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Composés hybrides w-alcanol / hydroquinone à activité neurotrophique. Synthèse et étude des propriétés physicochimiques et biologiques.

Abstract : Lesions of the Central Nervous System, whether they are accidental or illness-related, cause great damage. Axonal injuries are always followed by a scaring process. The “glial scar” thus formed constitutes a physical and a chemical barrier that regenerating neurons are unable to cross. Comprised of astrocytes, oligodendrocyes, microgliocyes and fibroblasts, it over-expresses inhibitory agents such as myelin proteins and semaphorine 3A (Sema3A) that are very inhibitory towards axonal growth. In addition, hyperactive microgliocytes, present within the scar, generate very important amounts of Radical Oxygen Species (ROSs) that are very toxic to regenerating neurons.
To address such disorders, innovative therapeutics could use hybrid compounds bearing two distinct activities. Both a neurotrophic activity allowing proper “neuro-regeneration” and an antioxidant activity allowing proper “neuro-protection” by scavenging ROSs.
To that intent, five series of hybrid compounds bearing a long chain fatty alcohol and a quinol ring (Quinol Fatty Alcohols) were synthesized. C-alkylated QFAs were obtained by a Sonogashira cross-coupling reaction between various arylbromides and terminal alkynes. N- or O-alkylated homologues were obtained by SN2 type reactions.
These different compounds have very good antioxidant activities in their demethylated form sometimes reaching a hundred-fold increase relative to Trolox®, a known antioxidant. On the other hand, the QFAs, and especially QFA15, bearing 15 carbon atoms on the side chain, have the capacity to promote axonal growth. QFA15 allows proper axonal extension at nanomolar concentration, on both normal and inhibitory substrates. Preliminary pharmacological studies have shown that QFA15 requires intracellular cyclic nucleotides to exert its biological activity. Further studies are needed to determine the entire mechanism of action of QFA15.
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https://tel.archives-ouvertes.fr/tel-00116946
Contributor : Mazen Hanbali <>
Submitted on : Tuesday, November 28, 2006 - 8:11:29 PM
Last modification on : Thursday, April 23, 2020 - 2:26:34 PM
Long-term archiving on: : Tuesday, April 6, 2010 - 11:35:09 PM

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Mazen Hanbali. Composés hybrides w-alcanol / hydroquinone à activité neurotrophique. Synthèse et étude des propriétés physicochimiques et biologiques.. Autre. Université Louis Pasteur - Strasbourg I, 2005. Français. ⟨tel-00116946⟩

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