New Disaccharide‐Based Ether Lipids as SK3 Ion Channel Inhibitors. (9th June 2016)

• Record Type: Journal Article
• Authors: Berthe, Wilfried; Sevrain, Charlotte M.; Chantôme, Aurélie; Bouchet, Ana Maria; Gueguinou, Maxime; Fourbon, Yann; Potier‐Cartereau, Marie; Haelters, Jean‐Pierre; Couthon‐Gourvès, Hélène; Vandier, Christophe; Jaffrès, Paul‐Alain
• Is Part Of: ChemMedChem. Volume 11:Number 14(2016)
• Page Start: 1531
• Page End: 1539
• Publication Date: 2016-06-09
• Subjects: cell migration -- glycolipids -- metastases -- ohmline -- potassium channels; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600147
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Compound2 [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. Compound2, 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. Abstract : Mitigating metastases : Among the new disaccharide‐based ether lipids developed in this study, compound2 was found to exhibit outstanding selective inhibition of SK3 ion channel activity, inducing a decrease in SK3‐dependent cell migration. This modulation is explained by a displacement of the SK3 protein outside caveolae.