New Disaccharide-Based Ether Lipids as SK3 Ion Channel Inhibitors.
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.
Université de Brest, CEMCA, CNRS UMR 6521, IBSAM, 6 Avenue Le Gorgeu, 29238, Brest, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Wilfried
W
Berthe
Université de Brest, CEMCA, CNRS UMR 6521, IBSAM, 6 Avenue Le Gorgeu, 29238, Brest, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Charlotte M
CM
Sevrain
INSERM, UMR 1069, Université François Rabelais, Tours, 37032, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Aurélie
A
Chantôme
INSERM, UMR 1069, Université François Rabelais, Tours, 37032, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Ana Maria
AM
Bouchet
INSERM, UMR 1069, Université François Rabelais, Tours, 37032, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Maxime
M
Gueguinou
INSERM, UMR 1069, Université François Rabelais, Tours, 37032, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Yann
Y
Fourbon
INSERM, UMR 1069, Université François Rabelais, Tours, 37032, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Marie
M
Potier-Cartereau
Université de Brest, CEMCA, CNRS UMR 6521, IBSAM, 6 Avenue Le Gorgeu, 29238, Brest, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Jean-Pierre
JP
Haelters
Université de Brest, CEMCA, CNRS UMR 6521, IBSAM, 6 Avenue Le Gorgeu, 29238, Brest, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Hélène
H
Couthon-Gourvès
INSERM, UMR 1069, Université François Rabelais, Tours, 37032, France.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France.
Christophe
C
Vandier
Université de Brest, CEMCA, CNRS UMR 6521, IBSAM, 6 Avenue Le Gorgeu, 29238, Brest, France. pjaffres@univ-brest.fr.|Network "Ion Channels and Cancer - Canceropole Grand Ouest", (IC-CGO), France. pjaffres@univ-brest.fr.
Paul-Alain
PA
Jaffrès
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004187:Disaccharides / Q000138:chemical synthesis / Q000494:pharmacology*; D006017:Glycolipids / Q000138:chemical synthesis / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D014297:Trimethylsilyl Compounds / Q000737:chemistry
C574297:1-O-hexadecyl-2-O-methylglycero-3-lactose; C000622561:3-(hexadecyloxy)-2-methoxypropyl-6-O-glucopyranosyl-1-6-galactopyranoside; D000970:Antineoplastic Agents; D004187:Disaccharides; D006017:Glycolipids; C406328:KCNN3 protein, human; D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D014297:Trimethylsilyl Compounds
cell migration; glycolipids; metastases; ohmline; potassium channels