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Deiana, M., Chand, K., Jamroskovic, J., Obi, I., Chorell, E. & Sabouri, N. (2020). A Light‐up Logic Platform for Selective Recognition of Parallel G‐Quadruplex Structures via Disaggregation‐Induced Emission. Angewandte Chemie International Edition, 59(2), 896-902
Open this publication in new window or tab >>A Light‐up Logic Platform for Selective Recognition of Parallel G‐Quadruplex Structures via Disaggregation‐Induced Emission
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2020 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 59, no 2, p. 896-902Article in journal (Refereed) Published
Abstract [en]

The design of turn‐on dyes with optical signals sensitive to the formation of supramolecular structures provides fascinating and underexplored opportunities for G‐quadruplex (G4) DNA detection and characterization. Here, we show a new switching mechanism that relies on the recognition‐driven disaggregation (on‐signal) of an ultrabright coumarin‐quinazoline conjugate. The synthesized probe selectively lights‐up parallel G4 DNA structures via the disassembly of its supramolecular state, demonstrating outputs that are easily integrable into a label free molecular logic system. Finally, our molecule preferentially stains the G4‐rich nucleoli of cancer cells.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2020
Keywords
aggregation, biosensor, DNA, G-quadruplex, logic gate
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-164662 (URN)10.1002/anie.201912027 (DOI)000505279500057 ()31644837 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW2015-0189Swedish Research Council, VR-NT 2017-05235Swedish Research Council, VR-MH 2018-02651The Kempe Foundations, SMK-1632
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2020-02-20Bibliographically approved
Jamroskovic, J., Doimo, M., Chand, K., Obi, I., Kumar, R., Brännström, K., . . . Sabouri, N. (2020). Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization. Journal of the American Chemical Society, 142(6), 2876-2888
Open this publication in new window or tab >>Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
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2020 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, no 6, p. 2876-2888Article in journal (Refereed) Published
Abstract [en]

The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.

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-169314 (URN)10.1021/jacs.9b11232 (DOI)000514255300025 ()31990532 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Kempe Foundations, SMK-1632Åke Wiberg FoundationSwedish Cancer SocietyVästerbotten County Council, VLL-643451Västerbotten County Council, VLL-832001EU, Horizon 2020, 751474
Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2020-04-15Bibliographically approved
Prasad, B., Das, R. N., Jamroskovic, J., Kumar, R., Hedenström, M., Sabouri, N. & Chorell, E. (2020). The Relation Between Position and Chemical Composition of Bis-Indole Substituents Determines Their Interactions With G-Quadruplex DNA. European Journal of Chemistry
Open this publication in new window or tab >>The Relation Between Position and Chemical Composition of Bis-Indole Substituents Determines Their Interactions With G-Quadruplex DNA
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2020 (English)In: European Journal of Chemistry, ISSN 2153-2249, E-ISSN 2153-2257Article in journal (Refereed) Accepted
Abstract [en]

G‐quadruplex (G4) DNA structures are linked to fundamental biological processes and human diseases, which has triggered the development of compounds that affect these DNA structures. However, more knowledge is needed about how small molecules interact with G4 DNA structures. This study describes the development of a new class of bis‐indoles (3,3‐diindolyl‐methyl derivatives) and detailed studies of how they interact with G4 DNA using orthogonal assays, biophysical techniques, and computational studies. This revealed compounds that strongly bind and stabilize G4 DNA structures, and detailed binding interactions which e.g. show that charge variance can play a key role in G4 DNA binding. Furthermore, the structure‐activity relationships generated opened the possibilities to replace or introduce new substituents on the core structure, which is of key importance to optimize compound properties or introduce probes to further expand the possibilities of these compounds as tailored research tools to study G4 biology.

Place, publisher, year, edition, pages
Chemistry Europe, 2020
National Category
Chemical Engineering Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-171213 (URN)10.1002/chem.202000579 (DOI)
Available from: 2020-05-28 Created: 2020-05-28 Last updated: 2020-05-29
Jamroskovic, J., Obi, I., Movahedi, A., Chand, K., Chorell, E. & Sabouri, N. (2019). Identification of putative G-quadruplex DNA structures in S. pombe genome by quantitative PCR stop assay. DNA Repair, 82, Article ID 102678.
Open this publication in new window or tab >>Identification of putative G-quadruplex DNA structures in S. pombe genome by quantitative PCR stop assay
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2019 (English)In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 82, article id 102678Article in journal (Refereed) Published
Abstract [en]

In order to understand in which biological processes the four-stranded G-quadruplex (G4) DNA structures play a role, it is important to determine which predicted regions can actually adopt a G4 structure. Here, to identify DNA regions in Schizosaccharomyces pombe that fold into G4 structures, we first optimized a quantitative PCR (qPCR) assay using the G4 stabilizer, PhenDC3. We call this method the qPCR stop assay, and used it to screen for G4 structures in genomic DNA. The presence of G4 stabilizers inhibited DNA amplification in 14/15 unexplored genomic regions in S. pombe that encompassed predicted G4 structures, suggesting that at these sites the stabilized G4 structure formed an obstacle for the DNA polymerase. Furthermore, the formation of G4 structures was confirmed by complementary in vitro assays. In vivo, the S. pombe G4 unwinder Pif1 helicase, Pfh1, was associated with tested G4 sites, suggesting that the G4 structures also formed in vivo. Thus, we propose that the confirmed G4 structures in S. pombe form an obstacle for replication in vivo, and that the qPCR stop assay is a method that can be used to identify G4 structures. Finally, we suggest that the qPCR stop assay can also be used for identifying G4 structures in other organisms, as well as being adapted to screen for novel G4 stabilizers.

Keywords
G-quadruplex DNA, Schizosaccharomyces pombe, G4 stabilizer PhenDC3, Pif1 family helicase Pfh1, DNA replication, Quantitative PCR
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biochemistry
Identifiers
urn:nbn:se:umu:diva-162927 (URN)10.1016/j.dnarep.2019.102678 (DOI)000491627000009 ()31473486 (PubMedID)2-s2.0-85071382717 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, KAW2015-0189The Kempe Foundations, SMK1449 and SMK1632Swedish Society for Medical Research (SSMF)
Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-11-20Bibliographically approved
Prasad, B., Jamroskovic, J., Bhowmik, S., Kumar, R., Romell, T., Sabouri, N. & Chorell, E. (2018). Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA. Chemistry - A European Journal, 24(31), 7926-7938
Open this publication in new window or tab >>Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA
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2018 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 31, p. 7926-7938Article in journal (Refereed) Published
Abstract [en]

Small molecules that target G-quadruplex (G4) DNA structures are not only valuable to study G4 biology but also for their potential as therapeutics. This work centers around how different design features of small molecules can affect the interactions with G4 DNA structures, exemplified by the development of synthetic methods to bis-indole scaffolds. Our synthesized series of bis-indole scaffolds are structurally very similar but differ greatly in the flexibility of their core structures. The flexibility of the molecules proved to be an advantage compared to locking the compounds in the presumed bioactive G4 conformation. The flexible derivatives demonstrated similar or even improved G4 binding and stabilization in several orthogonal assays even though their entropic penalty of binding is higher. In addition, molecular dynamics simulations with the c-MYC G4 structure showed that the flexible compounds adapt better to the surrounding. This was reflected by an increased number of both stacking and polar interactions with both the residues in the G4 DNA structure and the DNA residues just upstream of the G4 structure.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018
Keywords
DNA structures, G-quadruplexes, bis-indoles, drug design, nitrogen heterocycles
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-148052 (URN)10.1002/chem.201800078 (DOI)000434216600019 ()29603472 (PubMedID)2-s2.0-85048327004 (Scopus ID)
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-11-01Bibliographically approved
Livendahl, M., Jamroskovic, J., Hedenström, M., Görlich, T., Sabouri, N. & Chorell, E. (2017). Synthesis of phenanthridine spiropyrans and studies of their effects on G-quadruplex DNA. Organic and biomolecular chemistry, 15(15), 3265-3275
Open this publication in new window or tab >>Synthesis of phenanthridine spiropyrans and studies of their effects on G-quadruplex DNA
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2017 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 15, no 15, p. 3265-3275Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are involved in many important biological processes and can be linked to several human diseases. Drug-like low molecular weight compounds that target G4 structures are therefore interesting not only for their potential therapeutic properties but also for their potential use as chemical research tools. We report here on the development of methods to synthesize spiropyrans using a condensation-cyclisation reaction of quaternary salts of [small alpha]-methyl quinoline or phenanthridine with salicylaldehydes. Evaluation of the synthesized phenanthridine spiropyrans' interactions with G4 DNA was performed with a Thioflavin T displacement assay, circular dichroism, Taq DNA polymerase stop assay, and NMR. This revealed that the substitution pattern on the phenanthridine spiropyrans was very important for their ability to bind and stabilize G4 structures. Some of the synthesized low molecular weight spirocyclic compounds efficiently stabilized G4 structures without inducing structural changes by binding the first G-tetrad in the G4 structure.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-134560 (URN)10.1039/C7OB00300E (DOI)000399201000022 ()28349141 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2018-06-09Bibliographically approved
Livendahl, M., Jamroskovic, J., Ivanova, S., Demirel, P., Sabouri, N. & Chorell, E. (2016). Design and Synthesis of 2,2'-Diindolylmethanes to Selectively Target Certain G-Quadruplex DNA Structures. Chemistry - A European Journal, 22(37), 13004-13009
Open this publication in new window or tab >>Design and Synthesis of 2,2'-Diindolylmethanes to Selectively Target Certain G-Quadruplex DNA Structures
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2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 37, p. 13004-13009Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) structures carry vital biological functions, and compounds that selectively target certain G4 structures have both therapeutic potential and value as research tools. Along this line, 2,2'-diindolylmethanes have been designed and synthesized in this work based on the condensation of 3,6- or 3,7-disubstituted indoles with aldehydes. The developed class of compounds efficiently stabilizes G4 structures without inducing conformational changes in such structures. Furthermore, the 2,2'-diindolylmethanes target certain G4 structures more efficiently than others and this G4 selectivity can be altered by chemical modifications of the compounds.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-124638 (URN)10.1002/chem.201602416 (DOI)000383763200005 ()27431593 (PubMedID)
Available from: 2016-08-18 Created: 2016-08-18 Last updated: 2018-06-07Bibliographically approved
Jamroskovic, J., Livendahl, M., Eriksson, J., Chorell, E. & Sabouri, N. (2016). Identification of Compounds that Selectively Stabilize Specific G-Quadruplex Structures by Using a Thioflavin T-Displacement Assay as a Tool. Chemistry - A European Journal, 22(52), 18932-18943
Open this publication in new window or tab >>Identification of Compounds that Selectively Stabilize Specific G-Quadruplex Structures by Using a Thioflavin T-Displacement Assay as a Tool
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2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 52, p. 18932-18943Article in journal (Refereed) Published
Abstract [en]

Small molecules are used in the G-quadruplex (G4) research field in vivo and in vitro, and there are increasing demands for ligands that selectively stabilize different G4 structures. Thioflavin T (ThT) emits an enhanced fluorescence signal when binding to G4 structures. Herein, we show that ThT can be competitively displaced by the binding of small molecules to G4 structures and develop a ThT-displacement high-throughput screening assay to find novel and selective G4-binding compounds. We screened approximately 28 000 compounds by using three different G4 structures and identified eight novel G4 binders. Analysis of the structural conformation and stability of the G4 structures in presence of these compounds demonstrated that the four compounds enhance the thermal stabilization of the structures without affecting their structural conformation. In addition, all four compounds also increased the G4-structure block of DNA synthesis by Taq DNA polymerase. Also, two of these compounds showed selectivity between certain Schizosaccharomyces pombe G4 structures, thus suggesting that these compounds or their analogues can be used as selective tools for G4 DNA studies.

Keywords
dyes, DNA structures, dyes, G-quadruplexes, high-throughput screening, nucleobases
National Category
Biochemistry and Molecular Biology Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-128197 (URN)10.1002/chem.201603463 (DOI)000393219300041 ()27862378 (PubMedID)2-s2.0-85002848668 (Scopus ID)
Available from: 2016-11-28 Created: 2016-11-28 Last updated: 2018-06-09Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6871-7663

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