Journal article
    Ghosh S, Mendoza O, Cubo L, Rosu F, Gabelica V, White AJP, Vilar Ret al., 2014,

    Assembly of Palladium(II) and Platinum(II) Metallo-Rectangles with a Guanosine-Substituted Terpyridine and Study of Their Interactions with Quadruplex DNA

    , CHEMISTRY-A EUROPEAN JOURNAL, Vol: 20, Pages: 4772-4779, ISSN: 0947-6539
  • Journal article
    D'Arcy M, Bullough F, Moffat C, Borgomeo E, Teh M, Vilar R, Weiss DJet al., 2014,

    Adsorption of Oxy-Anions in the Teaching Laboratory: An Experiment To Study a Fundamental Environmental Engineering Problem

    , JOURNAL OF CHEMICAL EDUCATION, Vol: 91, Pages: 505-510, ISSN: 0021-9584
  • Conference paper
    Leczkowska A, Vilar R, 2014,

    Targeting quadruplex nucleic acids with metal complexes

    , 16th International Conference on Biological Inorganic Chemistry (ICBIC), Publisher: SPRINGER, Pages: S378-S378, ISSN: 0949-8257
  • Conference paper
    Pujol A, Vilar R, 2014,

    Multimetallic and Bifunctional MRI-probes for imaging apoptotic cells.

    , 16th International Conference on Biological Inorganic Chemistry (ICBIC), Publisher: SPRINGER, Pages: S620-S620, ISSN: 0949-8257
  • Journal article
    Ali SMH, Yan Y-K, Lee PPF, Khong KZX, Sk MA, Lim KH, Klejevskaja B, Vilar Ret al., 2014,

    Copper(II) complexes of substituted salicylaldehyde dibenzyl semicarbazones: synthesis, cytotoxicity and interaction with quadruplex DNA

    , DALTON TRANSACTIONS, Vol: 43, Pages: 1449-1459, ISSN: 1477-9226
  • Journal article
    Karim NHA, Mendoza O, Shivalingam A, Thompson AJ, Ghosh S, Kuimova MK, Vilar Ret al., 2014,

    Salphen metal complexes as tunable G-quadruplex binders and optical probes

    , RSC ADVANCES, Vol: 4, Pages: 3355-3363, ISSN: 2046-2069
  • Journal article
    von Grebe P, Suntharalingam K, Vilar R, Sanz Miguel PJ, Herres-Pawlis S, Lippert Bet al., 2013,

    A Conformationally Flexible Dinuclear Pt<SUP>II</SUP> Complex with Differential Behavior of its Two States toward Quadruplex DNA

    , CHEMISTRY-A EUROPEAN JOURNAL, Vol: 19, Pages: 11429-11438, ISSN: 0947-6539
  • Journal article
    Whyte GF, Vilar R, Woscholski R, 2013,

    Molecular recognition with boronic acids-applications in chemical biology.

    , J Chem Biol, Vol: 6, Pages: 161-174, ISSN: 1864-6158

    Small molecules have long been used for the selective recognition of a wide range of analytes. The ability of these chemical receptors to recognise and bind to specific targets mimics certain biological processes (such as protein-substrate interactions) and has therefore attracted recent interest. Due to the abundance of biological molecules possessing polyhydroxy motifs, boronic acids-which form five-membered boronate esters with diols-have become increasingly popular in the synthesis of small chemical receptors. Their targets include biological materials and natural products including phosphatidylinositol bisphosphate, saccharides and polysaccharides, nucleic acids, metal ions and the neurotransmitter dopamine. This review will focus on the many ways in which small chemical receptors based on boronic acids have been used as biochemical tools for various purposes, including sensing and detection of analytes, interference in signalling pathways, enzyme inhibition and cell delivery systems. The most recent developments in each area will be highlighted.
  • Journal article
    Cowell S, Nguyen Q-D, Twyman F, Lavdas I, Carroll L, Vilar R, Aboagye Eet al., 2013,

    Towards multimodal molecular probes responsive to matrix metalloproteinases

    , JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol: 56, Pages: S235-S235, ISSN: 0362-4803
  • Conference paper
    Sala R, Quang-De N, Patel C, Mann D, Steinke JHG, Vilar R, Aboagye EOet al., 2013,

    Regulation of 18F-fluorothymidine uptake by thymidine kinase 1 protein phosphorylation.

    , 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
  • Journal article
    Zhou W, Suntharalingam K, Brand NJ, Barton PJR, Vilar R, Ying Let al., 2013,

    Possible Regulatory Roles of Promoter G-Quadruplexes in Cardiac Function-Related Genes - Human TnIc as a Model

    , PLOS One, Vol: 8, ISSN: 1932-6203

    G-quadruplexes (G4s) are four-stranded DNA secondary structures, which are involved in a diverse range of biological processes. Although the anti-cancer potential of G4s in oncogene promoters has been thoroughly investigated, the functions of promoter G4s in non-cancer-related genes are not well understood. We have explored the possible regulatory roles of promoter G4s in cardiac function-related genes using both computational and a wide range of experimental approaches. According to our bioinformatics results, it was found that potential G4-forming sequences are particularly enriched in the transcription regulatory regions (TRRs) of cardiac function-related genes. Subsequently, the promoter of human cardiac troponin I (TnIc) was chosen as a model, and G4s found in this region were subjected to biophysical characterisations. The chromosome 19 specific minisatellite G4 sequence (MNSG4) and near transcription start site (TSS) G4 sequence (−80 G4) adopt anti-parallel and parallel structures respectively in 100 mM KCl, with stabilities comparable to those of oncogene G4s. It was also found that TnIc G4s act cooperatively as enhancers in gene expression regulation in HEK293 cells, when stabilised by a synthetic G4-binding ligand. This study provides the first evidence of the biological significance of promoter G4s in cardiac function-related genes. The feasibility of using a single ligand to target multiple G4s in a particular gene has also been discussed.
  • Journal article
    Suntharalingam K, Mendoza O, Duarte AA, Mann DJ, Vilar Ret al., 2013,

    A platinum complex that binds non-covalently to DNA and induces cell death <i>via</i> a different mechanism than cisplatin

    , METALLOMICS, Vol: 5, Pages: 514-523, ISSN: 1756-5901
  • Journal article
    Ghosh S, Silber GT, White AJP, Robertson N, Vilar Ret al., 2013,

    Synthesis of a self-assembled copper(II) metallo-rectangle with a guanosine-substituted terpyridine

    , DALTON TRANSACTIONS, Vol: 42, Pages: 13813-13816, ISSN: 1477-9226
  • Book chapter
    Suntharalingam K, Vilar R, 2013,

    RECOGNITION OF G-QUADRUPLEXES BY METAL COMPLEXES

    , GUANINE QUARTETS: STRUCTURE AND APPLICATION, Editors: Spindler, Fritzsche, Publisher: ROYAL SOC CHEMISTRY, Pages: 263-274, ISBN: 978-1-84973-460-8
  • Journal article
    Leczkowska A, Vilar R, 2013,

    Interaction of metal complexes with nucleic acids

    , ANNUAL REPORTS ON THE PROGRESS OF CHEMISTRY, SECTION A: INORGANIC CHEMISTRY, VOL 109, Vol: 109, Pages: 299-316, ISSN: 0260-1818
  • Journal article
    Suntharalingam K, Leczkowska A, Furrer MA, Wu Y, Kuimova MK, Therrien B, White AJP, Vilar Ret al., 2012,

    A Cyclometallated Platinum Complex as a Selective Optical Switch for Quadruplex DNA

    , CHEMISTRY-A EUROPEAN JOURNAL, Vol: 18, Pages: 16277-16282, ISSN: 0947-6539

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