Design and synthesis of gallocyanine inhibitors of DKK1/LRP6 interactions for treatment of Alzheimer's disease

Savvas Thysiadis; Sotirios Katsamakas; Spyros Mpousis; Nicolaos Avramidis; Spiros Efthimiopoulos; Vasiliki Sarli

doi:10.1016/j.bioorg.2018.06.018

Design and synthesis of gallocyanine inhibitors of DKK1/LRP6 interactions for treatment of Alzheimer's disease

Bioorg Chem. 2018 Oct:80:230-244. doi: 10.1016/j.bioorg.2018.06.018. Epub 2018 Jun 12.

Authors

Savvas Thysiadis¹, Sotirios Katsamakas², Spyros Mpousis¹, Nicolaos Avramidis³, Spiros Efthimiopoulos⁴, Vasiliki Sarli⁵

Affiliations

¹ Department of Chemistry, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece.
² Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece.
³ Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, Panepistimiopolis, Ilisia, Greece.
⁴ Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, Panepistimiopolis, Ilisia, Greece. Electronic address: efthis@biol.uoa.gr.
⁵ Department of Chemistry, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece. Electronic address: sarli@chem.auth.gr.

PMID: 29966869
DOI: 10.1016/j.bioorg.2018.06.018

Abstract

Based on NCI8642, a series of gallocyanine derivatives was synthesized with modifications of the substituent groups in position 1, 2 and 4 of the phenoxazinone scaffold. The effectiveness of gallocyanines to inhibit DKK1/LRP6 interactions and Tau phosphorylation induced by prostaglandin J2 and DKK1 was elucidated by both experimental data and molecular docking simulations. Bis-alkylated with flexible alkyl ester groups on C1 and bis-benzyl gallocyanines provided the most active inhibitors, while amino derivatives on C2 of NCI8642 that have alkoxy or benzyloxy substituents on C4, were less active. Furthermore, it is shown that treating of SHSY5Y cells with NCI8642 derivatives activates Wnt signaling and increases the levels of pGSK3β kinase and β-catenin.

Keywords: Alzheimer’s disease; DKK1/LRP6 interactions; Gallocyanine derivatives; Phenoxazinone; Tau phosphorylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Binding Sites
Cell Line, Tumor
Drug Design*
Humans
Hydrogen Bonding
Intercellular Signaling Peptides and Proteins / chemistry
Intercellular Signaling Peptides and Proteins / metabolism*
Low Density Lipoprotein Receptor-Related Protein-6 / antagonists & inhibitors
Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
Molecular Docking Simulation
Oxazines / chemistry*
Oxazines / pharmacology
Oxazines / therapeutic use
Phosphorylation / drug effects
Protein Interaction Domains and Motifs / drug effects
Structure-Activity Relationship
Wnt Signaling Pathway / drug effects
tau Proteins / metabolism

Substances

DKK1 protein, human
Intercellular Signaling Peptides and Proteins
LRP6 protein, human
Low Density Lipoprotein Receptor-Related Protein-6
Oxazines
tau Proteins
gallocyanine