Glyco-Phospho-Glycero Ether Lipids (GPGEL): synthesis and evaluation as small conductance Ca2+-activated K+ channel (SK3) inhibitors

Abstract

The SK3 channel, a member of the small conductance calcium-dependent potassium channels (SKCa), plays a central role with respect to the motility of highly metastatic cancerous cells (e.g. MDA-MB435s – breast cancer cell). Edelfosine, an ether lipid derivative, is able to partially inhibit this channel activity and thus reduce the SK3-dependent cell motility, but, due to its toxicity, analogues of this compound were highly desired. Ohmline, an edelfosine analogue that possesses a lactose unit in its polar domain, was the first efficient and non-toxic SK3 inhibitor that exhibits an amphiphilic structure. In the present work, we have modified the polar head of Ohmline by placing a disubstituted phosphate group between a disaccharide unit (lactose, maltose, and melibiose) and the glycerol ether-lipid moiety. It was first observed that this modification increases the water solubility of these compounds. All these novel compounds are efficient SK3 channel inhibitors with an activity comparable to Ohmline (patch-clamp measurements). These compounds are also able to reduce the SK3-dependent cell motility with similar efficacies to Ohmline. In a broader perspective it is shown that the presence of one anionic charge (coming from the presence of a phosphate group) in the polar head group does not alter the SK3 channel inhibition and provides insights into the future development of a class of migration-targeted anticancer agents.