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Using Macrocyclic G-Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G-Quadruplex DNA
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.
AstraZeneca, Mölndal, Gothenburg, Sweden.
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0003-2523-1940
2022 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 28, no 65, article id e202202020Article in journal (Refereed) Published
Abstract [en]

This study aims to deepen the knowledge of the current state of rational G4-ligand design through the design and synthesis of a novel set of compounds based on indoles, quinolines, and benzofurans and their comparisons with well-known G4-ligands. This resulted in novel synthetic methods and G4-ligands that bind and stabilize G4 DNA with high selectivity. Furthermore, the study corroborates previous studies on the design of G4-ligands and adds deeper explanations to why a) macrocycles offer advantages in terms of G4-binding and -selectivity, b) molecular pre-organization is of key importance in the development of strong novel binders, c) an electron-deficient aromatic core is essential to engage in strong arene-arene interactions with the G4-surface, and d) aliphatic amines can strengthen interactions indirectly through changing the arene electrostatic nature of the compound. Finally, fundamental physicochemical properties of selected G4-binders are evaluated, underscoring the complexity of aligning the properties required for efficient G4 binding and stabilization with feasible pharmacokinetic properties.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022. Vol. 28, no 65, article id e202202020
Keywords [en]
arene-arene interactions, G-quadruplex DNA, G4-ligand, macrocycle, molecular design
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-199908DOI: 10.1002/chem.202202020ISI: 000855541300001PubMedID: 35997141Scopus ID: 2-s2.0-85138242355OAI: oai:DiVA.org:umu-199908DiVA, id: diva2:1700978
Funder
The Kempe Foundations, SMK‐1632Swedish Research Council, 2017‐05235
Note

This article also appears in: Society Volumes: Sweden.

Available from: 2022-10-04 Created: 2022-10-04 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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Andréasson, MånsBhuma, NareshChorell, Erik

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