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Jamroskovic, Jan
Publications (4 of 4) Show all publications
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
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