| 1. |
- Klahn, Luisa, et al.
(författare)
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Functional connectivity alterations of the somatomotor network in euthymic bipolar disorder
- 2023
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Ingår i: Neuroscience Applied. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- While individuals with bipolar disorder are assumed to recover between mood episodes, some nevertheless experience lingering subsyndromal symptoms and suffer from cognitive and functional impairments. Here, we propose that these enduring impairments may be linked to aberrations in brain networks. To test this, we conducted a resting-state functional magnetic resonance imaging (fMRI) study and used network-based statistic to compare functional connectivity between euthymic individuals with bipolar disorder (N=96) and healthy control individuals (N=61) both within and between resting-state networks. We also investigated the association of functional connectivity with lingering psychomotor symptoms and illness severity in bipolar disorder. We found stronger functional connectivity between the somatomotor network and the frontoparietal network in individuals with bipolar disorder compared with healthy controls, but weaker functional connectivity within the somatomotor network as well as between the somatomotor and the visual network. Results remained after adjusting for antipsychotic medication. No significant association with psychomotor performance and illness severity was found. We conclude that stronger functional connectivity between the somatomotor and frontoparietal network might be associated with lingering symptoms in bipolar euthymia. Dysconnectivity within the somatomotor network might relate to psychomotor symptoms beyond the impact of medication. Our findings contribute to the sparse field of somatomotor network aberrancies in bipolar disorder and may present a potential target for brain stimulation treatment.
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| 2. |
- Hennrich, O., et al.
(författare)
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Biotransformation-coupled mutasynthesis for the generation of novel pristinamycin derivatives by engineering the phenylglycine residue
- 2023
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Ingår i: Rsc Chemical Biology. - 2633-0679. ; 4:12, s. 1050-1063
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Tidskriftsartikel (refereegranskat)abstract
- Streptogramins are the last line of defense antimicrobials with pristinamycin as a representative substance used as therapeutics against highly resistant pathogenic bacteria. However, the emergence of (multi)drug-resistant pathogens renders these valuable antibiotics useless; making it necessary to derivatize compounds for new compound characteristics, which is often difficult by chemical de novo synthesis due to the complex nature of the molecules. An alternative to substance derivatization is mutasynthesis. Herein, we report about a mutasynthesis approach, targeting the phenylglycine (Phg) residue for substance derivatization, a pivotal component of streptogramin antibiotics. Mutasynthesis with halogenated Phg(-like) derivatives altogether led to the production of two new derivatized natural compounds, as there are 6-chloropristinamycin I and 6-fluoropristinamycin I based on LC-MS/MS analysis. 6-Chloropristinamycin I and 6-fluoropristinamycin I were isolated by preparative HPLC, structurally confirmed using NMR spectroscopy and tested for antimicrobial bioactivity. In a whole-cell biotransformation approach using an engineered E. coli BL21(DE3) pET28-hmo/pACYC-bcd-gdh strain, Phg derivatives were generated fermentatively. Supplementation with the E. coli biotransformation fermentation broth containing 4-fluorophenylglycine to the pristinamycin mutasynthesis strain resulted in the production of 6-fluoropristinamycin I, demonstrating an advanced level of mutasynthesis. Here, we report the development of a mutasynthesis approach for the derivatisation of pristinamycin I based on the phenylglycine residue in combination with a biotransformation process for mutasynthon provision.
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| 3. |
- Jian, L. A., et al.
(författare)
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Discovery of Aminoratjadone Derivatives as Potent Noncovalent CRM1 Inhibitors
- 2023
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Ingår i: Journal of Medicinal Chemistry. - 0022-2623. ; 66:17, s. 11940-50
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells frequently utilize elevated nuclear exportto escapetumor suppression and gain proliferative advantage. Chromosome RegionMaintenance 1 (CRM1/XPO1) mediates macromolecule nuclear export andplays an important role in tumorigenesis and progression. The clinicalapproval of its covalent inhibitor KPT-330 (Selinexor) validates thefeasibility of targeting CRM1 to treat cancers. Here, we synthesizedfour aminoratjadone derivatives and found that two of them, KL1 and KL2, are noncovalent CRM1 inhibitors.The two compounds underwent spontaneous hydrolysis in aqueous buffers,and the resulting products were more active against CRM1. High-resolutioncrystal structures revealed the CRM1-binding mode of these compoundsand explained the observed structure-activity relationships.In cells, KL1 and KL2 localized CRM1 inthe nuclear periphery and led to depletion of nuclear CRM1, therebyinhibiting the nuclear export and growth of colorectal cancer cellsat submicromolar concentrations. This work lays the foundation forfurther development of aminoratjadone-based noncovalent CRM1 inhibitors.
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| 4. |
- Jimidar, Claire Cheyenne, et al.
(författare)
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Masked Amino Trimethyl Lock (H2N-TML) Systems: New Molecular Entities for the Development of Turn-On Fluorophores and Their Application in Hydrogen Sulfide (H2S) Imaging in Human Cells
- 2022
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 28
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Tidskriftsartikel (refereegranskat)abstract
- Masked trimethyl lock (TML) systems as molecular moieties enabling the bioresponsive release of compounds or dyes in a controlled temporal and spatial manner have been widely applied for the development of drug conjugates, prodrugs or molecular imaging tools. Herein, we report the development of a novel amino trimethyl lock (H2N-TML) system as an auto-immolative molecular entity for the release of fluorophores. We designed Cou-TML-N3 and MURh-TML-N3, two azide-masked turn-on fluorophores. The latter was demonstrated to selectively release fluorescent MURh in the presence of physiological concentrations of the redox-signaling molecule H2S in vitro and was successfully applied to image H2S in human cells.
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| 5. |
- Kagho, Mervic D., et al.
(författare)
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Total Synthesis via Biomimetic Late-Stage Heterocyclization: Assignment of the Relative Configuration and Biological Evaluation of the Nitraria Alkaloid (±)-Nitrabirine
- 2021
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 86, s. 14903-14914
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Tidskriftsartikel (refereegranskat)abstract
- The racemic total synthesis of nitrabirine (5) together with its previously undescribed epimer 2-epi nitrabirine (5′) is accomplished via a six-step route based on a biomimetic late-stage heterocyclization. This allowed the assignment of the relative configuration of nitrabirine by the lanthanide-induced shifts (LIS) experiment, which was later on confirmed by X-ray diffraction of obtained single crystals. Furthermore, oxidation studies demonstrated that the direct N-oxidation of nitrabirine does not yield nitrabirine N-oxide as reported earlier. In contrast, the reaction of hydrogen peroxide with nitrabirine (5) yields the salt 24′, whereas 2-epi nitrabirine (5′) surprisingly leads to a previously uncharacterized product 22 under the same conditions. Finally, a Fischer indole reaction gave access to novel tetracyclic nitrabirine derivatives 26a-d. A comprehensive biological evaluation of nitrabirine (5), 2-epi nitrabirine (5′), and all derivatives synthesized in this study revealed general biofilm dispersal effects against Candida albicans. Moreover, specific compounds showed moderate antibacterial activities as well as potent cytotoxic activities.
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| 6. |
- Kanstrup, C., et al.
(författare)
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Artificial Fluorescent Glucosinolates (F-GSLs) Are Transported by the Glucosinolate Transporters GTR1/2/3
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 24:2
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Tidskriftsartikel (refereegranskat)abstract
- The glucosinolate transporters 1/2/3 (GTR1/2/3) from the Nitrate and Peptide transporter Family (NPF) play an essential role in the transport, accumulation, and distribution of the specialized plant metabolite glucosinolates. Due to representing both antinutritional and health-promoting compounds, there is increasing interest in characterizing GTRs from various plant species. We generated seven artificial glucosinolates (either aliphatic or benzenic) bearing different fluorophores (Fluorescein, BODIPY, Rhodamine, Dansylamide, and NBD) and investigated the ability of GTR1/2/3 from Arabidopsis thaliana to import the fluorescent glucosinolates (F-GSLs) into oocytes from Xenopus laevis. Five out of the seven F-GSLs synthesized were imported by at least one of the GTRs. GTR1 and GTR2 were able to import three F-GSLs actively above external concentration, while GTR3 imported only one actively. Competition assays indicate that the F-GSLs are transported by the same mechanism as non-tagged natural glucosinolates. The GTR-mediated F-GSL uptake is detected via a rapid and sensitive assay only requiring simple fluorescence measurements on a standard plate reader. This is highly useful in investigations of glucosinolate transport function and provides a critical prerequisite for elucidating the relationship between structure and function through high-throughput screening of GTR mutant libraries. The F-GSL themselves may also be suitable for future studies on glucosinolate transport in vivo.
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| 7. |
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| 8. |
- Klahn, Philipp, et al.
(författare)
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Advances in the Synthesis of Enterobactin, Artificial Analogues, and Enterobactin-Derived Antimicrobial Drug Conjugates and Imaging Tools for Infection Diagnosis
- 2022
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Ingår i: Synthesis-Stuttgart. - : Georg Thieme Verlag KG. - 0039-7881. ; 54:16, s. 3499-3557
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Tidskriftsartikel (refereegranskat)abstract
- Iron is an essential growth factor for bacteria, but although highly abundant in nature, its bioavailability during infection in the human host or the environment is limited. Therefore, bacteria produce and secrete siderophores to ensure their supply of iron. The triscatecholate siderophore enterobactin and its glycosylated derivatives, the salmochelins, play a crucial role for iron acquisition in several bacteria. As these compounds can serve as carrier molecules for the design of antimicrobial siderophore drug conjugates as well as siderophore-derived tool compounds for the detection of infections with bacteria, their synthesis and the design of artificial analogues is of interest. In this review, we give an overview on the synthesis of enterobactin, biomimetic as well as totally artificial analogues, and related drug-conjugates covering up to 12/2021.
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| 9. |
- Menzler, M., et al.
(författare)
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Testing of Diamond Electrodes as Biosensor for Antibody-Based Detection of Immunoglobulin Protein with Electrochemical Impedance Spectroscopy
- 2022
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Ingår i: C-Journal of Carbon Research. - : MDPI AG. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- To control the increasing virus pandemics, virus detection methods are essential. Today's standard virus detections methods are fast (immune assays) or precise (PCR). A method that is both fast and precise would enable more efficient mitigation measures and better life comfort. According to recent papers, electrochemical impedance spectroscopy (EIS) has proven to detect viruses fast and precise. Boron-doped diamond (BDD) was used as a high-performance electrode material in these works. The aim of this work was to perform an initial test of BDD-based EIS for biosensing. As an easily available standard biomaterial, human immunoglobulin G (IgG) was used as analyte. Niobium plates were coated via hot-filament activated chemical vapor deposition with polycrystalline diamond, and doped with boron for electrical conductivity. An anti-human IgG antibody was immobilised on the BDD electrodes as a biosensing component. Four different analyte concentrations up to 1.1 mu g per litre were tested. During EIS measurements, both impedance over frequency curves and Nyquist plot demonstrated no clear sign of a change of the charge transfer resistance. Thus, no positive statement about a successful biosensing could be made so far. It is assumed that these issues need to be investigated and improved, including the relation of BDD electrode size to electrolyte volume, termination of the BDD electrodes (H, O) for a successful functionalisation and EIS frequency range. The work will be continued concerning these improvement issues in order to finally use virus materials as analyte.
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| 10. |
- Rohrbacher, C., et al.
(författare)
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Synthesis of an Antimicrobial Enterobactin-Muraymycin Conjugate for Improved Activity Against Gram-Negative Bacteria
- 2023
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Ingår i: Chemistry-a European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 29:5
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Tidskriftsartikel (refereegranskat)abstract
- Overcoming increasing antibiotic resistance requires the development of novel antibacterial agents that address new targets in bacterial cells. Naturally occurring nucleoside antibiotics (such as muraymycins) inhibit the bacterial membrane protein MraY, a clinically unexploited essential enzyme in peptidoglycan (cell wall) biosynthesis. Even though a range of synthetic muraymycin analogues has already been reported, they generally suffer from limited cellular uptake and a lack of activity against Gram-negative bacteria. We herein report an approach to overcome these hurdles: a synthetic muraymycin analogue has been conjugated to a siderophore, i. e. the enterobactin derivative Ent(KL), to increase the cellular uptake into Gram-negative bacteria. The resultant conjugate showed significantly improved antibacterial activity against an efflux-deficient E. coli strain, thus providing a proof-of-concept of this novel approach and a starting point for the future optimisation of such conjugates towards potent agents against Gram-negative pathogens.
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| 11. |
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