liu.seSök publikationer i DiVA
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Synthesis and Characterization of Oligothiophene-Porphyrin-Based Molecules That Can Be Utilized for Optical Assignment of Aggregated Amyloid-beta Morphotypes
Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.ORCID-id: 0000-0002-5582-140X
2018 (Engelska)Ingår i: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 6, artikel-id 391Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
FRONTIERS MEDIA SA , 2018. Vol. 6, artikel-id 391
Nyckelord [en]
oligothiophene; porphyrin; protein deposits; imaging; fluorescence
Nationell ämneskategori
Biofysik
Identifikatorer
URN: urn:nbn:se:liu:diva-151479DOI: 10.3389/fchem.2018.00391ISI: 000443424100001PubMedID: 30234103OAI: oai:DiVA.org:liu-151479DiVA, id: diva2:1250667
Anmärkning

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

Tillgänglig från: 2018-09-24 Skapad: 2018-09-24 Senast uppdaterad: 2018-10-19
Ingår i avhandling
1. Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials
Öppna denna publikation i ny flik eller fönster >>Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.      

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2018. s. 83
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1947
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:liu:diva-150522 (URN)10.3384/diss.diva-150522 (DOI)9789176852552 (ISBN)
Disputation
2018-11-09, Planck, Fysikhuset, Campus Valla, Linköping, 09:15 (Svenska)
Opponent
Handledare
Tillgänglig från: 2018-08-27 Skapad: 2018-08-24 Senast uppdaterad: 2019-09-26Bibliografiskt granskad

Open Access i DiVA

fulltext(7085 kB)238 nedladdningar
Filinformation
Filnamn FULLTEXT01.pdfFilstorlek 7085 kBChecksumma SHA-512
d8856003b0b38dbcc9c0b20f3a1abcdc1267d6f2dea6066a3676f1516e2c4c6f28438d22a8fdbe4cae30cd41493e117c4536595798c277981a6f36bbbae8039d
Typ fulltextMimetyp application/pdf

Övriga länkar

Förlagets fulltextPubMed

Sök vidare i DiVA

Av författaren/redaktören
Arja, KatriannElgland, MathiasNilsson, Peter
Av organisationen
KemiTekniska fakulteten
I samma tidskrift
Frontiers in Chemistry
Biofysik

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 238 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 581 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf