Synthesis and studies of photoactive organic compounds with potential biological applications

Doctoral Dissertation uoadl:2963246 29 Read counter

Department of Chemistry
Library of the School of Science
Deposit date:
Mikroulis Theodoros
Dissertation committee:
Γεώργιος Χ. Βουγιουκαλάκης, Αναπληρωτής Καθηγητής, Τμήμα Χημείας Εθνικό Καποδιστριακό Πανεπιστήμιο Αθηνών
Δημήτριος Γεωργιάδης, Καθηγητής, Τμήμα Χημείας, Εθνικό Καποδιστριακό Πανεπιστήμιο Αθηνών
Αθανάσιος Γκιμήσης, Καθηγητής, Τμήμα Χημείας, Εθνικό Καποδιστριακό Πανεπιστήμιο Αθηνών
Kristian Berg, Καθηγητής, Institue for Cancer Research, Department of Radiation Biology, Oslo University Hospital & Department of Pharmacy, University of Oslo
Miguel Angel Miranda Alonso, Καθηγητής, Institute of Chemical Technology, Polytechnic University of Valencia
Peter Remsen Ogilby, Department of Chemistry, Aahrus University
Μανώλης Στρατάκης, Καθηγητής, Τμήμα Χημείας, Πανεπιστήμιο Κρήτης
Original Title:
Synthesis and studies of photoactive organic compounds with potential biological applications
Translated title:
Synthesis and studies of photoactive organic compounds with potential biological applications
Luminol is an unparalleled chemiluminescent agent that has found numerous applications over the years, among others in forensics, real time imaging or as a ROS detection probe. This thesis presents a systematic study on the effects of substitution on the chemiluminescence quantum efficiency of luminol, as well as the synthesis of several luminol-based derivatives and dyads that could hold potential for use as bioimaging agents or as photosensitizers in cancer therapy.
In chapter 1, a brief introduction is given on the main themes explored within this dissertation, in order to provide the background for the research presented in the next chapters. In this regard, the basic principles of chemiluminescence are presented first, followed by the mechanism of luminol’s chemiluminescence and the contemporary methods for its further functionalisation. We then dive into the characteristics and current treatment of glioblastoma multiforme, a highly invasive type of brain cancer, and look at the basic principles of photodynamic therapy. Finally, the chemistry and functionalisation methods of porphyrins (with a greater focus on protoporphyrin IX – PPIX) and fullerene C60 are presented.
Chapter 2 explores the way substitution of luminol at C-6 and/or C-8 with electron donating groups (specifically Me, or Ph) affects the derivatives’ chemiluminescence efficiency. To this end, a novel synthetic approach for the derivatisation of luminol is developed, using a Suzuki-Miyaura coupling strategy in its key step. This approach offers a straightforward and more reproducible way of accessing such compounds, in comparison to the already reported methods. A complete series of mono and di-substituted luminol derivatives (at positions 6 and 8) is synthesised, along with their respective anhydrides. Then, studies carried out by collaborators on the chemiluminescence quantum yields of the former, the fluorescence quantum yields of the latter, along with related quantum chemistry computations are briefly reported, towards the determination of the steric and electronic effects that might enhance or lessen the observed chemiluminescence.
The most potent of those luminol derivatives (in terms of light emission), is then utilised in chapter 3 to synthesise a mitochondrial targeting luminol derivative that can be used as an effective light source to trigger the excitation of PPIX—an often-used photosensitizer in photodynamic therapy—from inside the cell, thus allowing the treatment of non-accessible, aggressive tumours such as glioblastoma multiforme without the need for surgery. Mitochondrial targeting is achieved by linking the luminol with a triphenyl phosphonium cation via an alkyl chain. Two derivatives with different lengths of spacers are synthesised and evaluated in terms of their chemiluminescence efficiency and their ability to induce photodynamic action once inside the cell. A quenching effect from the triphenyl phosphonium cation is also reported herein for the first time.
Chapter 4 serves as an extension of chapter 3 in the sense that it explores the synthesis of two PPIX-luminol dyads (with different lengths of spacers) through a “click” reaction between an azide functionalised PPIX derivative and N-propargyl luminol. These dyads could potentially be used as self-activating ROS generators. Studying the efficiency of the photoinduced energy or electron transfer between luminol and PPIX in these dyads, could provide, in the future, an understanding on how the distance between the two moieties affects this process.
Finally, chapter 5 looks into the synthesis of two C60-luminol dyads. Given that fullerenes are great electron acceptors, it is expected that upon triggering luminol’s chemiluminescence, an effective through-space energy transfer will occur from luminol to the C60. The two dyads reported herein bear spacers of different lengths to also evaluate how the proximity of the two groups affects the energy transfer process.
Main subject category:
Chemiluminescence, Photodynamic Therapy, Protoporphyrin IX, Glioblastoma Multiforme, Fullerene
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