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Redefining the essential molecular aspects that drive interactions between small molecules and G-quadruplex DNA
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University.ORCID iD: 0000-0001-8089-2333
2023 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Omvärdering av de centrala molekylära aspekterna som styr interaktionen mellan små molekyler och G-quadruplex DNA (Swedish)
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 [en]
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: urn:nbn:se:umu:diva-202119ISBN: 978-91-7855-970-1 (electronic)ISBN: 978-91-7855-969-5 (print)OAI: oai:DiVA.org:umu-202119DiVA, id: diva2:1723107
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
List of papers
1. Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures
Open this publication in new window or tab >>Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures
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
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-176145 (URN)10.1039/d0sc03519j (DOI)000575657200026 ()2-s2.0-85092433736 (Scopus ID)
Funder
The Kempe Foundations, SMK-1632Swedish Research Council, VR-NT 2017-05235Wenner-Gren Foundations
Available from: 2020-10-22 Created: 2020-10-22 Last updated: 2023-01-02Bibliographically approved
2. Using Macrocyclic G-Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G-Quadruplex DNA
Open this publication in new window or tab >>Using Macrocyclic G-Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G-Quadruplex DNA
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
Keywords
arene-arene interactions, G-quadruplex DNA, G4-ligand, macrocycle, molecular design
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-199908 (URN)10.1002/chem.202202020 (DOI)000855541300001 ()35997141 (PubMedID)2-s2.0-85138242355 (Scopus ID)
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
3. The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands
Open this publication in new window or tab >>The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands
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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
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-202112 (URN)10.1016/j.ejmech.2023.115103 (DOI)000922160800001 ()2-s2.0-85146280645 (Scopus ID)
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
4. The Synergism of the Dispersion and Electrostatic Components in the Arene-Arene Interactions Between Ligands and G4 DNA
Open this publication in new window or tab >>The Synergism of the Dispersion and Electrostatic Components in the Arene-Arene Interactions Between Ligands and G4 DNA
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(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-202114 (URN)
Available from: 2023-01-02 Created: 2023-01-02 Last updated: 2023-01-02
5. Development of a G4 Ligand-Conjugated Oligonucleotide Modality that Selectively Targets Individual G4 DNA Structures
Open this publication in new window or tab >>Development of a G4 Ligand-Conjugated Oligonucleotide Modality that Selectively Targets Individual G4 DNA Structures
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(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-202117 (URN)
Available from: 2023-01-02 Created: 2023-01-02 Last updated: 2023-01-02

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