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  • 1.
    Das, Rabindra Nath
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andréasson, Måns
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kumar, Rajendra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures2020In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 11, no 38, p. 10529-10537Article in journal (Refereed)
    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.

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  • 2.
    Jamroskovic, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Doimo, Mara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chand, Karam
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Obi, Ikenna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kumar, Rajendra
    Umeå University, Faculty of Science and Technology, Department of Physics. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hedenström, Mattias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Das, Rabindra Nath
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Akhunzianov, Almaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia.
    Deiana, Marco
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kasho, Kazutoshi
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sulis Sato, Sebastian
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pourbozorgi-Langroudi, Parham
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mason, James E.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Medini, Paolo
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sabouri, Nasim
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization2020In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, no 6, p. 2876-2888Article in journal (Refereed)
    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.

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  • 3.
    Kumar, Rajendra
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chand, Karam
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bhowmik, Sudipta
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Biophysics, Molecular Biology & Bioinformatics, University of Calcutta, 92, APC Road, Kolkata 700009, India.
    Das, Rabindra Nath
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bhattacharjee, Snehasish
    Hedenström, Mattias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Subtle structural alterations in G-quadruplex DNA regulate site specificity of fluorescence light-up probes2020In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 48, no 3, p. 1108-1119Article in journal (Refereed)
    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.

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  • 4.
    Kumar, Rajendra
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Lizana, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Division of CBRN Security and Defence, FOI-Swedish Defence Research Agency, Umeå, Sweden.
    Genomic 3D compartments emerge from unfolding mitotic chromosomes2019In: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 128, no 1, p. 15-20Article in journal (Refereed)
    Abstract [en]

    The 3D organisation of the genome in interphase cells is not a randomly folded polymer. Rather, experiments show that chromosomes arrange into a network of 3D compartments that correlate with biological processes, such as transcription, chromatin modifications and protein binding. However, these compartments do not exist during cell division when the DNA is condensed, and it is unclear how and when they emerge. In this paper, we focus on the early stages after cell division as the chromosomes start to decondense. We use a simple polymer model to understand the types of 3D structures that emerge from local unfolding of a compact initial state. From simulations, we recover 3D compartments, such as TADs and A/B compartments that are consistently detected in chromosome capture experiments across cell types and organisms. This suggests that the large-scale 3D organisation is a result of an inflation process.

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  • 5.
    Kumar, Rajendra
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Sobhy, Haitham
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). FOI Swedish Def Res Agcy, Div CBRN Secur & Def, S-90621 Umea, Sweden.
    Lizana, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Genome contact map explorer: a platform for the comparison, interactive visualization and analysis of genome contact maps2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 17, article id e152Article in journal (Refereed)
    Abstract [en]

    Hi-C experiments generate data in form of large genome contact maps (Hi-C maps). These show that chromosomes are arranged in a hierarchy of three-dimensional compartments. But to understand how these compartments form and by how much they affect genetic processes such as gene regulation, biologists and bioinformaticians need efficient tools to visualize and analyze Hi-C data. However, this is technically challenging because these maps are big. In this paper, we remedied this problem, partly by implementing an efficient file format and developed the genome contact map explorer platform. Apart from tools to process Hi-C data, such as normalization methods and a programmable interface, we made a graphical interface that let users browse, scroll and zoom Hi-C maps to visually search for patterns in the Hi-C data. In the software, it is also possible to browse several maps simultaneously and plot related genomic data. The software is openly accessible to the scientific community.

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  • 6. Pant, A.
    et al.
    Kumar, Rajendra
    Umeå University, Faculty of Science and Technology, Department of Physics. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wani, N. A.
    Verma, S.
    Sharma, R.
    Pande, V.
    Saxena, A. K.
    Dixit, R.
    Rai, R.
    Pandey, K. C.
    Allosteric Site Inhibitor Disrupting Auto-Processing of Malarial Cysteine Proteases2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 16193Article in journal (Refereed)
    Abstract [en]

    Falcipains are major haemoglobinases of Plasmodium falciparum required for parasite growth and development. They consist of pro- and mature domains that interact via 'hot-spot' interactions and maintain the structural integrity of enzyme in zymogen state. Upon sensing the acidic environment, these interactions dissociate and active enzyme is released. For inhibiting falcipains, several active site inhibitors exist, however, compounds that target via allosteric mechanism remains uncharacterized. Therefore, we designed and synthesized six azapeptide compounds, among which, NA-01 & NA-03 arrested parasite growth by specifically blocking the auto-processing of falcipains. Inhibitors showed high affinity for enzymes in presence of the prodomain without affecting the secondary structure. Binding of NA-03 at the interface induced rigidity in the prodomain preventing structural reorganization. We further reported a histidine-dependent activation of falcipain. Collectively, for the first time we provide a framework for blocking the allosteric site of crucial haemoglobinases of the human malaria parasite. Targeting the allosteric site could provide high selectivity and less vulnerable to drug resistance.

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  • 7.
    Prasad, Bagineni
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Das, Rabindra Nath
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jamroskovic, Jan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kumar, Rajendra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hedenström, Mattias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sabouri, Nasim
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The Relation Between Position and Chemical Composition of Bis-Indole Substituents Determines Their Interactions With G-Quadruplex DNA2020In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 26, no 43, p. 9561-9572Article in journal (Refereed)
    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.

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  • 8.
    Prasad, Bagineni
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jamroskovic, Jan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bhowmik, Sudipta
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Biophysics, Molecular Biology & Bioinformatics, University of Calcutta, Kolkata, India.
    Kumar, Rajendra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Romell, Tajanena
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sabouri, Nasim
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA2018In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 31, p. 7926-7938Article in journal (Refereed)
    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.

  • 9.
    Sobhy, Haitham
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kumar, Rajendra
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Lewerentz, Jacob
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lizana, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Division of CBRN Security and Defence, FOI–Swedish Defence Research Agency, Umeå, Sweden.
    Highly interacting regions of the human genome are enriched with enhancers and bound by DNA repair proteins2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 4577Article in journal (Refereed)
    Abstract [en]

    In specific cases, chromatin clearly forms long-range loops that place distant regulatory elements in close proximity to transcription start sites, but we have limited understanding of many loops identified by Chromosome Conformation Capture (such as Hi-C) analyses. In efforts to elucidate their characteristics and functions, we have identified highly interacting regions (HIRs) using intra-chromosomal Hi-C datasets with a new computational method based on looking at the eigenvector that corresponds to the smallest eigenvalue (here unity). Analysis of these regions using ENCODE data shows that they are in general enriched in bound factors involved in DNA damage repair and have actively transcribed genes. However, both highly transcribed regions as well as transcriptionally inactive regions can form HIRs. The results also indicate that enhancers and super-enhancers in particular form long-range interactions within the same chromosome. The accumulation of DNA repair factors in most identified HIRs suggests that protection from DNA damage in these regions is essential for avoidance of detrimental rearrangements.

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