Synthese potentiell neuroprotektiver Wirkstoffe basierend auf heterozyklischen Grundstrukturen

Neurodegenerative Erkrankungen werden durch verstärkten neuronalen Zelltod verursacht. Apoptose ist die bekannteste Form des Zelltods und nach wie vor ein aktuelles Forschungsthema. Die Arbeitsgruppe von Pellechia entwickelte das neuroprotektive Molekül BI-6C9, welches ein Protein, das am Apoptose-...

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Bibliographic Details
Main Author: Pfaff, Anna Lena
Contributors: Schlitzer, Martin (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2019
Online Access:PDF Full Text
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The aim oft the present work was the development of new neuroprotective compounds to prevent apoptosis. Neurodegenerative diseases are caused by significantly increased neuronal cell death. Apoptosis is the best-known type of cell death and still a current research topic. The working group of Pellechia developed the neuroprotective molecule BI-6C9. BI 6C9 inhibits a proteine which is involved in the apoptosis signaling pathway and showed good neuroprotective abilities in vitro but not in vivo. A disadvantage is its poor water solubility. Preliminary work in the Schlitzer working group identified two heterocycles with potentially neuroprotective structural features, 1-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5)-one and 3-phenylthiazolidine-2,4-dione. They were developed based on the fragment BI-2A7, which is part of BI-6C9 and shows little neuroprotective abilities itself. Neuroprotective abilities and toxicity of all compounds were tested in the Culmsee working group in Marburg. The synthesized derivatives of the pyrazolo[3,4-d]pyrimidinones included molecules with different substitution patterns on the aryl moiety in 1-position as well as derivatives with substituents in 6-position. 3-Arylsubstituted thiazolidine-2,4-diones were condensed with various benzaldehydes to obtain 3-arylsubstituted 5-benzylidene-thiazolidine-2,4-diones. Preliminary work based on a scaffold-hopping strategy included the synthesis of compounds based on BI-6C9 with changes in the different molecule building blocks, e.g. using phenoxyaniline instead of diphenylthioethers as starting material. Continued synthesis of BI-6C9-derived compounds including building blocks with fluorescent or antioxidative properties was performed successfully. Another focus was put on derivatives with amino acid moiety. A variety of amino acids was reacted with four different core structures differing in the group linking the phenyl rings to yield several compound series in order to establish structure-activity relationships. Benzophenone- and diphenylthioether-based compounds mostly showed low neuroprotective abilities and toxic effects. Using 4-(4-nitrophenylsulfanyl)aniline as starting material yielded substances with better neuroprotection but were still toxic. Derivatives based on N phenyl-p-phenylene-1,4-diamine and different amino acids resulted in water soluble, less neurotoxic compounds. The neuroprotective abilities of these substances started at lower concentrations compared to similar compounds with other phenyl-linking groups. The best compounds tested showed neuroprotective effects at ten-fold lower concentration compared to BI-6C9 in combination with water solubility.