In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (A beta). Accordingly, compounds 2a-c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with A beta aggregation and with the A beta self-oligomerization process (2a). Compounds 2a-c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site These moieties are likely responsible for the observed reduction of hAChE-induced A beta aggregation since they physically hamper A beta binding to the enzyme surface. Moreover, 2a was able to significantly interfere with A beta self-oligornerization, while 2b,c showed improved inhibition of hAChE-induced A beta aggregation.
Multifunctional Cholinesterase and Amyloid Beta Fibrillization Modulators. Synthesis and Biological Investigation / Butini S; Brindisi M; Brogi S; Maramai S; Guarino E; Panico A; Saxena A; Chauhan V; Colombo R; Verga L; De Lorenzi E; Bartolini M; Andrisano V; Novellino E; Campiani G; Gemma S. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - STAMPA. - 4:12(2013), pp. 1178-1182. [10.1021/ml4002908]
Multifunctional Cholinesterase and Amyloid Beta Fibrillization Modulators. Synthesis and Biological Investigation
BARTOLINI, MANUELA;ANDRISANO, VINCENZA;
2013
Abstract
In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (A beta). Accordingly, compounds 2a-c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with A beta aggregation and with the A beta self-oligomerization process (2a). Compounds 2a-c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site These moieties are likely responsible for the observed reduction of hAChE-induced A beta aggregation since they physically hamper A beta binding to the enzyme surface. Moreover, 2a was able to significantly interfere with A beta self-oligornerization, while 2b,c showed improved inhibition of hAChE-induced A beta aggregation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.