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Synthesis and Characterization of Oligothiophene-Porphyrin-Based Molecules That Can Be Utilized for Optical Assignment of Aggregated Amyloid-beta Morphotypes
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.ORCID iD: 0000-0002-5582-140X
2018 (English)In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 6, article id 391Article in journal (Refereed) Published
Abstract [en]

Molecular tools for fluorescent imaging of protein aggregates are essential for understanding the significance of these pathological hallmarks in proteopathic neurodegenerative diseases, such as Alzheimers disease. Here, we report the synthesis of a series of oligothiophene porphyrin hybrids, OTPHs, and the evaluation of these dyes for fluorescent imaging of beta-amyloid aggregates in tissue sections from a transgenic mouse model with Alzheimers disease pathology. The OTPHs proved to be successful for spectral and lifetime imaging assessment of protein deposits and our findings confirm that the enhanced spectral range and distinct lifetime diversity of these novel tools allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye. In addition, the chemical identity of the porphyrin moiety, as well as the spacing between the two optical active moieties, influenced the OTPHs performance for fluorescent assignment of the protein deposits. We foresee that our findings will aid in the chemical design of dyes that can be utilized as optical tools for studying the polymorphic nature of protein aggregates associated with proteopathic neurodegenerative diseases.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2018. Vol. 6, article id 391
Keywords [en]
oligothiophene; porphyrin; protein deposits; imaging; fluorescence
National Category
Biophysics
Identifiers
URN: urn:nbn:se:liu:diva-151479DOI: 10.3389/fchem.2018.00391ISI: 000443424100001PubMedID: 30234103OAI: oai:DiVA.org:liu-151479DiVA, id: diva2:1250667
Note

Funding Agencies|Swedish Research Council [621-2013-4754, 2016-00748]

Available from: 2018-09-24 Created: 2018-09-24 Last updated: 2018-10-19
In thesis
1. Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials
Open this publication in new window or tab >>Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.      

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 83
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1947
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-150522 (URN)10.3384/diss.diva-150522 (DOI)9789176852552 (ISBN)
Public defence
2018-11-09, Planck, Fysikhuset, Campus Valla, Linköping, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2018-08-27 Created: 2018-08-24 Last updated: 2018-10-12Bibliographically approved

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