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Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
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: urn:nbn:se:liu:diva-150522DOI: 10.3384/diss.diva-150522ISBN: 9789176852552 (print)OAI: oai:DiVA.org:liu-150522DiVA, id: diva2:1241630
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: 2019-09-26Bibliographically approved
List of papers
1. Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
Open this publication in new window or tab >>Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand
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2013 (English)In: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 34, no 9, p. 723-730Article in journal (Refereed) Published
Abstract [en]

Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant A 1-42 amyloid fibrils and A deposits in brain tissue sections from a transgenic mouse model with Alzheimers disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiopheneporphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.

Place, publisher, year, edition, pages
Wiley-VCH Verlag, 2013
Keywords
oligothiophene, porphyrin, protein deposits, imaging, fluorescence
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-93385 (URN)10.1002/marc.201200817 (DOI)000318354500004 ()
Note

Funding Agencies|Swedish Research Council||Knut and Alice Wallenberg Foundation||Swedish Foundation for Strategic Research||European Union FP7 HEALTH (Project LUPAS)||LiU Neuroscience Center||ERC Starting Independent Researcher grant (Project: MUMID)||

Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2018-08-24
2. Synthesis and Characterization of Oligothiophene-Porphyrin-Based Molecules That Can Be Utilized for Optical Assignment of Aggregated Amyloid-beta Morphotypes
Open this publication in new window or tab >>Synthesis and Characterization of Oligothiophene-Porphyrin-Based Molecules That Can Be Utilized for Optical Assignment of Aggregated Amyloid-beta Morphotypes
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
Keywords
oligothiophene; porphyrin; protein deposits; imaging; fluorescence
National Category
Biophysics
Identifiers
urn:nbn:se:liu:diva-151479 (URN)10.3389/fchem.2018.00391 (DOI)000443424100001 ()30234103 (PubMedID)
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
3. Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents
Open this publication in new window or tab >>Synthesis and Characterization of Novel Fluoro-glycosylated Porphyrins that can be Utilized as Theranostic Agents
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2018 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 7, no 7, p. 495-503Article in journal (Refereed) Published
Abstract [en]

Small molecules with modalities for a variety of imaging techniques as well as therapeutic activity are essential, as such molecules render opportunities to simultaneously conduct diagnosis and targeted therapy, so called theranostics. In this regard, glycoporphyrins have proven useful as theranostic agents towards cancer, as well as noncancerous conditions. Herein, the synthesis and characterization of heterobifunctional glycoconjugated porphyrins with two different sugar moieties, a common monosaccharide at three sites, and a 2-fluoro-2-deoxy glucose (FDG) moiety at the fourth site are presented. The fluoro-glycoconjugated porphyrins exhibit properties for multimodal imaging and photodynamic therapy, as well as specificity towards cancer cells. We foresee that our findings might aid in the chemical design of heterobifunctional glycoconjugated porphyrins that could be utilized as theranostic agents.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018
Keywords
cancer; glycoporphyrins; imaging; photodynamic therapy; photosensitizers
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:liu:diva-150279 (URN)10.1002/open.201800020 (DOI)000440286200002 ()30003003 (PubMedID)2-s2.0-85051290816 (Scopus ID)
Note

Funding Agencies|Swedish Foundation for Strategic Research; Swedish Research Council

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2019-04-01Bibliographically approved

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