The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands

Bhuma, Naresh; Chand, Karam; Andréasson, Måns; Mason, James; Das, Rabindra Nath; Patel, Ankit Kumar; Öhlund, Daniel; Chorell, Erik

doi:10.1016/j.ejmech.2023.115103

Cited by 6 publications

(7 citation statements)

References 46 publications

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“…Design and Synthesis of G4-Ligand-Conjugated Oligonucleotides (GL-Os). We recently reported on a novel G4-ligand (Figure 1A), 28 that both efficiently binds and stabilizes G4 DNA structures and that has drug-like properties (e.g., no permanent charges and has a low molecular weight), allowing further conjugation to an oligonucleotide guide sequence. To enable conjugation of this G4-Ligand (in this study, renamed GL) to the oligonucleotide sequence, an azido-substituted piperazine side chain was introduced for further conjugation through click chemistry (Figure 1B).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Overview of the strategy and chemistry employed in this study. (A) Summary of the presented strategy to target individual G4 DNA structures using G4-ligand-oligonucleotide (GL-O) compounds, G4-ligand correspond to compound number 14a in reference . (B) Synthesis of the azido-functionalized quinazoline-pyrimidine ligand for further conjugations with click chemistry.…”

Section: Introductionmentioning

confidence: 99%

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G4-Ligand-Conjugated Oligonucleotides Mediate Selective Binding and Stabilization of Individual G4 DNA Structures

Berner,

Das,

Bhuma

et al. 2024

J. Am. Chem. Soc.

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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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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

G4-Ligand-Conjugated Oligonucleotides Mediate Selective Binding and Stabilization of Individual G4 DNA Structures

Berner,

Das,

Bhuma

et al. 2024

J. Am. Chem. Soc.

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“…Analogous to our findings with the c-MYC G4, GL-O15 effectively enhanced G4 stabilization for the c-KIT and HelB G4s when a complementary flanking region was present on the DNA template. A much stronger reduction of full-length DNA product was observed in the presence of GL-O15 compared to GL for both G4s (c-KIT, compare [22][23][24][25]. This shows that our GL-O strategy in theory can be designed towards any G4 DNA structure by replacement of the guide oligonucleotide.…”

Section: Conjugation Of the G4-ligand To The Guide Oligonucleotide Re...mentioning

confidence: 93%

“…In the cellular context, such ligands have also been observed to down-regulate the transcription of oncogenes (22). In the same way, telomerase activity has been found to be inhibited by ligands that can stabilize the telomeric G-quadruplex structures (23,24). These types of compounds can thus be used to study G4 biology and for further developments towards therapeutics.…”

Section: Introductionmentioning

confidence: 99%

G4-Ligand Conjugated Oligonucleotides Mediate Selective Binding and Stabilization of Individual G4 DNA Structures

Berner,

Das,

Bhuma

et al. 2023

Preprint

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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 G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a longstanding problem in the field is how to achieve specificity amongst these different G4 structures. Here, we have 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 amounts 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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“…In this work, we designed a small series of molecules based on a quinazoline-pyrimidine scaffold of type 1 ( Figure 1 A) 35 to investigate how different substitution patterns affect the arene–arene interactions and thus the G4 binding and stabilization. We hypothesized that compound 2 , bearing no substituents on the quinazoline core, should display less favorable binding with the G4 if the dispersion in the arene–arene interactions is essential for the binding.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Dispersion and Electrostatic Components in Arene–Arene Interactions between Ligands and G4 DNA to Develop G4-Ligands

Andreasson,

Donzel,

Abrahamsson

et al. 2024

J. Med. Chem.

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G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene−arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.

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The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands

Cited by 6 publications

References 46 publications

G4-Ligand-Conjugated Oligonucleotides Mediate Selective Binding and Stabilization of Individual G4 DNA Structures

G4-Ligand-Conjugated Oligonucleotides Mediate Selective Binding and Stabilization of Individual G4 DNA Structures

G4-Ligand Conjugated Oligonucleotides Mediate Selective Binding and Stabilization of Individual G4 DNA Structures

Exploring the Dispersion and Electrostatic Components in Arene–Arene Interactions between Ligands and G4 DNA to Develop G4-Ligands

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