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  1. Article ; Online: An Octahedral Cobalt(III) Complex with Axial NH

    Ruehl, Carmen L / Lim, Aaron H M / Kench, Timothy / Mann, David J / Vilar, Ramon

    Chemistry (Weinheim an der Bergstrasse, Germany)

    2019  Volume 25, Issue 41, Page(s) 9691–9700

    Abstract: 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 ... ...

    Abstract 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 the 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.
    MeSH term(s) Animals ; Cattle ; Cobalt/chemistry ; Cobalt/pharmacology ; Coordination Complexes/chemistry ; Coordination Complexes/pharmacology ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; DNA Helicases/metabolism ; G-Quadruplexes/drug effects ; Genes, myc/drug effects ; Humans ; Ligands ; Molecular Docking Simulation ; Phenylenediamines/chemistry ; Phenylenediamines/pharmacology ; Promoter Regions, Genetic/drug effects
    Chemical Substances Coordination Complexes ; Ligands ; Phenylenediamines ; salphen ; Cobalt (3G0H8C9362) ; DNA (9007-49-2) ; calf thymus DNA (91080-16-9) ; DNA Helicases (EC 3.6.4.-)
    Language English
    Publishing date 2019-07-03
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1478547-X
    ISSN 1521-3765 ; 0947-6539
    ISSN (online) 1521-3765
    ISSN 0947-6539
    DOI 10.1002/chem.201901569
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Visualising G-quadruplex DNA dynamics in live cells by fluorescence lifetime imaging microscopy.

    Summers, Peter A / Lewis, Benjamin W / Gonzalez-Garcia, Jorge / Porreca, Rosa M / Lim, Aaron H M / Cadinu, Paolo / Martin-Pintado, Nerea / Mann, David J / Edel, Joshua B / Vannier, Jean Baptiste / Kuimova, Marina K / Vilar, Ramon

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 162

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Animals ; Cell Line, Tumor ; DNA/chemistry ; DNA/metabolism ; DNA Helicases/genetics ; DNA Helicases/metabolism ; Fanconi Anemia Complementation Group Proteins/genetics ; Fanconi Anemia Complementation Group Proteins/metabolism ; Fibroblasts ; Fluorescent Dyes/chemistry ; G-Quadruplexes ; Gene Knockdown Techniques ; Humans ; Indoles/chemistry ; Intravital Microscopy/methods ; Mice ; Microscopy, Fluorescence/methods ; Molecular Imaging/methods ; RNA Helicases/genetics ; RNA Helicases/metabolism
    Chemical Substances Fanconi Anemia Complementation Group Proteins ; Fluorescent Dyes ; Indoles ; DAPI (47165-04-8) ; DNA (9007-49-2) ; regulator of telomere length protein, mouse (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; Brip1 protein, mouse (EC 3.6.4.13) ; RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2021-01-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-20414-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pituitary and ovarian hormone activity during the 7-day hormone-free interval of various combined oral contraceptive regimens.

    Cho, Michael / Atrio, Jessica / Lim, Aaron H / Azen, Colleen / Stanczyk, Frank Z

    Contraception

    2014  Volume 90, Issue 1, Page(s) 94–96

    Abstract: Objective: The objective was to investigate changes in luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) and progesterone (P) during the hormone-free interval (HFI) of 6 combined oral contraceptives (COCs).: Design: Blood ... ...

    Abstract Objective: The objective was to investigate changes in luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) and progesterone (P) during the hormone-free interval (HFI) of 6 combined oral contraceptives (COCs).
    Design: Blood samples were obtained from 62 women.
    Results: When COCs were grouped by ethinyl estradiol (EE) dose, there was a significant positive mean slope for LH and FSH during the HFI for the 30- and 35 mcg-EE doses, whereas 20 showed a gradual nonsignificant slope. All E2 slopes were significant. P remained suppressed with all doses.
    Conclusion: A more rapid rebound of gonadotropin levels is found with higher doses of EE during the HFI.
    Implications: This study showed a more rapid rebound of pituitary hormone levels among women using higher-EE-dosage formulations, which was demonstrated by the statistically significant slope for mean LH and FSH from day 1 to day 7 of the HFI. The degree of suppression did not vary across progestin generations. It remains to be established whether women who experience side effects during their HFI may benefit from using a COC with a lower EE dose to minimize changes in endogenous pituitary hormone levels.
    MeSH term(s) Adolescent ; Adult ; Contraceptives, Oral, Combined/administration & dosage ; Estradiol/blood ; Ethinyl Estradiol/administration & dosage ; Female ; Follicle Stimulating Hormone/blood ; Humans ; Linear Models ; Luteinizing Hormone/blood ; Progesterone/blood ; Prospective Studies ; Young Adult
    Chemical Substances Contraceptives, Oral, Combined ; Ethinyl Estradiol (423D2T571U) ; Progesterone (4G7DS2Q64Y) ; Estradiol (4TI98Z838E) ; Luteinizing Hormone (9002-67-9) ; Follicle Stimulating Hormone (9002-68-0)
    Language English
    Publishing date 2014-07
    Publishing country United States
    Document type Clinical Trial ; Journal Article
    ZDB-ID 80106-9
    ISSN 1879-0518 ; 0010-7824
    ISSN (online) 1879-0518
    ISSN 0010-7824
    DOI 10.1016/j.contraception.2014.01.021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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