| 1. |
- Andréasson, Måns, et al.
(författare)
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Using Macrocyclic G-Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G-Quadruplex DNA
- 2022
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Ingår i: Chemistry - A European Journal. - : John Wiley & Sons. - 0947-6539 .- 1521-3765. ; 28:65
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Berner, Andreas, et al.
(författare)
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G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures
- 2023
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 146:10, s. 6926-6935
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Tidskriftsartikel (refereegranskat)abstract
- G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.
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| 3. |
- Bhuma, Naresh, et al.
(författare)
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The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands
- 2023
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 248
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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