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The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Medicinal Chemistry, Uppsala University, BMC, Uppsala, Sweden.ORCID iD: 0000-0001-7691-4392
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0001-8089-2333
Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
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2023 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 248, article id 115103Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are involved in central biological processes such as DNA replication and transcription. These DNA structures are enriched in promotor regions of oncogenes and are thus promising as novel gene silencing therapeutic targets that can be used to regulate expression of oncoproteins and in particular those that has proven hard to drug with conventional strategies. G4 DNA structures in general have a well-defined and hydrophobic binding area that also is very flat and featureless and there are ample examples of G4 ligands but their further progression towards drug development is limited. In this study, we use synthetic organic chemistry to equip a drug-like and low molecular weight central fragment with different side chains and evaluate how this affect the compound's selectivity and ability to bind and stabilize G4 DNA. Furthermore, we study the binding interactions of the compounds and connect the experimental observations with the compound's structural conformations and electrostatic potentials to understand the basis for the observed improvements. Finally, we evaluate the top candidates' ability to selectively reduce cancer cell growth in a 3D co-culture model of pancreatic cancer which show that this is a powerful approach to generate highly active and selective low molecular weight G4 ligands with a promising therapeutic window.

Place, publisher, year, edition, pages
Elsevier, 2023. Vol. 248, article id 115103
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-202112DOI: 10.1016/j.ejmech.2023.115103ISI: 000922160800001Scopus ID: 2-s2.0-85146280645OAI: oai:DiVA.org:umu-202112DiVA, id: diva2:1723074
Funder
The Kempe Foundations, SMK-1632Swedish Research Council, 2017–05235Swedish Research Council, 2017- 01531The Swedish Medical Association, SLS-890521Region Västerbotten, RV-930167Knut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, 2020.0189Swedish Cancer Society, 20 1339 PjFCancerforskningsfonden i Norrland, LP 21–2298Cancerforskningsfonden i Norrland, LP 22–2332
Note

Originally included in thesis in manuscript form.

Available from: 2023-01-02 Created: 2023-01-02 Last updated: 2023-09-05Bibliographically 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)
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Available from: 2023-01-05 Created: 2023-01-02 Last updated: 2023-01-02Bibliographically approved

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Bhuma, NareshChand, KaramAndréasson, MånsMason, James E.Das, Rabindra NathÖhlund, DanielChorell, Erik

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Bhuma, NareshChand, KaramAndréasson, MånsMason, James E.Das, Rabindra NathÖhlund, DanielChorell, Erik
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Department of ChemistryDepartment of Radiation SciencesWallenberg Centre for Molecular Medicine at Umeå University (WCMM)Oncology
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European Journal of Medicinal Chemistry
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