Functionalized Dipyrrins as Ligands for Photoactive Coordination Complexes

In this thesis a concept for the synthesis of metal and boron complexes, based on the dipyrromethene structure, is presented. Specifically, meso-substituted dipyrromethanes and dipyrromethenes (dipyrrins) have been used for the synthesis of these complexes. The pentafluorophenyl and the 4 fluoro-3-nitrophenyl moiety enabled the selective functionalization of the related para-fluorine position with various nucleophiles (amines, alcohols, or thiocarbohydrates) via nucleophilic aromatic substitution (SNAr). Dipyrromethanes were oxidized into the dipyrrins and enabled a targeted synthesis of the corresponding heteroleptic and homoleptic dipyrrinato complexes. Starting from the meso-substituted dipyrromethanes, a targeted synthesis of the respective boron-dipyrromethenes (BODIPYs) was also successful. The dipyrrinato compounds presented in these projects are relevant for the development of photosensitizers for photodynamic therapy (PDT). To investigate the (photo)toxic potential of the dipyrrinato complexes, the compounds were evaluated for their dark and phototoxicity in tumor cell and bacterial assays by employees of the biolitec research GmbH. Dipyrromethanes are important starting materials for the preparation of porphyrins, corroles, or other macrocyclic compounds. As well, dipyrromethanes are applied in the synthesis of BODIPYs and dipyrrinato metal complexes. In one project, meso-(4-amino-3-nitrophenyl)-substituted dipyrromethanes were investigated as suitable building blocks for the development of BODIPYs and dipyrrinato ruthenium(II) complexes. An efficient substitution of the para-fluorine of the 4-fluoro-3 nitrophenyl moiety was achieved with various amines via SNAr. The scope of suitable nucleophiles has also been extended to an azido group. Starting from these functionalized dipyrromethanes the corresponding BODIPYs were prepared. Furthermore, the pre-functionalized dipyrromethanes were oxidized to their respective dipyrrins and the subsequent synthesis of (p-cymene)(dipyrrinato)ruthenium(II) complexes was carried out via reaction with a chlorido(p-cymene)ruthenium(II) half-sandwich precursor. Finally, the exchange of the p-cymene ligand with 2,2’-bipyridine led to the bis(2,2’-bipyridyl)(dipyrrinato)ruthenium(II) complexes. In another BODIPY-related project, the concept of the BODIPY core substitution with bromine was combined with the introduction of functional groups via the nucleophilic substitution in the para-position of the 4-fluoro-3-nitrophenyl and pentafluorophenyl moiety at the respective meso-position of the BODIPYs, to adapt the properties of the BODIPY towards an application as photosensitizers. For this, pre-functionalized BODIPYs were reacted with N-bromosuccinimide (NBS). However, on modifying the BODIPY core structure with NBS, multiple brominations were observed and only the corresponding mono-brominated BODIPYs could be isolated in pure form in some cases. The application of 1,3,5,7-tetramethyl-substituted BODIPYs on the other hand enabled an effective combination of these concepts (selective bromination of the BODIPY core structure and the nucleophilic aromatic substitution). The scope of suitable nucleophiles was also extended to thiocarbohydrates. This functionalization with thioglucose and thiogalactose intended to contribute to an improvement of bioavailability. A phototoxicity against bacteria was observed already at low concentrations for certain BODIPYs. Notably, a high phototoxic activity was still found under more realistic testing conditions, i.e., on repeating the bacterial assays with the addition of 10% of serum. In a third project, the preparation of the dipyrrinato iridium(III) complexes was carried out with meso-substituted dipyrrins, again starting from dipyrromethanes carrying the pentafluorophenyl and the 4 fluoro-3-nitrophenyl moiety, respectively. A wide scope of functionalized dipyrrins was synthesized via the nucleophilic substitution on these two dipyrromethanes followed by oxidation to the corresponding dipyrrins. Starting from these pre-functionalized dipyrrins, heteroleptic dipyrrinato iridium(III) complexes with an additional pentamethylcyclopentadienyl ligand were synthesized. However, the synthesis of (dipyrrinato)bis(2-phenylpyridyl)iridium(III) complexes could only be achieved via the reaction of the functionalized dipyrrins with a cyclometalated chlorido(2-phenylpyridyl)iridium(III) precursor. In the course of these investigations (dipyrrinato)bis(2-phenylpyridyl)iridium(III) complexes with free para-fluorine position were also prepared and reacted with thiocarbohydrates. Again, the glycosylation was performed to improve the bioavailability. In the tumor cell and bacterial assays, the (dipyrrinato)bis(2-phenylpyridyl)iridium(III) complexes with terminal hydroxy groups and the glycosylated derivatives exhibited a high phototoxicity even at low concentrations. Also, certain (dipyrrinato)(cyclopentadienyl)iridium(III) complexes showed a pronounced activity against bacteria under irradiation as well as without light. In a side project, the preparation of homoleptic bis(dipyrrinato) and tris(dipyrrinato) complexes with meso-(3-nitrophenyl)-based dipyrrins was investigated. The syntheses of the corresponding complexes were carried by a direct complexation of the dipyrrins with the metal salts. However, only a limited number of the homoleptic dipyrrinato complexes could be synthesized with the tested dipyrrins. The tumor cell and bacterial assays indicated no significant dark or phototoxicity for the bis(dipyrrinato) and tris(dipyrrinato) complexes. BODIPYs are used as fluorescence dyes in imaging and as markers. Metal complexes of the 1,4,7,10-tetraazacyclododecane (cyclen) can cleave protein structures or DNA, making this type of metal complexes interesting for therapeutic applications. In a last project, a conjugate between a cyclen and a BODIPY was prepared. The coupling of these molecules was realized via a copper(I)-mediated 1,3-dipolar cycloaddition with an azido-BODIPY and a propargyl-substituted cyclen. Moreover, a subsequent complexation of the BODIPY-cyclen conjugate with copper(II) was investigated.

Author dc:creator

• Hohlfeld, Benjamin Florian

• dipyrrin
• BODIPY
• dipyrrinato complex
• nucleophilic aromatic substitution
• photodynamic therapy
• antimicrobial photodynamic inactivation

Licence dc:rights.uri

• http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen

Language dc:language

ger, eng

Identifier URI

http://dx.doi.org/10.17169/refubium-32472

OAI record oai:identifier

https://refubium.fu-berlin.de/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Arefubium.fu-berlin.de%3Afub188%2F32746