Conception de faux substrats fluorescents (FFS) dans le cadre de l’étude du transporteur vésiculaire de nucléotides et de la Sialine

Abstract : The concept of compounds called FFSs for false fluorescent substrates (or FFNs for neurotransmitters) was introduced by the group of Dr Sames who designed and optimized fluorescent molecules recognized as substrates by the Vesicular Monoamine Transporter (VMAT2). Once accumulated in synaptic vesicules, these compounds have allowed visualization of the monoaminergic neuronal activity in real time. This concept has been used as hypothesis for this thesis work. Indeed, we have designed, synthesized and evaluated the potential of two chemical families as fluorescent substrates of SLC17 transporter family: VNUT (Vesicular Nucleotide Transporter) and Sialin (sialic acid transporter). The synthesized fluorescent molecules must be able to replace/mimic the natural substrates of VNUT and Sialin ( ATP and Neu-5-Ac, respectively) and to cover a wide range of emission wavelengths to deal with biological problems. The development of such compounds was performed by rational design in synergy with the results of inhibition and transport tests and by virtual screening. Two compounds have been specifically studied. On one hand, ATP was modified by replacing the adenine pattern by a fluorophore (etheno, coumarins, quinolines…). On the other hand, a virtual hit (Fmoc-Lys(Cbz)-OH), derived from vHTS targeted to Sialin, was selected for the ease to incorporate fluorescent patterns. Therefore, fifty compounds were synthesized and evaluated for their inhibitory or substrate ability on selected targets. The promising results of several compounds as inhibitors give rise to perspectives for understanding vesicular machinery.
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Lilian Dubois. Conception de faux substrats fluorescents (FFS) dans le cadre de l’étude du transporteur vésiculaire de nucléotides et de la Sialine. Chimie organique. Université René Descartes - Paris V, 2013. Français. ⟨NNT : 2013PA05P638⟩. ⟨tel-01151635⟩

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