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Publications (10 of 10) Show all publications
Andréasson, M., Donzel, M., Abrahamsson, A., Berner, A., Doimo, M., Quiroga, A., . . . Chorell, E. (2024). Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands. Journal of Medicinal Chemistry, 67(3), 2202-2219
Open this publication in new window or tab >>Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands
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2024 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 67, no 3, p. 2202-2219Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-220319 (URN)10.1021/acs.jmedchem.3c02127 (DOI)38241609 (PubMedID)2-s2.0-85183093324 (Scopus ID)
Funder
The Kempe Foundations, JCK-3159The Kempe Foundations, SMK-1632Swedish Research Council, 2017-05235Swedish Research Council, 2021-04805Knut and Alice Wallenberg Foundation
Available from: 2024-02-13 Created: 2024-02-13 Last updated: 2024-02-13Bibliographically approved
Berner, A., Das, R. N., Bhuma, N., Golebiewska, J., Abrahamsson, A., Andréasson, M., . . . Chorell, E. (2023). G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures. Journal of the American Chemical Society, 146(10), 6926-6935
Open this publication in new window or tab >>G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures
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2023 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 146, no 10, p. 6926-6935Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-222294 (URN)10.1021/jacs.3c14408 (DOI)001179314400001 ()38430200 (PubMedID)2-s2.0-85186374110 (Scopus ID)
Funder
The Kempe Foundations, JCK-3159The Kempe Foundations, SMK-1632The Kempe Foundations, SMK21-0059Swedish Research Council, 2017-05235Swedish Research Council, 2021-04805Swedish Research Council, 2018-0278Cancerforskningsfonden i Norrland, AMP19-968Knut and Alice Wallenberg Foundation, SMK21-0059
Available from: 2024-03-20 Created: 2024-03-20 Last updated: 2024-03-20Bibliographically approved
Andréasson, M. (2023). Redefining the essential molecular aspects that drive interactions between small molecules and G-quadruplex DNA. (Doctoral dissertation). Umeå: Umeå University
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
Bhuma, N., Chand, K., Andréasson, M., Mason, J. E., Das, R. N., Patel, A. K., . . . Chorell, E. (2023). The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands. European Journal of Medicinal Chemistry, 248, Article ID 115103.
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
Prasad, B., Doimo, M., Andréasson, M., L'Hôte, V., Chorell, E. & Wanrooij, S. (2022). A complementary chemical probe approach towards customized studies of G-quadruplex DNA structures in live cells. Chemical Science, 13(8), 2347-2354
Open this publication in new window or tab >>A complementary chemical probe approach towards customized studies of G-quadruplex DNA structures in live cells
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2022 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 13, no 8, p. 2347-2354Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are implicated in central biological processes and are considered promising therapeutic targets because of their links to human diseases such as cancer. However, functional details of how, when, and why G4 DNA structures form in vivo are largely missing leaving a knowledge gap that requires tailored chemical biology studies in relevant live-cell model systems. Towards this end, we developed a synthetic platform to generate complementary chemical probes centered around one of the most effective and selective G4 stabilizing compounds, Phen-DC3. We used a structure-based design and substantial synthetic devlopments to equip Phen-DC3 with an amine in a position that does not interfere with G4 interactions. We next used this reactive handle to conjugate a BODIPY fluorophore to Phen-DC3. This generated a fluorescent derivative with retained G4 selectivity, G4 stabilization, and cellular effect that revealed the localization and function of Phen-DC3 in human cells. To increase cellular uptake, a second chemical probe with a conjugated cell-penetrating peptide was prepared using the same amine-substituted Phen-DC3 derivative. The cell-penetrating peptide conjugation, while retaining G4 selectivity and stabilization, increased nuclear localization and cellular effects, showcasing the potential of this method to modulate and direct cellular uptake e.g. as delivery vehicles. The applied approach to generate multiple tailored biochemical tools based on the same core structure can thus be used to advance the studies of G4 biology to uncover molecular details and therapeutic approaches. This journal is

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2022
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-193064 (URN)10.1039/d1sc05816a (DOI)000751956900001 ()2-s2.0-85125772577 (Scopus ID)
Funder
Swedish Research Council, VR-NT 2017-05235The Kempe Foundations, SMK-1632Knut and Alice Wallenberg Foundation, VR-MH 2018-0278EU, Horizon 2020, 751474
Available from: 2022-03-21 Created: 2022-03-21 Last updated: 2023-03-24Bibliographically approved
Andréasson, M., Bhuma, N., Pemberton, N. & Chorell, E. (2022). Using Macrocyclic G-Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G-Quadruplex DNA. Chemistry - A European Journal, 28(65), Article ID e202202020.
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
Deiana, M., Obi, I., Andréasson, M., Tamilselvi, S., Chand, K., Chorell, E. & Sabouri, N. (2021). A Minimalistic Coumarin Turn-On Probe for Selective Recognition of Parallel G-Quadruplex DNA Structures. ACS Chemical Biology, 16(8), 1365-1376
Open this publication in new window or tab >>A Minimalistic Coumarin Turn-On Probe for Selective Recognition of Parallel G-Quadruplex DNA Structures
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2021 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 16, no 8, p. 1365-1376Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are widespread in the human genome and are implicated in biologically important processes such as telomere maintenance, gene regulation, and DNA replication. Guanine-rich sequences with potential to form G4 structures are prevalent in the promoter regions of oncogenes, and G4 sites are now considered as attractive targets for anticancer therapies. However, there are very few reports of small “druglike” optical G4 reporters that are easily accessible through one-step synthesis and that are capable of discriminating between different G4 topologies. Here, we present a small water-soluble light-up fluorescent probe that features a minimalistic amidinocoumarin-based molecular scaffold that selectively targets parallel G4 structures over antiparallel and non-G4 structures. We showed that this biocompatible ligand is able to selectively stabilize the G4 template resulting in slower DNA synthesis. By tracking individual DNA molecules, we demonstrated that the G4-stabilizing ligand perturbs DNA replication in cancer cells, resulting in decreased cell viability. Moreover, the fast-cellular entry of the probe enabled detection of nucleolar G4 structures in living cells. Finally, insights gained from the structure–activity relationships of the probe suggest the basis for the recognition of parallel G4s, opening up new avenues for the design of new biocompatible G4-specific small molecules for G4-driven theranostic applications.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2021
National Category
Medicinal Chemistry Biochemistry and Molecular Biology Biophysics
Identifiers
urn:nbn:se:umu:diva-187118 (URN)10.1021/acschembio.1c00134 (DOI)000697396400009 ()34328300 (PubMedID)2-s2.0-85113337330 (Scopus ID)
Funder
The Kempe Foundations, SMK-1632Knut and Alice Wallenberg Foundation, KAW2015-0189Swedish Cancer Society, CAN 2019/126Swedish Research Council, 2017-05235Swedish Research Council, 2018-02651
Available from: 2021-09-01 Created: 2021-09-01 Last updated: 2023-03-23Bibliographically approved
Das, R. N., Andréasson, M., Kumar, R. & Chorell, E. (2020). Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures. Chemical Science, 11(38), 10529-10537
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
Das, R. N., Berner, A., Bhuma, N., Golebiewska, J., Abrahamsson, A., Andréasson, M., . . . Chorell, E.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
Andréasson, M., Donzel, M., Abrahamsson, A., Berner, A., Doimo, M., Quiroga, A., . . . Chorell, E.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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8089-2333

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