Discovery of novel phenoxazinone derivatives as DKK1/LRP6 interaction inhibitors: Synthesis, biological evaluation and structure-activity relationships

Savvas Thysiadis; Spyros Mpousis; Nicolaos Avramidis; Sotirios Katsamakas; Athanasios Balomenos; Rosaria Remelli; Spyros Efthimiopoulos; Vasiliki Sarli

doi:10.1016/j.bmc.2016.01.025

Discovery of novel phenoxazinone derivatives as DKK1/LRP6 interaction inhibitors: Synthesis, biological evaluation and structure-activity relationships

Bioorg Med Chem. 2016 Mar 1;24(5):1014-22. doi: 10.1016/j.bmc.2016.01.025. Epub 2016 Jan 16.

Authors

Savvas Thysiadis¹, Spyros Mpousis¹, Nicolaos Avramidis², Sotirios Katsamakas³, Athanasios Balomenos², Rosaria Remelli⁴, Spyros Efthimiopoulos², Vasiliki Sarli¹

Affiliations

¹ Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece.
² Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, Panepistimiopolis, Ilisia 15784, Greece.
³ Department of Pharmacy, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece.
⁴ VIB Discovery Sciences Bio-incubator Leuven, Gaston Geenslan 1, 3001 Leuven, Belgium.

PMID: 26819000
DOI: 10.1016/j.bmc.2016.01.025

Abstract

Amino derivatives of NCI8642 were synthesized and evaluated as inhibitors of DKK1/LRP6 interactions. The new inhibitors were able to activate the Wnt signaling pathway as indicated by the increased levels of β-catenin, and decrease the DKK1-induced Tau phosphorylation at serine 396.

Keywords: DKK1/LRP6 interaction inhibitors; NCI8642; Phenoxazinone; Tau phosphorylation inhibitors; Wnt signaling.

Publication types

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

MeSH terms

HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins / metabolism*
Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
Models, Molecular
Oxazines / chemical synthesis
Oxazines / chemistry*
Oxazines / pharmacology*
Phosphorylation / drug effects
Protein Interaction Maps / drug effects*
Signal Transduction / drug effects
Structure-Activity Relationship
Wnt Proteins / metabolism
beta Catenin / metabolism

Substances

DKK1 protein, human
Intercellular Signaling Peptides and Proteins
LRP6 protein, human
Low Density Lipoprotein Receptor-Related Protein-6
Oxazines
Wnt Proteins
beta Catenin
phenoxazinone