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New Disaccharide-Based Ether Lipids as SK3 Ion Channel Inhibitors

Abstract : 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.
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Submitted on : Wednesday, February 22, 2017 - 4:32:13 PM
Last modification on : Wednesday, May 25, 2022 - 9:40:03 AM

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Wilfried Berthe, Charlotte Sevrain, Aurélie Chantôme, Ana Maria Bouchet, Maxime Gueguinou, et al.. New Disaccharide-Based Ether Lipids as SK3 Ion Channel Inhibitors. ChemMedChem, 2016, 11 (14), pp.1531 - 1539. ⟨10.1002/cmdc.201600147⟩. ⟨hal-01474320⟩



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