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A Minimalistic Coumarin Turn-On Probe for Selective Recognition of Parallel G-Quadruplex DNA Structures
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0002-7815-4494
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0003-0364-8964
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0001-8089-2333
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2021 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 16, no 8, p. 1365-1376Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2021. Vol. 16, no 8, p. 1365-1376
National Category
Medicinal Chemistry Biochemistry and Molecular Biology Biophysics
Identifiers
URN: urn:nbn:se:umu:diva-187118DOI: 10.1021/acschembio.1c00134ISI: 000697396400009PubMedID: 34328300Scopus ID: 2-s2.0-85113337330OAI: oai:DiVA.org:umu-187118DiVA, id: diva2:1590120
Funder
The Kempe Foundations, SMK-1632Knut and Alice Wallenberg Foundation, KAW2015-0189Swedish Cancer Society, CAN 2019/126Swedish Research Council, 2017-05235Swedish Research Council, 2018-02651Available from: 2021-09-01 Created: 2021-09-01 Last updated: 2023-03-23Bibliographically approved

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Deiana, MarcoObi, IkennaAndréasson, MånsTamilselvi, ShanmugamChand, KaramChorell, ErikSabouri, Nasim

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Deiana, MarcoObi, IkennaAndréasson, MånsTamilselvi, ShanmugamChand, KaramChorell, ErikSabouri, Nasim
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