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  • 1.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Andrés Castán, José María
    Univ Angers, CNRS, MOLTECH-ANJOU, France.
    Josse, Pierre
    Univ Angers, CNRS, MOLTECH-ANJOU, France.
    Kahsay, Abraha
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Sánchez, Darío Puchán
    Univ Angers, CNRS, MOLTECH-ANJOU, France.
    Morice, Korentin
    Univ Angers, CNRS, MOLTECH-ANJOU, France.
    Gillet, Natacha
    ENS de Lyon, CNRS, Laboratoire de Chimie UMR 5182, Université Claude Bernard Lyon 1, France.
    Ravindranath, Ranjitha
    ENS de Lyon, CNRS, Laboratoire de Chimie UMR 5182, Université Claude Bernard Lyon 1, France; Indian Institute for Science Education and Research (IISER), Tirupati, India.
    Patel, Ankit Kumar
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sengupta, Pallabi
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Rodriguez-Marquez, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Khrouz, Lhoussain
    ENS de Lyon, CNRS, Laboratoire de Chimie UMR 5182, Université Claude Bernard Lyon 1, France.
    Dumont, Elise
    ENS de Lyon, CNRS, Laboratoire de Chimie UMR 5182, Université Claude Bernard Lyon 1, France; Institut Universitaire de France, 5 rue Descartes, France.
    Abad Galán, Laura
    ENS de Lyon, CNRS, Laboratoire de Chimie UMR 5182, Université Claude Bernard Lyon 1, France.
    Allain, Magali
    Univ Angers, CNRS, MOLTECH-ANJOU, France.
    Walker, Bright
    Department of Chemistry, Kyung Hee University, Seoul, South Korea.
    Ahn, Hyun Seo
    Yonsei University, 50 Yonsei-ro ,Seodaemun-gu, Seoul, South Korea.
    Maury, Olivier
    ENS de Lyon, CNRS, Laboratoire de Chimie UMR 5182, Université Claude Bernard Lyon 1, France.
    Blanchard, Philippe
    Univ Angers, CNRS, MOLTECH-ANJOU, France.
    Le Bahers, Tangui
    ENS de Lyon, CNRS, Laboratoire de Chimie UMR 5182, Université Claude Bernard Lyon 1, France; Institut Universitaire de France, 5 rue Descartes, France.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    von Hofsten, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Monnereau, Cyrille
    ENS de Lyon, CNRS, Laboratoire de Chimie UMR 5182, Université Claude Bernard Lyon 1, France.
    Cabanetos, Clément
    Univ Angers, CNRS, MOLTECH-ANJOU, France; Yonsei University, 50 Yonsei-ro ,Seodaemun-gu, Seoul, South Korea; Yonsei University, Building Blocks for FUture Electronics Laboratory (2BFUEL), Seoul, South Korea.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression2023Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, nr 12, s. 6264-6285Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Photodynamic therapy (PDT) ideally relies on the administration, selective accumulation and photoactivation of a photosensitizer (PS) into diseased tissues. In this context, we report a new heavy-atom-free fluorescent G-quadruplex (G4) DNA-binding PS, named DBI. We reveal by fluorescence microscopy that DBI preferentially localizes in intraluminal vesicles (ILVs), precursors of exosomes, which are key components of cancer cell proliferation. Moreover, purified exosomal DNA was recognized by a G4-specific antibody, thus highlighting the presence of such G4-forming sequences in the vesicles. Despite the absence of fluorescence signal from DBI in nuclei, light-irradiated DBI-treated cells generated reactive oxygen species (ROS), triggering a 3-fold increase of nuclear G4 foci, slowing fork progression and elevated levels of both DNA base damage, 8-oxoguanine, and double-stranded DNA breaks. Consequently, DBI was found to exert significant phototoxic effects (at nanomolar scale) toward cancer cell lines and tumor organoids. Furthermore, in vivo testing reveals that photoactivation of DBI induces not only G4 formation and DNA damage but also apoptosis in zebrafish, specifically in the area where DBI had accumulated. Collectively, this approach shows significant promise for image-guided PDT.

    Fulltekst (pdf)
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  • 2.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Parallel G-quadruplex DNA structures from nuclear and mitochondrial genomes trigger emission enhancement in a nonfluorescent nano-aggregated fluorine-boron-based dye2023Inngår i: The Journal of Physical Chemistry Letters, E-ISSN 1948-7185, Vol. 14, nr 7, s. 1862-1869Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular self-assembly is a powerful tool for the development of functional nanostructures with adaptive optical properties. However, in aqueous solution, the hydrophobic effects in the monomeric units often afford supramolecular architectures with typical side-by-side π-stacking arrangement with compromised emissive properties. Here, we report on the role of parallel DNA guanine quadruplexes (G4s) as supramolecular disaggregating-capture systems capable of coordinating a zwitterionic fluorine-boron-based dye and promoting activation of its fluorescence signal. The dye's high binding affinity for parallel G4s compared to nonparallel topologies leads to a selective disassembly of the dye's supramolecular state upon contact with parallel G4s. This results in a strong and selective disaggregation-induced emission that signals the presence of parallel G4s observable by the naked eye and inside cells. The molecular recognition strategy reported here will be useful for a multitude of affinity-based applications with potential in sensing and imaging systems.

    Fulltekst (pdf)
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  • 3.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jamroskovic, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A Site-Specific Self-Assembled Light-up Rotor Probe for Selective Recognition and Stabilization of c-MYC G-Quadruplex DNA2020Inngår i: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 12, nr 24, s. 12950-12957Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Direct and unambiguous evidence of the formation of G-quadruplexes (G4s) in human cells have shown their implication in several key biological events and has emphasized their role as important targets for small-molecule cancer therapeutics. Here, we report on the first example of a self-assembled multitasking molecular-rotor G4-binder able to discriminate between an extensive panel of G4 and non-G4 structures and to selectively light-up (up to 105-fold), bind (nanomolar range), and stabilize the c-MYC promoter G4 DNA. In particular, association with the c-MYC G4 triggers the disassembly of its supramolecular state (disaggregation-induced emission, DIE) and induces geometrical restrictions (motion-induced change in emission, MICE) leading to a significant enhancement of its emission yield. Moreover, this optical reporter is able to selectively stabilize the c-MYC G4 and inhibit DNA synthesis. Finally, by using confocal laser-scanning microscopy (CLSM) we show the ability of this compound to localize primarily in the subnuclear G4-rich compartments of cancer cells. This work provides a benchmark for the future design and development of a new generation of smart sequence-selective supramolecular G4-binders that combine outstanding sensing and stability properties, to be utilized in anti-cancer therapy.

    Fulltekst (pdf)
    fulltext
  • 4.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jamroskovic, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A Light‐up Logic Platform for Selective Recognition of Parallel G‐Quadruplex Structures via Disaggregation‐Induced Emission2020Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 59, nr 2, s. 896-902Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The design of turn‐on dyes with optical signals sensitive to the formation of supramolecular structures provides fascinating and underexplored opportunities for G‐quadruplex (G4) DNA detection and characterization. Here, we show a new switching mechanism that relies on the recognition‐driven disaggregation (on‐signal) of an ultrabright coumarin‐quinazoline conjugate. The synthesized probe selectively lights‐up parallel G4 DNA structures via the disassembly of its supramolecular state, demonstrating outputs that are easily integrable into a label free molecular logic system. Finally, our molecule preferentially stains the G4‐rich nucleoli of cancer cells.

  • 5.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Jamroskovic, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Unravelling the cellular emission fingerprint of the benchmark G-quadruplex-interactive compound Phen-DC32020Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 56, nr 91, s. 14251-14254Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Phen-DC3 is among the most commonly used G-quadruplex (G4)-stabilizers in vitro and in cells. Here, we show that the G4-interactive binding interactions enable one to tune the optical properties of Phen-DC3 allowing the detection of G4 structures in cancer cells. This work opens up new directions for the use of Phen-DC3 as a selective G4 fluorescent reporter.

    Fulltekst (pdf)
    fulltext
  • 6.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Josse, Pierre
    Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, Angers, France.
    Dalinot, Clément
    Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, Angers, France.
    Osmolovskyi, Artem
    Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, Angers, France.
    Marqués, Pablo Simón
    Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, Angers, France.
    Castán, José María Andrés
    Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, Angers, France.
    Abad Galán, Laura
    Univ Lyon, ENS de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Lyon, France.
    Allain, Magali
    Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, Angers, France.
    Khrouz, Lhoussain
    Univ Lyon, ENS de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Lyon, France.
    Maury, Olivier
    Univ Lyon, ENS de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Lyon, France.
    Le Bahers, Tangui
    Univ Lyon, ENS de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Lyon, France.
    Blanchard, Philippe
    Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, Angers, France.
    Dabos-Seignon, Sylvie
    Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, Angers, France.
    Monnereau, Cyrille
    Univ Lyon, ENS de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Lyon, France.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Cabanetos, Clément
    Univ Angers, CNRS, MOLTECH-ANJOU, SFR MATRIX, Angers, France; IRL CNRS 2002, 2BFUEL, CNRS -Yonsei University, Seoul, South Korea.
    Site-selected thionated benzothioxanthene chromophores as heavy-atom-free small-molecule photosensitizers for photodynamic therapy2022Inngår i: Communications Chemistry, E-ISSN 2399-3669, Vol. 5, artikkel-id 142Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Photodynamic therapy is a clinically approved anticancer modality that employs a light-activated agent (photosensitizer) to generate cytotoxic reactive oxygen species (ROS). There is therefore a growing interest for developing innovative photosensitizing agents with enhanced phototherapeutic performances. Herein, we report on a rational design synthetic procedure that converts the ultrabright benzothioxanthene imide (BTI) dye into three heavy-atom-free thionated compounds featuring close-to-unit singlet oxygen quantum yields. In contrast to the BTI, these thionated analogs display an almost fully quenched fluorescence emission, in agreement with the formation of highly populated triplet states. Indeed, the sequential thionation on the BTI scaffold induces torsion of its skeleton reducing the singlet-triplet energy gaps and enhancing the spin-orbit coupling. These potential PSs show potent cancer-cell ablation under light irradiation while remaining non-toxic under dark condition owing to a photo-cytotoxic mechanism that we believe simultaneously involves singlet oxygen and superoxide species, which could be both characterized in vitro. Our study demonstrates that this simple site-selected thionated platform is an effective strategy to convert conventional carbonyl-containing fluorophores into phototherapeutic agents for anticancer PDT.

    Fulltekst (pdf)
    fulltext
  • 7.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mosser, Maëlle
    Le Bahers, Tangui
    Dumont, Elise
    Dudek, Marta
    Denis-Quanquin, Sandrine
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Andraud, Chantal
    Matczyszyn, Katarzyna
    Monnereau, Cyrille
    Guy, Laure
    Light-induced in situ chemical activation of a fluorescent probe for monitoring intracellular G-quadruplex structures2021Inngår i: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 13, nr 32, s. 13795-13808Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Light-activated functional materials capable of remote control over duplex and G-quadruplex (G4) nucleic acids formation at the cellular level are still very rare. Herein, we report on the photoinduced macrocyclisation of a helicenoid quinoline derivative of binaphthol that selectively provides easy access to an unprecedented class of extended heteroaromatic structures with remarkable photophysical and DNA/RNA binding properties. Thus, while the native bisquinoline precursor shows no DNA binding activity, the new in situ photochemically generated probe features high association constants to DNA and RNA G4s. The latter inhibits DNA synthesis by selectively stabilizing G4 structures associated with oncogenic promoters and telomere repeat units. Finally, the light sensitive compound is capable of in cellulo photoconversion, localizes primarily in the G4-rich sites of cancer cells, competes with a well-known G4 binder and shows a clear nuclear co-localization with the quadruplex specific antibody BG4. This work provides a benchmark for the future design and development of a brand-new generation of light-activated target-selective G4-binders.

    Fulltekst (pdf)
    fulltext
  • 8.
    Deiana, Marco
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Andréasson, Måns
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Tamilselvi, Shanmugam
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A Minimalistic Coumarin Turn-On Probe for Selective Recognition of Parallel G-Quadruplex DNA Structures2021Inngår i: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 16, nr 8, s. 1365-1376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    G-quadruplex (G4) DNA structures are widespread in the human genome and are implicated in biologically important processes such as telomere maintenance, gene regulation, and DNA replication. Guanine-rich sequences with potential to form G4 structures are prevalent in the promoter regions of oncogenes, and G4 sites are now considered as attractive targets for anticancer therapies. However, there are very few reports of small “druglike” optical G4 reporters that are easily accessible through one-step synthesis and that are capable of discriminating between different G4 topologies. Here, we present a small water-soluble light-up fluorescent probe that features a minimalistic amidinocoumarin-based molecular scaffold that selectively targets parallel G4 structures over antiparallel and non-G4 structures. We showed that this biocompatible ligand is able to selectively stabilize the G4 template resulting in slower DNA synthesis. By tracking individual DNA molecules, we demonstrated that the G4-stabilizing ligand perturbs DNA replication in cancer cells, resulting in decreased cell viability. Moreover, the fast-cellular entry of the probe enabled detection of nucleolar G4 structures in living cells. Finally, insights gained from the structure–activity relationships of the probe suggest the basis for the recognition of parallel G4s, opening up new avenues for the design of new biocompatible G4-specific small molecules for G4-driven theranostic applications.

    Fulltekst (pdf)
    fulltext
  • 9.
    Dudek, Marta
    et al.
    Advanced Materials Engineering and Modelling Group, Faculty of Chemistry, Wroclaw University of Science and Technology, Wyb. Wyspianskiego 27, Wroclaw, Poland.
    Deiana, Marco
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Szkaradek, Kinga
    Theoretical Photochemistry and Photophysics Group, Faculty of Chemistry, Wroclaw University of Science and Technology, Wyb. Wyspianskiego 27, Wroclaw, Poland.
    Janicki, Mikołaj J.
    Theoretical Photochemistry and Photophysics Group, Faculty of Chemistry, Wroclaw University of Science and Technology, Wyb. Wyspianskiego 27, Wroclaw, Poland.
    Pokładek, Ziemowit
    Advanced Materials Engineering and Modelling Group, Faculty of Chemistry, Wroclaw University of Science and Technology, Wyb. Wyspianskiego 27, Wroclaw, Poland.
    Góra, Robert W.
    Theoretical Photochemistry and Photophysics Group, Faculty of Chemistry, Wroclaw University of Science and Technology, Wyb. Wyspianskiego 27, Wroclaw, Poland.
    Matczyszyn, Katarzyna
    Advanced Materials Engineering and Modelling Group, Faculty of Chemistry, Wroclaw University of Science and Technology, Wyb. Wyspianskiego 27, Wroclaw, Poland.
    Light-Induced Modulation of Chiral Functions in G-Quadruplex-Photochrome Systems2021Inngår i: The Journal of Physical Chemistry Letters, E-ISSN 1948-7185, Vol. 12, nr 39, s. 9436-9441Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The design of artificially engineered chiral structures has received much attention, but the implementation of dynamic functions to modulate the chiroptical response of the systems is less explored. Here, we present a light-responsive G-quadruplex (G4)-based assembly in which chirality enrichment is induced, tuned, and fueled by molecular switches. In particular, the mirror-image dependence on photoactivated azo molecules, undergoing trans-to-cis isomerization, shows chiral recognition effects on the inherent flexibility and conformational diversity of DNA G4s having distinct handedness (right- and left-handed). Through a detailed experimental and computational analysis, we bring compelling evidence on the binding mode of the photochromes on G4s, and we rationalize the origin of the chirality effect that is associated with the complexation event.

    Fulltekst (pdf)
    fulltext
  • 10.
    Jamroskovic, Jan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Deiana, Marco
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Probing the folding pathways of four-stranded intercalated cytosine-rich motifs at single base-pair resolution2022Inngår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 199, s. 81-91Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cytosine-rich DNA can fold into four-stranded intercalated structures called i-motifs (iMs) under acidic conditions through the formation of hemi-protonated C:C+ base pairs. However, the folding and stability of iMs rely on many other factors that are not yet fully understood. Here, we combined biochemical and biophysical approaches to determine the factors influencing iM stability under a wide range of experimental conditions. By using high-resolution primer extension assays, circular dichroism, and absorption spectroscopies, we demonstrate that the stabilities of three different biologically relevant iMs are not dependent on molecular crowding agents. Instead, some of the crowding agents affected overall DNA synthesis. We also tested a range of small molecules to determine their effect on iM stabilization at physiological temperature and demonstrated that the G-quadruplex-specific molecule CX-5461 is also a promising candidate for selective iM stabilization. This work provides important insights into the requirements needed for different assays to accurately study iM stabilization, which will serve as important tools for understanding the contribution of iMs in cell regulation and their potential as therapeutic targets.

    Fulltekst (pdf)
    fulltext
  • 11.
    Jamroskovic, Jan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kumar, Rajendra
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Akhunzianov, Almaz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia.
    Deiana, Marco
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kasho, Kazutoshi
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sulis Sato, Sebastian
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pourbozorgi-Langroudi, Parham
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mason, James E.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Medini, Paolo
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization2020Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, nr 6, s. 2876-2888Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.

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