Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3

Killian Oukoloff; Nicolas Coquelle; Manuela Bartolini; Marina Naldi; Rémy Le Guével; Stéphane Bach; Béatrice Josselin; Sandrine Ruchaud; Marco Catto; Leonardo Pisani; Nunzio Denora; Rosa Maria Iacobazzi; Israel Silman; Joel L Sussman; Frédéric Buron; Jacques-Philippe Colletier; Ludovic Jean; Sylvain Routier; Pierre-Yves Renard

Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3

Killian Oukoloff ¹ Nicolas Coquelle ² Manuela Bartolini ³ Marina Naldi ³ Rémy Le Guével ⁴ Stéphane Bach ⁵ Béatrice Josselin ⁵ Sandrine Ruchaud ⁵ Marco Catto ⁶ Leonardo Pisani ⁶ Nunzio Denora ⁶ Rosa Maria Iacobazzi ⁷ Israel Silman ⁸ Joel L Sussman ⁸ Frédéric Buron ⁹ Jacques-Philippe Colletier ² Ludovic Jean ¹ Sylvain Routier ⁹ Pierre-Yves Renard ¹

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse

2 IBS - UMR 5075 - Institut de biologie structurale

3 UNIBO - Alma Mater Studiorum University of Bologna

4 ImPACcell - Plate-forme ImPACcell

5 P3H - Phophorylation de protéines et Pathologies Humaines

6 Università degli studi di Bari

7 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico

8 Weizmann Institute of Science

9 ICOA - Institut de Chimie Organique et Analytique

Abstract : Both cholinesterases (AChE and BChE) and kinases, such as GSK-3α/β, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3α/β (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5 nM for human acetylcholinesterase (hAChE) and 7 nM for GSK-3α/β. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp.

Keywords : Synthesis SAR Kinases Acetylcholinesterase Alzheimer's disease Butyrylcholinesterase Crystallography Cyclin-dependent kinase 5 Glycogen synthase kinase-3

Document type :

Journal articles

Domain :

Chemical Sciences / Medicinal Chemistry

Chemical Sciences / Cristallography

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Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3

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