- Tytuł:
- 8-hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases
- Autorzy:
-
Sałat, Kinga
Skrzypczak-Wiercioch, Anna
Fernández, Ana Patricia
Stojan, Jure
Nachon, Florian
Knez, Damijan
Pišlar, Anja
Chioua, Mourad
Diez-Iriepa, Daniel
Binda, Claudia
Serrano, Julia
Sánchez-García, Aitana
Marco-Contelles, José
López-Munoz, Francisco
Meden, Anže
Denic, Milica
Gottinger, Andrea
Brazzolotto, Xavier
Gobec, Stanislav
Kos, Janko
Martínez-Murillo, Ricardo
Žakelj, Simon
Chantegreil, Fabien - Opis:
- We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesteraseehBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 Z 1.06 0.31 nmol/L) and hMAO-B (IC50 Z 4.46 0.18 mmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the bloodebrain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson’s disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1dE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.
- Dostawca treści:
- Repozytorium Uniwersytetu Jagiellońskiego
Artykuł