New Disaccharide-Based Ether Lipids as SK3 Ion Channel Inhibitors
Résumé
The SK3 potassium channel is involved in the development of
bone metastasis and in the settlement of cancer cells in Ca2+
-rich environments. Ohmline, which is a lactose-based glyceroether
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-a-d-glucopyranosyl-b-d-galactopyranoside], which
possesses an a-glucopyranosyl-(1!6)-b-galactopyranosyl
moiety, was found to decrease SK3 current amplitude (70% inhibition
at 10 mm), displace SK3 protein outside caveolae, and
decrease constitutive Ca2+ 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.