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Convergent Synthesis of a Linker-Connected Fluorescent Ebselen-Coumarin Heterodimer
1 , 2 , 2 , 2 , * 1
1  Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany
2  Department of Organic Chemistry, Wrocław University of Technology (A2), Wyspiańskiego 27, 50-370 Wrocław, Poland

Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

OBJECTIVE. Ebselen (1) is a multifunctional drug with a wide range of pharmacological effects that are predominantly due to its interaction with selenoenzymes, e.g. glutathione peroxidase, thioredoxin reductase [1,2]. Such enzymes play an important role in protecting biomembranes and other cellular components from oxidative stress [2]. Fluorescence-labeled probes containing ebselen can be suitable for further biological and medicinal studies, to profile enzyme activities, identify target enzymes and characterize their functions [3].

SYNTHESIS. The synthetic route starts with the procedure for synthesizing ebselen [4]. Anthranilic acid as the starting material was converted into a diazonium salt, which was treated with disodium diselenide to obtain the 2,2´-diselenobisbenzoate (2). After treating 2 with thionyl chloride, a reaction with an appropriate para-substituted aniline derivative with a protected primary aliphatic amine group was performed to give the first component, compound 3. To obtain the PEG linker for the connection of the two components, the amino group of 2-(2-aminoethoxy)ethanol was first Cbz-protected. Afterwards, the hydroxyl group was alkylated with tert.-butyl bromoacetate followed by a Cbz deprotection. The resulting primary aliphatic amine was coupled with the second component, the fluorescent coumarin 343 (4). This was synthesized by submitting 8-hydroxyjulolidine-9-carboxaldehyde to a Knoevenagel condensation. In the final steps, both the ebselen derivative 3 and the PEG-coumarin 343 building block were deprotected and the desired probe 5 was assembled.

APPLICATION. The new probe will be provided to biochemical and pharmacological studies.