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Bhowmik, Sudipta
Publications (2 of 2) Show all publications
Kumar, R., Chand, K., Bhowmik, S., Das, R. N., Bhattacharjee, S., Hedenström, M. & Chorell, E. (2020). Subtle structural alterations in G-quadruplex DNA regulate site specificity of fluorescence light-up probes. Nucleic Acids Research, 48(3), 1108-1119
Open this publication in new window or tab >>Subtle structural alterations in G-quadruplex DNA regulate site specificity of fluorescence light-up probes
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2020 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 48, no 3, p. 1108-1119Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are linked to key biological processes and human diseases. Small molecules that target specific G4 DNA structures and signal their presence would therefore be of great value as chemical research tools with potential to further advance towards diagnostic and therapeutic developments. However, the development of these types of specific compounds remain as a great challenge. In here, we have developed a compound with ability to specifically signal a certain c-MYC G4 DNA structure through a fluorescence light-up mechanism. Despite the compound's two binding sites on the G4 DNA structure, only one of them result in the fluorescence light-up effect. This G-tetrad selectivity proved to originate from a difference in flexibility that affected the binding affinity and tilt the compound out of the planar conformation required for the fluorescence light-up mechanism. The intertwined relation between the presented factors is likely the reason for the lack of examples using rational design to develop compounds with turn-on emission that specifically target certain G4 DNA structures. However, this study shows that it is indeed possible to develop such compounds and present insights into the molecular details of specific G4 DNA recognition and signaling to advance future studies of G4 biology.

Place, publisher, year, edition, pages
Oxford University Press, 2020
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-168878 (URN)10.1093/nar/gkz1205 (DOI)000515121900015 ()31912160 (PubMedID)2-s2.0-85082145471 (Scopus ID)
Funder
Swedish Research Council, VR-NT 2017-05235The Kempe Foundations, SMK-1632
Available from: 2020-03-19 Created: 2020-03-19 Last updated: 2023-03-23Bibliographically 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
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