2. Academic Validation
  3. Design and synthesis of gallocyanine inhibitors of DKK1/LRP6 interactions for treatment of Alzheimer's disease

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.
Savvas Thysiadis 1,  Sotirios Katsamakas 2,  Spyros Mpousis 1,  Nicolaos Avramidis 3,  Spiros Efthimiopoulos 4,  Vasiliki Sarli 5
Affiliations

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.

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