Silacrown Ethers: Synthesis and Influence on Ion Flux Across Myocardial Cell Membranes

There are over 100 known channelopathy diseases which are generally described as diseases associated with transport of ions across cell membranes. They include cardiovascular, degenerative neuropathy and renal diseases. For the most part channelopathy diseases have been considered “undruggable.” Crown ethers have been shown to have physiological effects ascribed to their ionophoric properties. However, high levels of toxicity precluded interest in evaluation as therapeutics. We prepared silacrown analogs of crown ethers. Initial studies focused on examples of large ring silacrown ethers having at least fourteen ring atoms with at least one lipophilic or hydrophobic substituent on the ring and/or on the silicon atom. The synthesis of silacrown ethers, ionophoric behavior, preliminary toxicity studies, evaluation in human and rabbit atrial tissue and preliminary studies in cardiac myocyte cell lines will be presented and compared to their carbon analogs. For HL-1 cells, an atrial muscle cell line, three different responses were observed for the compounds tested: no effect on Ca+2 or response to KCl-depolarization, strong inhibition of Ca+2 transients with some residual response to KCl-depolarization, and inhibition of Ca+2 transients and no subsequent response to KCl-depolarization.