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Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0001-6347-2169
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0001-8089-2333
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-7268-9519
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0003-2523-1940
2020 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 11, no 38, p. 10529-10537Article in journal (Refereed) Published
Abstract [en]

The recognition of G-quadruplex (G4) DNA structures as important regulatory elements in biological mechanisms, and the connection between G4s and the evolvement of different diseases, has sparked interest in developing small organic molecules targeting G4s. However, such compounds often lack drug-like properties and selectivity. Here, we describe the design and synthesis of a novel class of macrocyclic bis-indole quinolines based on their non-macrocyclic lead compounds. The effects of the macrocyclization on the ability to interact with G4 DNA structures were investigated using biophysical assays and molecular dynamic simulations. Overall, this revealed compounds with potent abilities to interact with and stabilize G4 structures and a clear selectivity for both G4 DNA over dsDNA and for parallel/hybrid G4 topologies, which could be attributed to the macrocyclic structure. Moreover, we obtained knowledge about the structure-activity relationship of importance for the macrocyclic design and how structural modifications could be made to construct improved macrocyclic compounds. Thus, the macrocyclization of G4 ligands can serve as a basis for the optimization of research tools to study G4 biology and potential therapeutics targeting G4-related diseases.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2020. Vol. 11, no 38, p. 10529-10537
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-176145DOI: 10.1039/d0sc03519jISI: 000575657200026Scopus ID: 2-s2.0-85092433736OAI: oai:DiVA.org:umu-176145DiVA, id: diva2:1478526
Funder
The Kempe Foundations, SMK-1632Swedish Research Council, VR-NT 2017-05235Wenner-Gren FoundationsAvailable from: 2020-10-22 Created: 2020-10-22 Last updated: 2023-01-02Bibliographically approved
In thesis
1. Redefining the essential molecular aspects that drive interactions between small molecules and G-quadruplex DNA
Open this publication in new window or tab >>Redefining the essential molecular aspects that drive interactions between small molecules and G-quadruplex DNA
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Omvärdering av de centrala molekylära aspekterna som styr interaktionen mellan små molekyler och G-quadruplex DNA
Abstract [en]

G-Quadruplex (G4) structures are secondary nucleic acid structures located in guanine-rich regions of DNA and RNA sequences, involved in gene regulation and cellular maintenance. Efforts to target G4s in a therapeutic setting are scarce, mainly due to vague details about the binding interactions between the ligands and the G4 structure combined with the lack of emphasis on drug-like properties early in the ligand development process. Furthermore, the ability to target specific G4 structures with small drug-like molecules remains a big challenge to overcome in the field. In this thesis, extensive organic synthesis developments coupled with computational-aided design and orthogonal in vitro assays has been used in tandem to reveal in-depth knowledge about ligand-to-G4 interactions. First, a macrocyclic approach was applied to design and discover novel G4 ligands which showed that macrocycles offer a solid foundation for ligand design. Next, computational tools to optimise the macrocyclic molecular conformation were used based on the macrocycles' abilities to stack on the G4 surface. In addition, macrocyclic, and non-macrocyclic ligands that bound G4 with high potency were shown to correlate with electron-deficient electrostatic potential (ESP) maps. The frequent inclusion of cationic residues in G4 ligands and their enhancement on ligand-to-G4 binding was, thereof, ascribed to their impact on the electrostatic character of the ligands' arene-arene interactions with the G4 surface, and not through direct electrostatic ionic interactions. In addition, the dispersion energetic component in the arene-arene interactions between the G4 ligand and the G4 was discovered to be paramount for ligand-to-G4 binding. The implementation of these descriptors in practice resulted in the discovery of potent G4 binders with adequate pharmacokinetic (PK) properties, accentuating the significance of understanding the molecular interactions between ligands and G4s in rational ligand design. Finally, a G4 ligand conjugated to an oligonucleotide was demonstrated as a modular approach to achieve selective binding of a ligand to a specific G4 structure. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 73
Keywords
G-Quadruplexes, DNA, Oncogenes, G4 ligands, heterocycles, macrocycles, organic synthesis, molecular interactions, rational compound design, medicinal chemistry.
National Category
Organic Chemistry
Research subject
medicinal chemistry; Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-202119 (URN)978-91-7855-970-1 (ISBN)978-91-7855-969-5 (ISBN)
Public defence
2023-01-27, KB.E3.03 (stora hörsalen), KBC-huset, Universitetsområdet, 907 36 Umeå, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2023-01-05 Created: 2023-01-02 Last updated: 2023-01-02Bibliographically approved

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Das, Rabindra NathAndréasson, MånsKumar, RajendraChorell, Erik

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