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Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Biophysics, Molecular Biology & Bioinformatics, University of Calcutta, Kolkata, India.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2018 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 31, p. 7926-7938Article in journal (Refereed) Published
Abstract [en]

Small molecules that target G-quadruplex (G4) DNA structures are not only valuable to study G4 biology but also for their potential as therapeutics. This work centers around how different design features of small molecules can affect the interactions with G4 DNA structures, exemplified by the development of synthetic methods to bis-indole scaffolds. Our synthesized series of bis-indole scaffolds are structurally very similar but differ greatly in the flexibility of their core structures. The flexibility of the molecules proved to be an advantage compared to locking the compounds in the presumed bioactive G4 conformation. The flexible derivatives demonstrated similar or even improved G4 binding and stabilization in several orthogonal assays even though their entropic penalty of binding is higher. In addition, molecular dynamics simulations with the c-MYC G4 structure showed that the flexible compounds adapt better to the surrounding. This was reflected by an increased number of both stacking and polar interactions with both the residues in the G4 DNA structure and the DNA residues just upstream of the G4 structure.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018. Vol. 24, no 31, p. 7926-7938
Keywords [en]
DNA structures, G-quadruplexes, bis-indoles, drug design, nitrogen heterocycles
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-148052DOI: 10.1002/chem.201800078ISI: 000434216600019PubMedID: 29603472Scopus ID: 2-s2.0-85048327004OAI: oai:DiVA.org:umu-148052DiVA, id: diva2:1218106
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-11-01Bibliographically approved

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Prasad, BagineniJamroskovic, JanBhowmik, SudiptaKumar, RajendraRomell, TajanenaSabouri, NasimChorell, Erik

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Prasad, BagineniJamroskovic, JanBhowmik, SudiptaKumar, RajendraRomell, TajanenaSabouri, NasimChorell, Erik
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Department of ChemistryDepartment of Medical Biochemistry and Biophysics
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Chemistry - A European Journal
Organic Chemistry

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