Premium
New Disaccharide‐Based Ether Lipids as SK3 Ion Channel Inhibitors
Author(s) -
Berthe Wilfried,
Sevrain Charlotte M.,
Chantôme Aurélie,
Bouchet Ana Maria,
Gueguinou Maxime,
Fourbon Yann,
PotierCartereau Marie,
Haelters JeanPierre,
CouthonGourvès Hélène,
Vandier Christophe,
Jaffrès PaulAlain
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600147
Subject(s) - disaccharide , chemistry , potassium channel , ion channel , moiety , stereochemistry , ether , biophysics , biochemistry , receptor , biology , organic chemistry
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 μ m ), displace SK3 protein outside caveolae, and decrease constitutive Ca 2+ entry (50 % inhibition at 300 n m ) and SK3‐dependent cell migration (30 % at 300 n m ) 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.