| 1. |
- Arja, Katriann, 1985-
(författare)
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Multimodal Porphyrin-Based Conjugates : Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Organic compounds that interact both with certain biological targets and display specific photophysical properties can be utilized as molecular tools to visualize and possibly effect disease related processes taking place in living organisms. In this regard, porphyrins are a class of naturally occurring molecules that possess intriguingly interesting photophysical properties where they can act as luminescent probes by emitting detectable light, as well as photosensitizers in the light mediated therapy called photodynamic therapy. In this thesis, the porphyrin structure has been synthetically combined with other molecule classes to achieve compounds with desirable multimodal characteristics.Firstly, luminescent conjugated oligothiophenes (LCOs) that have extensively, and with great success, been utilized as fluorescent ligands for amyloid formations, have been conjugated to porphyrins to render oligothiophene porphyrin hybrids (OTPHs) comprising two optically active modalities. When applied as fluorescent amyloidophilic dyes for visualization of amyloid-β (Aβ), one of the pathological hallmarks in Alzheimer’s disease, an enhanced optical assignment of distinct aggregated forms of Aβ was afforded. Thus, properly functionalized OTPHs could give us more information about pathological processes underlying devastating disorders, such as Alzheimer’s disease. In addition, the OTPHs can be associated with synthetic peptides inducing peptide folding into certain three-dimensional helical structures giving rise to novel optically active materials.Secondly, this thesis also embraces porphyrins’ potential as photosensitizers in photodynamic therapy to kill cancer cells. Grounded on the prerequisites for an optimal photosensitizer, we designed porphyrin-based conjugates equipped with common carbohydrates for improved cancer cell selectivity and with a fluorinated glucose derivative, 2-fluoro 2-deoxy glucose, for advantageous metabolism in cancer cells. Furthermore, incorporation of a radioisotopic fluorine-18 atom into the glycoporphyrins could give the means for diagnostic use of the conjugates in positron emission tomography (PET).In order to tether together the above-mentioned molecular moieties in a controlled fashion, we developed a robust synthetic strategy for asymmetrical functionalization of porphyrin core. The method involves chlorosulfonation of this otherwise inert tetrapyrrolic structure, followed by alkynylation. Parallelly to amide coupling reactions, copper(I)-catalyzed alkyne azide cycloaddition is used for fast and high-yielding late-stage conjugations. Overall, this thesis demonstrates how combining different molecular moieties in synthetic organic chemistry yields novel molecules with combined and improved multimodal properties for biological and medicinal applications, guided by the design-by-function methodology.
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| 2. |
- Elgland, Mathias, 1987-, et al.
(författare)
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beta-Configured clickable [F-18] FDGs as novel F-18-fluoroglycosylation tools for PET
- 2017
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Ingår i: New Journal of Chemistry. - : ROYAL SOC CHEMISTRY. - 1144-0546 .- 1369-9261. ; 41:18, s. 10231-10236
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Tidskriftsartikel (refereegranskat)abstract
- In oncology and neurology the F-18-radiolabeled glucose analogue 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) is by far the most commonly employed metabolic imaging agent for positron emission tomography (PET). Herein, we report a novel synthetic route to beta-configured mannopyranoside precursors and a chemoselective F-18-fluoroglycosylation method that employ two b-configured [F-18]FDG derivatives equipped with either a terminal azide or alkyne aglycon respectively, for use as a CuAAC clickable tool set for PET. The b-configured precursors provided the corresponding [F-18]FDGs in a radiochemical yield of 77-88%. Further, the clickability of these [F-18]FDGs was investigated by click coupling to the suitably functionalized Fmoc-protected amino acids, Fmoc-N-(propargyl)-glycine and Fmoc-3-azido-L-alanine, which provided the F-18-fluoroglycosylated amino acid conjugates in radiochemical yields of 75-83%. The F-18-fluoroglycosylated amino acids presented herein constitute a new and interesting class of metabolic PET radiotracers.
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| 3. |
- Elgland, Mathias, 1987-
(författare)
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Synthesis and application of β-configured [18/19F]FDGs : Novel prosthetic CuAAC click chemistry fluoroglycosylation tools for amyloid PET imaging and cancer theranostics
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Positron emission tomography (PET) is a non-invasive imaging method that renders three-dimensional images of tissue that selectively has taken up a radiolabelled organic compound, referred to as a radiotracer. This excellent technique provides clinicians with a tool to monitor disease progression and to evaluate how the patient respond to treatment. The by far most widely employed radiotracer in PET is called 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), which is often referred to as the golden standard in PET. From a molecular perspective, [18F]FDG is an analogue of glucose where a hydroxyl group has been replaced with a radioactive fluorine atom (18F). It is well known that covalent attachment of carbohydrates (i.e., glycosylation) to biomolecules tend to improve their properties in the body, in terms of; improved pharmacokinetics, increased metabolic stability and faster clearance from blood and other non-specific tissue. It is therefore natural to pursuit the development of a [18F]fluoroglycosylation method where [18F]FDG is chemically conjugated to a ligand with high affinity for a given biological target (e.g., tumors or disease-associated protein aggregates).This thesis describes a novel [18F]fluoroglycosylation method that in a simple and general manner facilitate the conjugation of [18F]FDG to biological ligands using click chemistry. The utility of the developed [18F]fluoroglycosylation method is demonstrated by radiolabelling of curcumin, thus forming a tracer that may be employed for diagnosis of Alzheimer’s disease. Moreover, a set of oligothiophenes were fluoroglycosylated for potential diagnosis of Alzheimer’s disease but also for other much rarer protein misfolding diseases (e.g., Creutzfeldt-Jakob disease and systemic amyloidosis). In addition, the synthesis of a series of 19F-fluoroglycosylated porphyrins is described which exhibited promising properties not only to detect but also to treat melanoma cancer. Lastly, the synthesis of a set of 19F-fluorinated E-stilbenes, structurally based on the antioxidant resveratrol is presented. The E-stilbenes were evaluated for their capacity to spectrally distinguish between native and protofibrillar transthyretin in the pursuit of finding diagnostic markers for the rare but severe disease, transthyretin amyloidosis.
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| 4. |
- Lantz, Linda, 1985-
(författare)
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Synthesis of donor–acceptor–donor thiophene based ligands that can be utilized for optical assignment of pathological targets
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Thiophene based ligands represent a class of molecular reporters proven superior in discerning pathological targets involved in neurodegenerative diseases, as well as bacterial infection. By fluorometric detection that depends on the milieu surrounding the ligand these biological processes can be studied with fluorescence spectroscopy and hyper-spectral confocal microscopy. The binding of a thiophene-based ligand to a biological target can entail specific fluorescent read-out through the conformation-sensitive ligand. Thus, the photo-physical properties of these molecules and the optical connection of binding make them valuable tools in the study of pathological events. As optical detection of pathological phenomena can be realized through several fluorescence parameters, including changes in fluorescent intensity, wavelength shifts, energy transfer, or emission lifetime, molecular studies of pathological targets in several biological systems have been realized by employing thiophene-based ligands. For instance, utilization of conjugated polydisperse and monodisperse thiophene-based molecules has in several studies demonstrated detection of disease associated protein aggregates in vitro, ex vivo and in vivo. My doctoral studies have included the synthesis and characterization of thiophene based donor-acceptor-donor (D–A–D) molecules and evaluation of how changes in side-chain positions, molecular length and number of negatively charged carboxylates impact interaction with biological targets. This thesis describes the utilization of the D–A–D molecules as fluorescent ligands for protein aggregates associated with Alzheimer’s disease and optical assignment of specific bacteria. The design and synthesis of these novel D–A–D thiophene-based fluorophores, with alterations in back bone, distribution of side chains and negatively charged groups, have generated novel insights regarding the ligands chemical structure on ligand performance, by the assessment of binding mode of the respective ligand to distinct pathological entities. Furthermore, the D–A–D molecules hold alternative photo-physical properties compared to thiophene-based ligand and these optical properties of the ligands have been employed to provide new insights in questions regarding protein aggregate polymorphism in Alzheimer’s disease. Overall, by organic synthesis we have fine-tuned the properties of thiophene-based D-A-D molecules and evaluated how modifications affect interactions with distinct biological, pathological targets and we foresee that D–A–D thiophene-based ligands will expand the toolbox for studying pathological targets in neurodegenerative diseases, as well as bacterial infection.
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| 5. |
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| 6. |
- Nilsson, Peter, et al.
(författare)
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Imaging distinct conformational states of amyloid-β fibrils in Alzheimer's disease using novel luminescent probes
- 2007
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 2:8, s. 553-560
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Tidskriftsartikel (refereegranskat)abstract
- Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1-42 peptide (Aβ1-42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1-42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APPswe) of Alzheimer's disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered center. This type of plaque appears to grow from more loosely assembled regions toward solidified amyloid tentacles. This work demonstrates how application of LCPs can prove helpful to monitor aggregate structure of in vivo formed amyloid deposits such as architecture, maturity, and origin.
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| 7. |
- Silverå Ejneby, Malin, 1987-, et al.
(författare)
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Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid
- 2018
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Ingår i: The Journal of General Physiology. - New York, United States : Rockefeller Institute for Medical Research. - 0022-1295 .- 1540-7748. ; 150:5, s. 731-750
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Tidskriftsartikel (refereegranskat)abstract
- Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (KV) channels. The hydrophobic part of DHAA anchors the compound near the channel’s positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel’s voltage sensor, leading to the channel opening. In this study, we show that the channel-opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached. Longer stalks render the compounds noneffective. This critical distance is consistent with a simple electrostatic model in which the charge location depends on the stalk length. By combining an effective anchor with the optimal stalk length, we create a compound that opens the human KV7.2/7.3 (M type) potassium channel at a concentration of 1 µM. These results suggest that a stalk between the anchor and the effector group is a powerful way of increasing the potency of a channel-opening drug.
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| 8. |
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| 9. |
- Hederos, Markus, 1976-, et al.
(författare)
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Synthesis and self-assembly of galactose-terminated alkanethiols and their ability to resist proteins
- 2005
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 21:7, s. 2971-2980
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis of two galactose-terminated alkanethiols with the structural formula X−OC2H5NHCO(CH2)15SH (X = 2,3,4,6-tetra-O-methyl-β-d-Gal or β-d-Gal) is described. Single-component and mixed self-assembled monolayers (SAMs) of the methylated and nonmethylated compounds were prepared on gold and subsequently characterized with ellipsometry, contact angle goniometry, and infraredreflection−absorption spectroscopy. Studies of the irreversible protein adsorption onto the SAMs using ex-situ ellipsometry revealed very low levels of fibrinogen and lysozyme adsorption onto mixed SAMs displaying advancing water contact angles between 24° and 45° and below 45°, respectively. A monomethylated compound (X = 6-O-methyl-β-d-Gal) was also synthesized and assembled on gold. This particular compound was found to possess wettability properties corresponding to the low adsorption regime of the mixed SAMs, and the results from the same set of fibrinogen and lysozyme adsorption experiments showed very low levels of protein adsorption. Our findings suggest that the protein rejecting properties rely on a fine balance between the surface energy and/or hydrogen bond donating/accepting properties of the SAM surface.
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| 10. |
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