Referenced in: none

Automatically associated channels: SK2 , SK3

Title: New Disaccharide-Based Ether Lipids as SK3 Ion Channel Inhibitors.

Authors: Wilfried Berthe, Charlotte M Sevrain, Aurelie Chantome, Ana Maria Bouchet, Maxime Guéguinou, Yann Fourbon, Marie Potier-Cartereau, Jean-Pierre Haelters, Hélène Couthon-Gourvès, Christophe Vandier, Paul-Alain Jaffrès

Journal, date & volume: ChemMedChem, 2016 Jun 9 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/27278812

Abstract
The SK3 potassium channel is involved in the development of bone metastasis and in the settlement of cancer cells in Ca(2+) -rich environments. Ohmline, which is a lactose-based glycero-ether lipid, is a lead compound that decreases SK3 channel activity and consequently limits the migration of SK3-expressing cells. Herein we report the synthesis of three new ohmline analogues in which the connection of the disaccharide moieties (1→6 versus 1→4) and the stereochemistry of the glycosyl linkage was studied. Compound 2 [3-(hexadecyloxy)-2-methoxypropyl-6-O-α-d-glucopyranosyl-β-d-galactopyranoside], which possesses an α-glucopyranosyl-(1→6)-β-galactopyranosyl moiety, was found to decrease SK3 current amplitude (70 % inhibition at 10 μm), displace SK3 protein outside caveolae, and decrease constitutive Ca(2+) entry (50 % inhibition at 300 nm) and SK3-dependent cell migration (30 % at 300 nm) at a level close to that of the benchmark compound ohmline. Compound 2, which decreases the activity of SK3 channel (but not SK2 channel), is a new drug candidate to reduce cancer cell migration and to prevent bone metastasis.